In real life, immediately after joint replacement, the artificial joint is actually bathed in blood (and clotted blood) instead of synovial fluid. Blood contains large molecules and cells of size ~ 5 to 20 μm suspended in plasma and considered to be a non-Newtonian (pseudoplastic) fluid with density of 1060 Kg/m³ and viscosity ~ 0.01 Pas at shear rates of 3000 s⁻¹ (as obtained in this work). The effect of these properties on friction and lubrication is not fully understood and, so far to our knowledge, hardly any studies have been carried out regarding friction of metal-on-metal bearings with various clearances in the presence of lubricants such as blood or a fluid containing macromolecules such as hyaluronic acid (HA) which is a major component of synovial fluid increasing its viscosity and lubricating properties. In this work, therefore, we have investigated the frictional behaviour of a group of Smith and Nephew Birmingham Hip Resurfacing implants with a nominal diameter of 50mm and diametral clearances in the range ~ 80 μm to 300 μm, in the presence of blood (clotted and whole blood), a combination of bovine serum (BS) with hyaluronic acid (HA) and carboxymethyl cellulose (CMC, as gelling agent) adjusted to a range of viscosities (~0.001-0.2 Pas), and bovine serum with CMC adjusted to a similar range of viscosities. These results suggested that reduced clearance bearings have the potential to generate high friction especially in the presence of blood which is indeed the in vivo lubricant in the early weeks after implantation. Friction factors in higher clearance bearings were found to be lower than those of the lower clearance bearings using blood as the lubricant. Similar trends, i.e. increase in friction factor with reduction in diametral clearance, were found to be also the case using a combination of BS+CMC or BS+HA+CMC as lubricants having viscosities in the range 0.1-0.2 and 0.03-0.14 Pas, respectively. On the other hand, all the lubricants with lower viscosities in the range 0.001-0.0013 and 0.001-0.013 Pas for both BS+CMC and BS+HA+CMC, respectively, showed the opposite effect, i.e. caused an increase in friction factor with increase in diametral clearance. Another six large diameter (50mm nominal) BHR deflected prostheses with various clearances (~ 50-280μm after cup deflection) were friction tested in vitro in the presence of blood and clotted blood to study the effect of cup deflection on friction. It was found that the biological lubricants caused higher friction factors at the lower diametral clearances for blood and clotted blood as clearance decreased from 280μm to 50μm (after deflection). The result of this investigation has suggested strongly that the optimum clearance for the 50 mm diameter MOM BHR implants to be ≥150μm and <235μm when blood lubricant used, so as to avoid high frictions (i.e. avoid friction factors >0.2) and be able to accommodate a mixed lubrication mode and hence lower the risk of micro- or even macro-motion specially immediately after hip implantation. These suggested optimum clearances will also allow for low friction (i.e. friction factors of <0.2-0.07) and reasonable lubrication (dominantly mixed regime) for the likely cup deflection occurring as a result of press-fit fixation.

In real life, immediately after joint replacement, the artificial joint is actually bathed in blood (and clotted blood) instead of synovial fluid. Blood contains large molecules and cells of size ~ 5 to 20 2m suspended in plasma and considered to be a non-Newtonian (pseudoplastic) fluid with density of 1060 Kg/m3 and viscosity ~ 0.01 Pas at shear rates of 3000 s-1 (as obtained in this work). The effect of these properties on friction and lubrication is not fully understood and, so far to our knowledge, hardly any studies have been carried out regarding friction of metal-on-metal bearings with various clearances in the presence of lubricants such as blood or a fluid containing macromolecules such as hyaluronic acid (HA) which is a major component of synovial fluid increasing its viscosity and lubricating properties. In this work, therefore, we have investigated the frictional behaviour of a group of Smith and Nephew Birmingham Hip Resurfacing implants with a nominal diameter of 50mm and diametral clearances in the range ~ 80 2m to 300 2m, in the presence of blood (clotted and whole blood), a combination of bovine serum (BS) with hyaluronic acid (HA) and carboxymethyl cellulose (CMC, as gelling agent) adjusted to a range of viscosities (~0.001-0.2 Pas), and bovine serum with CMC adjusted to a similar range of viscosities. These results suggested that reduced clearance bearings have the potential to generate high friction especially in the presence of blood which is indeed the in vivo lubricant in the early weeks after implantation. Friction factors in higher clearance bearings were found to be lower than those of the lower clearance bearings using blood as the lubricant. Similar trends, i.e. increase in friction factor with reduction in diametral clearance, were found to be also the case using a combination of BS+CMC or BS+HA+CMC as lubricants having viscosities in the range 0.1-0.2 and 0.03-0.14 Pas, respectively. On the other hand, all the lubricants with lower viscosities in the range 0.001-0.0013 and 0.001-0.013 Pas for both BS+CMC and BS+HA+CMC, respectively, showed the opposite effect, i.e. caused an increase in friction factor with increase in diametral clearance. Another six large diameter (50mm nominal) BHR deflected prostheses with various clearances (~ 50-2802m after cup deflection) were friction tested in vitro in the presence of blood and clotted blood to study the effect of cup deflection on friction. It was found that the biological lubricants caused higher friction factors at the lower diametral clearances for blood and clotted blood as clearance decreased from 2802m to 502m (after deflection). The result of this investigation has suggested strongly that the optimum clearance for the 50 mm diameter MOM BHR implants to be ¿1502m and <2352m when blood lubricant used, so as to avoid high frictions (i.e. avoid friction factors >0.2) and be able to accommodate a mixed lubrication mode and hence lower the risk of micro- or even macro-motion specially immediately after hip implantation. These suggested optimum clearances will also allow for low friction (i.e. friction factors of <0.2-0.07) and reasonable lubrication (dominantly mixed regime) for the likely cup deflection occurring as a result of press-fit fixation. / Smith & Nephew Orthopaedics Ltd.

Background Iron deficiency (ID) is the world‟s most prevalent micronutrient deficiency and predominantly affects developing countries, also South Africa. In areas with low fish consumption and high n-6 PUFA vegetable oil intake, there is a risk for having inadequate n-3 PUFA status. Both iron and n-3 PUFA play important roles in the immune response, and supplementation is a strategy to alleviate deficiencies. However, little is known about potential interactive effects between concurrent iron and n-3 PUFA supplementation on the immune system. This is also important in the context that iron supplementation may be unsafe and may increase morbidity and mortality. Aim The overall aim of this thesis was to assess the effects of iron and docosahexaenoic (DHA)/eicosapentaenoic acid (EPA) supplementation, alone and in combination, on the immune system of ID children. More specifically, these effects were investigated on the occurrence and duration of illness and school-absenteeism due to illness, peripheral blood mononuclear cell (PBMC), red blood cell (RBC) and plasma total phospholipid fatty acid composition, iron status, fatty acid-derived immune modulators and targeted PBMC gene expression. Furthermore, association of PBMC, RBC and plasma total phospholipid fatty acid composition with allergic disease, were also examined. Design In a 2-by-2 factorial, randomised, double-blind, placebo-controlled trial, South African children (n = 321, aged 6–11 y) were randomly assigned to receive oral supplements of either 1) iron (50 mg as ferrous sulphate) plus placebo; 2) DHA/EPA (420/80 mg) plus placebo; 3) iron plus DHA/EPA (420/80 mg); or 4) placebo plus placebo for 8.5 mo, four times per week. Absenteeism and illness symptoms were recorded and biochemical parameters for compliance as well as parameters fundamental to immune function were assessed at baseline and endpoint. Furthermore, in a cross-sectional design, associations of allergic disease with baseline fatty acid composition of PBMC, RBC and plasma were examined. Results The combination of iron and DHA/EPA significantly attenuated respiratory illness caused by iron supplementation. DHA/EPA supplementation alone improved respiratory symptoms at school, but increased headache-related absenteeism. DHA/EPA and iron supplementation individually tended to increase and decrease anti-inflammatory DHA and EPA-derived mediators, respectively. Furthermore the anti-inflammatory DHA-derived immune mediator, 17HDHA was higher in the DHA/EPA plus placebo and iron plus DHA/EPA groups than in the iron plus placebo group. Also, the pro-inflammatory arachidonic acid (AA)-derived modulators (5- and 15-hydroxyeicosapentaenoic acid) were significantly lower in the iron plus DHA/EPA group compared to the placebo plus placebo groups. In the study population, 27.2% of the children had allergic disease and AA in PBMC phospholipids was significantly lower in the allergic children than in the non-allergic children. In RBC phospholipids dihomo-gamma-linolenic acid (DGLA) and the ratio of DGLA: linoleic acid (LA) correlated negatively and the n-6:n-3 PUFA ratio positively with total immunoglobulin E (tIgE). Furthermore, trans-C18:1n-9, tended to be higher in the allergic group. Conclusion DHA/EPA prevented respiratory illness caused by iron supplementation and although DHA/EPA on its own reduced respiratory morbidity when the children were present at school, surprisingly it increased the likelihood of being absent with headache and fever. The biochemical findings compliment the clinical results and support previous observations about DHA/EPA supplementation to reduce inflammation, but add to the current knowledge base that a relatively high oral dose of non-haem iron modulates circulating lipid-derived immune modulators and related gene expression. Furthermore, when supplementing with iron and DHA/EPA combined, in this ID population with low fish intake, the anti-inflammatory effect of DHA/EPA is maintained concurrently with attenuation of respiratory morbidity. This finding support the notion that excess iron (probably as non-transferrin bound iron) becomes available for pathogens and is probably why we found that iron increased respiratory infectious morbidity. The improved clinical outcome with combined supplementation seems to be related to increased lipid-mediator synthesis gene expression and the availability of DHA/EPA, leading to a more pro-resolving profile and enhanced immune competence. Overall these results give better insight into immune function and infectious morbidity in relation to n-3 PUFA and iron status and treatment, as well as the possible association of fatty acid status with allergic disease in young South-African school children. / PhD (Nutrition), North-West University, Potchefstroom Campus, 2015

Background Iron deficiency (ID) is the world‟s most prevalent micronutrient deficiency and predominantly affects developing countries, also South Africa. In areas with low fish consumption and high n-6 PUFA vegetable oil intake, there is a risk for having inadequate n-3 PUFA status. Both iron and n-3 PUFA play important roles in the immune response, and supplementation is a strategy to alleviate deficiencies. However, little is known about potential interactive effects between concurrent iron and n-3 PUFA supplementation on the immune system. This is also important in the context that iron supplementation may be unsafe and may increase morbidity and mortality. Aim The overall aim of this thesis was to assess the effects of iron and docosahexaenoic (DHA)/eicosapentaenoic acid (EPA) supplementation, alone and in combination, on the immune system of ID children. More specifically, these effects were investigated on the occurrence and duration of illness and school-absenteeism due to illness, peripheral blood mononuclear cell (PBMC), red blood cell (RBC) and plasma total phospholipid fatty acid composition, iron status, fatty acid-derived immune modulators and targeted PBMC gene expression. Furthermore, association of PBMC, RBC and plasma total phospholipid fatty acid composition with allergic disease, were also examined. Design In a 2-by-2 factorial, randomised, double-blind, placebo-controlled trial, South African children (n = 321, aged 6–11 y) were randomly assigned to receive oral supplements of either 1) iron (50 mg as ferrous sulphate) plus placebo; 2) DHA/EPA (420/80 mg) plus placebo; 3) iron plus DHA/EPA (420/80 mg); or 4) placebo plus placebo for 8.5 mo, four times per week. Absenteeism and illness symptoms were recorded and biochemical parameters for compliance as well as parameters fundamental to immune function were assessed at baseline and endpoint. Furthermore, in a cross-sectional design, associations of allergic disease with baseline fatty acid composition of PBMC, RBC and plasma were examined. Results The combination of iron and DHA/EPA significantly attenuated respiratory illness caused by iron supplementation. DHA/EPA supplementation alone improved respiratory symptoms at school, but increased headache-related absenteeism. DHA/EPA and iron supplementation individually tended to increase and decrease anti-inflammatory DHA and EPA-derived mediators, respectively. Furthermore the anti-inflammatory DHA-derived immune mediator, 17HDHA was higher in the DHA/EPA plus placebo and iron plus DHA/EPA groups than in the iron plus placebo group. Also, the pro-inflammatory arachidonic acid (AA)-derived modulators (5- and 15-hydroxyeicosapentaenoic acid) were significantly lower in the iron plus DHA/EPA group compared to the placebo plus placebo groups. In the study population, 27.2% of the children had allergic disease and AA in PBMC phospholipids was significantly lower in the allergic children than in the non-allergic children. In RBC phospholipids dihomo-gamma-linolenic acid (DGLA) and the ratio of DGLA: linoleic acid (LA) correlated negatively and the n-6:n-3 PUFA ratio positively with total immunoglobulin E (tIgE). Furthermore, trans-C18:1n-9, tended to be higher in the allergic group. Conclusion DHA/EPA prevented respiratory illness caused by iron supplementation and although DHA/EPA on its own reduced respiratory morbidity when the children were present at school, surprisingly it increased the likelihood of being absent with headache and fever. The biochemical findings compliment the clinical results and support previous observations about DHA/EPA supplementation to reduce inflammation, but add to the current knowledge base that a relatively high oral dose of non-haem iron modulates circulating lipid-derived immune modulators and related gene expression. Furthermore, when supplementing with iron and DHA/EPA combined, in this ID population with low fish intake, the anti-inflammatory effect of DHA/EPA is maintained concurrently with attenuation of respiratory morbidity. This finding support the notion that excess iron (probably as non-transferrin bound iron) becomes available for pathogens and is probably why we found that iron increased respiratory infectious morbidity. The improved clinical outcome with combined supplementation seems to be related to increased lipid-mediator synthesis gene expression and the availability of DHA/EPA, leading to a more pro-resolving profile and enhanced immune competence. Overall these results give better insight into immune function and infectious morbidity in relation to n-3 PUFA and iron status and treatment, as well as the possible association of fatty acid status with allergic disease in young South-African school children. / PhD (Nutrition), North-West University, Potchefstroom Campus, 2015