A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2017. / Background: In spite of the contributions of cardiovascular disease (CVD) to morbidity and mortality in chronic kidney disease (CKD) worldwide, there are no studies that have looked at cardiovascular risk factors (CVRFs) and their association with cardiovascular changes in African children with CKD. Several CVRFs have been implicated in the initiation and progression of cardiovascular changes in children with CKD, and these changes have been reported even in early CKD. This study investigated CVRFs and their association with cardiovascular changes in South African children with CKD. Method: This comparative cross sectional study recruited children (5-18 years) with CKD being followed up at the Division of Paediatric Nephrology of the Charlotte Maxeke Johannesburg Hospital and the Chris Hani Baragwanath Academic Hospital. One hundred and six children with a spectrum of CKD including those on chronic dialysis (34 CKD I, 36 CKD II-IV and 36 CKD V-dialysis) were enrolled over a 12 month study period. All patients had a short history taken along with a physical examination. Blood samples for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase, total cholesterol, haemoglobin and C-reactive protein, Vitamin D, Fibroblast growth factor-23 (FGF-23), Fetuin-A and genomic DNA studies were taken. Where feasible, transthoracic echocardiography and high resolution ultrasonography of the common carotid artery was performed. Results: The overall median age of the patients was 11 years (8-14 years), with a male female ratio of 2.1:1. Several CVRFs detected include hypertension, proteinuria, anaemia, hypercholesterolaemia and dysregulated mineral bone metabolism. The most common CVRF detected was anaemia (39.6%) and its prevalence was highest in the dialysis group when compared with the other CKD groups. The overall median (range) cIMT was 0.505mm (0.380-0.675), and was highest in patients with dialysis dependant CKD (p=0.003). The distribution of left atrial diameter (LAD) and left ventricular mass (LVM) differed significantly (p<0.05) across the different CKD groups. Abnormal LAD was seen in 10% of patients; left ventricular hypertrophy (LVH) in 27%; left ventricular systolic dysfunction in 6% and diastolic dysfunction in one patient. Mean arterial pressure and haemoglobin levels were independently associated with cIMT; hypertension was independently associated with concentric LVH; and age and hypoalbuminaemia were independently associated with eccentric LVH. Overall, the dialysis group had the highest prevalence of vascular changes, cardiac changes and associated risk factors. A skewed pattern of Fetuin-A and FGF-23 levels with medians (range) of 57.7 (0.9-225.2) mg/dL and 28.9 (0-3893.0) pg/ml respectively, were observed. The levels of these two biomarkers varied significantly between the different CKD groups (p<0.05). Fetuin-A was independently associated with abnormal LAD but no similar relationship with other cardiovascular changes and plasma levels of Fetuin-A and FGF-23 was found. Plasma FGF-23 levels correlated better with markers of bone mineralization than Fetuin-A. Eight Fetuin-A SNPs were analysed; rs2248690, rs6787344, rs4831, rs4917, rs4918, rs2070633, rs2070634 and rs2070635. We found an association between log-transformed Fetuin-A levels and the SNP rs4918 G-allele compared to the rs4918 C-allele (p=0.046) and the rs2070633 T-allele when compared to the rs2070633 C-allele (p=0.015). Markers of MBD such as phosphate and PTH levels were associated with Fetuin-A SNPs. The rs6787344 G-allele was significantly associated with phosphate levels (0.042), and the rs4918 G-allele with PTH (p=0.044). Seven deaths were recorded in the dialysis group during the study period and severe hypertension and intracranial bleed were the most common causes of death. Modifiable risk factors such as increased total cholesterol (TC) and decreased albumin levels were more commonly seen among the deceased dialysis patients. Conclusion: A high prevalence of CVRFs and cardiovascular changes were observed in the study groups, even in those with mild to moderate disease. Information obtained from the study highlights the need to address modifiable CVRFs such as hypertension, anaemia and hypoalbuminaemia in children with CKD and also the need to determine new, population specific, paediatric reference values for cIMT in healthy African children. Finally, the study was able to demonstrate differences in the relationship between Fetuin A SNPs and Fetuin-A levels and cardiovascular changes in our study population when compared with previously published data. We postulate that these differences may be due to genetic differences between our population and other population groups previously studied. / LG2018

Exocrine pancreatic insufficiency (EPI) is a major complication of cystic fibrosis. Conventional treatment involves the replacement of pancreatic enzymes and intake of a low fat diet. However, contrary to previous therapeutic strategies, a high fat diet may be beneficial in EPI patients. The present study investigated the effects of dietary supplementation with Creon 10 000 a pancreatic enzyme preparation, in conjunction with a high-fat diet, on growth performance, digestibility and absorption of fat in a pig model of EPI by the surgical ligation of the pancreatic duct in 6 male pigs (Swedish Landrace X Yorkshire X Hampshire). Following surgery, and for the duration of the experimental period, pigs were fed a high fat diet (twice daily). The experimental period lasted for 15 days during which blood, urine and faecal samples were collected. In the last 7 days of the experimental period (days 8-14), Creon 10 000 was included in the high fat meals. Urine and faecal samples were analysed for dry matter, crude protein and fat content. Plasma was used to assess the lipaemic index and the plasma lipid profiles. Treatment with Creon 10 000 significantly increased body mass (P = 0.016) and the digestibility of dry matter, crude protein as well as the co-efficient of fat absorption were also significantly improved following treatment (P<0.05). Creon 10 000 improved the lipaemic index values and significant changes in plasma free fatty acid and triglyceride concentrations were observed but not in cholesterol or high and low density lipoproteins. This study supports previous reports that the administration of pancreatic enzyme preparations together with a high fat meal is a beneficial strategy for the nutritional management of EPI.

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Made available in DSpace on 2015-07-22T20:50:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-27 / Objetivos: O estudo teve como objetivo determinar a prevalência e a especificidade de anticorpos anti-HLA e a prevalência de anti-neutrófilos em doadoras de sangue brasileiras e avaliar o impacto da exclusão de doadoras multíparas positivas da doação de sangue. Métodos: Foram estudadas amostras de soro de 350 doadoras distribuídas em quatro grupos de acordo com o número de gestações que tiveram (50 nulíparas, 100 com uma gestação, 100 com duas gestações, e 100 multíparas). Para a pesquisa de anticorpos foi utilizada a metodologia do ELISA pelos kits LAT-M e LAT-1240 (One Lambda, Inc, EUA) que detectam e identificam anticorpos anti-HLA, classe I e II, respectivamente. Sessenta e cinco doadoras multíparas, com resultados positivos e negativos no ELISA também foram testadas pela metodologia do LABScreen (One Lambda, Inc, EUA) que fornece a especificidade de anticorpos anti-HLA. Além disso, foi utilizado o teste de Aglutinação de Granulócitos (GAT) e Imunofluorescência de Granulócitos (GIFT) para detectar anticorpos anti-neutrófilos específicos. Resultados: Oitenta doadoras das 350 mulheres estudadas (22,9%) foram positivas para anticorpos anti-HLA, sendo que 37% eram multíparas, 26% mulheres que tiveram duas gestações e 17% que tiveram uma gestação. Todas as amostras de doadoras nulíparas foram negativas para anti-HLA. A diferença de doadoras positivas em cada grupo foi estatisticamente significante na prevalência de anti-HLA entre o grupo de nulíparas e de doadoras que tiveram no mínimo uma gestação (p < 0,001). Os soros de doadoras positivas pelo teste LAT-M foram também testados pelo LAT-1240, e em sete casos os anticorpos não puderam ser identificados. Dezessete doadoras (28,3%), consideradas negativas pelo LAT-M, apresentaram resultados positivos pelo LABScreen. O GAT foi aplicado para investigação do soro de doadoras negativas para anti-HLA, sendo positivo em duas de 264 doadoras (0,8%). Entre as doadoras com GAT positivo uma entre 62 (1,6%) era multípara e uma doadora entre 71 (1,4%) teve duas gestações. O GIFT também foi aplicado para doadoras negativas para anti-HLA e apresentou positividade em quatro mulheres de 264 (1,5%), sendo que duas entre 62 (3,2%) eram multíparas e duas entre 71 (2,8%) tiveram duas gestações. Conclusões: Anticorpos anti-HLA são encontrados freqüentemente em plasma de doadoras de sangue brasileiras (22,9%), e se correlacionam estatisticamente com o maior número de gestações (p < 0,001), aumentando a porcentagem de positividade com o aumento do xvi número de gestações. Apesar de apresentar uma menor freqüência (1,9% do total de doadoras nos testes GAT e GIFT), os anticorpos anti-neutrófilos também são encontrados em doadoras, podendo este valor ser maior uma vez que as doadoras positivas para anti-HLA não foram testadas. O impacto da exclusão de doadoras multíparas da doação de sangue corresponde a 4% do total de doadores. Em conclusão, anticorpos anti-HLA e anti-neutrófilos estão presentes no plasma de doadoras brasileiras e constituem fator de risco para desencadear TRALI em receptores de sangue com antígenos correspondentes. / Purpose: The aim of this study were to determine the prevalence and the specificity of anti-HLA, class I and II, antibodies and the prevalence of anti-neutrophil antibodies in Brazilians female blood donors and to assess the impact of excluding the positive multiparous blood donors from the blood donation. Methods: Serum samples from 350 Brazilians female blood donors, distributed according to the number of previous pregnancy (50 nuliparous, 100 one pregnancy, 100 two pregnancies,100 multiparous), has been examined to detect and to identify anti-HLA, class I and II, antibodies by enzyme-linked immunosorbent assay (ELISA), by LAT-M and LAT-1240 Kits (ONE LAMBDA, INC, EUA). Sixty-five multiparous female blood donors, between positive and negative by LAT-M, were tested by flow cytometry, by LABScreen Kit (ONE LAMBDA, INC, EUA), that provide the specificity of anti-HLA antibodies. Furthermore, the Granulocyte Agglutination (GAT) and Granulocyte Immunofluorescence (GIFT) Test were used to detect specific anti-neutrophil antibodies. Results: Anti-HLA antibodies, class I and/or II, have been found in 80 of 350 female blood donors (22.9%), from whom 37% were multiparous donors, 26% woman with two previous pregnancies, and 17% woman with one previous pregnancy. All the nuliparous blood donors were negative to anti-HLA antibodies. The difference among positive female blood donors in pregnancy groups was significant statistically in prevalence between nuliparous group and woman with at least one previous pregnancy (p < 0.001). The serum of positive female blood donors by LAT-M test were also tested by LAT-1240 Test and in seven women the anti- HLA antibodies can not be identified. Seventeen female blood donors, that were considered negative by LAT-M, were positive for anti-HLA antibodies by LABScreen. The GAT was applied to investigate the serum of negative female blood donors to anti- HLA. Two women of 264 female blood donors (0.8%) were positive to anti-neutrophil, from whom 1.6% were multiparous (one of 62) and 1.4% were women with two previous pregnancies (one of 71). The GIFT was also applied to negative female blood donors to anti-HLA and the women were positive to anti-neutrophil in four of 264 female blood donors (1.5%), from whom two multiparous of 62 (3.2%) and two of 71 (2.8%) women with two previous pregnancy. Conclusion: Anti-HLA antibodies have often been found in plasma of Brazilian female blood donors (22.9%), and are statistically associated with the number of pregnancy (p < 0,001). The percentage of positive women increases with xviii the number of pregnancy. Although the anti-neutrophil antibodies had less prevalence (1.9% of all women tested by GAT and GIFT), they are found in female blood donors. This value can be higher because the positive women to anti-HLA antibodies were not tested. The impact to exclude the positive multiparous blood donors to the blood donate is 4% of all blood donors. In conclusion, anti-HLA and anti-neutrophil antibodies are found in plasma of Brazilian female blood donors and they are considered risk factor to trigger TRALI in blood receptors with cognate antigen. / TEDE / BV UNIFESP: Teses e dissertações

Objetivo: A finalidade deste estudo foi avaliar o Doppler venoso em gestações gemelares monocoriônicas (MC) com insuficiência placentária e a relação do fluxo sanguíneo venoso com a acidemia no nascimento ou óbito fetal. Método: Estudo prospectivo que incluiu 18 gestações gemelares MC com insuficiência placentária. Os critérios de inclusão foram: gestação gemelar MC e diamniótica, dopplervelocimetria da artéria umbilical (AU) alterada, membranas integras e ausência de defeitos congênitos fetais. Casos que apresentassem a síndrome de transfusão feto- fetal foram excluídos. Os seguintes parâmetros de Doppler foram avaliados: índice de pulsatilidade (IP) da AU, índice de pulsatilidade para veias (IPV) do ducto venoso (DV), IP e velocidade sistólica máxima (Vmax) da artéria cerebral média (ACM), a média da velocidade máxima (TAMxV) da veia umbilical (VU) e a TAMxV da veia portal esquerda (VPE). Os parâmetros dopplervelocimétricos foram transformados em escore zeta (desvios padrão da média) ou múltiplos da mediana (MoM), de acordo com os valores de referência. Amostras de sangue do cordão umbilical foram obtidas imediatamente após o parto para a mensuração do pH da artéria umbilical no nascimento. Resultado: O pH < 7,20 ocorreu em nove recém nascidos (25%), pH< 7,15 em quatro (11,1%) e em quatro (11,1%) casos houve óbito intrauterino. Os escores zeta da TAMxV da VU e da VPE foram significativamente menores no grupo com pH < 7,2 ou óbito intrauterino (respectivamente: -1,79 vs. - 1,22, p=0,006; -2,26 vs. -1,13, p=0,04). Nos casos com pH< 7,15 ou óbito intrauterino a pulsação da VU foi mais frequente (50% vs. 10,7%, p=0,03) e a TAMxV da VU foi significativamente mais baixa (-1,89 vs. -1,26, p= 0,003). A análise de regressão logística demonstrou que o escore zeta da TAMxV da VU prediz significativamente acidemia com pH< 7,20 ou óbito intrauterino (p=0,019). O parâmetro de Doppler que prediz significativamente pH< 7,15 ou óbito intrauterino foi a pulsação da VU (p=0,023). Conclusão: Os parâmetros de Doppler da VU podem predizer a acidemia no nascimento ou o óbito fetal em gestações gemelares MC complicadas por insuficiência placentária / Objectives: The aim of this study was to investigate fetal venous Doppler in monochorionic (MC) twin pregnancies complicated by placental insufficiency and the relationship between fetal venous flow and acidemia at birth or intrauterine fetal death. Methods: This was a prospective study of 18 MC twin pregnancies with placental insufficiency. Inclusion criteria were MC diamniotic twin pregnancies, abnormal umbilical artery (UA) Doppler, intact membranes, and absence of fetal congenital abnormalities. The twin-to-twin transfusion syndrome cases were excluded. The following Doppler measurements were studied: UA pulsatility index (PI), ductus venosus (DV) pulsatility index for veins (PIV), middle cerebral artery (MCA) PI and peak systolic velocity (PSV), intra-abdominal umbilical vein (UV) timeaveraged maximum velocity (TAMxV), and left portal vein (LPV) TAMxV. Doppler parameters were transformed into z-scores (SD values from the mean) or multiples of median (MoM) according to normative references. Blood samples were obtained from the umbilical cord immediately after delivery to measure the pH of the umbilical artery at birth. Results: pH<7.20 occurred in 9 newborns (25%), pH<7.15 in 4 (11.1%), and intrauterine fetal death in 4 (11.1%). The UV-TAMxV and the LPVTAMxV z-scores were significantly lower in the group presenting pH <7.20 or intrauterine fetal death (respectively: -1.79 vs. -1.22, p=0.006; -2.26 vs. -1.13, p=0.04). In cases with pH <7.15 or intrauterine fetal death, UV pulsations were more frequent (50% vs. 10.7%, p=0.03) and the UV-TAMxV z-score was significantly lower (-1.89 vs. -1.26, p=0.003). Logistic regression demonstrated that the UVTAMxV z-score significantly predicted pH at birth <7.20 or intrauterine fetal death (p=0.019). The Doppler parameter which independently predicted pH < 7.15 or intrauterine fetal death was the presence of pulsation in the umbilical vein (p=0.023). Conclusion: UV Doppler parameters may predict acidemia at birth or intrauterine fetal death in MC twins complicated by placental insufficiency

Objetivo: A finalidade deste estudo foi avaliar o Doppler venoso em gestações gemelares monocoriônicas (MC) com insuficiência placentária e a relação do fluxo sanguíneo venoso com a acidemia no nascimento ou óbito fetal. Método: Estudo prospectivo que incluiu 18 gestações gemelares MC com insuficiência placentária. Os critérios de inclusão foram: gestação gemelar MC e diamniótica, dopplervelocimetria da artéria umbilical (AU) alterada, membranas integras e ausência de defeitos congênitos fetais. Casos que apresentassem a síndrome de transfusão feto- fetal foram excluídos. Os seguintes parâmetros de Doppler foram avaliados: índice de pulsatilidade (IP) da AU, índice de pulsatilidade para veias (IPV) do ducto venoso (DV), IP e velocidade sistólica máxima (Vmax) da artéria cerebral média (ACM), a média da velocidade máxima (TAMxV) da veia umbilical (VU) e a TAMxV da veia portal esquerda (VPE). Os parâmetros dopplervelocimétricos foram transformados em escore zeta (desvios padrão da média) ou múltiplos da mediana (MoM), de acordo com os valores de referência. Amostras de sangue do cordão umbilical foram obtidas imediatamente após o parto para a mensuração do pH da artéria umbilical no nascimento. Resultado: O pH < 7,20 ocorreu em nove recém nascidos (25%), pH< 7,15 em quatro (11,1%) e em quatro (11,1%) casos houve óbito intrauterino. Os escores zeta da TAMxV da VU e da VPE foram significativamente menores no grupo com pH < 7,2 ou óbito intrauterino (respectivamente: -1,79 vs. - 1,22, p=0,006; -2,26 vs. -1,13, p=0,04). Nos casos com pH< 7,15 ou óbito intrauterino a pulsação da VU foi mais frequente (50% vs. 10,7%, p=0,03) e a TAMxV da VU foi significativamente mais baixa (-1,89 vs. -1,26, p= 0,003). A análise de regressão logística demonstrou que o escore zeta da TAMxV da VU prediz significativamente acidemia com pH< 7,20 ou óbito intrauterino (p=0,019). O parâmetro de Doppler que prediz significativamente pH< 7,15 ou óbito intrauterino foi a pulsação da VU (p=0,023). Conclusão: Os parâmetros de Doppler da VU podem predizer a acidemia no nascimento ou o óbito fetal em gestações gemelares MC complicadas por insuficiência placentária / Objectives: The aim of this study was to investigate fetal venous Doppler in monochorionic (MC) twin pregnancies complicated by placental insufficiency and the relationship between fetal venous flow and acidemia at birth or intrauterine fetal death. Methods: This was a prospective study of 18 MC twin pregnancies with placental insufficiency. Inclusion criteria were MC diamniotic twin pregnancies, abnormal umbilical artery (UA) Doppler, intact membranes, and absence of fetal congenital abnormalities. The twin-to-twin transfusion syndrome cases were excluded. The following Doppler measurements were studied: UA pulsatility index (PI), ductus venosus (DV) pulsatility index for veins (PIV), middle cerebral artery (MCA) PI and peak systolic velocity (PSV), intra-abdominal umbilical vein (UV) timeaveraged maximum velocity (TAMxV), and left portal vein (LPV) TAMxV. Doppler parameters were transformed into z-scores (SD values from the mean) or multiples of median (MoM) according to normative references. Blood samples were obtained from the umbilical cord immediately after delivery to measure the pH of the umbilical artery at birth. Results: pH<7.20 occurred in 9 newborns (25%), pH<7.15 in 4 (11.1%), and intrauterine fetal death in 4 (11.1%). The UV-TAMxV and the LPVTAMxV z-scores were significantly lower in the group presenting pH <7.20 or intrauterine fetal death (respectively: -1.79 vs. -1.22, p=0.006; -2.26 vs. -1.13, p=0.04). In cases with pH <7.15 or intrauterine fetal death, UV pulsations were more frequent (50% vs. 10.7%, p=0.03) and the UV-TAMxV z-score was significantly lower (-1.89 vs. -1.26, p=0.003). Logistic regression demonstrated that the UVTAMxV z-score significantly predicted pH at birth <7.20 or intrauterine fetal death (p=0.019). The Doppler parameter which independently predicted pH < 7.15 or intrauterine fetal death was the presence of pulsation in the umbilical vein (p=0.023). Conclusion: UV Doppler parameters may predict acidemia at birth or intrauterine fetal death in MC twins complicated by placental insufficiency

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