INTRODUCTION : Acute kidney injury (AKI) is a disorder that is defined by rising serum creatinine and reduced urine output. It occurs in approximately 1-7% of hospitalized patients and is a major predictor of morbidity and mortality. It increases the costs and duration of hospital stay. AKI has been extensively studied post cardiac surgery, but there has been little attention on AKI occurring after non cardiac surgery . There have been few studies on AKI from developing countries and a paucity of data of post non cardiac surgery AKI. OBJECTIVE : To identify which known risk factors for AKI are commonly encountered at Groote Schuur Hospital, to document 30 and 90 day mortality, length of hospital stay, recovery of renal function at 90 days and identify factors associated with outcome post non-cardiac surgery. DESIGN: Prospective observational study. SETTING: Surgical Wards and ICU. PARTICIPANTS: Patients with AKI post non-cardiac surgery admitted between July 2012 and July 2013, who were 18 years and above without underlying stage 5 chronic kidney disease. OUTCOME MEASURES: Mortality, identification of risk factors, length of hospital stay and recovery of renal function. RESULTS: Of 367 patients referred to renal unit with AKI, 60 patients met inclusion criteria. Patients had an average age of 52.8 years (standard deviation 16.6) and 70% (42/60) were male. 61.7% (37 /60) were Coloured, 20% (12/60) were White and 18.3% (11/60) were Black. These patients were exposed to the following risk factors: 80%(48/60) had emergency surgery, 66. 7%(40/60) had sepsis, 65%(39/60) had perioperative contrast exposure, 53.3%(32/60) had hypotension that required inotropic support in 50%(30/60). Mortality was 33.3% (20/60) at 30 days and 45% (27/60) at 90 days. Of the 33 patients who did not die, 81.8% (27 /33) recovered their renal function to normal baseline creatinine at 90 days. Of the 6 patients, whose renal function did not return to baseline, none required long term dialysis. Perioperative contrast exposure was associated with a longer median length of hospital stay compared to patients not exposed to contrast (21 vs 16 days respectively, p<0.05). Sepsis and age > 60 years was associated with poor recovery of renal function (p=0.005, p=0.01 respectively). No risk factor was identified to be associated with mortality. CONCLUSION: Risk factors for post non cardiac surgery AKI commonly encountered at Groote Schuur Hospital were emergency surgery, sepsis, hypotension, perioperative use of inotropes and perioperative contrast exposure. The latter was identified as a modifiable risk factor which significantly prolonged hospital stay. Sepsis and age > 60 years were associated with poorer recovery of renal function.

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrodynamic delivery is a powerful tool that allows delivery of macromolecules to the kidney culminating in gene expression. This finding is important in the fight against kidney disease. Current therapy for kidney injury, specifically acute kidney injury, is lacking. Supportive care in the form of IV fluids and medications aimed at restoring Glomerular Filtration Rate (GFR) and urine output are currently used. However, even with these treatments, prognoses of patients diagnosed with this disease remains poor. We believe that hydrodynamic delivery provides a mechanism that can be used to reverse and prevent AKI. Hydrodynamic delivery following ischemic injuries leads to reductions in serum creatinine and infiltrating mononuclear cells, as well as increased renal blood flow and survival. These changes are due to reductions in vascular congestion and inflammation typically seen following injury. To determine the underlying mechanisms of gene delivery preventing AKI, we used candidate genes identified in a proteomic screen on kidneys that recovered from AKI. We selected Isocitrate Dehydrogenase II (IDH2) and Sulfotransferase 1C2 (SULT1C2) for study and found that delivery prior to injury prevents serum creatinine increase and reduces cell death. We found that gene delivery of IDH2 prevents a glycolytic shift typically seen following ischemic injuries. The mechanism underlying the prevention of this shift are seen in increased ATP stores and spare respiratory capacity allowing the cell to remain in an oxidative state. Additionally, we show that SULT1C2 post-translationally modifies the mitochondria membrane, increasing oxidative phosphorylation providing the cell with additional energy needed in times of oxidative stress. These candidate genes allow cells to remain in an oxidative state preventing the activation of cell death pathways typically activated following injury, thereby preserving normal kidney function.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20969号 / 医博第4315号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 濵﨑 洋子, 教授 三森 経世 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

No description available.

M.Med.(Haematology), Faculty of Health Sciences, University of the Witwatersrand, 2008 / This study aimed to identify the relevance of these prognostic features in the modern treatment era in South African children. A retrospective analysis of the presentation clinical and laboratory features and treatment outcomes of all children treated for Precursor B cell ALL at the Johannesburg Hospital was performed. Between January 1997 and May 2007, 100 children were reviewed. Clinical features (age, race and gender) emerged as significant prognostic variables. Laboratory features (white cell count and genetic features) lacked significance. Early morphologic response on day 15 identified a subgroup associated with a favourable outcome. However the presence of > 5% blasts was not significantly predictive of relapse or death at this time point. Minimal residual disease (MRD) detection by modified immunoglobulin gene rearrangement and flow cytometry techniques did not improve the predictive value of the morphological assessment. In a low resource setting, the challenge is to design cost effective MRD detection methods to improve the identification of patients at risk for relapse.

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, 2016 / Background: Despite preventive guidelines, iatrogenic contrast-induced nephropathy (CIN) ranks third as a cause of hospital acquired acute kidney injury (AKI), and impacts significantly on morbidity and mortality and is associated with high hospital costs. In Sub-Saharan Africa, the rates and risk factors for CIN remain unexplored. Despite the positive association of genetic polymorphisms in the TNFα and IL10 genes with CIN in Asian populations, the CIN genetic susceptibility in other races is unknown. Serum creatinine is a sub-optimal biomarker for the early diagnosis of CIN resulting in delayed interventions. This study investigated rates, risk factors and outcomes of CIN, the influence of genetic susceptibility to CIN in the black population and lastly, the accuracy of novel biomarkers in the early diagnosis of CIN and prognosticating patient outcomes. Methods: This was a prospective case-controlled study conducted at Charlotte Maxeke Johannesburg Academic Hospital, in South Africa from January 1, 2014 to December 30, 2015.Hospitalized patients undergoing enhanced computed tomography and angiography were consecutively recruited to the study and followed up for development of CIN. CIN was defined as an increase in serum creatinine >25% or an absolute increase of >44 μmol/l from baseline at 48-72 hours after exposure to contrast media. In the second part of the study, a nested case-controlled cohort that included 30 CIN patients and 60 controls (those undergoing contrast administrations and not meeting CIN criteria) were ethnically matched for gender, and age in a case: control ratio of 1:2 at all-time intervals. Sera for neutrophil gelatinaseassociated lipocalin-2 (NGAL), cystatin C, beta-2 microglobulin (β2M), interleukin 18 (IL18), IL10, and tumor necrosis factor alpha (TNFα) were collected at four time points: baseline (pre-contrast), 24 hours, 48 hours and ≥5-7 days after contrast administration and their concentrations were determined using luminex assays and an enzyme linked immunosorbent assay for β2M as per manufacturer’s instructions. The areas under receiver operating characteristic curves (AUROC) were generated to determine accuracy of novel biomarkers to diagnose CIN and CIN mortality. Genomic DNA was extracted from peripheral blood samples of 208 black South Africans using the Maxwell DNA purification kit (Promega AS1010, USA) and their genotypes for - 308(rs1800629) and -857(rs1799724) in the TNFα gene and -592(rs1800872), - 819(rs1800871), -1082 (rs1800896) and +1582(rs1554286) in the IL10 gene were determined by restriction fragment length polymorphism (RFLP). Results: We recruited 371 hospitalized patients (mean age 49.3±15.9); the rates of CIN were4.6% and 16.4% respectively, using an absolute or relative increase in serum creatinine from baseline. Anaemia was an independent predictor for the development of CIN (RR 1.71, 95% 1.01-2.87; p=0.04). The median serum albumin was 34 g/l (IQR: 29-39.5) vs. 38 g/l (IQR: 31-42), p=0.01 in the CIN and control groups respectively.Mortality was significantly increased in the CIN group (22.4% vs. 6.8%; p<0.001), and CIN together with anaemia predicted mortality with a 2-fold (p=0.01) and a 3-fold (RR p=0.003) riskrespectively. The median cystatin C at 24 hours (p<0.001) and β2M(at all-time points)levels were significantly higher in the CIN group compared to controls. The median cystatin C at 24 hours and β2Mlevels at 48 hours were 856.59 ng/ml (IQR 620.75-1002.96) vs. 617.42 ng/ml (IQR 533.11-805.20); p<0.001 and 5.3 μg/ml (IQR 3.8-6.9) vs. 3.3 μg/ml (IQR 2.7-4.5); p<0.001 with AUROCs of 0.75 and 0.78 respectively for early CIN discrimination.Pre-contrast IL18 (p <0.001), β2M (p=0.04) and TNFα (p<0.001) levels were significantly higher in the nonsurviving group and their AUROC were 0.83, 0.82 and 0.94 for CIN+ mortality. Baseline NGAL was a better marker for excluding patients at higher risk of developing CIN with negative predictive and positive predictive values of 0.81 and 0.50 respectively. The frequency of TNFα -308 AA genotype was significantly increased in the CIN group compared to controls (13.3% vs.1.82%, p=0.016) and the presence of the TNFα-308 AA (high producer) vs. GA genotypes was associated with a 9-fold CIN risk (9.24, 95% CI, 1.88-45, p=0.006). The IL10-1082 AA-allele (low producer) was significantly higher in the non-surviving CIN+ patients compared to controls (p=0.01). Conclusions:CIN occurred at a relatively high rate in our study and predicted poorer clinical outcomes. The presence of CIN and anaemia positively predicted mortality. Caution should be exercised in patients with anaemia and hypoalbuminaemia undergoing contrast studies. Serumcystatin C was the best novel biomarker for the early diagnosis of CIN and while baseline NGAL is superior as a biomarker for excluding patients at higher risk for CIN. IL18, β2M and TNFα are the best novel biomarkers for predicting the prognosis of patients with CIN. Increased frequency of the TNFα-308 AA genotype is a predisposing factor for CIN development. The low producer IL10-1082 AA genotype decreases survival in patient with CIN. / MT2017

Children treated for acute lymphoblastic leukemia (ALL) are immunodeficient and therefore at an increased risk of infection and cancer recurrence. Natural killer (NK) cells are a subset of lymphocytes that are very efficient at combatting infections and cancer; however, children treated for ALL have impaired NK cell number and function. Exercise has the potential to bolster NK cell number and function, at least in healthy children and adults. Limited evidence suggests exercise may also have beneficial effects on NK cells in children treated for cancer. However, these previous exercise immunology studies in children with cancer have yielded low sample sizes. Therefore, the aim of this study was to assess the: 1a) feasibility, 1b) acceptability and 1c) safety of performing an exercise intervention in children with ALL. The secondary objectives were to assess the 2a) effects of acute exercise on NK cell number, function and receptor expression in children receiving maintenance therapy for ALL compared to healthy children, as well as to 2b) assess how the NK response changes over 4 months of therapy, and to 2c) assess the link between physical activity and NK cell number and function at rest in children receiving maintenance therapy for ALL. Children undergoing maintenance therapy for ALL (n=4) were recruited from McMaster Children’s Hospital, and healthy sex and pubertal-status matched children (n=4) were recruited from the Hamilton community. ALL patients completed a total of 3 exercise visits, occurring monthly after their regularly scheduled chemotherapy session. At each exercise visit, children were asked to complete 30 minutes of continuous biking, followed by 1 hour of rest. Blood samples were drawn at rest prior to exercise (PRE), immediately after exercise (POST) and 1 hour into recovery (REC). Healthy children only completed one exercise visit. During recovery, participants were asked to complete a physical activity enjoyment scale (PACES) questionnaire and a structured interview in order to assess exercise acceptability and to gauge participant feedback on study components, respectively. Participants were outfitted with an accelerometer to track physical activity levels between visits. Feasibility was assessed by tracking recruitment statistics, study completion rates and exercise completion rates. Acceptability of accelerometer wear was assessed by tracking accelerometer wear and log rates. Safety was assessed by tracking adverse events. All parameters were reported using descriptive statistics. We approached 22 patients to participate, and 4 children completed the study (100% completion rate) out of a goal of 15. Primary deterrents to participation were that patients and families did not want to extend time spent at the hospital or had time restrictions and that patients were uncomfortable with blood collection methods. Exercise was feasible (94% exercise completion rate), acceptable (4.2 ± 0.38 out of 5 PACES score), and safe. Accelerometer wear rates (61.9% (range 3.7-100.0%)) and log completion rates (69.0% (25.9-100.0)) were moderate. Exercise transiently increased NK cell number and function in healthy children and some children with ALL. There were no patterns in the change of the NK cell response to acute exercise over time. We were unable to assess the link between physical activity and NK cells due to a paucity of data. This study cautiously suggests that exercise is a feasible, acceptable and safe intervention that may increase NK cell number and function in children treated for ALL. / Thesis / Master of Science in Medical Sciences (MSMS) / Children treated for leukemia have weak immune systems, making them more susceptible to developing infections and cancer recurrence. Natural killer cells are a special immune cell that is very effective at combatting cancer and infections; however, children treated for leukemia have very low amounts of natural killer cells and they do not function well. Exercise is a simple way to boost the immune system in healthy adults and children, by increasing the number and function of natural killer cells. We don’t know what effect exercise has on natural killer cells in children with leukemia. Previous studies looking at the effects of exercise on the immune system of children with cancer have not been able to recruit enough children to participate. Therefore, it is also important to investigate why children with cancer may not want to participate in exercise studies looking at immune function. The main goals of this thesis were to assess how likely we are to recruit enough children being treated for leukemia to participate in a study looking at how exercise changes natural killer cells, if our participants enjoyed being part of this study, and how safe exercise is for children being treated for leukemia. We also wanted to learn about how natural killer cells respond to exercise in children being treated for leukemia. We found that most of the children and families that decided not to participate in our study felt they did not have time, and the second most common reason for not participating was because the children experienced anxiety surrounding blood draws for the study. The children that decided to participate in the study enjoyed the exercise and being in the study. We also found that the exercise was safe. Finally, we saw that exercise was able to increase natural killer cell numbers and function in some, but not all, children treated for leukemia. The results of this study suggest that exercise may be a realistic and safe way to improve immune function in some children with leukemia.

Treatment of severe acute pancreatitis is considered to be conservative. The only generally accepted indication for surgery in severe acute pancreatitis patients is an established infection of the necrotic tissue and persisting or progressing symptoms of multiorgan failure despite the maximal intensive treatment. For surgical treatment are also indicated patients with complications of severe acute pancreatitis (erosive hemorrhage, perforation of GIT etc.). In the proposed work, attention is drawn to those cases, where the general condition of the patient deteriorates combined with a progression of ACS and where a decompressive laparotomy can improve the prognosis of the disease. In our group of 214 patients with severe acute pancreatitis, who were treated over the last six years, 70 patients were indicated for surgery. Out of this count, in 17 cases the indication for decompressive laparotomy was a raise of intraabdominal pressure up to the values of ACS together with the symptoms of organ dysfunction, 6 patients died and 11 younger patients survived.

No description available.

Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a decrease in succinate dehydrogenase (SDH) activity. Interestingly, our results indicated that FH induced by anti-CD44 mAb is regulated through the activation of the ERK1/2 pathway. Therefore, our findings highlight new elements in support for the use of anti-CD44 mAbs in AML therapies and open new perspectives to use metabolic profiling as a tool to support the potential possibilities for the development of CD44-targeted therapy of AML.