Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests antibody-mediated platelet destruction occurs in the spleen via Fcγ receptors (FcγR). However, it has been demonstrated that anti-GPIbα-mediated ITP is often refractory to therapies targeting FcγR pathways. Utilizing a panel of murine monoclonal antibodies (mAbs) against murine and human GPIIbIIIa and GPIbα, it was found that anti-GPIbα induces not only platelet activation to a much greater extent than anti-GPIIbIIIa antibodies, but also significant surface expression of neuraminidase 1 and platelet desialylation. Utilizing inhibitors of platelet activation and desialylation, it was found that these two processes are not mutually exclusive, but rather exist in a positive feedback loop, leading to FcγR-independent platelet clearance in the liver likely via Ashwell-Morell receptors. Furthermore, in a murine model of ITP, sialidase inhibitor treatment rescued platelet counts in predominantly anti-GPIbα -mediated thrombocytopenia.

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV–1–infected patients dramatically since it was launched in 1996, but there are still many challenges in the provision of HAART, especially to children in resource limited countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI) forms part of the recommended national first line antiretroviral treatment regimen for children older than 3 years and weighing more than 10 kg in South Africa. Limited pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1– infected children is available. EFV is primarily metabolised by hepatic CYP2B6 isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual variability in hepatic expression and activity. The single nucleotide change, 516G>T, on the CYP2B6 gene has consistently been associated with elevated EFV plasma levels in different ethnic populations and these are more frequently observed in populations of African descent. The recommended therapeutic range of EFV plasma levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml. In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders, with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy (ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic, Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics approval was obtained to conduct this study. The objectives of this investigation were to: develop and validate a suitable LCMS/ MS method to accurately determine plasma EFV levels from this study population, determine the prevalence and effect of CYP2B6 516G>T polymorphism on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F) value of EFV, identify covariates that influence the clearance of EFV in HIV–1– infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24 months post–HAART initiation. The main findings of the measured mid–dose EFV plasma concentrations showed that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant number of the samples (47.5%) were outside the accepted therapeutic range during this 24 month follow–up period. Possible reasons contributing to this include genetic variation in drug metabolism and non–adherence. Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42% 516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant frequency was relatively high at 41%. This also supports and explains why such a large number (29.5%) of the mid–dose interval plasma samples were above (>4 ug/ml) the accepted therapeutic range. Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T genotypes were consistently predictive of the log EFV concentrations at all times (P = 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple comparisons by groups revealed that the EFV plasma concentrations between the T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically significant. However, the differences between the EFV plasma concentrations of the T/T and G/T groups were not significantly different (P=0.074). This supports previous results that the presence of the 516 T–allelic variant is responsible for the higher EFV plasma concentrations within individuals presenting with this single nucleotide mutation on the CYP2B6 gene. This EFV–based treatment was well tolerated even at plasma concentrations above the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously. 89% of the participants were virally suppressed at 24 months post–HAART. The efficacy of this EFV–based treatment did not affect the three genotype groups differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post– HAART initiation. We found no association of the CYP2B6 516G>T polymorphism and side effects reported after 1 month of treatment within this study population. The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were, 2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion variability (IOV) in a PK model for a longitudinal study was again highlighted by this investigation. To our knowledge, this is the first study in black South African HIV–1–infected children with measured sequential EFV plasma concentrations which also investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma concentrations and the population clearance (CL/F) value of EFV in a longitudinal study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV–1–infected patients dramatically since it was launched in 1996, but there are still many challenges in the provision of HAART, especially to children in resource limited countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI) forms part of the recommended national first line antiretroviral treatment regimen for children older than 3 years and weighing more than 10 kg in South Africa. Limited pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1– infected children is available. EFV is primarily metabolised by hepatic CYP2B6 isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual variability in hepatic expression and activity. The single nucleotide change, 516G>T, on the CYP2B6 gene has consistently been associated with elevated EFV plasma levels in different ethnic populations and these are more frequently observed in populations of African descent. The recommended therapeutic range of EFV plasma levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml. In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders, with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy (ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic, Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics approval was obtained to conduct this study. The objectives of this investigation were to: develop and validate a suitable LCMS/ MS method to accurately determine plasma EFV levels from this study population, determine the prevalence and effect of CYP2B6 516G>T polymorphism on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F) value of EFV, identify covariates that influence the clearance of EFV in HIV–1– infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24 months post–HAART initiation. The main findings of the measured mid–dose EFV plasma concentrations showed that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant number of the samples (47.5%) were outside the accepted therapeutic range during this 24 month follow–up period. Possible reasons contributing to this include genetic variation in drug metabolism and non–adherence. Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42% 516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant frequency was relatively high at 41%. This also supports and explains why such a large number (29.5%) of the mid–dose interval plasma samples were above (>4 ug/ml) the accepted therapeutic range. Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T genotypes were consistently predictive of the log EFV concentrations at all times (P = 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple comparisons by groups revealed that the EFV plasma concentrations between the T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically significant. However, the differences between the EFV plasma concentrations of the T/T and G/T groups were not significantly different (P=0.074). This supports previous results that the presence of the 516 T–allelic variant is responsible for the higher EFV plasma concentrations within individuals presenting with this single nucleotide mutation on the CYP2B6 gene. This EFV–based treatment was well tolerated even at plasma concentrations above the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously. 89% of the participants were virally suppressed at 24 months post–HAART. The efficacy of this EFV–based treatment did not affect the three genotype groups differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post– HAART initiation. We found no association of the CYP2B6 516G>T polymorphism and side effects reported after 1 month of treatment within this study population. The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were, 2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion variability (IOV) in a PK model for a longitudinal study was again highlighted by this investigation. To our knowledge, this is the first study in black South African HIV–1–infected children with measured sequential EFV plasma concentrations which also investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma concentrations and the population clearance (CL/F) value of EFV in a longitudinal study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.

This study aimed to examine potential mechanisms for glucocorticoid (GC)-induced decreases in glucose clearance, and to determine if a reduction in oxidative stress load via dietary pre-treatment with an antioxidant-rich diet has a positive net effect on glucose tolerance following a sub-chronic treatment with the GC analogue dexamethasone (DEX). Rats fed a diet supplemented with 700IU of -tocopherol for two weeks had improved glucose clearance after five days of DEX-treatment relative to unsupplemented rats as well as decreased markers of oxidative stress. Following an intraperitoneal bolus of insulin, phosphorylation of AMP activated protein kinase (AMPK) was preserved in the supplemented groups despite no significant differences in upstream insulin signalling cascade intermediates between DEX-treated groups. This was corroborated by a similar increase (p<0.05) in phosphorylation of the downstream AMPK substrate acetyl CoA carboxylase. This study demonstrated that -tocopherol supplementation can attenuate GC-induced decreases in glucose clearance in an AMPK-dependent manner. / Nutrition and Metabolism

In this thesis, the relationships among oesophageal motility, bolus clearance and sensory perception of oesophageal stimuli in patients with several dysphagia syndromes were investigated. The work is divided into the following major sections: 1) Current advances in the application of impedance and its utility in distinguishing clearance characteristics between primary and secondary peristalsis; 2) The advances in our understanding of peristaltic motor characteristics, oesophageal bolus clearance and symptom perception in dysphagia syndromes; 3) Peristaltic dysfunction, impaired bolus clearance and symptom perception in gastro-oesophageal reflux disease (GORD) and in patients with globus; 4) TRPV1 expression in oesophageal mucosa in patients with GORD. The main findings from this work are: 1) Secondary peristalsis is less effective as primary peristalsis regarding esophageal transit and clearance of a liquid bolus. 2) In patients with non-obstructive dysphagia (NOD), bolus clearance by both morphologically normal and aberrant secondary peristaltic sequences is impaired. 3) Although, when compared with healthy controls, patients with NOD have a higher prevalence of non-specifically abnormal motor patterns, there is a poor correlation between dysphagia and oesophageal dysmotility. 4) Whereas manometry identified motility abnormalities in one quarter of patients with GORD, impedance demonstrated that the majority of these patients, as well as some patients with normal manometry, had defective bolus clearance. 5) Although patients with erosive GORD have delayed oesophageal bolus clearance, manometric characteristics in these patients are comparable to those seen in non-erosive reflux disease (NERD). These findings are compatible with the hypothesis that abnormal oesophageal bolus clearance may reflect a continuum of dysfunction secondary to increasing oesophageal mucosal damage. 6) Patients with globus are characterized by oesophageal visceral hypersensitivity and aberrant viscerosomatic referral of mechanical and electrical stimuli to the oesophagus. These findings support the hypothesis that oesophageal hypersensitivity with associated viscerosomatic referral patterns are an important pathogenetic mechanism for globus. 7) Patients with erosive GORD exhibit greater gene expression of TRPV1 in oesophageal mucosa when compared with NERD or healthy controls. These findings support the hypothesis that chronic inflammation may lead to the release of mediators which may modulate function of primary sensory neurons.

Hohenheim, Univ., Diss., 2007.

<p>Syftet med detta arbete var att undersöka om det fanns intresse för att införande av DUKC (Dynamic Under Keel Clearance) systemet i Sverige.Vi utgick ifrån en hamn i Australien, Port Hedland, som använt systemet sedan 1996, sedan tog vi reda på vad som användes i Sverige. För att få en bra grund sökte vi information om vad som krävdes för att DUKC skulle fungera tillfredställande. Vi Tog också del av en studie som man utfört i Mälaren som grundar sig på fartygs dynamiska rörelser och djupgående.Utifrån vår insamlade data ville vi fråga en sjöfartsrelaterad grupp och undersöka hur intresset för DUKC såg ut och skickade ut en enkät som även innehöll ett informationsblad.Efter sammanställning av erhållna svara framgick det att intresset för att införa just DUKC systemet inte var så stort men däremot ett system som gör det möjligt att säkerställa de krav som finns idag.</p>

This thesis considers the various perspectives of universities, academic staff and publishers to the copyright ownership of teaching and research outputs produced by UK universities, with a particular focus on how this affects the provision of online and/or open access to those outputs by university libraries. It presents ten papers written over a twenty year time frame that consider these issues within the context of a number of practitioner research projects and demonstrate how practices are changing over time. The papers employ a range of methodologies including questionnaire surveys, comparative design studies, interviews and content analyses. The key findings relating to research outputs (the scholarly royalty-free literature) are that rights are still mainly relinquished to academic staff by UK HEIs, although some HEIs are beginning to assert the right to re-use those works in various ways. Whilst academics are relied upon to either retain copyright or communicate their HEI s copyright policy terms to publishers, in most cases they (reluctantly) assign copyright to publishers. Publishers are increasingly allowing green open access to their scholarly works in some form, but under a growing array of restrictions and conditions principally embargo periods. Publishers terms of re-use for such works (when made explicit) are often restrictive, however most academics would be happy for their works to be re-used non-commercially as long as their moral rights remain protected. This situation creates challenges for both Institutional Repository Managers and copyright clearance staff in Libraries to manage access to, and re-use of, these outputs. The key findings relating to teaching outputs are that copyright mainly lies with HEIs although there are signs that HEIs are moving towards a shared ownership position through licensing. Academics seem to expect some degree of shared ownership, but as with research outputs, are principally concerned that their moral rights are protected. UK HEI copyright policies in this area are fledgling and do not comprehensively address either moral rights issues or other key copyright issues pertaining to OERs. Failure of universities to address these issues is impacting on the motivation of academics to share OERs.

Class of 2015 Abstract / Objectives: To compare and evaluate effects on kidney function of mannitol dieresis versus saline diuresis on kidney function with cisplatin therapy. Methods: Patient charts documented between January 2010 and July 2013 were obtained and reviewed from a database of a university associated medical center. The patient’s lowest creatinine clearance (CrCl) and potassium levels during any time in therapy were compared against the baseline. Statistical testing for primary and secondary outcomes was calculated using the Independent-Samples T-Test. Results: A total of 140 patients were reviewed – 68 patients were included in the mannitol arm, 72 in the saline arm. All baseline characteristics reviewed were not statistically different between groups except for sex, which was skewed towards males in the saline arm of the study. Baseline CrCl was 97.14 ml/min in the mannitol arm, and 93.69 ml/min in the saline arm (p=0.91). The average change in CrCl was found to be -16.72 ml/min (95% CI, -21.85 to -11.59) in the mannitol arm, -14.00 ml/min (95% CI, -18.82 to -9.20) in the saline arm; this was not statistically different (p=0.41). There was an average change of -0.31 mmol/L in blood potassium levels in mannitol patients, and a change of 0.014 mmol/L in saline patients; this was found to be significantly different (p<0.01). Conclusions: In this single-center retrospective study, there appeared to be no benefit in using mannitol diuresis over saline diuresis. The use of mannitol incurs additional cost and place additional restrictions on administration.

Volvo Cars proving ground in Hällered is a place for cars to be tested around the clock, in the most rough environments. Testing the wheel clearance today is done by putting modelling clay in the wheelhouse, and then drive through several different obstacles. By doing this, the wheel clearance can be measured where the wheel has left a mark on the modelling clay. The thesis is based on a question if wheel clearance testing can be performed on a test rig, and therefore the issue we decided to work with was what differences in the modelling clay marks could be observed between running the test on the proving ground and simulating the same movement on the test rig. We have made several limitations, the most obvious limit we have chosen is to only focus on the movement in vertical direction. We used a camera measuring system that was mounted onto our test vehicle. It measures the position from a set origin to the wheel centre in three dimensions over time. We ran tests out on the proving ground, focusing on one obstacle. The test was run for two reasons, to get the imprints from the tire on the clay and to obtain the measurement data from the measuring system. We then identified the maximum reached positive wheel position in vertical direction by using a MATLAB script. We then used the test rig to position the front wheels in the same three-dimensional positions as when the wheel centre reached its maximum vertical value according to the measuring data mentioned above. We measured the imprints of the wheel in the modelling clay after the positioning procedure in the test rig and began to compare the different clay imprints and evaluating the results. The measurements indicated a significant difference between the two, even though the positioning used in the three dimensions were identical. We discuss the possible reasons for any source of error that we could think of. We also come up with suggestions how to reduce the impact of some of the sources of error.