Pyridazinediones and amino acid receptors: theoretical studies, design, synthesis, and evaluation of novel analogues

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands

Has the Rate of CD4 Cell Count Decline before Initiation of Antiretroviral Therapy Changed over the Course of the Dutch HIV Epidemic among MSM?

Introduction:Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.Methods:Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Pre-university students' perceptions about the life cycle of bioplastic and fossil-based plastics

Sustainability has become a prominent theme in society and can be considered as an integral part of scientific citizenship. This study investigates to what extent the production, use and re-use of (bio)plastics initiates students’ reasoning and to identify the kind of content knowledge students put forward. The structure of students’ arguments was mapped according to Toulmin's model of argumentation, i.e., claim, data, warrant & backing and qualifier & rebuttals. Students (N = 27, grade 10 & 11) participated in groups of three. The students were introduced to the topic of the production, use and re-use of plastics by watching a video, answering questions, reading articles and having interviews and group discussions. Students were prompted to argue on the sustainability of bioplastics and fossil-based plastics. The results show that students frequently used arguments related to preventing pollution, designing to recycle and designing to degrade. However, themes such as avoiding waste, origin of energy and materials, energy efficiency and costs were rarely used or even absent in students’ reasoning. Overall, the students’ reasoning contained all of Toulmin's categories, and especially the increase in the number of qualifier & rebuttals is interpreted as an indication of awareness of the complexity of the issue at hand. This study underlines that students are able to bring in relevant scientific knowledge when confronted with a suitable sustainability issue, but also more societally oriented arguments enriched their perspective. Implications for the design of interventions aiming to engage students in life cycle analysis (on plastics) are discussed

Pre-university students' perceptions about the life cycle of bioplastic and fossil-based plastics

Sustainability has become a prominent theme in society and can be considered as an integral part of scientific citizenship. This study investigates to what extent the production, use and re-use of (bio)plastics initiates students’ reasoning and to identify the kind of content knowledge students put forward. The structure of students’ arguments was mapped according to Toulmin's model of argumentation, i.e., claim, data, warrant & backing and qualifier & rebuttals. Students (N = 27, grade 10 & 11) participated in groups of three. The students were introduced to the topic of the production, use and re-use of plastics by watching a video, answering questions, reading articles and having interviews and group discussions. Students were prompted to argue on the sustainability of bioplastics and fossil-based plastics. The results show that students frequently used arguments related to preventing pollution, designing to recycle and designing to degrade. However, themes such as avoiding waste, origin of energy and materials, energy efficiency and costs were rarely used or even absent in students’ reasoning. Overall, the students’ reasoning contained all of Toulmin's categories, and especially the increase in the number of qualifier & rebuttals is interpreted as an indication of awareness of the complexity of the issue at hand. This study underlines that students are able to bring in relevant scientific knowledge when confronted with a suitable sustainability issue, but also more societally oriented arguments enriched their perspective. Implications for the design of interventions aiming to engage students in life cycle analysis (on plastics) are discussed

Transient Lowering of the Viral Set Point After Temporary Antiretroviral Therapy of Primary HIV Type 1 Infection

Whether temporary antiretroviral treatment during primary HIV infection (PHI) lowers the viral set point or affects the subsequent CD4 count decline remains unclear. The objectives of this study were to analyze the clinical, viral, and immunological effects of temporary early HAART during PHI. This is a cohort study of patients with laboratory evidence of PHI. Independent predictors of early HAART and the viral set point were analyzed using multiple regression analysis. Plasma HIV-1 RNA (pVL) and CD4 trajectories were analyzed using linear mixed models. A total of 332 patients were included in the analysis. Sixty-four patients started HAART within 180 days of seroconversion. A higher baseline pVL was independently predictive of the start of early HAART (OR: 2.69/log10pVL, p = 0.001). Thirty-two patients who interrupted early HAART were compared with 250 patients who remained untreated for more than 180 days after seroconversion. Temporary early HAART was not significantly associated with a longer AIDS-free survival but did result in an initial, but transient lowering of the viral set point. The viral set point was initially 0.6 log copies/ml lower after interruption of early HAART (p<0.001) and remained lower during 83 weeks of follow-up. No significant difference in the slopes of CD4 decline was detected between the groups. Temporary HAART in PHI is started more frequently in patients with a higher pVL and can transiently lower the viral set point compared to never treated patients.Immunogenetics and cellular immunology of bacterial infectious disease

Validation of the QTL on SSC4 for meat and carcass quality traits in a commercial crossbred pig population

Porcine chromosome 4 harbours many quantitative trait loci (QTL) affecting meat quality, fatness and carcass composition traits, detected in resource pig populations previously. However, prior to selection in commercial breeds, QTL identified in an intercross between divergent breeds require confirmation, so that they can be segregated. Consequently, the objective of this study was to validate several QTL on porcine chromosome 4 responsible for meat and carcass quality traits. The experimental population consisted of 14 crossbred paternal half-sib families. The region of investigation was the q arm of SSC4 flanked by the markers S0073 and S0813. Regression analysis resulted in the validation of three QTL within the interval: Minolta a* loin, back fat thickness and the weight of trimmed ham. The results were additionally confirmed by factor analysis. Candidate genes were proposed for meat colour, which was the most evident QTL validated in this study