2014

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonThe presence of human pharmaceuticals in the environment has raised concerns regarding their potential adverse effects on non-target aquatic organisms. Pharmaceuticals are designed to target specific molecular pathways in humans in order to produce known pharmacological and physiological responses, before toxicological effects are seen. The “Read-Across Hypothesis” stipulates that pharmaceuticals can produce similar biological effects in fish, as in humans, if the molecular target is conserved, and the internal (blood plasma) concentrations are similar. The read-across hypothesis was tested using ibuprofen, a non-steroidal anti-inflammatory drug, and the model fish test species, the fathead minnow (Pimephales promelas), to determine if ibuprofen can cause similar target-mediated effects in teleost fish and humans, at comparable blood plasma concentrations. Fathead minnows were exposed, using continuous flow-through systems, for ≤96 hours to a range of ibuprofen water concentrations (100, 270, 370 and 500 µg/L) to determine if plasma concentrations similar to human therapeutic plasma concentrations (HTPCs, or Cmax) could be established in fish blood plasma. The mode of action of ibuprofen was used to identify relevant endpoints (i.e. cyclooxygenase (COX) enzyme) in order to examine target-mediated effects following drug exposure. The water and plasma ibuprofen concentrations were determined using LC-MS/MS. The measured ibuprofen plasma concentrations in individual fish were linked to target-mediated effects on COX gene expression, COX enzyme activity and prostaglandin E2 (PGE2) synthesis (products of COX activity), which were quantified using molecular (QPCR) and biochemical (colourimetric and enzyme immunoassay) assays, and linked with the Cmax of ibuprofen. It was demonstrated that in fish with a mean ibuprofen plasma concentration 1.8-fold below the Cmax, PGE2 concentrations (the most robust endpoint) was significantly inhibited following ibuprofen exposure. However, in fish exposed to an ibuprofen concentration closer to (2 to 3-fold above) environmentally relevant water concentrations (i.e. 9 µg/L), when the mean plasma concentration was 224-fold below the Cmax, fish did not respond to ibuprofen exposure. This study provides qualitative and quantitative evidence for the applicability of the “read-across hypothesis”, and highlights its potential utility for prioritising pharmaceuticals for environmental risk assessment.The Biotechnology and Biological Sciences Research Council (BBSRC) and AstraZeneca SHE Research Programme, UK

The effects of plus lenses on eye movements

This study assessed eye movements of fourteen esophoric subjects at near utilizing the OBER2 digital eye movement registration system. The OBER2 has specialized goggles that monitor eye movements as a subject views a reading passage. Subjects read one passage with their habitual distance prescription and another passage with the plus amount required to shift their esophoric posture into exophoria. Our purpose was to quantify the eye movements with the near add to determine if the increased lens power would improve the subject\u27s visual performance and eye movement ability. Statistical analysis was done on the eye movement data under both reading conditions and no significant difference was found

A Generalized Trust Calculation Algorithm

Abstract the current world is a digital world. And certainly we are living simultaneously with digital equipment. The digital computer is no exception. Human life, now a days, largely depends upon computer systems. We use computers for complex mathematical calculations, gaming, day to day account keeping, train tickets reservation, flight ticket reservation, war weapon launching, and space science. The list is keeps on going. The computer based systems are invented or discovered to make human life easier. But the journey is not so easy. If any system starts malfunctioning or behaving abnormally then it starts harming to the human race. As for example: If a war weapon controlling system is mal-programmed then it may possible that weapon may be launched if there is no bellicose situation or may be placed on different trajectory. Another example we may suggest from internet hacking. The confidential data may be hacked and can be used for malicious purpose. Both the example suggests one single point. Even though we use computer based system to make our life easier, it is not advisory to trust on the system without any examination. The trust is not a functionality of the system, but is a very important attribute. It is considered as a soft security. The more trusty a system is, the more reliable it will be. And it will be safer to use the system. The calculation of trust is not depending on one parameter. Various parameters need to take into accounts to calculate the trust. In this article we are proposing an algorithm for achieving the same. This algorithm is based on two concrete mathematical tools: The Markov Chain and The Baye’s Theorem. The Markov chain or model is used to calculate the trust based on some previous trust factors. The Baye’s theorem is used to find the probability of finding the truthfulness of the data. Keywords: Multi-Agent System, JADE,Markove Chain, Baye’s Theorm, Trust Calculatio

Evaluation of the Heart of Birmingham teaching Primary Care Trust (HoBtPCT): My Choice Weight Management Programme:report commissioned by Heart of Birmingham teaching Primary Care Trust

This report details an evaluation of the My Choice Weight Management Programme undertaken by a research team from the School of Pharmacy at Aston University. The My Choice Weight Management Programme is delivered through community pharmacies and general practitioners (GPs) contracted to provide services by the Heart of Birmingham teaching Primary Care Trust. It is designed to support individuals who are ‘ready to change’ by enabling the individual to work with a trained healthcare worker (for example, a healthcare assistant, practice nurse or pharmacy assistant) to develop a care plan designed to enable the individual to lose 5-10% of their current weight. The Programme aims to reduce adult obesity levels; improve access to overweight and obesity management services in primary care; improve diet and nutrition; promote healthy weight and increased levels of physical activity in overweight or obese patients; and support patients to make lifestyle changes to enable them to lose weight. The Programme is available for obese patients over 18 years old who have a Body Mass Index (BMI) greater than 30 kg/m2 (greater than 25 kg/m2 in Asian patients) or greater than 28 kg/m2 (greater than 23.5 kg/m2 in Asian patients) in patients with co-morbidities (diabetes, high blood pressure, cardiovascular disease). Each participant attends weekly consultations over a twelve session period (the final iteration of these weekly sessions is referred to as ‘session twelve’ in this report). They are then offered up to three follow up appointments for up to six months at two monthly intervals (the final of these follow ups, taking place at approximately nine months post recruitment, is referred to as ‘session fifteen’ in this report). A review of the literature highlights the dearth of published research on the effectiveness of primary care- or community-based weight management interventions. This report may help to address this knowledge deficit. A total of 451 individuals were recruited on to the My Choice Weight Management Programme. More participants were recruited at GP surgeries (n=268) than at community pharmacies (n=183). In total, 204 participants (GP n=102; pharmacy n=102) attended session twelve and 82 participants (GP n=22; pharmacy 60) attended session fifteen. The unique demographic characteristics of My Choice Weight Management Programme participants – participants were recruited from areas with high levels of socioeconomic deprivation and over four-fifths of participants were from Black and Minority Ethnic groups; populations which are traditionally underserved by healthcare interventions – make the achievements of the Programme particularly notable. The mean weight loss at session 12 was 3.8 kg (equivalent to a reduction of 4.0% of initial weight) among GP surgery participants and 2.4 kg (2.8%) among pharmacy participants. At session 15 mean weight loss was 2.3 kg (2.2%) among GP surgery participants and 3.4 kg (4.0%) among pharmacy participants. The My Choice Weight Management Programme improved the general health status of participants between recruitment and session twelve as measured by the validated SF-12 questionnaire. While cost data is presented in this report, it is unclear which provider type delivered the Programme more cost-effectively. Attendance rates on the Programme were consistently better among pharmacy participants than among GP participants. The opinions of programme participants (both those who attended regularly and those who failed to attend as expected) and programme providers were explored via semi-structured interviews and, in the case of the participants, a selfcompletion postal questionnaire. These data suggest that the Programme was almost uniformly popular with both the deliverers of the Programme and participants on the Programme with 83% of questionnaire respondents indicating that they would be happy to recommend the Programme to other people looking to lose weight. Our recommendations, based on the evidence provided in this report, include: a. Any consideration of an extension to the study also giving comparable consideration to an extension of the Programme evaluation. The feasibility of assigning participants to a pharmacy provider or a GP provider via a central allocation system should also be examined. This would address imbalances in participant recruitment levels between provider type and allow for more accurate comparison of the effectiveness in the delivery of the Programme between GP surgeries and community pharmacies by increasing the homogeneity of participants at each type of site and increasing the number of Programme participants overall. b. Widespread dissemination of the findings from this review of the My Choice Weight Management Project should be undertaken through a variety of channels. c. Consideration of the inclusion of the following key aspects of the My Choice Weight Management Project in any extension to the Programme: i. The provision of training to staff in GP surgeries and community pharmacies responsible for delivery of the Programme prior to patient recruitment. ii. Maintaining the level of healthcare staff input to the Programme. iii. The regular schedule of appointments with Programme participants. iv. The provision of an increased variety of printed material. d. A simplification of the data collection method used by the Programme commissioners at the individual Programme delivery sites

Bioapplicable, nanostructured and nanocomposite materials for catalytic and biosensor applications

Novel, nanostructured porous nanocomposites and bioapplicable materials have been successfully developed for catalytic, sensor and reinforcement applications. Nonsurfactant templated method of pore formation and electrospinning of nanofibers are the two main technologies that have been employed separately and together, to develop novel and potentially commercialize-able products. The porous composite products thus developed take the form of fine particles and nanofiber mats.For the first time, porous silver nanoparticle/silica composites were synthesized using a simple method of silver nitrate reduction. The glucose template present inside the mesoporous silica material reduces silver nitrate to silver nanoparticles. The particles thus formed are lodged inside the porous silica matrix. The synthesis procedure is very simple, economical, and the samples produced have good catalytic properties.Organic/inorganic hybrid nanofiber mats were fabricated for the first time using the electrospinning technology. The fiber mats have high surface area and good mechanical properties. These fibers mats are then used in reinforcement applications, by utilizing them as fillers in dental materials. The mechanical properties of dental materials thus produced is seen to improve dramatically with the addition of just a small amount of fiber sample.An in-situ method was used to produce silver and gold nanoparticles inside porous silica nanofibers via electrospinning. Metal salts used to produce the nanoparticles are mixed with silica and polymer precursors and spun into fibers. The fibers are then heat-treated to reduce the metal salt into metal nanoparticles. The factors affecting the size and distribution of the nanoparticles inside the porous fibers were studied. The fibers thus produced were then tested for catalytic activity.Horseradish peroxidase (HRP) enzyme was also encapsulated in porous silica nanofibers via electrospinning. The fibers showed significant enhancement in enzyme activity, which was three orders of magnitude greater than that of the non-templated, conventional microporous silica materials. The factors affecting the enzyme activity, like pH, temperature, etc., was also studied. The response time of the encapsulated enzymes to the external reagents was ~ 2 to 3 seconds, showing high efficiency of the fibers to sensor applications.Finally, the encapsulation and alignment of quantum dots in silica nanofibers for sensor and telecommunication applications was attempted. MnO2 and several enzymes encapsulated porous silica samples were also synthesized for universities and companies as part of the ongoing collaborative research work for various catalytic applications.All the above-mentioned products have high surface area, maintain high enzyme activity, and protect the enzymes and nanoparticles from high temperatures, pH fluctuations and strong chemicals. The morphology, size, porosity, composition of the developed products were studied in detail, via infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, scanning electron microscopy, transmission electron microscopy, X-ray diffraction spectroscopy, etc. Inexpensive raw materials, convenient synthesis method, distinctive structure and physical-chemical properties make the developed products greatly suitable for a wide range of potential applications.Ph.D., Polymer Materials -- Drexel University, 200

Synthesis and Antiprotozoal Activity of Dicationic 2, 6-Diphenylpyrazines and Aza-Analogues

Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8 to 37 nM) and P. f. (10 to 52 nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results

Unveiling the synergistic effect of amorphous CoW-phospho-borides for overall alkaline water electrolysis

Amorphous transition-metal-phospho-borides (TMPBs) are emerging as a new class of hybrid bifunctional catalysts for water-splitting. The present work reports the discovery of CoWPB as a new promising material that adds to the smaller family of TMPBs. The optimized compositions, namely Co4WPB5 and Co2WPB1 could achieve 10 mA/cm2 at just 72 mV and 262 mV of overpotentials for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), respectively, in 1 M KOH. Furthermore, the catalyst showed good performance in a 2-electrode assembly (1.59 V for 10 mA/cm2) with considerable stability (70 h stability, 10,000 operating cycles). Detailed morphological and electrochemical characterizations unveiled insights into the role of all elements in catalyst's improved performance. The presence of W was found to be crucial in improving the electronic conductivity and charge redistribution, making CoWPB suitable for both HER and OER. In computational simulation analysis, two configurations with different atomic environments, namely, CoWPBH and CoWPBO were found to have the lowest calculated overpotentials for HER and OER, respectively. It was found that the surface P-sites in CoWPBH were HER-active while the Co-sites in CoWPBO were OER-active sites. The study presents new knowledge about active sites in such multi-component catalysts that will foster more advancement in the area of water electrolysis

Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort

INTRODUCTION: Vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis and is over-expressed in breast cancer. At least four polymorphisms in the VEGF gene have been associated with changes in VEGF expression levels: -2578C/A, -1154G/A and -634G/C are all located in the promoter region; and +936C/T is located in the 3'-untranslated region. METHOD: We examined the association between these four VEGF polymorphisms and risk for breast cancer among postmenopausal women in CPS-II (Cancer Prevention Study II) Nutrition Cohort. This cohort was established in 1992 and participants were invited to provide a blood sample between 1998 and 2001. Included in this analysis were 501 postmenopausal women who provided a blood sample and were diagnosed with breast cancer between 1992 and 2001 (cases). Control individuals were 504 cancer-free postmenopausal women matched to the cases with respect to age, race/ethnicity, and date of blood collection (controls). RESULTS: We found no association between any of the polymorphisms examined and overall breast cancer risk. However, associations were markedly different in separate analyses of invasive cancer (n = 380) and in situ cancer (n = 107). The -2578C and -1154G alleles, which are both hypothesized to increase expression of VEGF, were associated with increased risk for invasive breast cancer (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.00–2.14 for -2578 CC versus AA; OR 1.64, 95% CI 1.02–2.64 for -1154 GG versus AA) but they were not associated with risk for in situ cancer. The +936C allele, which is also hypothesized to increase VEGF expression, was not clearly associated with invasive breast cancer (OR 1.21, 95% CI 0.88–1.67 for +936 CC versus TT/CT), but it was associated with reduced risk for in situ cancer (OR 0.59, 95% CI 0.37–0.93 for CC versus TT/CT). The -634 C/G polymorphism was not associated with either invasive or in situ cancer. CONCLUSION: Our findings provide limited support for the hypothesis that the -2578C and -1154G VEGF alleles are associated with increased risk for invasive but not in situ breast cancer in postmenopausal women

A Pooled Analysis of Body Mass Index and Mortality among African Americans

Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995–2009; Adventist Health Study 2, 2002–2008; Black Women's Health Study, 1995–2009; Cancer Prevention Study II, 1982–2008; Multiethnic Cohort Study, 1993–2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993–2009; Southern Community Cohort Study, 2002–2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30–104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25–27.4, 27.5–29.9, 30–34.9, 35–39.9, 40–49.9, and 50–60 kg/m2 were 1.02 (0.92–1.12), 1.06 (0.95–1.18), 1.32 (1.18–1.47), 1.54 (1.29–1.83), 1.93 (1.46–2.56), and 1.93 (0.80–4.69), respectively among men and 1.06 (0.99–1.15), 1.15 (1.06–1.25), 1.24 (1.15–1.34), 1.58 (1.43–1.74), 1.80 (1.60–2.02), and 2.31 (1.74–3.07) respectively among women (reference category 22.5–24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans