Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5–2.5 nm. The host-guest association constant Ka was 1,639 M−1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

The effectiveness of female -sensitive substance abuse treatment

This research investigated whether female-sensitive treatment was more effective than a traditional mixed-gender modal. The study participants were evaluated for levels of depression, self-esteem, social support, and presence and severity of addiction. Analyses were conducted to see which demographic, treatment, and service variables were associated with treatment survival rates. It was found that the chemical dependent treatments evaluated all produced equally ineffective results. The women surveyed did have significantly high levels of depression and presence and severity of addiction, yet moderate levels of self-esteem and social support. A mixed-gender chemical dependency model which provided mental health services focusing on depression was recommended. Ancillary services which provided self-esteem building and social support was also suggested. ^

Evaluation of the Scent Collection System for Its Effectiveness in Volatile Organic Compound Collection and Use in Canine Training

As a result of increased terrorist activity around the world, the development of a canine training aid suitable for daily military operations is necessary to provide effective canine explosive detection. Since the use of sniffer dogs has proven to be a reliable resource for the rapid detection of explosive volatiles organic compounds, the present study evaluated the ability of the Human Scent Collection System (HSCS) device for the creation of training aids for plasticized / tagged explosives, nitroglycerin and TNT containing explosives, and smokeless powders for canine training purposes. Through canine field testing, it was demonstrated that volatiles dynamically collected from real explosive material provided a positive canine response showing the effectiveness of the HSCS in creating canine training aids that can be used immediately or up to several weeks (3) after collection under proper storage conditions. These reliable non-hazardous training aids allow its use in areas where real explosive material aids are not practical and/or available.

A dosimetry and radiobiological model for intravascular brachytherapy treatment planning with radioisotope emitting stents

The aim of this study was to develop a practical, versatile and fast dosimetry and radiobiological model for calculation of the 3D dose distribution and radiobiological effectiveness of radioactive stents. The algorithm was written in Matlab 6.5 programming language and is based on the dose point kernel convolution. The dosimetry and radiobiological model was applied for evaluation of the 3D dose distribution of 32P, 90Y, 188Re and 177Lu stents. Of the four, 32P delivers the highest dose, while 90Y, 188Re and 177Lu require high levels of activity to deliver a significant therapeutic dose in the range of 15-30 Gy. Results of the radiobiological model demonstrated that the same physical dose delivered by different radioisotopes produces significantly different radiobiological effects. This type of theoretical dose calculation can be useful in the development of new stent designs, the planning of animal studies and clinical trials, and clinical decisions involving individualized treatment plans.

Evaluating the effectiveness of signal timing optimization based on microscopic simulation evaluation

The optimization of the timing parameters of traffic signals provides for efficient operation of traffic along a signalized transportation system. Optimization tools with macroscopic simulation models have been used to determine optimal timing plans. These plans have been, in some cases, evaluated and fine tuned using microscopic simulation tools. A number of studies show inconsistencies between optimization tool results based on macroscopic simulation and the results obtained from microscopic simulation. No attempts have been made to determine the reason behind these inconsistencies. This research investigates whether adjusting the parameters of macroscopic simulation models to correspond to the calibrated microscopic simulation model parameters can reduce said inconsistencies. The adjusted parameters include platoon dispersion model parameters, saturation flow rates, and cruise speeds. The results from this work show that adjusting cruise speeds and saturation flow rates can have significant impacts on improving the optimization/macroscopic simulation results as assessed by microscopic simulation models.

Design and evaluation of a consulting system for database design

Database design is a difficult problem for non-expert designers. It is desirable to assist such designers during the problem solving process by means of a knowledge based (KB) system. Although a number of prototype KB systems have been proposed, there are many shortcomings. Firstly, few have incorporated sufficient expertise in modeling relationships, particularly higher order relationships. Secondly, there does not seem to be any published empirical study that experimentally tested the effectiveness of any of these KB tools. Thirdly, problem solving behavior of non-experts, whom the systems were intended to assist, has not been one of the bases for system design. In this project, a consulting system, called CODA, for conceptual database design that addresses the above short comings was developed and empirically validated. More specifically, the CODA system incorporates (a) findings on why non-experts commit errors and (b) heuristics for modeling relationships. Two approaches to knowledge base implementation were used and compared in this project, namely system restrictiveness and decisional guidance (Silver 1990). The Restrictive system uses a proscriptive approach and limits the designer's choices at various design phases by forcing him/her to follow a specific design path. The Guidance system approach, which is less restrictive, involves providing context specific, informative and suggestive guidance throughout the design process. Both the approaches would prevent erroneous design decisions. The main objectives of the study are to evaluate (1) whether the knowledge-based system is more effective than the system without a knowledge-base and (2) which approach to knowledge implementation - whether Restrictive or Guidance - is more effective. To evaluate the effectiveness of the knowledge base itself, the systems were compared with a system that does not incorporate the expertise (Control). An experimental procedure using student subjects was used to test the effectiveness of the systems. The subjects solved a task without using the system (pre-treatment task) and another task using one of the three systems, viz. Control, Guidance or Restrictive (experimental task). Analysis of experimental task scores of those subjects who performed satisfactorily in the pre-treatment task revealed that the knowledge based approach to database design support lead to more accurate solutions than the control system. Among the two KB approaches, Guidance approach was found to lead to better performance when compared to the Control system. It was found that the subjects perceived the Restrictive system easier to use than the Guidance system.

Longitudinal Clinical Evaluation of Undercut Areas and Rest Seats of Abutment Teeth in Removable Partial Denture Treatment

PURPOSE: Adequate preparation of abutment teeth for removable partial denture (RPD) rest seats allows appropriate masticatory force transmission, retention, and stability of supporting structures. It follows that careful preparation will be important for the longevity of the rehabilitation. The present study aimed to clinically evaluate rest seats and undercut areas of abutment teeth in RPD wearers after 2 years of use. MATERIALS AND METHODS: A total of 193 occlusal, incisal, and cingulum rest seats were evaluated in terms of shape, rest adaptation, wear, caries, fractures, and surface type (enamel, composite resin, or amalgam). Two hundred and fourteen undercut areas were evaluated in terms of surface type (enamel or restoration) and integrity. This study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte, resolution 196/1996, protocol number 11/05. RESULTS: Intact preparations accounted for 92.2% of the total. Application of the Pearson test (p= 0.289) found no statistically significant differences among the materials on which the rest seats were prepared. For the undercut areas, 20.7% of those obtained on restorative material were nonintact. In addition, Fisher's exact test showed a statistically significant difference (p= 0.001) in surface type; enamel surfaces were shown to be 14 times more stable than restored surfaces. CONCLUSIONS: The results of this study suggest that rest seats are stable, regardless of the material on which they are prepared. Retentive areas were shown to be more stable when they were located in enamel.

Longitudinal Clinical Evaluation of Undercut Areas and Rest Seats of Abutment Teeth in Removable Partial Denture Treatment

PURPOSE: Adequate preparation of abutment teeth for removable partial denture (RPD) rest seats allows appropriate masticatory force transmission, retention, and stability of supporting structures. It follows that careful preparation will be important for the longevity of the rehabilitation. The present study aimed to clinically evaluate rest seats and undercut areas of abutment teeth in RPD wearers after 2 years of use. MATERIALS AND METHODS: A total of 193 occlusal, incisal, and cingulum rest seats were evaluated in terms of shape, rest adaptation, wear, caries, fractures, and surface type (enamel, composite resin, or amalgam). Two hundred and fourteen undercut areas were evaluated in terms of surface type (enamel or restoration) and integrity. This study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte, resolution 196/1996, protocol number 11/05. RESULTS: Intact preparations accounted for 92.2% of the total. Application of the Pearson test (p= 0.289) found no statistically significant differences among the materials on which the rest seats were prepared. For the undercut areas, 20.7% of those obtained on restorative material were nonintact. In addition, Fisher's exact test showed a statistically significant difference (p= 0.001) in surface type; enamel surfaces were shown to be 14 times more stable than restored surfaces. CONCLUSIONS: The results of this study suggest that rest seats are stable, regardless of the material on which they are prepared. Retentive areas were shown to be more stable when they were located in enamel.

The effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma : a randomized controlled trial (EAGLE)

Medical Research Council (ref G0701604) and administered by the NIHR-EME (ref 09-800-26)

Costs, quality of life and cost-effectiveness of open and arthroscopic repair for rotator cuff tears : economic evaluation alongside the UKUFF trial

FUNDING & ACKNOWLEDGEMENTS This project was funded by the NIHR Health Technology Assessment programme (project number 05/47/02) and is published in full in Health Technology Assessment; Vol. 19, No. 80. Further information available at: http://www.nets.nihr.ac.uk/projects/hta/054702 This paper presents independent research commissioned by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, CCF, NETSCC, the HTA programme or the Department of Health. Due to the confidential nature of the trial data supporting this publication not all of the data can be made accessible to other researchers. Please contact the UKUFF study principal investigator Andrew Carr (andrew.carr@ndorms.ox.ac.uk) for more information. The authors wish to thank the UKUFF trial collaborators for their contribution in managing the conduct of the trial, and for their comments on the interim economic results: Marion Campbell and Hannah Bruhn (Centre for Healthcare Randomised Trials, HSRU, University of Aberdeen), Jonathan Rees MD and David Beard (NDORMS, University of Oxford; NIHR Oxford Biomedical Research Centre), Jane Moser (NDORMS, University of Oxford), Raymond Fitzpatrick and Jill Dawson (NDPH, University of Oxford).

Aspects of postural alignment and postural control relevant for the evaluation and the treatment of idiopathic scoliosis patients

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Aspects of postural alignment and postural control relevant for the evaluation and the treatment of idiopathic scoliosis patients

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Evaluation of semi-passive treatment technologies for septic lagoon capacity expansion

In Canada, increases in rural development has led to a growing need to effectively manage the resulting municipal and city sewage without the addition of significant cost- and energy- expending infrastructure. Storring Septic Service Limited is a family-owned, licensed wastewater treatment facility located in eastern Ontario. It makes use of a passive waste stabilization pond system to treat and dispose of waste and wastewater in an environmentally responsible manner. Storring Septic, like many other similar small-scale wastewater treatment facilities across Canada, has the potential to act as a sustainable eco-engineered facility that municipalities and service providers could utilize to manage and dispose of their wastewater. However, it is of concern that the substantial inclusion of third party material could be detrimental to the stability and robustness of the pond system. In order to augment the capacity of the current facility, and ensure it remains a self-sustaining system with the capacity to safely accept septage from other sewage haulers, it was hypothesized that pond effluent treatment could be further enhanced through the incorporation of one of three different technology solutions, which would allow the reduction of wastewater quality parameters below existing regulatory effluent discharge limits put in place by Ontario’s Ministry of the Environment and Climate Change (MOECC). Two of these solutions make use of biofilm technologies in order to enhance the removal of wastewater parameters of interest, and the third utilizes the natural water filtration capabilities of zebra mussels. Pilot-scale testing investigated the effects of each of these technologies on treatment performance under both cold and warm weather operation. This research aimed to understand the important mechanisms behind biological filtration methods in order to choose and optimize the best treatment strategy for full-scale testing and implementation. In doing so, a recommendation matrix was elaborated provided with the potential to be used as a universal operational strategy for wastewater treatment facilities located in environments of similar climate and ecology.

Estimating Dynamic Treatment Effects from Project STAR (Working Paper 36)

This paper considers the analysis of data from randomized trials which offer a sequence of interventions and suffer from a variety of problems in implementation. In experiments that provide treatment in multiple periods (T>1), subjects have up to 2^{T}-1 counterfactual outcomes to be estimated to determine the full sequence of causal effects from the study. Traditional program evaluation and non-experimental estimators are unable to recover parameters of interest to policy makers in this setting, particularly if there is non-ignorable attrition. We examine these issues in the context of Tennessee's highly influential randomized class size study, Project STAR. We demonstrate how a researcher can estimate the full sequence of dynamic treatment effects using a sequential difference in difference strategy that accounts for attrition due to observables using inverse probability weighting M-estimators. These estimates allow us to recover the structural parameters of the small class effects in the underlying education production function and construct dynamic average treatment effects. We present a complete and different picture of the effectiveness of reduced class size and find that accounting for both attrition due to observables and selection due to unobservable is crucial and necessary with data from Project STAR

Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial

Background
Primary angle-closure glaucoma is a leading cause of irreversible blindness worldwide. In early-stage disease, intraocular pressure is raised without visual loss. Because the crystalline lens has a major mechanistic role, lens extraction might be a useful initial treatment.

Methods
From Jan 8, 2009, to Dec 28, 2011, we enrolled patients from 30 hospital eye services in five countries. Randomisation was done by a web-based application. Patients were assigned to undergo clear-lens extraction or receive standard care with laser peripheral iridotomy and topical medical treatment. Eligible patients were aged 50 years or older, did not have cataracts, and had newly diagnosed primary angle closure with intraocular pressure 30 mm Hg or greater or primary angle-closure glaucoma. The co-primary endpoints were patient-reported health status, intraocular pressure, and incremental cost-effectiveness ratio per quality-adjusted life-year gained 36 months after treatment. Analysis was by intention to treat. This study is registered, number ISRCTN44464607.

Findings
Of 419 participants enrolled, 155 had primary angle closure and 263 primary angle-closure glaucoma. 208 were assigned to clear-lens extraction and 211 to standard care, of whom 351 (84%) had complete data on health status and 366 (87%) on intraocular pressure. The mean health status score (0·87 [SD 0·12]), assessed with the European Quality of Life-5 Dimensions questionnaire, was 0·052 higher (95% CI 0·015–0·088, p=0·005) and mean intraocular pressure (16·6 [SD 3·5] mm Hg) 1·18 mm Hg lower (95% CI –1·99 to –0·38, p=0·004) after clear-lens extraction than after standard care. The incremental cost-effectiveness ratio was £14 284 for initial lens extraction versus standard care. Irreversible loss of vision occurred in one participant who underwent clear-lens extraction and three who received standard care. No patients had serious adverse events.

Interpretation
Clear-lens extraction showed greater efficacy and was more cost-effective than laser peripheral iridotomy, and should be considered as an option for first-line treatment.