Voluntary cyclotorsions were found not to have significant visually induced components in control studies where subjects were required to relax and observe the rotating visual stimuli used in the aforementioned pursuit and tracking tests. All voluntary cyclotorsions reported here were shown to be pure cycloversions occurring around the visual axes, even though only monocular visual stimuli (when occurring at all) were used. These results suggest that existing slow pursuit and saccadic systems control trained voluntary cycloversions. I propose that in making voluntary cycloversions, the visuomotor system utilizes the primitive slow phase and fast flicks from the phylogenetically old vestibulo-oculomotor reflex apparatus in a manner similar to the way the voluntary horizontal and vertical slow pursuit versional eye movement systems utilize this control apparatus.

Evaluation of the Pulmonary Ambulatory Care Clinic at David Grant Medical Center was an attempt to explore several questions that surround the care of patients with chronic obstructive pulmonary disease (COPD) and to assess the role and impact of pharmacists providing pharmaceutical care in an Air Force Medical Center. Four experimental designs were implemented. Thirty-eight ambulatory patients with COPD were randomized into a control group or into a program where pharmacists resolved drug-related problems (DRPs) and educated patients about optimal drug use and management of exacerbations. The groups were evaluated prospectively at baseline, three months and six months for the presence of DRPs, quality of life (QOL) scores, and health care resource utilization (HCRU) parameters. Significant improvements in Health Status Questionnaire scores of study group were at three (F = 4.56, p = 0.04) and six months (F = 3.84, p = 0.05). Chronic Respiratory Disease Index questionnaire scores significantly improved in study group at three months in fatigue category (F = 5.35, p = 0.02). Disease State Knowledge Test scores significantly improved at three (F = 3.90, p = 0.04) and six months (F = 13.37, p = 0.001) in study group. Twenty-two DRPs were resolved. The study group realized significant reductions in mean numbers of physician visits (F = 8.12, p $<$ 0.05), and emergency room visits (F = 5.41, p $<$ 0.05) at three and six months respectively. Mean number of physician visits in study group during six-month period was significantly lower prospectively than retrospectively (T = 3.56, p = 0.003) in the single subject design study. Retrospective study of seventy patients showed that mean numbers of chronic medications (F = 6.57, p $<$ 0.05) and pulmonary hospitalizations (F = 4.08, p $<$ 0.05) were significantly lower in mild patients than severe patients. These results of this four-part study design, showed that patient education and resolution of DRPs improved patients' QOL and increased their knowledge about their disease states. Teaching patients how to manage exacerbation resulted in a decrease in health care visits in this patient population. Categorization of severity by pulmonologist coincided with patients' utilization of HCRs.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

<p>Many anti-cancer drugs are poorly water-soluble and show undesirable pharmacokinetics and low bioavailability. Nanoparticles (NP) are used as delivery vehicles to improve bioavailability and biodistribution of such drugs. For clinical translation of an NP product, it is critical that the NP carry a large amount of drug and maintain good stability during circulation. A typical drug loading capacity of current NP formulations is less than 20% of the total mass, which is concerning from the standpoint of safety and administration convenience. Current NP formulations are also limited in retaining a drug during circulation and release the drug prematurely before they reach target tissues. These challenges are responsible at least partly for recent failure of leading NP products in clinical trials. </p> Given these challenges, I have focused on developing a stable NP formulation with high drug loading capacity, drug-rich nanocores stabilized by interfacial assemblies of iron-tannic acid (pTA) and albumin. Tannic acid is a polyphenol of natural origin and can form coordination complexes with Fe³⁺ ions that stabilize the interface between drug rich core droplets and aqueous solution. The underlying hypotheses are that (i) NP core formed solely of drug will offer a high drug loading capacity and (ii) the strong interaction of TA with drug molecules will maintain the nanocore stability and avoid premature drug release. Carfilzomib (CFZ), an epoxyketone peptide and a second-generation proteasome inhibitor, the use of which is limited to multiple myeloma due to the low stability, was chosen as a model drug to encapsulate in the new NP formulation. The NP surface was further functionalized with albumin, quinic acid derivative and plasmid DNA based on their affinity for TA complex. With an additional albumin coating, CFZ nanocore (CFZ-pTA-alb) showed sustained drug release and metabolic stability. In murine syngeneic model of B16F10 melanoma, systemically administered CFZ-pTA-alb showed enhanced biodistribution and anti-tumor effect than commercial cyclodextrin-based CFZ (CFZ-CD). With localized intratumoral administration, CFZ-pTA-alb also outperformed CFZ-CD in antitumor efficacy, potentially by prolonged drug retention, reduced damage to tumor-infiltrating lymphocytes, and enhanced delivery of tumor antigens to DCs.

Trimethyltin (TMT) is a neurotoxin occurring in the environment. Exposure to (TMT) is known to destroy specific neuronal components of the hippocampus in the rat and to cause clinical symptoms in exposed humans, including mnemonic deficits, that indicate hippocampal involvement. In addition to hippocampal cell loss TMT causes significant increases in cholinergic markers such as acetylcholinesterase (AChE) stain density and choline acetyltransferase (ChAT) activity in the hippocampus of rats. However, despite these observations the effect of TMT on hippocampal cholinergic system has not been investigated in detail. The purpose of the present study was to elucidate more fully the consequences of TMT administration on the rat cholinergic system. To this end the effects of increasing doses of TMT and time after TMT administration on choline acetyltransferase (ChAT) activity as well as TMT's effect on cholinergic muscarinic receptors was examined. Results indicate that 4 and 6 mg/kg doses of TMT measurable neuropathological effects on pyramidal cells of the hippocampus. ChAT activity was increased in the hippocampus as a result of the 6 mg/kg dose. Six mg/kg TMT was observed to affect morphology differentially over time, with the various sub-fields examined being affected at different time intervals. The effect of time on increased ChAT activity after TMT-treatment was observed in the dentate gyrus prior to the CA1 region. The effect of 6 mg/kg TMT on muscarinic receptor distribution over time is first observed in CA1 and CA3c then CA3a-b of the subtype M$\sb2$. The subtype M$\sb1$ receptors are also affected in these regions but at later time intervals. The total distribution of muscarinic receptors is reduced in regions CA1 and CA3c. This is observed at similar time intervals as for M$\sb1$ receptors. The conclusions made as a result of these findings are: (1) That TMT's effect on ChAT activity and morphology of the rat hippocampus is both dose and time dependent; (2) That adverse effects of TMT on ChAT activity and morphology in sub-regions of the hippocampus are observed at different time intervals; and (3) That the distribution of the muscarinic receptors examined are affected by TMT in a regional manner dependent upon the time following administration of TMT.

Nitrogen dioxide (NO$\sb2$), an air pollutant produced by burning fossil fuels and a component of cigarette smoke, is thought to contribute to the pathogenesis of pulmonary diseases, such as emphysema. To gain information on the mechanism by which NO$\sb2$ damages the lung, in vitro exposures of $\alpha\sb1$-proteinase inhibitor ($\alpha\sb1$-PI), elastin, bovine serum albumin (BSA), human serum albumin (HSA) and synthetic poly-L-lysine were performed. A genetic deficiency of $\alpha\sb1$-PI predisposes humans to emphysema and NO$\sb2$ has been hypothesized to damage $\alpha\sb1$-PI, which would leave proteases such as human neutrophil elastase, (HNE) free to attack lung structural proteins. The ability of $\alpha\sb1$-PI to inhibit HNE declined with exposure to 50% of the control value at molar ratios of NO$\sb2$:$\alpha\sb1$-PI of 400:1 and greater. Exposure of $\alpha\sb1$-PI to NO$\sb2$ resulted in a 50% loss of immunoreactivity with either monoclonal or polyclonal antibodies in an enzyme-linked immunosorbent assay at molar ratios of NO$\sb2$:$\alpha\sb1$-PI of essentially 100:1 and greater. The mechanisms of these effects were investigated via ultraviolet-visible spectroscopy and amino acid analysis. The remaining target molecules were labeled by reductive methylation of amino groups with $\sp3$H-HCHO prior to treatment with NO$\sb2$ in aqueous solutions at physiological pH. Time course exposure of 5 mg $\sp3$H-insoluble bovine ligamentum nuchae elastin suspensions with up to 120 $\mu$moles of NO$\sb2$ resulted in 90% solubilization of the label. Amino acid analysis of the soluble and insoluble fractions from these exposures confirmed that 80% of the $\sp3$H-dimethyllysine residues were in the soluble fraction. Since these results suggested a specific reactivity of NO$\sb2$ with lysine residues, 400 $\mu$g $\sp3$H-poly-L-lysine was exposed to 120 $\mu$moles NO$\sb2$. Gel filtration chromatography revealed that the 50,000 M$\sb{\rm r}$ $\sp3$H-poly-L-lysine had been degraded to small peptides of 1-3,000 M$\sb{\rm r}$. Similar exposures were conducted using $\sp3$H-BSA and $\sp3$H-HSA, followed by gel filtration chromatography and SDS-PAGE with fluorography. The results suggest that NO$\sb2$ preferentially reacts with Lys-Lys or other specific sequences, resulting in peptide bond cleavage. Under the conditions used, 23% of the BSA tyrosine residues were nitrated and aggregates of HSA indicative of bityrosine cross-link formation were observed. These findings are the first indication that NO$\sb2$ can cause protein fragmentation and provide additional data on the potential of NO$\sb2$ to damage lung proteins, such as elastin.

Most studies of the induction of cytokine synthesis in monocytes have used an exogenous triggering agent such as Lipolpoysaccharide (LPS). However, during nonseptic chronic inflammatory responses (e.g., rheumatoid arthritis) monocyte activation occurs as a result of T cell generated signals. This report demonstrated that plasma membranes from anti-CD3 activated peripheral CD4$\sp{+}$ T cells (Tm$\sp{\rm A}$) but not from resting CD4$\sp{+}$ cells (Tm$\sp{\rm R}$) induced monocytes to synthesize IL-1 in the absence of costimulatory cytokines. The expression kinetics of the molecule(s) unique to activated T cells which interact with monocyte receptors to induce IL-1 demonstrated that optimal expression occurred at 6h post activation. This matched Lederman's, et al., (1992) previously reported kinetics of expression of CD40 ligand (CD40L) on activated peripheral T cells, implicating the CD40-CD40L interaction as a candidate for the initiator of IL-1 induction in monocytes. In this work, it was demonstrated that the signal could be reduced up to 85% by addition of 5c8, a monoclonal anti-CD40L antibody. In addition, a monoclonal anti-CD40 IgM (BL-C4) induced resting monocytes to synthesize IL-1. Experiments demonstrated that crosslinking the CD40 molecules on monocytes was critical for IL-1 induction. Tm$\sp{\rm A}$ but not Tm$\sp{\rm R}$ also up-regulated cell surface expression of adhesion/costimulatory molecules on monocytes including CD40, ICAM-1, and LFA-3. Anti-CD40 signaling up-regulated expression of ICAM-1 and LFA-3. Experiments suggested that signaling through CD40 may utilize a protein tyrosine kinase (PTK) mediated pathway but not a protein kinase C mediated pathway and studies using THP-1, a premonocytic cell line, indicated that the transcription factor, NF-$\kappa$B, was activated through anti-CD40 signaling. Since CD40 ligand-transfected cells alone did not induce IL-1 but Tm$\sp{\rm A}$ did, it was considered that an additional costimulatory cell surface molecule was required. Preliminary experiments suggested that CD69 may be required. In summary, these results indicate that contact-dependent T cell-monocyte interactions, alone, can activate inflammatory cytokine production by resting monocytes and that a critical component of this interaction is the CD40-CD40L signaling event.

This study was undertaken to determine the degree of relationship in perceptions held by three health care administrative groups between the desirable and actual role functions of the hospital nursing service administrator. This descriptive study surveyed hospital Chief Executive Officers (CEOs), and Nursing Service Administrators (NSAs) in 100 randomly selected general hospitals, and chairpersons of graduate programs in nursing service administration. The instrument for this study was the Beliefs Concerning Role of Hospital Nursing Service Administrator, a 12-item instrument designed to determine some of the desirable (optimal) and actual (currently performed) role functions of the hospital Nursing Service Administrator (NSA), as perceived by the three health care adminstrative groups in the study. Descriptive statistics were used to analyze the data gathered from the 12 position statements, warranting the following conclusions: (1) The Cramer's V measure of association revealed little or no association among Chief Executive Officers, Nursing Service Administrators, and Chairpersons on the 12 role functions perceived as desirable (or necessary for optimal effectiveness) for the individual currently in the position of Nursing Service Administrator. (2) The Somers' d measure of association revealed that little or no association existed between the Chief Executive Officers' and the Nursing Service Administrators' perceptions on the 12 role functions currently performed by the Nursing Service Administrator. (3) The Somers' d measure of association revealed that little or no association existed between the size of the hospital and the total responses of the hospital personnel to each of the 12 role functions perceived as desirable (or necessary), and those currently performed by the Nursing Service Administrator (NSA). (4) The Cramer's V measure of association revealed that little or no association existed between the type of control of the hospital (ownership) and the total responses of the hospital personnel to each of the 12 role functions perceived as desirable (or necessary), and those currently performed by the Nursing Service Administrator. (5) Demographic data from the Nursing Service Administrators in the study who held the master's degree in nursing revealed greater than half indicated that the master's in business administration would have been the best type of preparation for their current position. (Abstract shortened with permission of author.)

A training program was developed to help registered nurses in an acute care facility to learn nursing process theory and to transfer that theory to nursing practice. A total sample of 102 newly-hired nurses who had participated in this training program were pre- and post- tested on class content; they also filled out a questionnaire which provided demographic and attitudinal data related to the use of nursing process as a model for nursing care. An audit sample of 82 nurses, who were a part of the total sample, were audited one month after the training program to collect data on documentation in patients' charts of the understanding and utilization of nursing process; 246 audits were completed. Concomitantly, an audit was performed to determine total nursing staff compliance with requirements that the nursing process be used and documented in patients' charts. Performance behaviors, i.e., pre- and post-test scores, common test scores, self-perceived understanding scores, and percent complete on audit were collected and analyzed. Additionally, data on age, experience, and type of nursing education were collected and analyzed. Results indicated that the nurses who attended this training program evidenced an understanding of nursing process theory and documented their implementation of the process into nursing practice. Despite differences in age, experience, and educational programs which appeared to be statistically significant, the performances of nurses who had attended this training program showed no significant differences in practice.

While over 140 million people worldwide are at risk of drinking arsenic contaminated groundwater above the WHO guideline of 10 μg/L, the need for an efficient treatment scheme in actual groundwater conditions is growing. This study examines the use of zinc carbonate minerals for in situ removal of As(V) from contaminated groundwater. Batch adsorption isotherms compare the adsorption of As(V) to reagent grade ZnCO 3 and freshly precipitated ZnCO 3 minerals on calcite particles in buffered electrolyte solution and real groundwater. Column studies examine the exchange of calcite particles for zinc-carbonate minerals through injection of a zinc chloride solution and the subsequent removal of As(V). While arsenic adsorption in batch studies is greatly reduced in actual groundwater relative to synthetic solution, As(V) mobility is significantly impeded in column studies with R greater than 12,000 for both synthetic and actual groundwater. Plausible explanations for arsenic removal mechanisms are discussed.