Melamine and cyanuric acid are widely used in industry and in scientific research. The mixture of melamine and cyanuric acid can form a hydrogen-bonded network structure which has been used as a surface template in supramolecular chemistry. In this work, the thermochemical properties of melamine and cyanuric acid were characterized using mass spectrometry measurements and computational studies. The proton affinity and the gas-phase acidity were determined with the application of the extended Cooks kinetic method. A triple-quadrupole mass spectrometer equipped with an electrospray source was employed for this study. For melamine, the proton affinity, the gas-phase basicity, and the protonation entropy were determined to be 226.2 ± 2.0 kcal/mol, 218.4 ± 2.0 kcal/mol and 26.2 ± 2.0 cal/mol K, respectively. For cyanuric acid, the deprotonation enthalpy, the gas-phase acidity, and the deprotonation entropy were determined to be 330.7 ± 2.0 kcal/mol, 322.9 ± 2.0 kcal/mol and 26.1 ± 2.0 cal/mol K, respectively. The geometries and energetics of melamine, cyanuric acid, and related molecules/ions were calculated at the B3LYP/6-31+G(d) level of theory. The theoretical proton affinity and deprotonation enthalpy were calculated using the corresponding isodesmic proton transfer reactions. The computationally predicted proton affinity of melamine (225.9 kcal/mol) and gas-phase deprotonation enthalpy of cyanuric acid (328.4 kcal/mol) were in good agreement with the experimental results. Melamine is best represented as the imide-like triazine-triamine form and the triazine nitrogen is more basic than the amino group nitrogen. Cyanuric acid is best represented as the keto-like tautomer and the N-H group is the most likely proton donor. Cyclohexane-based molecular switches have been of great interest in recent years. This work focused on the investigations of the thermochemical properties related to the switching process. A group of cyclohexane-based model compounds were selected for this study. The model compounds included trans -2-aminocyclohexanol, trans -4-aminocyclohexanol and trans -2-dimethylaminocyclohexanol. The proton affinities of the compounds were determined using the extended Cooks kinetic method. The values obtained were 238.5 ± 2.0 kcal/mol ( trans -2-dimethylaminocyclohexanol), 225.5 ± 2.0 kcal/mol ( trans -2-aminocyclohexanol) and 220.4 ± 2.0 kcal/mol ( trans -4-aminocyclohexanol). Various molecular structures related to the model compounds and the switching molecules were calculated at the B3LYP/6-31+G(d) level of theory. The theoretical proton affinities of all the molecules investigated were also calculated at the same level of theory using corresponding isodesmic reactions. The results show that the proton affinities decrease as the relative positions of amino and alcohol groups change from ortho to meta to para . The stronger proton affinity of the ortho isomer may be due to the efficient intramolecular hydrogen bonding in the protonated form. The proton affinity of trans -2-dimethylaminocyclohexanol is stronger than that of trans -2-aminocyclohexanol by about 13 kcal/mol. Substitution of hydrogen atoms by methyl groups at nitrogen promotes the intramolecular hydrogen bonding between the amino group and the hydroxyl group upon protonation. This, in turn, may enhance the proton affinity of methylated molecule. Computational studies also show interesting trends for stabilities and proton affinities of the different structures. These data may be useful as a guide for designing efficient conformational switches.

The purpose of this study was to identify and describe the types of coping styles used by stroke patients and their caregivers following a stroke. The main objective was to examine the relationship of these coping styles as well as the relationship of physical functional impairment and time since stroke to depression in stroke patients and their caregivers. A sample of sixty subjects, including thirty stroke patients and their respective caregivers, volunteered to participate in the study. Two-way analysis of variance, one-way analysis of variance and correlation analysis were used to analyze the data. The results of the study indicated that stroke patients who used problem-focused coping were less depressed than patients who used emotion-focused coping as a way of managing the stress following a stroke. Results, however, did not indicate that coping style was a statistically significant factor in determining depression in caregivers of stroke patients. Further analysis of the Coping Responses Inventory showed that certain coping style sub-scales played a role in determining depression scores in both patients and caregivers. As patients' scores on the problem-focused sub-scales of Positive Reappraisal and Problem Solving increased, their depression scores decreased. As patients' scores on the emotion-focused sub-scales of Cognitive Avoidance, Acceptance or Resignation and Emotional Discharge increased, their depression scores also increased. Caregiver scores on the problem-focused sub-scales did not indicate a statistically significant relationship with depression scores. As caregiver scores on the emotion-focused sub-scales of Cognitive Avoidance and Acceptance or Resignation increased, however, their depression scores also increased. Results also revealed that patients with lower levels of physical functioning, along with their respective caregivers, had higher depression scores than patients with higher levels of physical functioning and their caregivers. Finally, the results indicated that time since stroke was not a statistically significant factor in determining level of depression following a stroke. Implications for clinical practice are discussed as well as recommendations for further research.

Most humans aspire to live long, healthy lives. It has been assumed that one's length and quality of life were primarily determined by genetics; it is now believed that aging is influenced more by factors within an individual's control. This study sought to identify the factors consistently related to successful aging. Relationships between various participant demographic variables were examined in relation to a) a general quality of life index, b) a geriatric-specific quality of life index tailored to include items believed to more closely associate with successful aging, and c) participants' subjective ratings of aging "success". English-speaking individuals over the age of 60 were recruited as participants from community centers and senior housing communities. The hypothesis that the correlation between the QLI-G40 total score and the subjective rating of aging success ( r = .59) would be more strongly positive than the correlation between the QLI-GEN-III total score and the subjective rating of aging success ( r = .55), was not supported. A Fisher's r -to- z transformation, which resulted in a Fisher's z -score of .36 ( p = .719), showed that the difference between these two independent Pearson's correlations was not statistically significant. It was also found that the "Control" domain of the geriatric-specific QLI (items related to health, health-limitation perception and autonomy/independence) was most strongly correlated with subjective ratings of aging success. Future researchers should administer multiple questionnaires over several sessions to establish concurrent validity with existing measures in the continued development of a geriatric-specific QLI. Future research should continue to emphasize the use of subjective assessments, as there is a great deal of behavioral variation among those aging well into late life.

Serotonin (5-hydroxytryptamine, 5-HT) has been heavily implicated in the pathophysiology of depression and although its changes in the brain has been well studied using microdialysis, the analysis of its time data is often insufficient as pharmacokinetic (PK) and pharmacodynamic (PD) concepts are often neglected. The works in this dissertation attempt to further explore 5-HT time data via mechanism-based PK/PD modeling. The first work explored the dorsal raphe nucleus (DRN) in which the desensitization of 5-HTIA autoreceptors has been implicated in the several-week delay in onset of therapeutic response to antidepressants. An extension of a standard indirect-response pharmacodynamic modeling approach was used to account for the stimulation of locally administered citalopram on the production of 5-HT in the DRN and the nucleus accumbens. The overall model reasonably captured the time courses of 5-HT in both regions of the brain and predicted 5-HT concentrations in the DRN under a different (subcutaneous) dosing scheme. This model is the first to quantitatively explore an important control mechanism of central 5-HT output as perturbed by an antidepressant administration. The second work explored the combination treatment of citalopram, a serotonin selective reuptake inhibitor (SSRI), and WAY-100635, a 5-HT 1A receptor antagonist. Citalopram plasma kinetics was designated as fixed functions driving the dynamics of 5-hydroxytryptamine (5-HT) output in rat ventral hippocampus assumed in a standard indirect-response PD model which was then extended to fit the PD data for the combination treatment to account for two drugs acting synergistically on separate processes to modulate the same PD endpoint. Contrary to previous conclusions drawn based on peak 5-HT level, simulations from this modeling work showed that the potentiation of WAY-100635 in terms of AUEC (area under the effect curve) is minimally significant. Mechanism based PK/PD modeling as a way to explore pharmacological mechanism is further demonstrated in the third work which explored the mechanism of cancer cell kill in the presence of P-glycoprotein induction. Results from this modeling work suggest the need for reducing therapy-induced P-glycoprotein induction via optimizing dosing schedules to achieve maximal cancer cell reduction.

This study used a posttest only control group design to measure the attitudes of people who experience a major mental disability towards others with a mental illness. Each group watched a video: the experimental group a video on mental illness and the control group a video on anger management. Each group discussed the video and their own experiences. The hypothesis was that knowledge on the part of the participants of the life circumstances of others with a mental disability would increase acceptance of people with a mental disability. The results were not significant at $p=.5$. Differences at a 1-month follow-up were also not significant at $p=.066$.

Qualitative research conducted in athletic training in the last two decades has increased but still lacks depth and breadth in pedagogy and education. This is especially evident in the multifaceted clinical education environment where diverse and alternative teaching techniques are necessary. Storytelling is one such teaching technique. It was the purpose of this study to uncover and illustrate the phenomenon of storytelling and its relationship to athletic training students' perceptions of their clinical education experience. Eight athletic training students were selected from a Northern California university undergraduate athletic training education program. The research data consisted of transcriptions from a series of three individual interviews. Athletic training students believed that stories influenced their experience in the clinical education environment in a variety of ways. In the analysis of the research data the following themes emerged: “The Environment and Shaping a Learning Community”, “Connections and Relationships of Shared Experience”, and “Defining and Developing Identity”. The theme “The Environment and Shaping a Learning Community” referred to the ability of shared experience presented in story to affect the clinical education environment through the perpetuation of the hierarchy of experience, the establishment of social norms and maintenance of the language. Respondents explained story's ability to shape the learning community by bringing together students for a collective purpose; through the establishment of relationships, and the sharing of common experience. The theme “Connections and Relationships of Shared Experience” referred to the capacity of story to build connections to learning and knowledge and cultivate human relationships. Respondents expressed that story encouraged learning as a process of self reflection, provided listeners with the opportunity to actively participate and to live vicariously through another's experience and connect didactic knowledge to the practical skills often used in the athletic training room. The theme “Defining and Developing Identity” referred to story's ability to create and reaffirm an athletic training student's personal and professional identity. This study has shown that the pedagogical technique of storytelling impacted athletic training students' clinical education experiences. Additionally, the shared experience improved the learning climate, made learning meaningful and created positive perceptions of student experience. Lastly, the findings from this study offer storytelling as a viable and useful pedagogical technique to the clinical education environment.

The present investigation focused on three different aspects of polyamine involvement in induction of cell differentiation and neurite outgrowths: effects of polyamines on isolated bovine brain tubulin assembly, effects of polyamines on dopamine levels in PC12 cells, and influence of differentiating agents on polyamine and acetylpolyamine levels in PC12 cells. Among the polyamines, only spermine significantly induced tubulin assembly starting at 60 $\mu$M concentration (p $<$ 0.05). Colchicine at 100 $\mu$M concentration, and calcium chloride at 5 mM concentration inhibited spermine-induced polymerization (p $<$ 0.05). Spermine-induced polymerization was not stable in the presence of calcium or at 4$\sp\circ$C. NGF and dexamethasone increased the dopamine levels compared to that of control. Dopamine levels were increased up to 170% and 160% of control (p $<$ 0.05) with 10 $\mu$M N$\sp8$-acetylspermidine and 10 $\mu$M 7-(N-(3-aminopropyl)amino) heptan-2-one (APAH), respectively, after 48 hours. APAH is an inhibitor of N$\sp8$-acetylspermidine deacetylase. These effects of N$\sp8$-acetylspermidine and APAH appeared to be concentration dependent. Other polyamines did not have any significant effects on dopamine levels in PC12 cells. NGF and dexamethasone did not appear to have a significant effects on polyamine and acetylated polyamine levels in PC12 cells at the time periods studied. The amount of N$\sp8$-acetylspermidine detected after 24 hour treatment with 100 $\mu$M N$\sp8$-acetylspermidine was 18 $\pm$ 3 pmols/mg protein. The levels were increased up to 38 $\pm$ 6 and 52 $\pm$ 11 pmols/mg protein after days 3 and 7, respectively, with 100 $\mu$M N$\sp8$-acetylspermidine treatment. N$\sp8$-Acetylspermidine levels were detectable as early as day 1 with 100 $\mu$M APAH treatment and the levels detected after 1, 3, and 7 day treatments were 7.4 $\pm$ 0.9, 14 $\pm$ 1.2 and 21 $\pm$ 3 pmols/mg protein, respectively. The changes in the dopamine and N$\sp8$-acetylspermidine levels in PC12 cells starting at 10 $\mu$M APAH and N$\sp8$-acetylspermidine from day 1 onwards are well correlated with the morpholigical changes observed from day 3 onwards in an earlier study from our laboratory. The results from the present study suggest that polyamine-induced cell differentiation in PC12 cells is related to the formation of a metabolite N$\sp8$-acetylspermidine and NGF-induced cell differentiation does not appear to involve accumulation of N$\sp8$-acetylspermidine.

Endosome is a major barrier to efficient gene transfection by synthetic vectors because if the vectors are trapped in the endosome, they will traffic to the lysosome where the DNA is enzymatically degraded. Our hypothesis which serves as the rationale for the design of ortho ester-based lipids and lipoplexes is that cationic lipids which can quickly hydrolyze into membrane-destabilizing fragments in response to a small drop of pH should improve the gene transfection efficiency by facilitating the endosome escape. We designed and synthesized five ortho ester-based acid-labile cationic lipids ( 1-5 ) and developed nine lipoplexes comprising the five lipids. HPLC and LC/MS studies revealed that the ortho ester linkage in lipids ( 1-5 ) hydrolyzed at mildly acidic endosomal pH 5.5. Dioleyl glycerol was identified to be the major hydrolysis product of lipids 1, 2, and 3 . Oleoyl alcohol and 1-oleyloxy-2-trimethylamionium-3-propanol were identified to be the major hydrolysis products of lipids 4 and 5 . Photon Correlation Spectrometry (PCS) studies revealed that acidic endosomal pHs triggered the aggregation of lipoplexes comprising 1, 2, and 3 . Lipoplexes comprising 4 and 5 retained their size over 50 hours at acidic pHs. The fluorescence assay indicated that the ortho ester-based lipoplexes comprising lipids 1, 2, and 3 quickly destabilized a model biomembrane in response to the acidic pH. Acidic pH did not cause the membrane destabilization by lipoplexes comprising 4 and 5 . These results demonstrate that ortho ester-based lipoplexes comprising lipids 1, 2, and 3 hydrolyze into membrane-destabilizing fragments in response to acidic pH. Luciferase gene transfection was conducted on CV-1cultured cells. The lipoplexes comprising ortho ester-based cationic lipids 1, 2, and 3 significantly enhanced the luciferase gene expression. Two lipoplexes 2 /DOPE/DNA and 3 /DOPE/DNA mediated 45-fold and 116-fold, respectively, higher luciferase expression in CV-1 cells compared to the pH-insensitive lipoplex DOTAP/DOPE/DNA. The gene transfection efficiency correlates well with the pH-triggered membrane-destabilization by the ortho ester-based lipoplexes.

Etoposide has been shown to be effective in the treatment of testicular and small-cell lung cancers, lymphoma, leukemia and Kaposi's sarcoma. Several clinical investigations have suggested that the prolonged maintenance of greater than 1 $\mu$g/ml concentration in plasma would provide better therapeutic response in patients. Thus use of a sustained/controlled release formulation of etoposide was indicated. This investigation focused on the potential for the development of a sustained/controlled release dosage form of etoposide for a 7-15 day delivery using selected polylactic and polylactic-co-glycolic acid polymers. During the course of studies involving the enhancement of aqueous solubility of etoposide in our laboratory evidence of a potential thermally induced polymorphic transition was detected. Therefore, further characterization of this phenomenon was also included in this investigation. Thermal behavior of etoposide was characterized by differential scanning calorimetry, thermal gravimetric analysis, X-ray diffractometry, mass spectroscopy, IR spectra and HPLC analyses. A method for the preparation of micromatrices of etoposide was developed utilizing a suspension and solvent evaporation technique. DSC, IR and NMR investigations did not indicate any potential etoposide-polymer interaction. Etoposide I, a monohydrate, underwent a dehydration reaction between 85-115$\sp\circ$C to yield Etoposide Ia, which upon further heating melted at 198$\sp\circ$C and crystallized to a new polymorph, Etoposide IIa at 206$\sp\circ$C. Etoposide IIa was found to melt at 269$\sp\circ$C and converted to its hydrated form, Etoposide II when exposed to atmosphere at room temperature. The polymorphic transition was found to be irreversible and monotropic. Etoposide I, the currently marketed drug was used in all delivery systems examined. Formulation studies with polylactic acid polymers indicated that the molecular weight of the polymer was a key parameter in influencing the percent of drug entrapped in the micromatrices, particles size distribution and the drug release profiles. Glycolide-containing polymers demonstrated control of etoposide release only at low drug loadings: larger micromatrices showing better control. Polylactic acid 50,000 at 1:5 and 1:15 drug to polymer ratios exhibited maximum rate of drug release of 1.57 mg/hr. At this release rate, a delivery system containing 350 mg of etoposide could be expected to maintain a plasma concentration of 1.08 $\mu$g/ml over a period of 7 days. Additionally, drug release profile of polylactide-co-glycolide (85:15, 75-180 $\mu$m) microsphere formulation with 1:10 drug to polymer ratio, was found to be more appropriate for a 15-day release system based upon 700 mg of etoposide.

Depression is a common neuropsychiatric illness with a lifetime prevalence of 17% in the United States. The disease can severely impact the daily living and quality of life in patients. The monoamine hypothesis of depression implicates the neurotransmitter serotonin as mediating the pathophysiology. Selective serotonin reuptake inhibitors (SSRIs), a popular and efficacious class of antidepressants, increase serotonin concentrations in the brain. However, full clinical benefit may not be obtained for four to six weeks. This period of waiting for SSRIs to work becomes quite daunting for patients. Research has focused on delineating the control mechanisms surrounding the dorsal raphé nucleus (DRN), the serotonergic control center located in the midbrain. Much evidence points to changes in several receptor systems as the underlying cause of the delay. One particular serotonin receptor, 5-HT 1A , has been established to play a role in affecting the time course of clinical effect. We have targeted another receptor as a possible contributor to the delay: the stimulatory 5-HT 2A heteroreceptors located on GABAergic interneurons of the DRN. The 5-HT 2A receptors of the GABAergic interneurons receive stimulatory input from serotonergic collaterals branching off the DRN serotonergic neurons. The resultant stimulation causes GABA release and inhibition of the serotonergic neurons via GABA A receptors of the DRN, completing a feedback loop. We hypothesize that the 5-HT 2A receptors desensitize under constant stimulation, as in the case with SSRI administration, and as a result contribute to the time delay in the onset of action of SSRIs. Using the microdialysis technique, various receptor agonists and antagonists were administered to examine receptor changes and its influence on serotonin release in male Wistar rats. Our results demonstrate that GABA A receptors exert a large inhibitory influence on serotonergic neurotransmission. Local GABA release results from 5-HT 2A receptor stimulation. Furthermore, serotonin appears to trend back towards basal levels, suggesting a possible desensitization process occurring under constant agonism of 5-HT 2A receptors. The development of our pharmacodynamic model quantitatively shows a slow desensitization process, which may also contribute to the time delay observed with the onset of action of SSRIs.