Malaria (vector: Anopheles gambiae) is a major infectious disease that kills about 1 million people each year. For the improvement of its treatment and vector control during the past decades, several issues such as high medicine cost, insecticide resistance, and lack of an effective vaccine have prevented adequate control of malaria. Additionally, the low selectivity of malaria vector insecticides also presents a public health problem. The purpose of developing novel carbamate insecticides in our laboratory is to offer effective and selective insecticide options to achieve the ultimate goal of malaria control. First, 50% inhibition concentration (IC50) data was collected from three mammalian AChEs with eight commercial carbamate insecticides by using the Ellman assay. The IC50 values varied from 57 nM to 7358 nM. The AChE sensitivity pattern and level were shown to be similar between the recombinant mouse and ICR male mouse brain cortex homogenate (slope = 0.99, R2 = 0.96). Then eight novel carbamate insecticides that are possible malaria vector control agents were selected for further neurotoxicity testing in non-target organisms. For commercial carbamate insecticides, the IC50 varied from 9.1 nM to 2,094 nM. For the novel carbamate insecticides, it varied from 58 nM to 388,800 nM. Based on IC50 data from previous work on A. gambiae, the selectivity index (IC50 of non-target species / IC50 A. gambiae) ranged from 0.17 to 5.64 and from 0.47 to 19,587 for commercial and novel carbamate insecticides, respectively. Subsequently, the AChE protein sequence alignment comparison and cladogram were used to compare the genetic and evolutionary relationship among five different organisms. The alignment score ranged from 88 for mouse vs. human to 54 for hen vs. T. californica. The evolutionary relationships among species was obtained from the cladogram. Recombinant mouse vs. recombinant human was shown to have the most similar inhibitor potency profiles (alignment score = 88, closest taxa position on cladogram, similar AChE sensitivity pattern [R2 = 0.81] and level [P > 0.05] to the novel carbamates). Neurotoxic esterase (NTE) assay showed that the novel carbamates did not significantly inhibit NTE, inhibition of which underlies a significant hazard for anticholinesterases, especially organophosphates, in several nontarget vertebrate organisms. The NTE activity in the presence of novel carbamate insecticides ranged from 93% to 116% of the control, while in the commercial group, bendiocarb significantly inhibited NTE, leaving only 76.5% of the initial reactivity at 1 mM inhibitor concentration. Further in vivo bioassay using Daphnia magna was conducted to compare the aquatic toxicity of commercial and novel carbamates. The data showed that except for PRC331 (3-tert-butylphenylmethylcarbamate), all novel carbamates were of similar potency as bendiocarb (LC50 = 611 nM) for aquatic toxicity, and their LC50 values ranged from 172 nM (PRC331) to 1109 nM. In conclusion, the novel carbamate insecticides would appear to be an improvement over commercial carbamate insecticides because of greater selectivity, negligible NTE inhibition capacity, but in some cases with potent in vivo toxicity to Daphnia magna. However, since the envisioned usage of these compounds is in bednets or as indoor residual sprays (IRS), any environmental exposures to nontarget aquatic organisms are expected to be minimal. / Master of Science

The purpose of the present study was to determine the degree of relationship between neurotoxic chemicals in the blood of chemically sensitive patients and psychoneurological functioning. Blood samples were drawn from 30 patients being treated for environmental illness. All patients were administered a standardized intermediate psychoneurological examination. Results indicate a significant positive relationship between psychoneurological (cognitive neurobehavioral) functioning and the number of and total parts per billion of certain environmental toxins (solvents) in the blood of the subjects. The symptoms most commonly exhibited included deficits in short-term memory, problems with coordination and motor sequencing, somatosensory deficits, and cognitive dysfunction.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Abstract not available

Chemotherapy induced peripheral neuropathy (CIPN) remains one of the most serious and challenging symptoms oncology nurses encounter in caring for patients receiving neurotoxic chemotherapy. CIPN is under-addressed, under-reported, and symptoms are minimized by healthcare providers, which adversely affect patient quality of life, physical function, and emotional well-being. There is an absence of research examining nurses’ knowledge and practice behaviors related to CIPN. The purpose of this study was to explore oncology nurses knowledge, practice behaviors, confidence, and the relationship between education, experience, and knowledge specific to CIPN. Data was collected at Oncology Nursing Society (ONS) Chapter meetings throughout central and south Florida. The sample consisted of 70 oncology nurses who provide direct care to patients with cancer. Participants completed the CIPN: Assessment of Oncology Nurses’ Knowledge and Practice–Revised questionnaire. Demographic data revealed the overall years of nursing experience mean to be 24.7 (SD=12.2), mean years of oncology experience to be 13.5 (SD=7.5), and mean age to be 50.3 years (SD=9.5). The participants varied in highest attained level of education with the majority having Bachelor of Science degrees (40.0%). The results of this study revealed adequate nursing knowledge pertaining to CIPN 13.0 (SD=1.9) (81%). Fifty-percent of nurses reported always or frequently screening for CIPN. The majority of participants reported always or frequently; evaluating fine motor skills (68.6%), documenting findings (64.3%), assessing risk factors (55.7%), assessing motor function (52.9%), performing assessment prior to each neurotoxic chemotherapy infusion (58.6%), eliciting patient symptoms (65.7%), teaching strategies for adaptation (57.1%), and teaching safety precautions (74.3%). Nurses less frequently reported always or frequently assessing deep tendon reflexes (17.2%) and assessing muscle strength (35.7%). The majority reported confidence in sharp vs. dull sensation testing (62.8%), and manual muscle strength testing (52.9%), while the majority lacked confidence performing deep tendon reflex testing (71.5%), tuning fork vibration sensation testing (72.8%), and Romberg testing (72.8%). There was a significant relationship between highest educational level achieved and knowledge of CIPN (r=.252, p=.037). This is one of two studies documenting oncology nurses’ knowledge, practice behaviors, and confidence specific to CIPN. Findings lay the foundation in documenting the need for providing oncology nurses with continued education, and the need to teach oncology nurses the skills necessary to confidently assess for CIPN and interpret the findings.

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references.

Thesis (M.S.)--Brigham Young University. Dept. of Physiology and Developmental Biology, 2007. / Includes bibliographical references (p. 38-40).

Thesis (M.S.)--The University of North Carolina at Greensboro, 2009. / Directed by Keith Erikcon; submitted to the Dept. of Nutrition. Title from PDF t.p. (viewed Jun. 4, 2010). Includes bibliographical references (p. 65-86).

Alzheimer's disease is a progressive neurodegenerative disorder, in which there is a marked decline in neurotransmitters, especially those of the cholinergic pathways. One of the approaches to the symptomatic treatment of Alzheimer's disease is the inhibition of the breakdown of the neurotransmitter acetylcholine, using an acetylcholinesterase inhibitor. One such drug tested, is the organophosphate, metrifonate. Any drug used for the treatment of neurodegenerative disorders should preferably not induce further neurological damage. Thus, in the present study, we investigated whether or not metrifonate is neuroprotective. The in vivo and in vitro effect of this drug on free radicals generation shows that metrifonate increases the level ofthese reactive species. Lipid peroxidation induced using quinolinic acid (QA) and iron (II) and show that metrifonate increased the peroxidative damage induced by using quinolinic acid. Metrifonate is also able to induce lipid peroxidation both in vivo and in vitro. This was reduced in vitro in the presence of melatonin. Using iron (II), in vi/ro, there was no significant difference in the level of lipid peroxidation in the presence of this drug. An investigation of the activity of the mitochondrial electron transport chain and complex I of the electron transport chain in the presence of metrifonate revealed that metrifonate reduces the activity of the electron transport chain at the level of complex I. The activity of the mitochondrial electron transport chain was restored in the presence of melatonin. Pineal organ culture showed that metrifonate does not increase melatonin production. Histological and apoptosis studies show that tissue necrosis and apoptosis respectively, occur in the presence of this agent, which is reduced in the presence of melatonin. Metal binding studies were performed USing ultraviolet spectroscopy, and electrochemical analysis to examine the interaction of metrifonate with iron (II) and iron (III). No shift in the peak was observed in the ultraviolet spectrum when iron (ll) was added to metrifonate. Electrochemical studies show that there may be a very weak or no ligand formed between the metal and drug. This study shows that while drugs such as metrifonate may be beneficial in restoring cognitive function in Alzheimer's disease, it could also have the potential to enhance neurodegeneration, thus worsening the condition, in the long term. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

The crotoxin complex protein is the major neurotoxic component in the venom of the Brazilian rattlesnake, Crotalus durissus terrificus. The purified protein can be crystallized in the form of thin platelets (less than 500 Å thick) suitable for electron crystallography and image processing techniques. The unit cell dimensions of the crystal are a = 38.8 Å, b = 38.8 Å, c = 256 Å, and α = β = γ = 90°. These crystals can grow in layers. For a three-dimensional image reconstruction this necessitates the determination of the crystal thickness in order to combine information from low dose images of crystals of the same thickness. In the past, the highest resolution image (to 3.9 Å) recorded from a crotoxin complex crystal on the electron microscope was from a crystal embedded in glucose. However, since glucose cannot be removed in order to accurately determine the crystal thickness, a different embedding technique (amorphous ice embedding) and tried. It was determined that high resolution image information (to 3.9 Å) can be recorded from crotoxin complex crystals embedded in amorphous ice. Five images of crystals preserved in amorphous ice, all exhibiting resolution to at least 9 Å, were first processed by a global averaging method from which two-dimensional projection maps were calculated. These maps were not interpretable due to variations in the images as demonstrated by a second processing method. In the second processing method the images were divided into smaller areas, or patches, and these patches were averaged. The patchwork images produced from the second process indicate that there is variation across the original images. The most likely explanation for the variation is the bending, or lack of flatness, of the crystals on the grid. The determination of mass thickness of the crystals from optical density differences between the crystals and the carbon support in images of freeze-dried crystals was explored. It was found that this method could not determine the mass thickness of crotoxin complex crystals to within one layer (64 Å), but could clearly distinguish between one and three overlapping layers of freeze-dried purple membrane which was used as a test specimen.