Medicine and Health Sciences Commons^™

Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage

Theses and Dissertations

The effects of cannabinoids in reducing somatic signs of opioid withdrawal have been known for some time. In morphine dependent rodents, opioid withdrawal following precipitation with the mu opioid antagonist naloxone elicits robust withdrawal behaviors including jumps, paw flutters, head shakes, diarrhea and weight loss. Delta-9-tetrahydrocannabinol has been shown to reduce this opioid withdrawal in mice via activation of the cannabinoid type-1 (CB1) receptor and recently it has been shown that inhibition of the catabolic enzymes for endocannabinoids also reduce somatic signs of opioid withdrawal. Specifically, inhibition the enzyme fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid …

Radiosensitization Of Head & Neck Carcinoma Cells By Linifanib, A Receptor Tyrosine Kinase Inhibitor, Heng-Wei Hsu

Loma Linda University Electronic Theses, Dissertations & Projects

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. …

Beta 2 Nicotinic Acetylcholine Receptor Contributions To Anxiety-Like Behavior, Shawn Anderson

Theses and Dissertations

Nicotine is a major psychoactive ingredient in tobacco that is thought to promote smoking behavior via nicotinic acetylcholine receptors (nAChRs) in the brain. Given reports that people smoke to relieve anxiety and that anxiety precipitates relapse, the overarching goal of this dissertation research is to assess beta 2 subunit containing nAChR (beta2*nAChR) contributions to anxiety-like behavior. Nicotine’s activity at beta2*nAChRs is concentration-dependent, with high concentrations facilitating activation followed by rapid desensitization and low concentrations preferentially desensitizing beta2*nAChRs; hence, activation or inhibition of beta2*nAChRs may support smoking behavior. Rodent studies reveal that nicotine affects anxiety-like behavior dose-dependently: low doses promote anxiolysis- …

Behavioral And Genomic Characterization Of Scheduled Ethanol Deprivation, Jonathan Warner

Theses and Dissertations

Alcoholism is a persistent substance abuse disorder that is associated with negative health, social, and economic outcomes. Treatment strategies for alcohol use disorders are limited, and only three drugs have been approved by the FDA for treatment. Although behavioral therapy and drug combination strategies improve abstinence outcomes, the majority of those in treatment will not achieve long-term abstinence. Therefore, better treatment strategies are needed. While much progress has been made toward understanding the neurobiology of alcoholism, this knowledge has not been effectively translated into treatment strategies. Animal models of alcohol drinking have been crucial to this research effort, but until …

Er Stress Coupled Pannexin Channel Activation Via Stim Proteins, Ankur Bodalia

Electronic Thesis and Dissertation Repository

Many neurodegenerative diseases, including Alzheimer’s Disease, are associated with ER stress. It is suggested that plasma membrane channels contribute to the increased ionic influx and subsequent cell death in response to ER stress. Pannexin channels, which have been implicated in various pathophysiological conditions, are a suitable candidate for facilitating this response. However, mechanisms of pannexin channel activation are poorly defined. I investigated the potential regulation of pannexin activity by the ER stress sensor, STIM. It was hypothesized that pannexin channel activation during ER stress is contingent on the recruitment of STIM proteins. In neurons, pannexin activation was observed in response …

The Role Of Nitric Oxide Dysregulation In Tumor Maintenance, Christopher Rabender

Theses and Dissertations

The inflammatory nature of the tumor microenvironment provides a cytokine and chemokine rich proliferative environment. Much of the responsibility of this environment is due to the production of Reactive Oxygen Species (ROS). These studies examined the proliferative rich tumor environment from a new perspective of Nitric Oxide Synthase (NOS) dysregulation. NOS’s have the ability to become uncoupled and generate superoxide in lieu of nitric oxide (NO). A requirement of NOS for the production of NO is the cofactor tetrahydrobiopterin (BH4) and when it is missing NOS becomes uncoupled and turns into a peroxynitrite synthase. Here I demonstrate that NOS is …

Functional Characterization Of Crip1a Knockout Mice, Joanna Jacob

Theses and Dissertations

CB1 cannabinoid receptors are G-protein-coupled receptors that mediate the central nervous system (CNS) effects of marijuana and endocannabinoids. Recently, cannabinoid receptor interacting protein 1a (CRIP1a) was discovered as a novel protein that binds to the CB1 receptor C-terminus and inhibits CB1 receptor activity without affecting CB1 expression. This thesis investigated the functions of CRIP1a by characterizing the first CRIP1a knockout (KO) mouse line. The absence of CRIP1a was confirmed in KO mice using quantitative PCR and immunoblotting. I hypothesized that CRIP1a KO mice would exhibit enhanced CB1 receptor-mediated G-protein activity in the CNS, as well as cannabimemetic phenotypes and enhanced …

An Evidence Based Recommendation For The Use Of 5% Human Albumin Vs. Normal Saline With Hypotension Secondary To Hypovolemia In Adult Post Operative Patients, Katherine Anne Marshall

Master of Science in Nursing Evidence-Based Practice Projects

Problem: 5% human albumin is used very frequently in the hospital setting with hypotensive post-surgical patients. There are associated risks with the use of human albumin and it has been shown that normal saline is at least as effective in treating extreme hypotension in this patient population.

Significance: Associated risks that are present with the use of human albumin may be equal to those of the risks of whole blood transfusions. In addition weight gain and fluid retention are complications associated with the use of human albumin versus the use of normal saline. Furthermore, human albumin costs $40.59 more than …

Genetic Dissection Of Quantitative Trait Loci For Substances Of Abuse, Jo Lynne Harenza

Theses and Dissertations

It has been reported that an individual’s initial level of response to a drug might be predictive of his or her future risk of becoming dependent, thus basal gene expression profiles underlying those drug responses may be informative for both predicting addiction susceptibility and determining targets for intervention. This dissertation research aims to elucidate genetic risk factors underlying acute alcohol and nicotine dependence phenotypes using mouse genetic models of addiction. Phenotyping, brain region-specific mRNA expression profiling, and genetic mapping of a recombinant inbred panel of over 25 mouse strains were performed in order to identify quantitative trait loci (QTL) harboring …

Identification And Characterization Of Ethanol Responsive Genes In Acute Ethanol Behaviors In Caenorhabditis Elegans, Joseph Alaimo

Theses and Dissertations

Alcohol abuse and dependence are complex disorders that are influenced by many genetic and environmental factors. Acute behavioral responses to ethanol have predictive value for determining an individual’s long-term susceptibility to alcohol abuse and dependence. These behavioral responses are strongly influenced by genetics. Here, we have explored the role of genetic influences on acute behavioral responses to ethanol using the nematode worm, Caenorhabditis elegans. First, we explored the role of ethanol metabolism in acute behavior responses to ethanol. Natural variation in human ethanol metabolism machinery is one of the most reported and reproducible associations found to alter drinking behavior. Ethanol …

Fetal And Neonatal Exposure To Nicotine Augments Hepatic Fatty Acid Synthesis In Rat Offspring Long-Term, Noelle L. Ma

Electronic Thesis and Dissertation Repository

While nicotine replacement therapy (NRT) is presumed to be a safer alternative to smoking in pregnancy, the long-term consequences in offspring are still largely unknown. Animal studies now suggest that maternal nicotine exposure during pregnancy and lactation (MNE-PL) leads to a wide variety of adverse outcomes for the offspring, including increased adiposity. The focus of this study was to investigate how MNE-PL in rats may lead to liver dysfunction long-term in offspring through alterations in gene expression and epigenetic modifications. Postnatal day 180 (PND180) offspring exposed to nicotine during pregnancy and lactation (1mg/kg/day) exhibited increased circulating and hepatic triglycerides concomitant …

Pharmacogenetics Of Oral Anticoagulants And Antiplatelets, Inna Gong

Electronic Thesis and Dissertation Repository

Thromboembolic disorders are a major cause of morbidity and mortality. Therapeutic intervention with anticoagulants and antiplatelets greatly reduces the risk of arterial and venous thrombosis. However, the observed large interindividual variation in responsiveness to these drugs indicates that subsets of patients are not attaining optimal therapy, resulting in either lack of antithrombotic effect or elevated bleeding risk. Recently, single nucleotide polymorphisms (SNPs) have been linked to the variation observed in efficacy and toxicity for many cardiovascular drugs.

Warfarin has been the gold standard anticoagulant for prevention of stroke and thromboembolism in atrial fibrillation (AF) and venous thromboembolism (VTE) patients. SNPs …

Perinatal Nicotine Exposure And Programming Of Hie Sensitive Phenotype In Neonatal Rat Brains, Yong Li

Loma Linda University Electronic Theses, Dissertations & Projects

Large epidemiological and animal studies have revealed a clear association of adverse intrauterine environment with the increased risk of metabolic, cardiovascular and neurological diseases. Maternal smoking is the single most widespread perinatal insult in the world and has been associated with adverse pregnancy outcomes for mother, fetus and the newborn. Our study aims to test the hypothesis that perinatal nicotine exposure induces reprogramming of susceptibility to hypoxic ischemic brain injury in the immature brain, focusing on the roles of AT1R and/or AT2R and trying to reveal the underlying epigenetic mechanisms. Therefore, we established two rat models: perinatal nicotine exposure model …

Cytotoxic Properties Of Novel Platinum Compounds, Bbr3610-Dach And Trans-4-Nbd In Tumor Cells: Cellular Effects Of 1, 2-Dach And Nbd Ligands, Vijay Menon

Theses and Dissertations

Platinum-based chemotherapeutics are used for the treatment of a wide range of cancers and a number of attempts have been made toward developing compounds with better cellular stability and similar or enhanced cytotoxicity as compared to their predecessors. The first part of the work reported here focuses on the cellular effects of the metabolically stable dinuclear platinum compound, BBR3610-DACH. Comet assay showed this compound to form interstrand crosslinks, a highly toxic DNA lesion in HCT116 cells, at equimolar concentrations to its parental compound, BBR3610. Cell cycle studies showed that BBR3610-DACH causes G1/S and G2/M cell cycle arrest with S phase …

Determinants Of Abuse-Related Effects Of Monoamine Releasers In Rats, Clayton T. Bauer

Theses and Dissertations

Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous …

Effects Of Mu Opioid Receptor Agonists On Intracranial Self-Stimulation In The Absence And Presence Of “Pain” In Rats, Ahmad Altarifi

Theses and Dissertations

Pain is a significant health problem. Mu opioid receptor agonists are used clinically as analgesics, but their use is constrained by high abuse liability. Intracranial self-stimulation (ICSS) is a preclinical behavioral procedure that has been used to assess abuse potential of opioids, and drug-induced facilitation of ICSS is interpreted as an abuse-related effect. ICSS can also be used as a behavioral baseline to detect affective dimensions of pain. Specifically, pain-related depression of ICSS can model pain-related depression of behavior and mood, and drug-induced blockade of pain-related ICSS depression can serve as a measure of affective analgesia. This dissertation used mu …

Effect Of Cannabinoids On Pain-Stimulated And Pain-Depressed Behavior In Rats, Andrew Kwilasz

Theses and Dissertations

Cannabinoids produce antinociception in many preclinical models of acute and chronic pain. In contrast, cannabinoids produce inconsistent analgesia in humans, showing little or no efficacy in treating acute pain, with modest efficacy in treating chronic inflammatory pain. This discrepancy may reflect an overreliance on preclinical assays of pain-stimulated behaviors, defined as behaviors that increase in rate or intensity following delivery of a noxious stimulus. In these assays, antinociception is indicated by a reduction in pain-stimulated behaviors, and antinociception is produced either by a reduction in sensory sensitivity to the noxious stimulus (i.e. true analgesia) or by false positive motor impairment. …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …

Ethanol Regulation Of Glucocorticoid Responsive Genes, Blair Costin

Theses and Dissertations

Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. Acute ethanol activates the hypothalamic pituitary adrenal (HPA) axis causing the release of adrenal glucocorticoid hormones, but following chronic ethanol the HPA axis is dysregulated in both humans and rodents. Thus, there is growing evidence that glucocorticoids might also modulate behavioral and molecular responses to ethanol. Previous microarray studies in the Miles’ laboratory have shown that the well-known glucocorticoid responsive gene, Serum and Glucocorticoid-regulated Kinase 1, Sgk1, is prominently up regulated by acute ethanol (2 g/kg) in the prefrontal cortex (PFC) of …

The Role Of Nicotinic Acetylcholine Receptors In Ethanol Responsive Behaviors And Drinking, Anton Dawson

Theses and Dissertations

The high co-morbidity between alcohol (ethanol) and nicotine abuse suggests that nicotinic acetylcholine receptors (nAChRs), which are thought to underlie nicotine dependence, may also be involved in alcohol dependence. A genomic region that encodes the Alpha5* nAChR subtype has recently been shown to be associated with alcohol dependence phenotypes in humans. Therefore, the aim of this study was to determine the role of Alpha5* nAChRs in ethanol-responsive behaviors upon acute administration in mice as well as in their drinking behavior. We conducted tests in mice lacking the Alpha5 coding gene (Chrna5) in ethanol-induced hypothermia, hypnosis, anxiolysis, and conditioned place preference. …

Regulation Of Alpha Synuclein Following Chronic Methamphetamine Administration In Guinea Pigs: Correlation With Memory And Synaptic Plasticity, Adnouse Blanc

PCOM Biomedical Studies Student Scholarship

Methamphetamine (METH) is a highly addictive drug of abuse that has a severe impact on neuronal changes in the brain including modulations of plasticity, cognitive dysfunction, as well as memory impairment. These changes can be seen as modifications in the expression of biochemical markers associated with synaptic plasticity. One such marker associated with memory impairment is alpha synuclein (α-syn). Alteration of α-syn expression has been linked to memory impairment in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here we assess the effect of chronic METH treatment in correlation to cognitive functions.

Twenty-nine guinea pigs (male, 150-250 g) were …

Is Local Infiltration Analgesia (Lia) A Safe And Effective Method For Post-Operative Pain Management After A Unilateral Total Knee Arthroplasty (Tka)?, Brooke A. Bonnette

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not local infiltration analgesia (LIA) is a safe and effective method for post-operative pain management after a unilateral total knee arthroplasty (TKA).
STUDY DESIGN: Review of three English language primary studies published in 2010 and 2011.

DATA SOURCES: Three randomized controlled trials comparing local infiltration analgesia to three separate controls: epidural analgesia, placebo infiltration and femoral nerve block found using PubMed.

OUTCOMES MEASURED: Clinical outcome was measured by total morphine use postoperatively and average knee pain intensity at rest and upon movement postoperatively. Total morphine use …

What Is The Effectiveness Of Onabotulinumtoxina (Botox®) In Reducing The Number Of Chronic Migraines (Cm) In Patients 18-65 Years Old?, Kristin A. Beddingfield

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not onabotulinumtoxinA (Botox®) is effective in reducing the number of chronic migraines (CM) in patients 18-65 years old? Study Design: Review of three published, double blind randomized controlled trials were used for this review, which were found on PubMed; were selected based on their relevance to the clinical question and if they included patient oriented outcomes.

OUTCOMES MEASURED: The outcomes measured were headache/migraine free days measured by >50% responder rate analysis, the Treatment Responder Rate based on Physician Global Assessment, and total adverse events reported by …

In Adults With Acute Diarrhea, Which Treatment Is More Effective Between Loperamide And Racecadotril?, Lorena A. Castillo

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine which treatment is more effective between loperamide and racecadotril to treat acute diarrhea in adults.

STUDY DESIGN: Review of three English language primary randomized controlled studies published from 1999-2005.

DATA SOURCES: First study was a RCT that was double blinded, double placebo, parallel study group and second and third study was RCT single blinded, comparative parallel group that all compared efficacy of loperamide and racecadotril. These were all found by using PubMed, COCHRANE and NCBI.

OUTCOMES MEASURED: Each of the studies measured the efficacy of each …

Does N-Acetylcysteine Supplementation Alleviate Compulsive Behavior In Adults With Impulse Control Disorders?, Tova Diamond

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not “Does N-acetylcysteine supplementation alleviate compulsive behavior in adults with impulse control disorders?”

STUDY DESIGN: Review of three English primary studies published between 2007 and 2009.

DATA SOURCES: One double-blind RCT, one open label trial followed by double-blind RCT, one case study. Studies were found using PubMed, Cochrane Systematic Reviews, OVID and Ebsco databases.

OUTCOMES MEASURED: Primary outcomes measured include severity of trichotillomania symptoms measured by MGHHPS, reduction of pathological gambling symptoms measured by YBOCS-PG, and reduction of compulsive grooming urges measured by patient reports.

RESULTS: In …

Is Omalizumab A Safe And Effective Treatment For Chronic Urticaria?, Ashley L. Davis

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not omalizumab is a safe and effective treatment for chronic urticaria.

STUDY DESIGN: Review of two randomized controlled studies and one crossover study. All three studies are published in English between 2008-2011.

DATA SOURCES: Two randomized, double blind, placebo controlled studies and one crossover study found using PubMed and EBSCOhost.

OUTCOMES MEASURED: Each trial measured the duration, size, number and/or intensity of wheals. This was done by using the urticaria activity score (UAS). Quality of life was also measured using Dermatology Life Quality Index (DLQI), …

What Is The Effectiveness Of Roxithromycin In Management Of The Signs And Symptoms Of Rheumatoid Arthritis?, Adriana Distanislao

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not roxithromycin is effective in management of the signs and symptoms of rheumatoid arthritis.

STUDY DESIGN: Review of three primary studies in the English language published in 2006, 2009, and 2011.

DATA SOURCES: Randomized, controlled and double blind clinical trials testing the effectiveness roxithromycin in management of inflammation and signs and symptoms of rheumatoid arthritis were found using the PubMed and Ovid databases.

OUTCOMES MEASURED: Improvement in the signs and symptoms of tenderness/inflammation using the American College of Rheumatology-20 (ACR-20) scoring approach, improvement of quality of …

Is Fentanyl Pectin Nasal Spray Safe And Effective For Patients With Breakthrough Cancer Pain?, Salina G. Elengical

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether fentanyl pectin nasal spray (FPNS) is safe and effective treatment for patients with breakthrough cancer pain.

STUDY DESIGN: Review of three English language primary randomized controlled trials published 2010-2011.

DATA SOURCES: Multicenter, randomized, double-blind, double-dummy, placebo-controlled trials comparing fentanyl pectin nasal spray, immediate-release morphine sulfate, and/or nasal spray placebo were found using PubMed, COCHRANE, and Medline databases.

OUTCOME MEASURED: All three studies essentially used similar parameters to measure effectiveness and safety of fentanyl pectin nasal spray compared to oral immediate-release morphine sulfate and/or placebo. Baseline pain intensity …

Is Starting Antiretroviral Therapy (Art) In Hiv Positive Adults With Cd4 Cell Count Of <300 Cells/Μl Within Four Weeks Of Initiating New Tuberculosis (Tb) Therapy More Effective In Reducing Mortality Rates Than Starting Art Four Weeks Or Later After Initiating New Tb Therapy?, Janna Erlien

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not starting antiretroviral therapy (ART) in HIV positive adults with CD4 cell count of /µl within four weeks of initiating new tuberculosis therapy more effective in reducing mortality rates than starting ART four weeks or later after initiating new tuberculosis therapy.

STUDY DESIGN: Systematic review of three English language primary studies published in the New England Journal of Medicine in 2011.

DATA SOURCES: Three open label, randomized, controlled trials published in 2011, comparing the timing of ART for HIV+ adults with confirmed or suspected new TB …

Does Daily Intake Of Glucosamine Supplements Prevent The Need For Knee Replacements Later In Life For Adult Patients Predisposed To Osteoarthritis?, Nancy Helmy

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not daily intake of glucosamine supplements prevents the need for knee replacements later in life for adults predisposed to osteoarthritis.

STUDY DESIGN: Review of three English language primary randomized controlled trial studies published between 2001 and 2008

DATA SOURCES: Three double blind randomized control trials comparing glucosamine supplements to placebo were found using PubMed.

OUTCOMES MEASURED: Outcomes were measured using radiographic studies of the knees, joint space measurements, and symptoms were evaluated using Lequesne and WOMAC indexes.

RESULTS: The Reginster (2001) and Pavelka (2002) studies demonstrated no …