Life Sciences Commons^™

Strategies For Protection Of The Blood Brain Barrier In Rodent Models Of Intracerebral Hemorrhage, Derek Sunil Nowrangi

Loma Linda University Electronic Theses, Dissertations & Projects

Intracerebral Hemorrhage (ICH) is a devastating disease that causes a cascade of both mechanical and molecular injury to the central nervous system. It is a debilitating disease that has no well-established treatments, thus leaving an important area to study the pathophysiology of the disease so that new clinically translatable treatments can be found. In the development of translational treatments in experimental ICH, several challenges exist including the designing of studies, method to deliver drugs, proper dosages, and development of models. In our exploration to establish new therapies for ICH, we studied several methods and models that may help to develop …

Harnessing Blood Clot Removal Mechanisms After Germinal Matrix Hemorrhage, Jerry J. Flores

Loma Linda University Electronic Theses, Dissertations & Projects

Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity, mortality, and acquired infantile hydrocephalus in preterm infants in the United States, with little progress made in its clinical management. Blood clots have been shown to elicit secondary brain injury after GMH, by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development. Current evidence suggests that rapid hematoma resolution is necessary to quickly improve neurological outcomes after hemorrhagic stroke. N-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been shown to be neuroprotective after stroke. FPR2 activation has been associated with the …

Functional Compartmentalization Of Mlck In Fetal Arteries, Dane William Sorensen

Loma Linda University Electronic Theses, Dissertations & Projects

Changes in vascular structure and reactivity are amongst the most important that occur during the transition from fetal to newborn life, and are guided by the principle of ensuring adequate coupling of blood flow to metabolism. A clinical consequence of maladaptive fetal vascular adaptation to hypoxia is an increased probability for loss of cerebral autoregulation, increased risk for neonatal encephalopathy, and hypoxicischemic cerebral injury. MLCK is a very specific calcium-calmodulin dependent enzyme, with its only known substrate being MLC20, and is essential for the ability of VSMCs within resistance arteries to appropriately contract or relax in response to changes in …

Cosyntropin As A Therapeutic Intervention Following Traumatic Brain Injury, Lorraine C. Siebold

Loma Linda University Electronic Theses, Dissertations & Projects

Traumatic brain injury (TBI) is a major health concern in the United States. With over two million occurrences and approximately 50,000 deaths annually, TBI is a leading cause of death in young adults and is associated with cognitive deficits influenced by acute and persistent neuroinflammation. Melanocortins, such as adrenocorticotropic hormone (ACTH), are agonists for melanocortin receptors located in the adrenal glands and peripheral immune cells as well as throughout the central nervous system. Melanocortins ameliorate inflammation and provide a novel therapeutic approach for TBI. The focus of this dissertation was to describe and quantify effects of cosyntropin, a synthetic ACTH …

Effects Of Gestational Corticosteroids And Caloric Restriction On The Neonatal Cerebrovasculature, Naomi Franco

Loma Linda University Electronic Theses, Dissertations & Projects

The prenatal environment plays a major role in influencing the health of adult offspring. Maternal food restriction (MFR) during pregnancy is a common stressor that correlates to long-term consequences, including increased risk of cardiovascular and metabolic diseases in adult offspring. Numerous studies report persistent changes following MFR, with an emphasis on the heart and kidney. These consequences are thought to occur via programming, in which a stressor, during critical developmental windows, permanently alters the structure and function of selective fetal tissues. Furthermore, the elevation of maternal glucocorticoids associated with intrauterine stressors is a proposed mechanism of several programming events, including …

Effects Of Omega-3s And Vitamin E Prophylactic Diets And The Implications Of Lipid Transport In Spinal Cord Injury, Kathia Cordero-Caban

Loma Linda University Electronic Theses, Dissertations & Projects

Traumatic injury to the central nervous system (CNS) presents a devastating problem to our society. Although current interventions are promising, no effective treatments are available. The neural membrane fatty acid composition is markedly altered during the first few days after spinal cord injury (SCI). SCI results in autonomic dysfunction, paralysis, spasticity, and significant chronic neuropathic pain. The trauma leads to significantly increased levels of free radical and oxidative stress that contribute to obstructing tissue healing and recovery. A growing body of evidence shows that administration of hydrophobic molecules such as Vitamin E and long-chain omega-3 polyunsaturated fatty acids (ω3PUFAs) are …

Prenatal Undernutrition, Metyrapone, And The Cerebrovasculature, Lara Durrant

Loma Linda University Electronic Theses, Dissertations & Projects

The link between intrauterine environmental conditions and adult cardiovascular system is well established. Independent of lifestyle factors such as poor diet and exercise habits, individuals who have been exposed to stressful conditions in utero show an increased risk of health problems such as hypertension, stroke, and type II diabetes. In support of the Fetal Origin of Adult Disease hypothesis, many labs have reported permanent anatomical and physiological changes associated with fetal stress and nutrient deficiency, with a focus on organ systems such as the kidney and heart. One key idea proposed by many of these studies is the glucocorticoid hypothesis, …

Mechanism Of Chimeric Vaccine Mediated Immune Suppression Of Human Dendritic Cells, Jacques Christian Mbongue

Loma Linda University Electronic Theses, Dissertations & Projects

Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of …

Caveolins And Njks Influence Brain Endothelial Permeability After Juvenile Tbi, David Olufemi Ajao

Loma Linda University Electronic Theses, Dissertations & Projects

Disruption of blood-brain barrier (BBB) is a key secondary event that exacerbates brain damage following traumatic brain injury (TBI). BBB disruption is particularly damaging to the developing brain – which is highly vulnerable to various stress stimuli, resulting in increased brain swelling, disrupted cerebral blood flow (CBF) autoregulation, long-term disabilities and death following TBI in young demographic. Unsurprisingly, BBB disruption and the resultant cerebral edema have emerged as therapeutic targets in juvenile TBI. It is therefore important to understand the molecular players and mechanisms involved in TBI-induced BBB disruption in the juvenile brain. To this end, the endothelial caveolins and …

Fetal Programming And Later Obesity In A Predominantly Latino Wic Population, Eric George Walsh

Loma Linda University Electronic Theses, Dissertations & Projects

Background: In utero stressors may work to program the metabolism of the developing fetus in such a way that predisposes him/her to obesity later on. Studies have shown that breastfeeding is protective against childhood obesity and suggest that after six months the weight gain in breastfed babies slows opposed to formula fed babies who continue with rapid weight gain. This slowing of weight gain has been shown to be protective against adiposity and later life weight gain.

Purpose: This study looks to further explore these findings in a low income Latino population adding mother’s feelings about the pregnancy and the …

Aging And Sympathetic Neurotransmission In Two Strains Of Rats That Differ In Longevity And Immune Profiles, Sam David Perez

Loma Linda University Electronic Theses, Dissertations & Projects

Age-related changes in sympathetic neurotransmission in immune organs may be associated with immunosenescence; however no causal relationship has been established. From previous studies in Fischer rats (F344), we have found that during middle age, sympathetic nerve activity (SNA) rises in the spleen followed by a decline in noradrenergic (NA) innervation. Also, increased sympathetic signaling via betaadrenergic receptor (β-AR) and reduced proliferation of lymphocytes are evident with increasing age. Although SNA progressively rises with age, effects of age on sympathetic factors may be different across rat strains. If causal relationships exist between sympathetic activity and immune function, they may be related …

Experimental Models Of Brain Hemorrhage Using Clostridial Collagenase, Tim Lekic

Loma Linda University Electronic Theses, Dissertations & Projects

Stroke is the third leading cause of death and is the leading cause of disability in the United States, and the most severe form is known as intracerebral hemorrhage, which is bleeding into the brain. The goal of this study is to establish novel animal models to buildup foundations for translational research of intracerebral hemorrhage. We, for the first time, established four animal models, including cerebellum hemorrhage, pontine hemorrhage, neonatal matrix hemorrhage and maternal postpartum hemorrhage. Those models are established according to intracerebral hemorrhage patient subpopulations, and characterized the neurobehavioral and morphological outcomes. These studies have established the requisite for …

Isolation Of The Cytosolic C-Terminus Segment Of Mammalian Kca Channel A Subunit, Wilton Remigio

Loma Linda University Electronic Theses, Dissertations & Projects

The last 20 years of research into ion channels has unraveled unexpected features of the BK_ca channel as a rheostast for cell activity in excitable tissues and homeostatically fine tuning many biological activation processes in the cell. Great attention has been dedicated to the allosteric regulatory mecanisms by which the BK_ca channel is activated or inhibited. Most of these mechanisms point to the involvment of cytoplasmic, C-terminal, ‘tail’ domain of the channel. Many laboratories have cloned portions of the ‘tail’ domain in an attempt to to study specific regulatory sites. Very little is known about the BK ‘tail’ …

Behavior And Physiology Of Hermit Crabs During Burial: Shell Abandonment And Lactate Accumulation, Janelle Allison Shives

Loma Linda University Electronic Theses, Dissertations & Projects

Organisms living in the intertidal zone must adapt to environmental and physical stressors. One physical stressor that these organisms may face, and that may require specific behavioral and physiological responses, is burial by sediment. In this thesis I report the results of experiments in which I subjected the intertidal hermit crab, Pagurus samuelis, to burial and analyzed aspects of subsequent behavior and physiology. In the first set of experiments, hermit crabs were buried with the shell aperture facing either up or down, and at one of three depths (2, 4, or 6 cm). The factors hermit crab weight, shell …

Postnatal Maturation Modulates Cerebrovascular Myogenic Tone, Shelton M. Charles

Loma Linda University Electronic Theses, Dissertations & Projects

The present study focused on the main hypothesis that maturation decreases contractile reliance on calcium influx and myofilament Ca2+ sensitivity, and increases reliance on release of calcium from intracellular stores to develop and maintain pressure-evoked myogenic tone in rat cerebral blood vessels. To test this hypothesis, pressure-induced myogenic tone and changes in artery wall ([Ca2+]i) were measured simultaneously in isolated endothelium denuded, fura-2 loaded middle cerebral arteries (MCA) from pup (PI4) and adult (6 months old) SD rats. We studied the mechanism that govern myogenic tone and examined the hypothesis that during maturation, MCA from rat pups are more reliant …

Role Of No In The Regulation Of Cortisol Synthesis In Long-Term Hypoxic Sheep Fetal Adrenal, Tshepo Rothi Monau

Loma Linda University Electronic Theses, Dissertations & Projects

Our laboratory has demonstrated that sheep fetuses adapt to long-term hypoxia (LTH) by maintaining normal level of basal plasma cortisol despite increased adrenocorticotropic hormone (ACTH). But the mechanisms involved are not fully understood. Studies have shown that nitric oxide (NO) inhibits synthesis of steroid hormones in a variety of tissues, and in different animal species. Studies also showed that hypoxia increases both expression and activity levels of the nitric oxide (NO) generating enzyme, nitric oxide synthase (NOS), in certain tissues. We have here investigated the expression level and localization of NOS isoforms in sheep fetal adrenals. We also investigated the …

Buccal Bone Changes Following Rapid Maxillary Expansion (Rmf), Long-Term Results, Elena S. Iacob

Loma Linda University Electronic Theses, Dissertations & Projects

The purpose of this study was to use Cone Beam Computed Tomography (CBCT) images to quantitatively evaluate buccal bone changes of maxillary first premolar (P1), second premolar (P2) and first molar (M1) shortly after Rapid Maxillary Expansion (RME) and at the end of orthodontic treatment, as well as to evaluate the variables that may be associated with the short-term and long-term changes. Forty-seven consecutive patients (25 males and 22 females) with a mean age of 14.5years and who required RME as part of their orthodontic treatment and had pre-RME (T1) and post-RME (T2) CBCT images available were used for the …

Maturational Changes In Myosin Light Chain Kinase Activity In Ovine Carotids, Elisha Raju Injeti

Loma Linda University Electronic Theses, Dissertations & Projects

Vascular reactivity changes dramatically during postnatal maturation due in large part to developmental changes in myofilament calcium sensitivity. Recent findings suggest that reactivity of the thick filament component of calcium sensitivity is upregulated in fetal compared to adult arteries. In light of these findings, the present study tests the hypothesis that upregulation of fetal thick filament reactivity is due to upregulation of myosin light chain kinase (MLCK) activity. To test this hypothesis, MLCK abundance and its activity is measured in intact arteries. The results indicate that MLCK abundance is 6.03 ± 0.96 fold greater in adult than in fetal arteries. …

Anti-Inflammatory Effects Of Ppar-Gamma In Surgical Brain Injury (Sbi), Amy Hyong

Loma Linda University Electronic Theses, Dissertations & Projects

Introduction: Brain injury can be caused by neurosurgical procedures themselves, due to direct trauma, retractor stretch, intraoperative hemorrhage and electrocautery damage. As a result of this surgical brain injury (SBI) postoperative complications such as inflammation, brain edema, and cell death can occur in the susceptible brain areas. Cerebral inflammation is a known contributor to the pathophysiology of brain injury. Following brain injury, the release of inflammatory mediators facilitates the development of BBB breakdown, cerebral edema, oxidative stress and neuronal death, resulting in further tissue damage in the brain and poor neurological outcomes. This study evaluates whether the use of a …

Parental Readiness For Change And Involvement In Treating Children With Obesity, Aileen Arratoonian Vedda

Loma Linda University Electronic Theses, Dissertations & Projects

Several studies have demonstrated benefits of parental involvement in intervention programs for Childhood Obesity. However, limited research is available on Parent Readiness for Change. This study utilized archival data from the LLU Growing Fit Obesity Clinic to assess Parent Readiness for Change (PRC) and involvement in a 12- week multidisciplinary program for obese children, as a predictor of medical and psychological outcomes. Data from forty-nine children aged 6-16 (M= 10.47) were eligible and included. Their caregivers who participated in the program included; 86% mothers, 7 % fathers, and 7 % relatives. The caregiver mean age was M=39.6. PRC was assessed …

Effect Of Long-Term Hypoxia On Myometrial Contractility In The Pregnant Sheep, Timothy Kimo Arakawa

Loma Linda University Electronic Theses, Dissertations & Projects

Previous research from our laboratory has shown that myometrial contractility is reduced in pregnant sheep exposed to long-term hypoxia (LTH). The studies in this dissertation examined the effect of LTH on various aspects of Ca² regulation, large-conductance, Ca²⁺ activated (BK) channels activity and protein expression, and cGMP-depended protein kinase (PKG) activity. Myometrium was collected from near-term pregnant sheep exposed to high altitude-associated LTH and from normoxic pregnant controls. After pretreatment with 10^-8 M oxytocin (OT), circular and longitudinal myometrial strips were treated with nifedipine (L-type Ca²⁺ channel blocker), ruthenium red, ryanodine (blockers of IPssensitive stores), 2-Nitro-4-carboxyphenyI-N,N-diphenyIcarbamate …

Neuronal Connections From The Cervix To The Spinal Cord Before Parturition, Mary Medina Groves

Loma Linda University Electronic Theses, Dissertations & Projects

By the day before birth, the density of nerve fibers in the cervix has increased compared to earlier in pregnancy or in nonpregnant mice. Similar findings are reported in parturient women. To test the hypothesis that connections between the cervix and spinal cord are enhanced by term, the cervix of nonpregnant and time-dated pregnant mice (day 15 or 18 post-breeding) was injected with pseudorabies virus (PRV), a trans-synaptic retrograde neural tract tracer. Mice were euthanized and perfused 5 days later. The spinal cord and cervix were removed and postfixed overnight, immersed in sucrose, and cryostat sections through the thoracic to …

Hypochlorous Acid Mediated Damage Of Chromatin, Joseph Insugn Kang

Loma Linda University Electronic Theses, Dissertations & Projects

Hypochlorous acid (HOCl), the primary product of activated neutrophils at sites of inflammation, can damage both DNA and associated histone proteins. HOCl damage to cytosine bases in DNA generates the chlorination damage products 5-chlorocytosine (ClC) and 5-chlorouracil (ClU) as well as the oxidation damage products 5- hydroxycytosine (HOC) and 5-hydroxyuracil (HOU). Histone damage by HOCl can be measured by quantitation of 3-chlorotyrosine and 3,5-dichlorotyrosine, stable and unique markers of protein damage caused by HOCl. The studies presented here investigate how and where these damage products occur and what implications they might have in the correlation between chronic inflammation and carcinogenesis. …

Radiation-Induced Glutamate Transport Alterations In Neuron-Astrocyte Coupling, Martha Celia Sanchez

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure of the central nervous system (CNS) to ionizing radiation is known to result in behavioral, cognitive, and motor deficits - effects similar to those seen in many neurodegenerative disorders. Neurons and astrocytes, two principal cell types in the brain, coexist as an interdependent metabolic unit via the neurotransmitter glutamate. Disruption of this metabolic coupling would have widespread effects within the CNS, therefore it is hypothesized that ionizing radiation impairs glutamate transport and metabolism, and increases oxidative stress, ultimately impairing neuron-astrocyte coupling. We propose to investigate the mechanism and determine the impetus for radiation-induced neurotoxicity by measuring the temporal sequence …

Electromagnetic Differences In The Brain During Memory Retrieval, Warren Scott Merrifield

Loma Linda University Electronic Theses, Dissertations & Projects

The primary objectives for this experiment were to analyze the neuroanatomical correlates of autobiographical, episodic and semantic memory, use a different paradigm to promote episodic memory retrieval, and employ a different analysis technique to understand retrieval processes. Autobiographical and episodic memories are personal memories from the past. Autobiographical is more general (e.g. a street name of a house growing up) and episodic is more specific to time (e.g. 13th birthday party that took place on a street). For autobiographical and episodic memory retrieval operations, there is no general consensus as to the localization of function, but bilateral activation of the …

Regulation Of Alpha-1-Adrenoceptor-Mediated Contractions Of The Uterine Artery By Pkc, Hongying Zhang

Loma Linda University Electronic Theses, Dissertations & Projects

Pregnancy is associated with a significant decrease in uterine vascular tone and a striking increase in uterine blood flow, which ensures normal fetal development. Multiple mechanisms are involved in the adaptation of uterine artery contractility during pregnancy. Both protein kinase C (PKC) and activation of ai-adrenoceptors play important roles in the regulation of uterine artery contractility. In addition, PKC mediates the pregnancyassociated decrease in myogenic tone of the uterine artery, and interacts with ajadrenoceptors leading to modulation of ai-adrenoceptor-mediated contractions of vascular smooth muscle. Yet, whether or to what extent PKC regulates ai-adrenoceptormediated contractions of the uterine artery and their …

Maturational Changes In Cerebrovascular Thick- And Thin-Filament Regulation, Renan Joel Sandoval

Loma Linda University Electronic Theses, Dissertations & Projects

The present study focused on the main hypothesis that age-related changes in myofilament Ca²⁺ sensitivity involve simultaneous changes in the relations between cytosolic Ca²⁺ transients, myosin phosphorylation, and force development. To define the effects of late fetal and early postnatal maturation, parallel experiments were carried out using cerebral arteries from both term lamb fetuses (140-141 days of gestation) and nonpregnant adult sheep. Fetal and adult cerebral arteries were stimulated by either mechanically, electromechanically, and/or pharmacomechanically-induced contractions, and the relations of cytosolic Ca²⁺, MLC phosphorylation, and contractile tensions were measured. These measurements allowed for stimulus and age-dependent …

Gene Expression In The Mouse Placenta: Developmental And Stress Responses, Ciprian P. Gheorghe

Loma Linda University Electronic Theses, Dissertations & Projects

Successful placental development is crucial for optimal growth, maturation, and survival of the embryo/fetus. Placental failure and placental pathology contributes to both morbidity and mortality of the fetus. We sought to understand normal placental development and also placental responses to stress using oligonucleotide microarray technology. To examine genetic aspects of normal placental development, we investigated gene expression patterns in the murine placenta at embryonic day 10.5 (E10.5), E12.5, E15.5, and E17.5. Hypoxia has been identified as a major stressor in placental and fetal development. In order to comprehend more completely hypoxic stress responses we sought to measure gene expression changes …

The Relationship Between High Sensitivity C-Reactive Protein, Metabolic Syndrome And Exercise, Micheline A. Vargas

Loma Linda University Electronic Theses, Dissertations & Projects

Background: It is well known that regular physical activity is associated with lower risk of chronic diseases such as diabetes and cardiovascular disease. Physical activity is also considered an important determinant of metabolic syndrome. All levels of metabolic syndrome, diabetes, and cardiovascular disease are thought to involve inflammation. Physical activity may reduce risk, at least in part, by modifying the inflammatory process. Recent studies have demonstrated an inverse relationship between inflammatory markers, such as high sensitivity C-reactive protein (hs-CRP), and physical activity. Elevated hs-CRP appears to be an independent predictor of both CVD and diabetes. Recent evidence also suggests that …

Effects Of Advancing Age On Er Calcium Regulation In Rat Superior Cervical Ganglia, Conwin Kodel Vanterpool

Loma Linda University Electronic Theses, Dissertations & Projects

Intracellular calcium ([Ca²⁺]i) release from endoplasmic reticulum (ER) stores plays an important role in cell signaling. These stores are rapidly refilled via voltage-gated calcium channels or spontaneously via store-operated calcium channels and subsequent pumping by ER Ca²⁺-ATPases. Calcium release is triggered by the activation of the ryanodine receptor (RyR) channels and their function is in part dependent on their expression. We analyzed the [Ca²⁺]i transients in fura 2-loaded superior cervical ganglion (SCG) cells from 6, 12, 20, and 24-month-old Fischer 344 rats for their ability to rapidly and spontaneously refill. For rapid refilling, the …