Medical Sciences Commons^™

Qualitatively Assessing The Expression Of Kynurenine Pathway Metabolic Enzymes In Human Glioma Tissue, Kaushik Varadarajan

Honors College Theses

Gliomas are the most common brain tumor and glioblastoma multiforme (GBM) is the most common type of glioma observed in patients. Prognosis with late stage glioma and GBM is very poor even with recent advances in treatment. Along with treating the tumor, manners of bypassing the blood brain barrier and ensuring the tumor uptakes the treatment is necessary. Because the treatments can harm regular brain cells there is concern about the viability and toxic side effects of many treatments. With all of these challenges posed it is important to understand how glial tumors can be so recurring and difficult to …

Molecular Docking And Inhibition Of Matrix Metalloproteinase-2 By Novel Difluorinatedbenzylidene Curcumin Analog, Aamir Ahmad, Afreen Sayed, Kevin R. Ginnebaugh, Vivek Sharma, Anita Suri, Arundhati Saraph, Subhash Padhye, Fazlul H. Sarkar

Department of Pathology

We recently described the synthesis and characterization of a novel difluorinatedbenzylidene analog of curcumin, commonly referred as CDF, which demonstrated significantly enhanced bioavailability and in vivo anticancer activity. CDF targets many factors similar to curcumin, albeit with more potency, as reported previously. To further highlight this differential behavior of CDF, we chose matrix metalloproteinase protein MMP-2 which is involved in the processes of invasion and metastasis of human tumors. Both curcumin and CDF were characterized for their binding characteristics using in silico docking studies; they were also evaluated via biological assays involving gelatin zymography, miRNA analysis, invasion assays and ELISA. …

Evidence Of Distinctive Structural Alterations That Differentiate Adhd Boys With And Without A Comorbid Reading Disability, Dhruman Dilip Goradia

Wayne State University Dissertations

Attention deficit hyperactivity disorder (ADHD) and reading disability (RD) are neurodevelopmental disorders that often co-occur. Children with ADHD and co-occurring RD (ADHD/+RD) tend to show greater cognitive deficits than children with ADHD alone (ADHD/-RD). However, the extents to which comorbid RD impact structural alteration in children with ADHD have never been investigated. The overall goal of this study was to assess structural alterations in the subcortical, cortical and white matter that may differentiate ADHD/-RD from ADHD/+RD. The general hypothesis was that ADHD/+RD would show extensive alterations in regions implicated in ADHD than ADHD/-RD as well as show additional abnormalities in …

Neural Alterations Influencing Skilled Reading In Adhd: A Task-Based Fmri Study, Brianne Mohl

Wayne State University Dissertations

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD (ADHD/+RD) also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though neither the neural correlates of the co-occurring disorders nor the association are well understood from a functional neuroimaging perspective. The goal was to assess to what extent ADHD/+RD differ from ADHD without RD (ADHD/-RD) and typically developing controls (TDC) in functional activation of attention- and reading-related areas during various …

Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment, Kelly Marie Mcgregor

Wayne State University Dissertations

Antidepressant drugs are widely used but their mechanism of action remains only partially understood. One leading hypothesis holds that a key effect of chronic treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) is loss of somatodendritic 5-HT1A receptor-mediated autoinhibition in serotonergic neurons of the dorsal raphe nucleus (DRN). However, technical limitations have prevented direct testing of this hypothesis. In the current study we took advantage of optogenetic strategies to assess the effects of the classic SSRI fluoxetine on 5-HT1A receptor-mediated autoinhibition. We conducted these experiments in mice expressing the light-sensitive ion channel Channelrhodopsin (ChR) in 5-HT neurons to facilitate their …

An Investigation Of The Relationship Between Axonal Injury, Biomarker Expression And Mechanical Response In A Rodent Head Impact Acceleration Model, Yan Li

Wayne State University Dissertations

In the United States 1.4 million people sustain traumatic brain injury (TBI) each year, resulting in 235,000 hospitalizations and 50,000 fatalities annually. Traumatic axonal injury (TAI) is a serious outcome of TBI that accounts for 40-50% of hospitalizations due to head injury and one third of the mortality due to TBI, and it is difficult to diagnose and evaluate. The purpose of this dissertation is to determine mechanical injury predictors for TAI and identify potential biomarkers to evaluate TAI.

In this dissertation, a modified Marmarou impact acceleration injury model was developed to allow the monitoring of velocity of the impactor …

The Relationship Between Axonal Injury, Biomarker Expression And Mechanical Response In A Rodent Head Impact Acceleration Model, Yan Li

Wayne State University Dissertations

In the United States 1.4 million people sustain traumatic brain injury (TBI) each year, resulting in 235,000 hospitalizations and 50,000 fatalities annually. Traumatic axonal injury (TAI) is a serious outcome of TBI that accounts for 40-50% of hospitalizations due to head injury and one third of the mortality due to TBI, and it is difficult to diagnose and evaluate. The purpose of this dissertation is to determine mechanical injury predictors for TAI and identify potential biomarkers to evaluate TAI.

In this dissertation, a modified Marmarou impact acceleration injury model was developed to allow the monitoring of velocity of the impactor …

Neural Correlates Of Episodic Memory Formation In Children And Adults, Lingfei Tang

Wayne State University Theses

The medial temporal lobe (MTL) and prefrontal cortex (PFC) are two key brain regions that support episodic memory formation in both children and adults, but the functional developmental of these regions remains unclear. In this study, we investigated the development of neural correlates of episodic memory formation using functional MRI with a subsequent memory paradigm, administered to a cross-sectional sample of 83 children and adults. We found that MTL subregions showed an age-related increase in activation supporting memory formation of complex scenes. In addition, a functionally defined scene-sensitive region in the posterior MTL also showed similar increase and predicted better …

Unstable Ventilatory Control During Sleep After High Spinal Cord Injury: The Contribution Of Chemosensitivity And Hypoventilation, Amy Therese Bascom

Wayne State University Dissertations

ABSTRACT

UNSTABLE VENTILATORY CONTROL DURING SLEEP AFTER HIGH SPINAL CORD INJURY: THE CONTRIBUTION OF CHEMOSENSITIVITY AND HYPOVENTILATION

by

Amy T. Bascom

May 2015

Advisor: Dr. Harry G. Goshgarian

Major: Anatomy and Cell Biology

Degree: Doctor of Philosophy

A high prevalence of sleep-disordered breathing (SDB) after spinal cord injury (SCI) has been reported in the literature; however, the underlying mechanisms are not well understood. My studies had 2 aims: 1) to determine the effect of the withdrawal of the wakefulness drive to breathe on the degree of hypoventilation in SCI patients and able-bodied controls and 2) to determine the response of …

Investigation Of Whether Sedentary And Physically Active Conditions Lead To Altered Gabaergic Signaling In The Rvlm, Maryetta Donna Dombrowski

Wayne State University Dissertations

Investigation of whether sedentary and physically active conditions lead to altered GABAergic signaling in the RVLM

MD Dombrowski, and PJ Mueller

Department of Physiology, Wayne State University, School of Medicine, Detroit, MI

A sedentary lifestyle is a major risk for cardiovascular disease. Cardiovascular disease has been associated with elevated basal sympathetic nerve activity. The rostral ventrolateral medulla is a bilateral brainstem region that is an important for the control of resting and reflex control of sympathetic nerve activity and blood pressure. The activity of these neurons in this region is tonically inhibited by the neurotransmitter γ-butyric amino acid (GABA). Interestingly, …

Reduction In Post-Botulinum Toxin Flu-Like Symptoms After Injection With Incobotulinum Toxin, Edwin George, Natalya Shneyder

Neurology Faculty Publications

OBJECTIVE: To determine if patients reporting flu-like symptoms (FLS) after botulinum toxin (BoNT) injections are less susceptible to this reaction after incobotulinum toxin.

BACKGROUND: Approximately 10% of patients injected with BoNT in our clinic complain of FLS, primarily malaise, myalgias and rhinorrhea, beginning a few days to one week after injection and lasting one week or less. A review by Baizabal-Carvallo et al. (Toxicon, 2011, 58:1-7) found rates of FLS between 1.7 and 20% in patients after various preparations of botulinum toxin A, and a subsequent study showed increased cytokines in patients with FLS (Neurotoxicity Research, …

Metabotropic Glutamate Receptor-1 As A Novel Target For The Antiangiogenic Treatment Of Breast Cancer, Cecilia L. Speyer, Ali H. Hachem, Ali A. Assi, Jennifer S. Johnson, John Austin Devries, David H. Gorski

Department of Surgery

Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer …

Autoantibodies To Agrin In Myasthenia Gravis Patients, Bin Zhang, Chengyong Shen, Beverly Bealmear, Samia Ragheb, Wen-Cheng Xiong, Richard A. Lewis, Robert P. Lisak, Lin Mei

Immunology and Microbiology Faculty Research Publications

To determine if patients with myasthenia gravis (MG) have antibodies to agrin, a proteoglycan released by motor neurons and is critical for neuromuscular junction (NMJ) formation, we collected serum samples from 93 patients with MG with known status of antibodies to acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related 4 (LRP4) and samples from control subjects (healthy individuals and individuals with other diseases). Sera were assayed for antibodies to agrin. We found antibodies to agrin in 7 serum samples of MG patients. None of the 25 healthy controls and none of the 55 control neurological patients had agrin antibodies. …

Carp-1 Functional Mimetics Are A Novel Class Of Small Molecule Inhibitors Of Malignant Pleural Mesothelioma Cells, Shazia Jamal, Vino T. Cheriyan, Magesh Muthu, Sara Munie, Edi Levi, Abdelkader E. Ashour, Harvey I. Pass, Anil Wali, Mandip Singh, Arun K. Rishi

Oncology Faculty Publications

Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of …

Pedigree Structure And Kinship Measurements Of A Mid-Michigan Community: A New North American Population Isolate Identified, Joseph D. Bonner, Rachel Fisher, James Klein, Qing Lu, Ellen Wilch, Karen H. Friderici, Jill L. Elfenbein, Debra L. Schutte, Brian C. Schutte

Human Biology Open Access Pre-Prints

Previous studies identified a cluster of individuals with an autosomal recessive form of deafness that resides in a small region of mid-Michigan. We hypothesized that affected members from this community descend from a defined founder population. Using public records and personal interviews, we constructed a genealogical database that includes the affected individuals and their extended families as descendants of 461 settlers who emigrated from the Eifel region of Germany between 1836 and 1875. The genealogical database represents a 13-generation pedigree that includes 27,747 descendants of these settlers. Among these descendants, 13,784 are presumed living. Many of the extant descendants reside …

Celiac Disease As A Model For The Evolution Of Multifactorial Disease In Humans, Aaron Sams, John Hawks

Human Biology Open Access Pre-Prints

Celiac disease (CD) is a multifactorial chronic inflammatory condition that results in injury of the mucosal lining of the small intestine upon ingestion of wheat gluten and related proteins from barley and rye. Although the exact mechanisms leading to CD are not fully understood, the genetic basis of CD has been relatively well characterized. In this review we briefly review the history of discovery, clinical presentation, pathophysiology, and current understanding of the genetics underlying CD risk. Then, we discuss what is known about the current distribution and evolutionary history of genes underlying CD risk in light of other evolutionary models …

Lactase Persistence Variants In Arabia And In The African Arabs, Edita Priehodova, Abdelhay Abdelsawy, Evelyne Heyer, Viktor Cerny

Human Biology Open Access Pre-Prints

Lactase persistence (LP), the state enabling the digestion of milk sugar in adulthood occurs only in some human populations. The convergent and independent origin of this physiological ability in Europe and Africa is linked with animal domestication that had either started in both places independently or had spread from the Near East by acculturation. However, it has recently been shown that at least in its southern parts, the population of Arabia not only has a different LP-associated mutation profile than the rest of Africa and Europe but had also experienced an independent demographic expansion occurring before the Neolithic around the …

Metabotropic Glutamate Receptor-1 Contributes To Progression In Triple Negative Breast Cancer, Malathi Banda, Cecilia L. Speyer, Sara N. Semma, Kingsley O. Osuala, Nicole Kounalakis, Keila E. Torres Torres, Nicola J. Barnard, Hyunjin J. Kim, Bonnie F. Sloane, Fred R. Miller, James S. Goydos, David H. Gorski

Department of Surgery

TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC …

Accumulation Of Subcortical Iron As A Modifier Of Volumetric And Cognitive Decline In Healthy Aging: Two Longitudinal Studies, Ana Marie Daugherty

Wayne State University Dissertations

Accumulation of non-heme iron in the brain has been theorized as a cellular mechanism underlying global neural and cognitive decline in normal aging and neurodegenerative disease. Relatively few studies of brain iron in normal aging exist and extant studies are almost exclusively cross-sectional. Here, I estimated iron content via T2* and measured volumes in several brain regions in two independent samples of healthy adults. The first sample (N = 89) was measured twice with a two-year delay; and the second sample (N = 32) was assessed four times over a span of 7 years. Latent models estimated change in iron …

Evaluation Of Presynaptic Dopamine Dynamics After: Toluene Inhalation Or Trkb Receptor Activation, Aaron Kwaku Apawu

Wayne State University Dissertations

Dopamine (DA) neurons in the striatum mediate several functions of the brain and have been linked to a host of neurological disorders including Parkinson's disease and addiction, both of which occur as a result of dysfunction in the DA system. In the present study, our first objective was to understand how the striatal DA system adapts to acute and repeated administration of inhalant toluene. The use of toluene as inhalant, like other drugs of abuse, is known to perturb DA neurotransmission in the brain reward pathway. However, the exact mechanism underling toluene's influence on striatal DA neurotransmission is unknown. The …

Alterations In The Mouse Striatum Following Acute And Repeated Ethanol Exposure, Brooke D. Newman

Wayne State University Dissertations

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator that has implicated in regard to several neurological disorders, including alcohol addiction. BDNF is also an important modulator of dopamine (DA), a neurotransmitter that is heavily implicated in addiction with one of the DA rich brain regions being referred to as the reward center of the brain. One of the focuses in alcohol dependence research includes determining risk factors that make an individual more susceptible to becoming dependent. BDNF has been of interest as a risk factor due to its involvement in ethanol consumption and addiction evidenced in a vast number of …

Longitudinal Change In Regional Cortices And Fluid Intelligence, Peng Yuan

Wayne State University Dissertations

Fluid intelligence (Gf) and crystalized intelligence (Gc) are two factors of the general intelligence. They have distinct age-related trajectories of change. Jung and Haier proposed Parieto-Frontal Integration Theory (P-FIT, 2007) to account for the inter-person variance in reasoning intelligence. Some brain regions such as prefrontal, parietal, temporal and anterior cingulate cortices were included in the P-FIT model and were hypothesized to be involved in fluid reasoning task. Therefore, in the current study, we examined latent growth curves (LGC) of longitudinal change in Gf, Gc, prefrontal cortex, parietal cortex, anterior cingulate, temporal cortex and primary visual cortex. Forty-six healthy middle-aged and …

The Effect Of Gaba A Antagonism On Locomotor Activity And Dopamine Release In The Mouse Caudate Putamen Following Acute Toluene Inhalation: An In-Vivo Microdialysis Study, Sean Callan

Wayne State University Theses

Toluene is ubiquitous solvent commonly inhaled recreationally. Despite its frequency of misuse, there is little understanding of how toluene acts within the brain. To examine this, this master's thesis examined the impact of acutely inhaled toluene on dopamine (DA) release in the mouse CPu in vivo using microdialysis techniques. Toluene inhalation produced dose-dependent increases in DA levels as well as changes in locomotor activity. These effects were potentiated by pre-treatment with the GABAA antagonist bicuculline via reverse microdialysis delivery. These results suggest that the DA dynamics of toluene abuse are related to toluene's previously explored effects on the GABA system. …

Inattention And Hyperactivity Among Preschool Age Children Born Prematurely, Andrew Heitzer

Wayne State University Theses

A large body of literature shows that compared to children born at term, preterm- children are at increased risk for difficulties with inattention and hyperactivity. Less consistency exists, however, in the limited body of research exploring the contribution of early biological risk to behavioral disinhibition within the population of children born prematurely. Therefore, our goal was to examine perinatal variables that may influence activity level and hyperactivity among preterm preschoolers. Ninety-eight preterm (23.4 - 33.9 weeks gestation) preschoolers (3-4 years) participated in the study. Direct measures of inattention and hyperactivity as well as parental ratings were used to evaluate behavior. …

Blast-Induced Tinnitus: A Combined Behavioral, Memri, And Electrophysiology Study, Jessica Pengyun Ouyang

Wayne State University Dissertations

ABSTRACT

BLAST-INDUCED TINNITUS: A COMBINED BEHAVIORAL, MEMRE, AND ELECTROPHYSIOLOGY STUDY

by

JESSICA OUYANG

May 2014 Advisor: Drs. Steve Cala & Jinsheng Zhang

Major: Physiology

Degree: Doctor of Philosophy

Tinnitus and hearing loss are the frequent auditory-related co-morbidities of blast trauma. The etiology of blast-induced tinnitus is also muddled by brain mechanisms associated with emotional and cognitive problems such as anxiety, memory loss, and depression. We set out to develop a realistic and ecologically valid model to address changes of cognitive status and psychological state that are associated with blast- induced tinnitus. In this study, 19 adult rats were randomly divided …

Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla

Wayne State University Dissertations

Epilepsy is a common neurological disorder of recurrent unprovoked seizures. It affects almost 1% of the world population. Although there is a wide range of anti-epileptic drugs (AEDs) available, they only treat the seizure symptoms and do not cure the disease itself. The poor role of AEDs can be attributed to the lack of knowledge of exact mechanisms and networks that produce epileptic activities in the neocortex. At present, the best cure for epilepsy is surgical removal of electrically localized epileptic brain tissue. Surgically removed brain tissue presents an excellent opportunity to discover the molecular and cellular basis of human …

How Studies Of Human Sex Ratios At Birth May Lead To The Understanding Of Several Forms Of Pathology, William H. James

Human Biology Open Access Pre-Prints

This paper deals with the problem of the causes of the variation of sex ratio (proportion male) at birth. This problem is common to a number of areas in biology and medicine e.g. obstetrics, neurology/psychiatry, parasitology, virology, oncology and teratology. It is established that there are significantly biased, but unexplained, sex ratios in each of these fields. Yet workers in them (with the possible exception of virology) have regarded the problem as a minor loose end, irrelevant to the field’s major problems. However, as far as I know, no-one has previously noted that unexplained biased sex ratios occur, and thus …

Identification Of Enzymes Causing Redox Cycling, Causing Oxidative Stress And Damaging Mitochondria, Kiran Sebastian

Honors College Theses

Oxidative stress is thought to contribute to the death of dopamine neurons and the consequential progression of Parkinson’s disease. Redox cycling of quinones, including compounds formed by dopamine oxidation, can lead to oxidative stress and damaging of the mitochondria. Which enzymes catalyze the redox cycling of quinones is unknown, however. Inhibitors of the mitochondrial respiratory chain (cyanide, rotenone) do not inhibit redox cycling. Mitochondrial NAD(P)H:quinone oxidoreductases are likely candidates, but dicumarol, a common inhibitor of such enzymes is not effective. We observed that Cibacron Blue does indeed inhibit NADH-dependent redox cycling to an extent. Our data shows that the rate …

Roles Of Neuregulin1 In Neuromuscular Junction Development, Jiajing Wang

Wayne State University Dissertations

Neuromuscular junction (NMJ) development is a multistep process mediated by coordinated interactions between nerve terminals, target muscles, and peri-synaptic glial cells, and thus requires reciprocal signals derived from every cell type. Neuregulin1s (NRG1s) are a family of predominantly neuronal growth and differentiation factors that are important for many aspects of nervous system development. In this thesis, both the effects of NRG1 on NMJ development and reciprocal effects of neurotrophic factors on NRG1 expression were studied as a means to define the complex regulatory communication at the NMJ. Using the chicken embryo as a model, methods were developed to study the …

Transcranial Sonothrombolysis Using High-Intensity Focused Ultrasound: Impact Of Increasing Output Power On Clot Fragmentation, Golnaz Ahadi, Christian S. Welch, Michele J. Grimm, David J. Fisher, Eyal Zadicario, Karin Ernström, Arne H. Voie, Thilo Hölscher

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The primary goal of this study was to investigate the relationship between increasing output power levels and clot fragmentation during high-intensity focused ultrasound (HIFU)-induced thrombolysis.

Methods

A HIFU headsystem, designed for brain applications in humans, was used for this project. A human calvarium was mounted inside the water-filled hemispheric transducer. Artificial thrombi were placed inside the skull and located at the natural focus point of the transducer. Clots were exposed to a range of acoustic output power levels from 0 to 400 W. The other HIFU operating parameters remained constant. To assess clot fragmentation, three filters of different …