The University of Texas Medical Branch is a component of the University of Texas System located in Galveston, Texas, United States, about 50 miles southeast of Downtown Houston. It is an academic health center with 11,000 employees and a medical school that is the oldest in Texas. In November 2014 it had an endowment of $508 million. Established in 1891 as the University of Texas Medical Department, UTMB has grown from one building, 23 students and 13 faculty members to more than 70 buildings, more than 2,500 students and more than 1,000 faculty. It has four schools, three institutes for advanced study, a comprehensive medical library, three on-site hospitals , a network of clinics that provide primary and specialized medical care and numerous research facilities.UTMB's primary missions are health science education, medical research and health care services. Its Emergency Room at John Sealy Hospital is certified as a Level I Trauma Center and serves as the lead trauma facility for a nine-county region in Southeast Texas; it is one of only three Level I Trauma centers serving all ages in Southeast Texas.In fiscal year 2012, UTMB received 20 percent of its $1.5 billion budget from the State of Texas to help support its teaching mission, hospital operation and Level 1 Trauma Center; UTMB generates the rest of its budget through its research endeavors, clinical services and philanthropy. It provides a significant amount of charity care , and treats complex cases such as transplants and burns.In 2003 UTMB received funding to construct a $150 million Galveston National Biocontainment Laboratory on its campus, one of the few non-military facilities of this level. It houses several Biosafety Level 4 research laboratories, where studies on highly infectious materials can be carried out safely. It has schools of medicine, nursing, allied health professions, and a graduate school of biomedical science, as well as an institute for medical humanities. UTMB also has a major contract with the Texas Department of Corrections to provide medical care to inmates at all TDC sites in the eastern portion of Texas. UTMB also has similar contracts with local governments needing inmate medical care. Wikipedia.
Ikegami T.,University of Texas Medical Branch
Antiviral Research | Year: 2012
Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, genus Phlebovirus, is the causative agent of Rift Valley fever (RVF), a mosquito-borne disease of ruminant animals and humans. The generation of a large sequence database has facilitated studies of the evolution and spread of the virus. Bayesian analyses indicate that currently circulating strains of RVFV are descended from an ancestral species that emerged from a natural reservoir in Africa when large-scale cattle and sheep farming were introduced during the 19th century. Viruses descended from multiple lineages persist in that region, through infection of reservoir animals and vertical transmission in mosquitoes, emerging in years of heavy rainfall to cause epizootics and epidemics. On a number of occasions, viruses from these lineages have been transported outside the enzootic region through the movement of infected animals or mosquitoes, triggering outbreaks in countries such as Egypt, Saudi Arabia, Mauritania and Madagascar, where RVF had not previously been seen. Such viruses could potentially become established in their new environments through infection of wild and domestic ruminants and other animals and vertical transmission in local mosquito species. Despite their extensive geographic dispersion, all strains of RVFV remain closely related at the nucleotide and amino acid level. The high degree of conservation of genes encoding the virion surface glycoproteins suggests that a single vaccine should protect against all currently circulating RVFV strains. Similarly, preservation of the sequence of the RNA-dependent RNA polymerase across viral lineages implies that antiviral drugs targeting the enzyme should be effective against all strains. Researchers should be encouraged to collect additional RVFV isolates and perform whole-genome sequencing and phylogenetic analysis, so as to enhance our understanding of the continuing evolution of this important virus. This review forms part of a series of invited papers in Antiviral Research on the genetic diversity of emerging viruses. © 2012 Elsevier B.V.
Shan C.,University of Texas Medical Branch
Nature Medicine | Year: 2017
Zika virus (ZIKV) infection of pregnant women can cause a wide range of congenital abnormalities, including microcephaly, in the infant, a condition now collectively known as congenital ZIKV syndrome. A vaccine to prevent or significantly attenuate viremia in pregnant women who are residents of or travelers to epidemic or endemic regions is needed to avert congenital ZIKV syndrome, and might also help to suppress epidemic transmission. Here we report on a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3′ untranslated region of the ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in type 1 interferon receptor–deficient A129 mice. Crucially, a single dose of 10-del ZIKV induced sterilizing immunity with a saturated neutralizing antibody titer, which no longer increased after challenge with an epidemic ZIKV, and completely prevented viremia. The immunized mice also developed a robust T cell response. Intracranial inoculation of 1-d-old immunocompetent CD-1 mice with 1 × 104 infectious focus units (IFU) of 10-del ZIKV caused no mortality, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the attenuated virulence of 10-del ZIKV may be due to decreased viral RNA synthesis and increased sensitivity to type-1-interferon inhibition. The attenuated 10-del ZIKV was incapable of infecting mosquitoes after oral feeding of spiked-blood meals, representing an additional safety feature. Collectively, the safety and efficacy results suggest that further development of this promising, live-attenuated ZIKV vaccine candidate is warranted. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
Crown E.D.,University of Texas Medical Branch
Experimental Neurology | Year: 2012
Effective treatments for patients suffering from chronic pain remain an area of intense focus within the pharmaceutical industry, as the development of novel therapies would help to treat an area of significant unmet medical need. The successful development of pharmacological agents to treat inflammatory and neuropathic pain conditions relies on a thorough understanding of the mechanisms that underlie the development and maintenance of chronic pain states. The goal of this review is to highlight recent discoveries regarding the intracellular signaling mechanisms that appear to play a critical role in persistent inflammatory and neuropathic pain. The review will focus on the mitogen activated protein kinase family of enzymes and the data suggesting that treatments designed to inhibit the activation of these enzymes may lead to significant advancements in the treatment of chronic pain. The review will also highlight the important interplay between neurons and non-neuronal cells (i.e., microglia and astrocytes) within the dorsal horn of the spinal cord in the generation and maintenance of chronic inflammatory and neuropathic pain. © 2011 Elsevier Inc.
Paessler S.,University of Texas Medical Branch |
Walker D.H.,University of Texas Medical Branch
Annual Review of Pathology: Mechanisms of Disease | Year: 2013
Four families of enveloped RNA viruses, filoviruses, flaviviruses, arenaviruses, and bunyaviruses, cause hemorrhagic fevers. These viruses are maintained in specific natural cycles involving nonhuman primates, bats, rodents, domestic ruminants, humans, mosquitoes, and ticks. Vascular instability varies from mild to fatal shock, and hemorrhage ranges from none to life threatening. The pathogenic mechanisms are extremely diverse and include deficiency of hepatic synthesis of coagulation factors owing to hepatocellular necrosis, cytokine storm, increased permeability by vascular endothelial growth factor, complement activation, and disseminated intravascular coagulation in one or more hemorrhagic fevers. The severity of disease caused by these agents varies tremendously; there are extremely high fatality rates in Ebola and Marburg hemorrhagic fevers, and asymptomatic infection predominates in yellow fever and dengue viral infections. Although ineffective immunity and high viral loads are characteristic of several viral hemorrhagic fevers, severe plasma leakage occurs at the time of viral clearance and defervescence in dengue hemorrhagic fever. © Copyright © 2013 by Annual Reviews. All rights reserved.
White M.C.,University of Texas Medical Branch
PLoS genetics | Year: 2010
We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, using SCA10 cells, and transfected cells and transgenic mouse brain expressing expanded intronic AUUCU repeats as disease models, we show evidence for a key pathogenic molecular mechanism of SCA10. First, we studied the fate of the mutant repeat RNA by in situ hybridization. A Cy3-(AGAAU)(10) riboprobe detected expanded AUUCU repeats aggregated in foci in SCA10 cells. Pull-down and co-immunoprecipitation data suggested that expanded AUUCU repeats within the spliced intronic sequence strongly bind to hnRNP K. Co-localization of hnRNP K and the AUUCU repeat aggregates in the transgenic mouse brain and transfected cells confirmed this interaction. To examine the impact of this interaction on hnRNP K function, we performed RT-PCR analysis of a splicing-regulatory target of hnRNP K, and found diminished hnRNP K activity in SCA10 cells. Cells expressing expanded AUUCU repeats underwent apoptosis, which accompanied massive translocation of PKCdelta to mitochondria and activation of caspase 3. Importantly, siRNA-mediated hnRNP K deficiency also caused the same apoptotic event in otherwise normal cells, and over-expression of hnRNP K rescued cells expressing expanded AUUCU repeats from apoptosis, suggesting that the loss of function of hnRNP K plays a key role in cell death of SCA10. These results suggest that the expanded AUUCU-repeat in the intronic RNA undergoes normal transcription and splicing, but causes apoptosis via an activation cascade involving a loss of hnRNP K activities, massive translocation of PKCdelta to mitochondria, and caspase 3 activation.
Szabo C.,University of Texas Medical Branch
Antioxidants and Redox Signaling | Year: 2012
Significance: Diabetes and its complications represent a major socioeconomic problem. Recent Advances: Changes in the balance of hydrogen sulfide (H2S) play an important role in the pathogenesis of β-cell dysfunction that occurs in response to type 1 and type 2 diabetes. In addition, changes in H2S homeostasis also play a role in the pathogenesis of endothelial injury, which develop on the basis of chronically or intermittently elevated circulating glucose levels in diabetes. Critical Issues: In the first part of this review, experimental evidence is summarized implicating H2S overproduction as a causative factor in the pathogenesis of β-cell death in diabetes. In the second part of our review, experimental evidence is presented supporting the role of H2S deficiency (as a result of increased H2S consumption by hyperglycemic cells) in the pathogenesis of diabetic endothelial dysfunction, diabetic nephropathy, and cardiomyopathy. Future Directions: In the final section of the review, future research directions and potential experimental therapeutic approaches around the pharmacological modulation of H2S homeostasis in diabetes are discussed. © 2012 Mary Ann Liebert, Inc.
Kayed R.,University of Texas Medical Branch
Acta neuropathologica communications | Year: 2014
Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.
Jacobs D.,University of Texas Medical Branch
New England Journal of Medicine | Year: 2014
An otherwise healthy 50-year-old woman presents with painless rectal bleeding; she occasionally sees small amounts of red blood on the toilet paper immediately after defecation and in the toilet water. She also has constipation and intermittent perianal itching with a sense of swelling and aching discomfort around the anal orifice. How should her case be evaluated and managed? Copyright © 2014 Massachusetts Medical Society.
Gelman B.B.,University of Texas Medical Branch
Current HIV/AIDS Reports | Year: 2015
HIV-1 infiltrates the central nervous system (CNS) during the initial infection and thereafter plays a persistent role in producing CNS dysfunction as the disease progresses. HIV-associated neurocognitive disorders (HAND) are highly prevalent in HIV-infected patient populations, including currently infected patients with good access to suppressive antiretroviral therapy (cART). cART decreased the severity of CNS dysfunction dramatically and, in doing so, upended the neuropathological foundation of HAND pathophysiology. It is clear that the working concept of pathophysiology prior to cART, which was driven by inflammation, encephalitis, and neurodegeneration, needs to be replaced. The NeuroAIDS field is reluctant to take that important step. This review explores the fact that the neuropathological concept that drove the field before the era of cART no longer seems to fit with what is commonly observed in patients treated successfully with cART. The field clings to the pre-cART idea that HAND is sequentially driven by virus replication in CNS, brain inflammation (encephalitis), and neurodegeneration. Neurovirological, clinicopathological, and gene expression correlations in cART-treated patients, however, provide little strong support for it. Introducing cART into clinical practice decreased HIVE, inflammation, and degeneration but did not cure HAND. Brain gene array data suggest that the neurovascular unit is a critical target in virally suppressed patients with HAND. The NeuroAIDS field needs an infusion of new ideas to steer research toward issues of the highest relevance to virally suppressed patients. With no suitable replacement immediately within reach, devaluating formative ideas is understandably difficult to accept. The cliniconeuropathological correlation in virally suppressed patients needs to be better defined. © 2015, The Author(s).
Kayed R.,University of Texas Medical Branch
Acta neuropathologica communications | Year: 2014
BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy which is primarily defined by the deposition of tau into globose-type neurofibrillary tangles (NFT). Tau in its native form has important functions for microtubule dynamics. Tau undergoes alternative splicing in exons 2, 3, and 10 which results in six different isoforms. Products of splicing on exon 10 are the most prone to mutations. Three repeat (3R) and four repeat (4R) tau, like other disease-associated amyloids, can form oligomers which may then go on to further aggregate and form fibrils. Recent studies from our laboratory and others have provided evidence that tau oligomers, not NFTs, are the most toxic species in neurodegenerative tauopathies and seed the pathological spread of tau.RESULTS: Analysis of PSP brain sections revealed globose-type NFTs, as well as both phosphorylated and unphosphorylated tau oligomers. Analysis of PSP brains via Western blot and ELISA revealed the presence of increased levels of tau oligomers compared to age-matched control brains. Oligomers were immunoprecipitated from PSP brain and were capable of seeding the oligomerization of both 3R and 4R tau isoforms.CONCLUSIONS: This is the first time tau oligomers have been characterized in PSP. These results indicate that tau oligomers are an important component of PSP pathology, along with NFTs. The ability of PSP brain-derived tau oligomers to seed 3R and 4R tau suggests that these oligomers represent the pathological species responsible for disease propagation and the presence of oligomers in a pure neurodegenerative tauopathy implies a common neuropathological process for tau seen in diseases with other amyloid proteins.