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Showing papers by "University of Texas Medical Branch published in 2007"


Journal ArticleDOI
TL;DR: The observation that a single amino acid substitution can influence vector specificity provides a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical vector, and has important implications with respect to how viruses may establish a transmission cycle when introduced into a new area.
Abstract: Chikungunya virus (CHIKV) is an emerging arbovirus associated with several recent large-scale epidemics. The 2005–2006 epidemic on Reunion island that resulted in approximately 266,000 human cases was associated with a strain of CHIKV with a mutation in the envelope protein gene (E1-A226V). To test the hypothesis that this mutation in the epidemic CHIKV (strain LR2006 OPY1) might influence fitness for different vector species, viral infectivity, dissemination, and transmission of CHIKV were compared in Aedes albopictus, the species implicated in the epidemic, and the recognized vector Ae. aegypti. Using viral infectious clones of the Reunion strain and a West African strain of CHIKV, into which either the E1–226 A or V mutation was engineered, we demonstrated that the E1-A226V mutation was directly responsible for a significant increase in CHIKV infectivity for Ae. albopictus, and led to more efficient viral dissemination into mosquito secondary organs and transmission to suckling mice. This mutation caused a marginal decrease in CHIKV Ae. aegypti midgut infectivity, had no effect on viral dissemination, and was associated with a slight increase in transmission by Ae. aegypti to suckling mice in competition experiments. The effect of the E1-A226V mutation on cholesterol dependence of CHIKV was also analyzed, revealing an association between cholesterol dependence and increased fitness of CHIKV in Ae. albopictus. Our observation that a single amino acid substitution can influence vector specificity provides a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical vector. This has important implications with respect to how viruses may establish a transmission cycle when introduced into a new area. Due to the widespread distribution of Ae. albopictus, this mutation increases the potential for CHIKV to permanently extend its range into Europe and the Americas.

1,303 citations


Journal ArticleDOI
TL;DR: The wave of increased HCV-related morbidity and mortality that the authors are now facing is the result of an unprecedented increase in the spread of HCV during the 20th century, and two 20th Century events appear to be responsible; the widespread availability of injectable therapies and the illicit use of injectables.
Abstract: Globally, hepatitis C virus (HCV) has infected an estimated 130 million people, most of whom are chronically infected. HCV-infected people serve as a reservoir for transmission to others and are at risk for developing chronic liver disease, cirrhosis, and primary hepatocellular carcinoma (HCC). It has been estimated that HCV accounts for 27% of cirrhosis and 25% of HCC worldwide. HCV infection has likely been endemic in many populations for centuries. However, the wave of increased HCV-related morbidity and mortality that we are now facing is the result of an unprecedented increase in the spread of HCV during the 20th century. Two 20th century events appear to be responsible for this increase; the widespread availability of injectable therapies and the illicit use of injectable drugs.

1,153 citations


Journal ArticleDOI
TL;DR: This review is a detailed review of published studies that have focused on the mechanistic basis of BPA action in diverse experimental models and an assessment of the strength of the evidence regarding the published BPA research.

850 citations


Journal ArticleDOI
TL;DR: This document is a summary statement of the outcome from he meeting: “Bisphenol A: An Examination of the Relevance of cological, In vitro and Laboratory Animal Studies for Assessng Risks to Human Health” sponsored by both the NIEHS and IDCR at NIH/DHHS.

681 citations


Journal ArticleDOI
25 Oct 2007-Cancer
TL;DR: Using 6 diagnostic categories for the classification of thyroid fine‐needle aspiration (FNA) cytology, the experience with FNA from 2 institutions was studied with emphasis on cytologic‐histologic correlation, source of errors, and clinical management.
Abstract: BACKGROUND. The Papanicolaou Society of Cytopathology recently proposed 6 diagnostic categories for the classification of thyroid fine-needle aspiration (FNA) cytology. Using these categories, the experience with FNA from 2 institutions was studied with emphasis on cytologic-histologic correlation, source of errors, and clinical management. METHODS. Patient cytology data were retrieved by a retrospective search of thyroid FNA in the institutional databases. Cytologic diagnoses were classified as unsatisfactory, benign, atypical cellular lesion (ACL), follicular neoplasm (FN), suspicious for malignancy, and positive for malignancy. Samples with a histologic discrepancy were re-evaluated, and clinical follow-up information was recorded. RESULTS. Of of 4703 FNA samples, 10.4% were classified as unsatisfactory, 64.6% were classified as benign, 3.2% were classified as ACL, 11.6% were classified as FN, 2.6% were classified as suspicious, and 7.6% were classified as malignant. Five hundred twelve patients had at least 1 repeat FNA, mainly for results in the unsatisfactory and ACL categories. One thousand fifty-two patients had surgical follow-up, including 14.9% of patients with unsatisfactory FNA results, 9.8% of patients with benign results, 40.6% of patients with ACL results, 63.1% of patients with FN results, 86.1% of patients with suspicious results, and 79.3% of patients with malignant results. The rates for histologically confirmed malignancy in these categories were 10.9%, 7.3%, 13.5%, 32.2%, 64.7%, and 98.6%, respectively. The cytologic-histologic diagnostic discrepancy rate was 15.3%. Sources of errors included diagnoses on inadequate specimens, sample errors, and overlapping cytologic features between hyperplastic nodules and follicular adenoma. The sensitivity and specificity of thyroid FNA for the diagnosis of malignancy were 94% and 98.5%, respectively. CONCLUSIONS. The current results indicated that FNA provides an accurate diagnosis of thyroid malignancy. The 6 diagnostic categories were beneficial for triaging patients for either clinical follow-up or surgical management. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.

633 citations


Journal ArticleDOI
TL;DR: In this article, the authors analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates.
Abstract: Background: Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates. Results: DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and antiinflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/ EBP, Oct, and GATA pathways. Conclusion: These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.

619 citations


Journal ArticleDOI
TL;DR: Even in a system with few financial barriers to care, a substantial portion of HIV-infected patients have poor retention in care, which predicts poorer survival with HIV infection.
Abstract: Background. Patients with human immunodeficiency virus (HIV) infection need lifelong medical care, but many do not remain in care. The effect of poor retention in care on survival is not known, and we sought to quantify that relationship.Methods. We conducted a retrospective cohort study involving persons newly identified as having HIV infection during 1997–1998 at any United States Department of Veterans Affairs hospital or clinic who started antiretroviral therapy after 1 January 1997. To be included in the study, patients had to have seen a clinician at least once after receiving their first antiretroviral prescription and to have survived for at least 1 year. Patients were divided into 4 groups on the basis of the number of quarters in that year during which they had at least 1 HIV primary care visit. Survival was measured through 2002. Because data were available for only a small number of women, female patients were excluded from the study.Results. A total of 2619 men were followed up for a mean of >4 years each. The median baseline CD4 + cell count and median log 10 plasma HIV concentration were 228 × 10 6 cells/L and 4.58 copies/mL, respectively. Thirty-six percent of the patients had visits in <4 quarters, and 16% died during follow-up. In Cox multivariate regression analysis, compared with persons with visits in all 4 quarters during the first year, the adjusted hazard ratio of death was 1.42 (95% confidence interval, 1.11–1.83; P < .01), 1.67 (95% confidence interval, 1.24–2.25; P < .001), and 1.95 (95% confidence interval, 1.37–2.78; P < .001) for persons with visits in 3 quarters, 2 quarters, and 1 quarter, respectively.Conclusions. Even in a system with few financial barriers to care, a substantial portion of HIV-infected patients have poor retention in care. Poor retention in care predicts poorer survival with HIV infection. Retaining persons in care may improve survival, and optimal methods to retain patients need to be defined.

551 citations


Journal ArticleDOI
TL;DR: This study suggests that BMP antagonists are candidate signaling components that make up the intestinal epithelial stem cell niche, and applies gene expression analysis of normal human colon tops and basal crypts to provide a comprehensive picture of human colonic epithelial cell differentiation.
Abstract: Human colonic epithelial cell renewal, proliferation, and differentiation are stringently controlled by numerous regulatory pathways. To identify genetic programs of human colonic epithelial cell differentiation in vivo as well as candidate marker genes that define colonic epithelial stem/progenitor cells and the stem cell niche, we applied gene expression analysis of normal human colon tops and basal crypts by using expression microarrays with 30,000 genes. Nine hundred and sixty-nine cDNA clones were found to be differentially expressed between human colon crypts and tops. Pathway analysis revealed the differential expression of genes involved in cell cycle maintenance and apoptosis, as well as genes in bone morphogenetic protein (BMP), Notch, Wnt, EPH, and MYC signaling pathways. BMP antagonists gremlin 1, gremlin 2, and chordin-like 1 were found to be expressed by colon crypts. In situ hybridization and RT-PCR confirmed that these BMP antagonists are expressed by intestinal cryptal myofibroblasts and smooth muscle cells at the colon crypt. In vitro analysis demonstrated that gremlin 1 partially inhibits Caco-2 cell differentiation upon confluence and activates Wnt signaling in normal rat intestinal epithelial cells. Collectively, the expression data set provides a comprehensive picture of human colonic epithelial cell differentiation. Our study also suggests that BMP antagonists are candidate signaling components that make up the intestinal epithelial stem cell niche.

538 citations


Journal ArticleDOI
TL;DR: The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population, which will improve the capability of performing more meaningful multicenter trials among burn centers.
Abstract: Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.

524 citations


Journal ArticleDOI
TL;DR: This literature review and the recommendations therein were prepared for the AGA Institute Clinical Practice and Economics Committee and were approved by the Committee on March 12, 2007 and by the AGA institute Governing Board on May 19, 2007.

479 citations


Journal ArticleDOI
TL;DR: Endoscopic submucosal esophageal myotomy is feasible, safe, and effective in the short term, and has the potential for being useful in patients with achalasia.
Abstract: BACKGROUND AND STUDY AIMS: The most permanent method of treating achalasia is a surgical myotomy. Because of the requirement for a mucosal incision and the risk of perforation, this procedure has not generally been approached endoscopically. We hypothesized that we could perform a safe and robust myotomy by working in the submucosal space, accessed from the esophageal lumen. MATERIALS AND METHODS: Four pigs were used for this experiment. Baseline lower esophageal sphincter (LES) pressures were recorded and the pigs underwent upper endoscopy using a standard endoscope. A submucosal saline lift was created approximately 5 cm above the LES and a small nick was made in the mucosa in order to facilitate the introduction of a dilating balloon. After dilation, the scope was introduced over the balloon into the submucosal space and advanced toward the now visible fibers of the LES. The circular layer of muscle was then cleanly incised using an electrocautery knife in a distal-to-proximal fashion, without complications. The scope was then withdrawn back into the lumen and the mucosal defect was closed with endoscopically applied clips. The entire procedure took less than 15 minutes. Manometry was repeated on day 5 after the procedure and the animals were euthanized on day 7. RESULTS: LES pressures fell significantly from an average of 16.4 mm Hg to an average of 6.7 mm Hg after the myotomy. The necropsy examinations revealed no evidence of mediastinitis or peritonitis. CONCLUSIONS: Endoscopic submucosal esophageal myotomy is feasible, safe, and effective in the short term. It has the potential for being useful in patients with achalasia. The submucosal space is a novel and potentially important field of operation for endoscopic procedures.

Journal ArticleDOI
TL;DR: The research overwhelmingly suggests evidence for concordant mental and physical health, as well as health behaviors among couples, and each area of health concordance research offers room for greater research and deeper understanding for the causes of health Concordance.

Journal ArticleDOI
TL;DR: Findings indicate that the opa1 GTPase contains crucial information required for the survival of RGCs and that Opa1 is essential for early embryonic survival.
Abstract: OPA1 is a ubiquitously expressed, nuclear dynamin-related GTPase, targeted to the inner mitochondrial membrane, which plays a role in mitochondrial fusion. Mutations in the OPA1 gene on chromosome 3q28-qter are associated with autosomal dominant optic atrophy (ADOA), the most common inherited optic neuropathy, in which retinal ganglion cells (RGCs) are lost and visual acuity is impaired from an early age. We have generated a novel ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in opa1 in order to explore the pathophysiology of ADOA. The heterozygous mutation, B6; C3-Opa1(Q285STOP), located in exon 8 immediately before the central dynamin-GTPase, leads to approximately 50% reduction in opa1 protein in retina and all tissues on western analysis. The homozygous mutation is embryonic lethal by 13.5 days post coitum, demonstrating the importance of Opa1 during early development. Fibroblasts taken from adult heterozygous mutant mice show an apparent alteration in morphology, with an increase in mitochondrial fission and fragmentation. Heterozygous mutants show a slow onset of degeneration in the optic nerve electron microscopy. Furthermore, they demonstrate a functional reduction in visual function on testing with the optokinetic drum and the circadian running wheel. These findings indicate that the opa1 GTPase contains crucial information required for the survival of RGCs and that Opa1 is essential for early embryonic survival. The Opa1 +/- mice described here provide a means to directly investigate the cellular pathophysiology of OPA1 ADOA.

Journal ArticleDOI
TL;DR: Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.
Abstract: Background Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. Methods We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3. Results Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. Conclusions Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

Journal ArticleDOI
TL;DR: Low-intensity resistance exercise training combined with blood flow restriction (REFR) increases muscle size and strength as much as conventional resistance exercise with high loads but without increasing the intensity of the exercise.
Abstract: Low-intensity resistance exercise training combined with blood flow restriction (REFR) increases muscle size and strength as much as conventional resistance exercise with high loads. However, the cellular mechanism(s) underlying the hypertrophy and strength gains induced by REFR are unknown. We have recently shown that both the mammalian target of rapamycin (mTOR) signaling pathway and muscle protein synthesis (MPS) were stimulated after an acute bout of high-intensity resistance exercise in humans. Therefore, we hypothesized that an acute bout of REFR would enhance mTOR signaling and stimulate MPS. We measured MPS and phosphorylation status of mTOR-associated signaling proteins in six young male subjects. Subjects were studied once during blood flow restriction (REFR, bilateral leg extension exercise at 20% of 1 repetition maximum while a pressure cuff was placed on the proximal end of both thighs and inflated at 200 mmHg) and a second time using the same exercise protocol but without the pressure cuff [control (Ctrl)]. MPS in the vastus lateralis muscle was measured by using stable isotope techniques, and the phosphorylation status of signaling proteins was determined by immunoblotting. Blood lactate, cortisol, and growth hormone were higher following REFR compared with Ctrl (P < 0.05). Ribosomal S6 kinase 1 (S6K1) phosphorylation, a downstream target of mTOR, increased concurrently with a decreased eukaryotic translation elongation factor 2 (eEF2) phosphorylation and a 46% increase in MPS following REFR (P < 0.05). MPS and S6K1 phosphorylation were unchanged in the Ctrl group postexercise. We conclude that the activation of the mTOR signaling pathway appears to be an important cellular mechanism that may help explain the enhanced muscle protein synthesis during REFR.

Journal ArticleDOI
TL;DR: This work shows that site-to-site allosteric coupling is maximized when intrinsic disorder is present in the domains or segments containing one or both of the coupled binding sites, and calls into question the classical mechanical view of energy propagation in proteins.
Abstract: Transcription factors and other allosteric cell signaling proteins contain a disproportionate number of domains or segments that are intrinsically disordered (ID) under native conditions. In many cases folding of these segments is coupled to binding with one or more of their interaction partners, suggesting that intrinsic disorder plays an important functional role. Despite numerous hypotheses for the role of ID domains in regulation, a mechanistic model has yet to be established that can quantitatively assess the importance of intrinsic disorder for intramolecular site-to-site communication, the hallmark property of allosteric proteins. Here, we present such a model and show that site-to-site allosteric coupling is maximized when intrinsic disorder is present in the domains or segments containing one or both of the coupled binding sites. This result not only explains the prevalence of ID domains in regulatory proteins, it also calls into question the classical mechanical view of energy propagation in proteins, which predicts that site-to-site coupling would be maximized when a well defined pathway of folded structure connects the two sites. Furthermore, in showing that the coupling mechanism conferred by intrinsic disorder is robust and independent of the network of interactions that physically link the coupled sites, unique insights are gained into the energetic ground rules that govern site-to-site communication in all proteins.

01 Jan 2007
TL;DR: The data suggest that enhanced activation of the mTOR signaling pathway is playing a role in the greater synthesis of muscle proteins when resistance exercise is followed by EAA+CHO ingestion.
Abstract: 1 Following Resistance Exercise Enhances mTOR Signaling and Protein 2 Synthesis in Human Muscle 3 4 Hans C. Dreyer, Micah J. Drummond, Bart Pennings, Satoshi Fujita, Erin L. Glynn, 5 David L. Chinkes, Shaheen Dhanani, Elena Volpi, and Blake B. Rasmussen 6 7 Departments of Physical Therapy, Internal Medicine, and Surgery 8 Division of Rehabilitation Sciences 9 University of Texas Medical Branch 10 11

Book ChapterDOI
14 Feb 2007
TL;DR: Support vector machines represent an extension to nonlinear models of the generalized portrait algorithm developed by Vapnik and Lerner, and are a group of supervised learning methods that can be applied to classification or regression.
Abstract: Kernel-based techniques (such as support vector machines, Bayes point machines, kernel principal component analysis, and Gaussian processes) represent a major development in machine learning algorithms. Support vector machines (SVM) are a group of supervised learning methods that can be applied to classification or regression. In a short period of time, SVM found numerous applications in chemistry, such as in drug design (discriminating between ligands and nonligands, inhibitors and noninhibitors, etc.), quantitative structure-activity relationships (QSAR, where SVM regression is used to predict various physical, chemical, or biological properties), chemometrics (optimization of chromatographic separation or compound concentration prediction from spectral data as examples), sensors (for qualitative and quantitative prediction from sensor data), chemical engineering (fault detection and modeling of industrial processes), and text mining (automatic recognition of scientific information). Support vector machines represent an extension to nonlinear models of the generalized portrait algorithm developed by Vapnik and Lerner. The SVM algorithm is based on the statistical learning theory and the Vapnik–Chervonenkis

Journal ArticleDOI
TL;DR: The results suggest that LOIS can be used for in vivo detection of gold nanorods at low concentrations and the nanoparticles can be engineered to enhance the diagnostic power of optoacoustic imaging.
Abstract: The development of a contrast agent for a laser optoacoustic imaging system (LOIS) can significantly widen preclinical and clinical applications of this imaging modality for early detection of cancerous tumors Gold nanorods were engineered to enhance the contrast for optoacoustic imaging Under in vivo conditions, 25 μL of gold nanorods solution at a concentration of 125 pM were injected into nude mice and detected using a single-channel acoustic transducer LOIS was used to visualize the distribution of gold nanoparticles at a concentration of 125 pM in vivo when 100 μL of solution of gold nanoparticles was delivered subcutaneously Our results suggest that LOIS can be used for in vivo detection of gold nanorods at low concentrations and the nanoparticles can be engineered to enhance the diagnostic power of optoacoustic imaging

Journal ArticleDOI
TL;DR: Enteric glia share the ability of astrocytes to regulate tight-junction integrity, and cellular interactions comparable with those maintaining blood-brain barrier function also regulate epithelial permeability at mucosal surfaces.

Journal ArticleDOI
TL;DR: It is shown here that infection of SARS-CoV triggers a weak IFN response in cultured human lung/bronchial epithelial cells without inducing the phosphorylation of IFN-regulatory factor 3 (IRF-3), a latent cellular transcription factor that is pivotal for type I IFN synthesis.

Journal ArticleDOI
TL;DR: Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with twin gestations.
Abstract: Background In singleton gestations, 17 alpha-hydroxyprogesterone caproate (17P) has been shown to reduce the rate of recurrent preterm birth. This study was undertaken to evaluate whether 17P would reduce the rate of preterm birth in twin gestations. Methods We performed a randomized, double-blind, placebo-controlled trial in 14 centers. Healthy women with twin gestations were assigned to weekly intramuscular injections of 250 mg of 17P or matching placebo, starting at 16 to 20 weeks of gestation and ending at 35 weeks. The primary study outcome was delivery or fetal death before 35 weeks of gestation. Results Six hundred sixty-one women were randomly assigned to treatment. Baseline demographic data were similar in the two study groups. Six women were lost to follow-up; data from 655 were analyzed (325 in the 17P group and 330 in the placebo group). Delivery or fetal death before 35 weeks occurred in 41.5% of pregnancies in the 17P group and 37.3% of those in the placebo group (relative risk, 1.1; 95% con...

Journal ArticleDOI
TL;DR: The status of 3D echocardiography is reviewed, the evidence for its use in various clinical situations is examined, and guidelines for appropriate application of this technique are proposed based on available evidence.
Abstract: Ultrasound technology has improved markedly in the past 10 to 15 years, prompting echocardiographers to extend its use in studying cardiac structure and function. New ultrasound equipment and techniques offer superior image quality, greater accuracy, and expanding capabilities. As a result, more and improved imaging modalities are available for evaluating cardiac anatomy, ventricular function, blood flow velocity, and valvular diseases. Threedimensional (3D) echocardiography offers the ability to improve and expand the diagnostic capabilities of cardiac ultrasound. However, as with any emerging technology, the enthusiasm to embrace a new technique must be tempered by a critical appraisal of the evidence supporting its use. It is essential to assess the limitations as well as the unique capabilities it provides. Cardiac imaging should be safe, accurate, versatile, comprehensive, and cost-effective, while providing important clinical information. Criteria for appropriate utilization should be based on current evidence and updated as new information becomes available. To justify the use of a new 3D modality, its unique contribution to clinical practice must be critically analyzed. In this article we review the status of 3D echocardiography, examine the evidence for its use in various clinical situations, and propose guidelines for appropriate application of this technique based on available evidence.

Journal ArticleDOI
TL;DR: It is hypothesized that anabolic nutrients would be sensed by both AMPK and mTOR, resulting in an acute and potent stimulation of human skeletal muscle protein synthesis via enhanced translation initiation and elongation.
Abstract: The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are important nutrient- and energy-sensing and signalling proteins in skeletal muscle. AMPK activation decreases muscle protein synthesis by inhibiting mTOR signalling to regulatory proteins associated with translation initiation and elongation. On the other hand, essential amino acids (leucine in particular) and insulin stimulate mTOR signalling and protein synthesis. We hypothesized that anabolic nutrients would be sensed by both AMPK and mTOR, resulting in an acute and potent stimulation of human skeletal muscle protein synthesis via enhanced translation initiation and elongation. We measured muscle protein synthesis and mTOR-associated upstream and downstream signalling proteins in young male subjects (n= 14) using stable isotopic and immunoblotting techniques. Following a first muscle biopsy, subjects in the ‘Nutrition’ group ingested a leucine-enriched essential amino acid–carbohydrate mixture (EAC). Subjects in the Control group did not consume nutrients. A second biopsy was obtained 1 h later. Ingestion of EAC significantly increased muscle protein synthesis, modestly reduced AMPK phosphorylation, and increased Akt/PKB (protein kinase B) and mTOR phosphorylation (P 0.05). We conclude that anabolic nutrients alter the phosphorylation status of both AMPK- and mTOR-associated signalling proteins in human muscle, in association with an increase in protein synthesis not only via enhanced translation initiation but also through signalling promoting translation elongation.

Journal ArticleDOI
TL;DR: Molecular epidemiologic data suggest there are seven genotypes of YFV that are geographically separated, and outbreaks of disease are more associated with particular genotypes, which present serious potential public health problems to large population centers.
Abstract: Yellow fever virus (YFV) is the prototype member of the genus Flavivirus, a group of viruses that are transmitted between vertebrates by arthropod vectors. The virus is found in tropical regions of Africa and South America and is transmitted to primates by mosquitoes: Aedes spp. in Africa and Haemagogus and Sabethes spp. in South America. Despite the availability of an effective vaccine, yellow fever (YF) is considered a reemerging disease owing to its increased incidence in the past 25 years. Molecular epidemiologic data suggest there are seven genotypes of YFV that are geographically separated, and outbreaks of disease are more associated with particular genotypes. In addition, the risk of urban YF, owing to transmission of the virus by Aedes aegypti, is increasing in Africa, as is the potential of urban YF returning to South America. Both present serious potential public health problems to large population centers.

Journal ArticleDOI
TL;DR: Findings indicate distinct temporal roles of RIG-I and TLR3 in mediating RSV-induced innate immune responses, which are coupled to distinct pathways controlling NF-κB activation.
Abstract: Respiratory syncytial virus (RSV) is one of the most common viral pathogens causing severe lower respiratory tract infections in infants and young children. Infected host cells detect and respond to RNA viruses using different mechanisms in a cell-type-specific manner, including retinoic acid-inducible gene I (RIG-I)-dependent and Toll-like receptor (TLR)-dependent pathways. Because the relative contributions of these two pathways in the recognition of RSV infection are unknown, we examined their roles in this study. We found that RIG-I helicase binds RSV transcripts within 12 h of infection. Short interfering RNA (siRNA)-mediated RIG-I "knockdown" significantly inhibited early nuclear factor-kappaB (NF-kappaB) and interferon response factor 3 (IRF3) activation 9 h postinfection (p.i.). Consistent with this finding, RSV-induced beta interferon (IFN-beta), interferon-inducible protein 10 (IP-10), chemokine ligand 5 (CCL-5), and IFN-stimulated gene 15 (ISG15) expression levels were decreased in RIG-I-silenced cells during the early phase of infection but not at later times (18 h p.i.). In contrast, siRNA-mediated TLR3 knockdown did not affect RSV-induced NF-kappaB binding but did inhibit IFN-beta, IP-10, CCL-5, and ISG15 expression at late times of infection. Further studies revealed that TLR3 knockdown significantly reduced NF-kappaB/RelA transcription by its ability to block the activating phosphorylation of NF-kappaB/RelA at serine residue 276. We further found that TLR3 induction following RSV infection was regulated by RIG-I-dependent IFN-beta secreted from infected airway epithelial cells and was mediated by both IFN response-stimulated element (ISRE) and signal transducer and activator of transcription (STAT) sites in its proximal promoter. Together these findings indicate distinct temporal roles of RIG-I and TLR3 in mediating RSV-induced innate immune responses, which are coupled to distinct pathways controlling NF-kappaB activation.

Journal ArticleDOI
TL;DR: Strong evidence is provided that somata of DRG neurons actively release transmitters and play a crucial role in bidirectional communication between neurons and surrounding satellite glial cells, and this results suggest that, contrary to the conventional view, neuronal somata have a significant role in cell–cell signaling.
Abstract: It has been generally assumed that the cell body (soma) of a neuron, which contains the nucleus, is mainly responsible for synthesis of macromolecules and has a limited role in cell-to-cell communication. Using sniffer patch recordings, we show here that electrical stimulation of dorsal root ganglion (DRG) neurons elicits robust vesicular ATP release from their somata. The rate of release events increases with the frequency of nerve stimulation; external Ca2+ entry is required for the release. FM1–43 photoconversion analysis further reveals that small clear vesicles participate in exocytosis. In addition, the released ATP activates P2X7 receptors in satellite cells that enwrap each DRG neuron and triggers the communication between neuronal somata and glial cells. Blocking L-type Ca2+ channels completely eliminates the neuron–glia communication. We further show that activation of P2X7 receptors can lead to the release of tumor necrosis factor-α (TNFα) from satellite cells. TNFα in turn potentiates the P2X3 receptor-mediated responses and increases the excitability of DRG neurons. This study provides strong evidence that somata of DRG neurons actively release transmitters and play a crucial role in bidirectional communication between neurons and surrounding satellite glial cells. These results also suggest that, contrary to the conventional view, neuronal somata have a significant role in cell–cell signaling.

Journal ArticleDOI
TL;DR: The generation and characterization of PrPC-deficient cattle produced by a sequential gene-targeting system are reported and at over 20 months of age the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal.
Abstract: Prion diseases are caused by propagation of misfolded forms of the normal cellular prion protein PrP(C), such as PrP(BSE) in bovine spongiform encephalopathy (BSE) in cattle and PrP(CJD) in Creutzfeldt-Jakob disease (CJD) in humans. Disruption of PrP(C) expression in mice, a species that does not naturally contract prion diseases, results in no apparent developmental abnormalities. However, the impact of ablating PrP(C) function in natural host species of prion diseases is unknown. Here we report the generation and characterization of PrP(C)-deficient cattle produced by a sequential gene-targeting system. At over 20 months of age, the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal. Brain tissue homogenates are resistant to prion propagation in vitro as assessed by protein misfolding cyclic amplification. PrP(C)-deficient cattle may be a useful model for prion research and could provide industrial bovine products free of prion proteins.

Journal ArticleDOI
TL;DR: It is shown that hepatitis A virus ablates type 1 IFN responses by targeting the 3ABC precursor of its 3Cpro cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway.
Abstract: Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its 3C(pro) cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of 3C(pro) and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3C(pro) protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver.

Journal ArticleDOI
TL;DR: It is concluded that interactions between NS 2 and E1 and p7 as well as between NS2 and NS3 are essential for virus assembly and/or release and that each of these viral proteins plays an important role in this process.
Abstract: There is little understanding of mechanisms underlying the assembly and release of infectious hepatitis C virus (HCV) from cultured cells. Cells transfected with synthetic genomic RNA from a unique genotype 2a virus (JFH1) produce high titers of virus, while virus yields are much lower with a prototype genotype 1a RNA containing multiple cell culture-adaptive mutations (H77S). To characterize the basis for this difference in infectious particle production, we constructed chimeric genomes encoding the structural proteins of H77S within the background of JFH1. RNAs encoding polyproteins fused at the NS2/NS3 junction ("H-NS2/NS3-J") and at a site of natural, intergenotypic recombination within NS2 ["H-(NS2)-J"] produced infectious virus. In contrast, no virus was produced by a chimera fused at the p7-NS2 junction. Chimera H-NS2/NS3-J virus (vH-NS2/NS3-J) recovered from transfected cultures contained compensatory mutations in E1 and NS3 that were essential for the production of infectious virus, while yields of infectious vH-(NS2)-J were enhanced by mutations within p7 and NS2. These compensatory mutations were chimera specific and did not enhance viral RNA replication or polyprotein processing; thus, they likely compensate for incompatibilities between proteins of different genotypes at sites of interactions essential for virus assembly and/or release. Mutations in p7 and NS2 acted additively and increased the specific infectivity of vH-(NS2)-J particles, while having less impact on the numbers of particles released. We conclude that interactions between NS2 and E1 and p7 as well as between NS2 and NS3 are essential for virus assembly and/or release and that each of these viral proteins plays an important role in this process.