scispace - formally typeset
Search or ask a question

Showing papers by "University of Texas Medical Branch published in 2002"


Journal ArticleDOI
TL;DR: Oxidative injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria.

911 citations


Journal ArticleDOI
TL;DR: Two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes suggest that the glycop Protein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV -2 at base line but not in those
Abstract: Background An effective prophylactic vaccine would help control the spread of genital herpes. Methods We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D–subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2–seronegative female subjects in Study 2. Results A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well t...

762 citations


Journal ArticleDOI
TL;DR: Overall effectiveness, the proportionate reduction in HIV seroconversion with condom use, is approximately 80%, similar to, although lower than, that for contraception.
Abstract: Background: The amount of protection that condoms provide for HIV and other sexually transmitted infections is unknown. Cohort studies of sexually active HIV serodiscordant couples with follow-up of the seronegative partner provide a situation in which a seronegative partner has known exposure to the disease and disease incidence can be estimated When some individuals use condoms and some do not namely some individuals use condoms 100% of the time and some never use (0%) condoms condom effectiveness can be estimated by comparing the two incidence rates. Condom effectiveness is the proportionate reduction in disease due to the use of condoms. Objectives: The objective of this review is to estimate condom effectiveness in reducing heterosexual transmission of HIV. Search strategy: Studies were located using electronic databases (AIDSLINE CINAHL Embase and MEDLINE) and handsearched reference lists. Selection criteria: For inclusion studies had to have: (1) data concerning sexually active HIV serodiscordant heterosexual couples (2) a longitudinal study design (3) HIV status determined by serology and (4) contain condom usage information on a cohort of always (100%) or never (0%) condom users. Data collection and analysis: Studies identified through the above search strategy that met the inclusion criteria were reviewed for inclusion in the analysis. Sample sizes number of seroconversions and the person-years of disease-free exposure time were recorded for each cohort. If available the direction of transmission in the cohort (male-to-female female-to-male) date of study enrollment source of infection in the index case and the presence of other STDs was recorded. Duplicate reports on the same cohort and studies with incomplete or nonspecific information were excluded. HIV incidence was estimated from the cohorts of "always" users and for the cohorts of "never" users. Effectiveness was estimated from these two incidence estimates. Main results: Of the 4709 references that were initially identified 14 were included in the final analysis. There were 13 cohorts of "always" users that yielded an homogeneous HIV incidence estimate of 1.14 [95% C.I.: .56 2.04] per 100 person-years. There were 10 cohorts of "never" users that appeared to be heterogeneous. The studies with the longest follow-up time consisting mainly of studies of partners of hemophiliac and transfusion patients yielded an HIV incidence estimate of 5.75 [95% C.I.: 3.16 9.66] per 100 person-years. Overall effectiveness the proportionate reduction in HIV seroconversion with condom use is approximately 80%. Reviewers conclusions: This review indicates that consistent use of condoms results in 80% reduction in HIV incidence. Consistent use is defined as using a condom for all acts of penetrative vaginal intercourse. Because the studies used in this review did not report on the "correctness" of use namely whether condoms were used correctly and perfectly for each and every act of intercourse effectiveness and not efficacy is estimated. Also this estimate refers in general to the male condom and not specifically to the latex condom since studies also tended not to specify the type of condom that was used. Thus condom effectiveness is similar to although lower than that for contraception. (authors)

685 citations


Journal ArticleDOI
TL;DR: The structural model suggests that water molecules, which were observed in the vicinity of highly conserved residues and in the retinal pocket, regulate the activity of rhodopsin-like GPCRs and spectral tuning in visual pigments, respectively.
Abstract: Activation of G protein-coupled receptors (GPCRs) is triggered and regulated by structural rearrangement of the transmembrane heptahelical bundle containing a number of highly conserved residues. In rhodopsin, a prototypical GPCR, the helical bundle accommodates an intrinsic inverse-agonist 11-cis-retinal, which undergoes photo-isomerization to the all-trans form upon light absorption. Such a trigger by the chromophore corresponds to binding of a diffusible ligand to other GPCRs. Here we have explored the functional role of water molecules in the transmembrane region of bovine rhodopsin by using x-ray diffraction to 2.6 A. The structural model suggests that water molecules, which were observed in the vicinity of highly conserved residues and in the retinal pocket, regulate the activity of rhodopsin-like GPCRs and spectral tuning in visual pigments, respectively. To confirm the physiological relevance of the structural findings, we conducted single-crystal microspectrophotometry on rhodopsin packed in our three-dimensional crystals and show that its spectroscopic properties are similar to those previously found by using bovine rhodopsin in suspension or membrane environment.

675 citations


Journal ArticleDOI
TL;DR: A molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone is defined, suggesting that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation.
Abstract: It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-kappaB transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-kappaB and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process.

568 citations


Journal ArticleDOI
TL;DR: This work used reduced-median-network approaches to analyze 560 complete European, Asian, and African mtDNA coding-region sequences from unrelated individuals to develop a more complete understanding of sequence diversity both within and between haplogroups.
Abstract: The evolution of the human mitochondrial genome is characterized by the emergence of ethnically distinct lineages or haplogroups. Nine European, seven Asian (including Native American), and three African mitochondrial DNA (mtDNA) haplogroups have been identified previously on the basis of the presence or absence of a relatively small number of restriction-enzyme recognition sites or on the basis of nucleotide sequences of the D-loop region. We have used reduced-median-network approaches to analyze 560 complete European, Asian, and African mtDNA coding-region sequences from unrelated individuals to develop a more complete understanding of sequence diversity both within and between haplogroups. A total of 497 haplogroup-associated polymorphisms were identified, 323 (65%) of which were associated with one haplogroup and 174 (35%) of which were associated with two or more haplogroups. Approximately one-half of these polymorphisms are reported for the first time here. Our results confirm and substantially extend the phylogenetic relationships among mitochondrial genomes described elsewhere from the major human ethnic groups. Another important result is that there were numerous instances both of parallel mutations at the same site and of reversion (i.e., homoplasy). It is likely that homoplasy in the coding region will confound evolutionary analysis of small sequence sets. By a linkage-disequilibrium approach, additional evidence for the absence of human mtDNA recombination is presented here.

545 citations


Journal ArticleDOI
TL;DR: The findings indicate that ghrelin is an important stomach hormone sensitive to nutritional intake; gh Relin may link enteric nutrition with secretion of GH, insulin, and gastrin.
Abstract: Ghrelin, an endogenous ligand for the GH secretagogue receptor was characterized recently from extracts of rat stomach. We describe the enteric distribution of ghrelin, ontogeny of stomach ghrelin gene expression, effects of dietary and endocrine manipulations, and vagotomy on stomach ghrelin mRNA and peptide levels and secretion in the rat. Ghrelin expression was examined by Northern blotting. Tissue and plasma ghrelin levels were measured by RIA. A gradient of ghrelin production occurs in the rat gastrointestinal tract with the highest ghrelin expression and peptide levels in the mucosal layer of the stomach-fundus and the lowest levels in the colon. Ghrelin was not detectable in the fetal stomach and increased progressively after birth especially during the second and third postnatal weeks. Plasma ghrelin levels also increased in parallel with stomach ghrelin levels postnatally. Exogenous GH treatment decreased stomach ghrelin expression significantly. A high-fat diet decreased plasma ghrelin levels, whereas a low-protein diet increased plasma ghrelin levels significantly. Intravenous administration of ghrelin stimulates gastrin and insulin secretion. Our findings indicate that ghrelin is an important stomach hormone sensitive to nutritional intake; ghrelin may link enteric nutrition with secretion of GH, insulin, and gastrin.

541 citations


Journal ArticleDOI
TL;DR: Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients.
Abstract: Background: This report presents results from the acute treatment phase of a clinical trial designed to confirm efficacy of a fixed dose of 20 mg of fluoxetine in children and adolescents with major depressive disorder (MDD). Method: After a 3-week screening period, 122 children and 97 adolescents with MDD ( DSM-IV ) were randomly assigned to placebo or fluoxetine. After a 1-week placebo lead-in, fluoxetine-treated patients received fluoxetine 10 mg/day for 1 week, then fluoxetine 20 mg/day for 8 weeks. Results: Fluoxetine was associated with greater mean improvement in Children's Depression Rating Scale-Revised (CDRS-R) score than placebo after 1 week ( p p p = .093). Significantly more fluoxetine-than placebo-treated patients completed acute treatment ( p = .001). There were no significant differences between treatment groups in discontinuations due to adverse events ( p = .408). Conclusions: Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients. Fluoxetine is the only antidepressant that has demonstrated efficacy in two placebo-controlled, randomized clinical trials of pediatric depression.

539 citations


Journal ArticleDOI
TL;DR: The pathogenesis of acute septic arthritis is multifactorial and depends on the interaction of the host immune response and the adherence factors, toxins, and immunoavoidance strategies of the invading pathogen.
Abstract: Acute septic arthritis may develop as a result of hematogenous seeding, direct introduction, or extension from a contiguous focus of infection. The pathogenesis of acute septic arthritis is multifactorial and depends on the interaction of the host immune response and the adherence factors, toxins, and immunoavoidance strategies of the invading pathogen. Neisseria gonorrhoeae and Staphylococcus aureus are used in discussing the host-pathogen interaction in the pathogenesis of acute septic arthritis. While diagnosis rests on isolation of the bacterial species from synovial fluid samples, patient history, clinical presentation, laboratory findings, and imaging studies are also important. Acute nongonococcal septic arthritis is a medical emergency that can lead to significant morbidity and mortality. Therefore, prompt recognition, rapid and aggressive antimicrobial therapy, and surgical treatment are critical to ensuring a good prognosis. Even with prompt diagnosis and treatment, high mortality and morbidity rates still occur. In contrast, gonococcal arthritis is often successfully treated with antimicrobial therapy alone and demonstrates a very low rate of complications and an excellent prognosis for full return of normal joint function. In the case of prosthetic joint infections, the hardware must be eventually removed by a two-stage revision in order to cure the infection.

501 citations


Journal ArticleDOI
TL;DR: It is concluded that physiological and near-physiological increases of testosterone in older men will increase muscle protein anabolism and muscle strength.
Abstract: We investigated the effects of 6 mo of near-physiological testosterone administration to older men on skeletal muscle function and muscle protein metabolism. Twelve older men (≥60 yr) with serum to...

500 citations


Journal ArticleDOI
TL;DR: Constitutive expression of viral proteins leads to common pathologic features of hepatitis C in the absence of specific anti-viral immune responses, while additional low level expression of nonstructural proteins increases the risk of cancer.

Journal ArticleDOI
TL;DR: The tissue-specific levels ofNEH1 and OGG1 mRNAs are distinct, and S phase-specific increase in NEH1 at both RNA and protein levels suggests that NEH 1 is involved in replication-associated repair of oxidized bases.
Abstract: 8-oxoguanine (8-oxoG), ring-opened purines (formamidopyrimidines or Fapys), and other oxidized DNA base lesions generated by reactive oxygen species are often mutagenic and toxic, and have been implicated in the etiology of many diseases, including cancer, and in aging. Repair of these lesions in all organisms occurs primarily via the DNA base excision repair pathway, initiated with their excision by DNA glycosylase/AP lyases, which are of two classes. One class utilizes an internal Lys residue as the active site nucleophile, and includes Escherichia coli Nth and both known mammalian DNA glycosylase/AP lyases, namely, OGG1 and NTH1. E. coli MutM and its paralog Nei, which comprise the second class, use N-terminal Pro as the active site. Here, we report the presence of two human orthologs of E. coli mutM nei genes in the human genome database, and characterize one of their products. Based on the substrate preference, we have named it NEH1 (Nei homolog). The 44-kDa, wild-type recombinant NEH1, purified to homogeneity from E. coli, excises Fapys from damaged DNA, and oxidized pyrimidines and 8-oxoG from oligodeoxynucleotides. Inactivation of the enzyme because of either deletion of N-terminal Pro or Histag fusion at the N terminus supports the role of N-terminal Pro as its active site. The tissue-specific levels of NEH1 and OGG1 mRNAs are distinct, and S phase-specific increase in NEH1 at both RNA and protein levels suggests that NEH1 is involved in replication-associated repair of oxidized bases.

Journal ArticleDOI
TL;DR: It is shown that CD81 cross-linking via immobilized E2 or mAbs specific for CD81 inhibits not only non major histocompatibility complex–restricted cytotoxicity mediated byNK cells but also interferon (IFN)-γ production by NK cells after exposure to interleukin (IL)-2, IL-12,IL-15, or CD16 cross- linking.
Abstract: Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide. Little is known about how this virus is able to persist or whether this persistence might be because of its ability to alter the early innate immune response. The major HCV envelope protein E2 has been shown to bind to CD81. Thus, HCV binding to natural killer (NK) cells could result in the cross-linking of CD81. To explore this possibility, we investigated whether cross-linking CD81 on NK cells could alter NK cell function. CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells. In this study, we show that CD81 cross-linking via immobilized E2 or mAbs specific for CD81 inhibits not only non major histocompatibility complex–restricted cytotoxicity mediated by NK cells but also interferon (IFN)-γ production by NK cells after exposure to interleukin (IL)-2, IL-12, IL-15, or CD16 cross-linking. These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells. Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-γ production by NK cells.

Journal ArticleDOI
TL;DR: It is demonstrated that RNA derived from this documented infectious molecular clone has a unique capacity for replication in Huh7 cells in the absence of additional cell culture-adaptive mutations.
Abstract: Dicistronic, selectable subgenomic replicons derived from the Con1 strain of hepatitis C virus (HCV) are capable of autonomous replication in cultured Huh7 cells (Lohmann et al., Science 285:110-113, 1999). However, adaptive mutations in the NS3, NS5A, and/or NS5B proteins are required for efficient replication of these RNAs and increase by orders of magnitude the numbers of G418-resistant colonies selected following transfection of Huh7 cells. Here, we demonstrate that a subgenomic replicon (NNeo/3-5B) derived from an infectious molecular clone of a second genotype 1b virus, HCV-N (Beard et al., Hepatology 30:316-324, 1999) is also capable of efficient replication in Huh7 cells. G418-resistant cells selected following transfection with NNeo/3-5B RNA contained abundant NS5A antigen and HCV RNA detectable by Northern analysis. Replicon RNA in one of three clonally isolated cell lines contained no mutations in the NS3-NS5B polyprotein, confirming that adaptive mutations are not required for efficient replication in these cells. However, the deletion of a unique 4-amino-acid insertion that is present within the interferon sensitivity-determining region (ISDR) of the NS5A protein in wild-type HCV-N drastically decreased the number of G418-resistant colonies obtained following transfection of Huh7 cells. This effect could be reversed by inclusion of a previously described Con1 cell culture-adaptive mutation (S2005→I), confirming that this natural insertion has a controlling role in determining the replication capacity of wild-type HCV-N RNA in Huh7 cells. Additional selectable, dicistronic RNAs encoding NS2-NS5B, E1-NS5B, or the full-length HCV polyprotein were also capable of replication and gave rise to G418-resistant cell clones following transfection of Huh7 cells. We conclude that RNA derived from this documented infectious molecular clone has a unique capacity for replication in Huh7 cells in the absence of additional cell culture-adaptive mutations.

Journal ArticleDOI
TL;DR: Mitochondrial DNA damage may result from RS production in vascular tissues and may in turn be an early event in the initiation of atherosclerotic lesions.
Abstract: Background— Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. Methods and Results— We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E−/− mice but also preceded atherogenesis in young apolipoprotein E−/− mice. Apolipoprotein E−/− mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a p...

Journal ArticleDOI
TL;DR: This study tests the hypothesis that a dose of 6 g of orally administered essential amino acids (EAAs) stimulates net muscle protein balance in healthy volunteers when consumed 1 and 2 h after resi...
Abstract: This study tests the hypothesis that a dose of 6 g of orally administered essential amino acids (EAAs) stimulates net muscle protein balance in healthy volunteers when consumed 1 and 2 h after resi...

Journal ArticleDOI
TL;DR: It is suggested that the decreased activity of FKHRL1 and FKHR in prostate cancers resulting from loss of PTEN leads to a decrease in TRAIL expression that may contribute to increased survival of the tumor cells.

Journal ArticleDOI
TL;DR: This pilot study demonstrated the capability of the OCT technique to monitor blood glucose concentration noninvasively in human subjects and the coherent detection of backscattered photons, which allows measurements of OCT signal from a specific tissue layer without unwanted signal from other tissue layers.
Abstract: OBJECTIVE —To study the feasibility of noninvasive blood glucose monitoring using optical coherence tomography (OCT) technique in healthy volunteers. RESEARCH DESIGN AND METHODS —An OCT system with the wavelength of 1,300 nm was used in 15 healthy subjects in 18 clinical experiments. Standard oral glucose tolerance tests were performed to induce changes in blood glucose concentration. Blood samples were taken from the right arm vein every 5 or 15 min. OCT images were taken every 10–20 s from the left forearm over a total period of 3 h. The slope of the signals was calculated at the depth of 200–600 μm from the skin surface. RESULTS —A total of 426 blood samples and 8,437 OCT images and signals were collected and analyzed in these experiments. There was a good correlation between changes in the slope of noninvasively measured OCT signals and blood glucose concentrations throughout the duration of the experiments. The slope of OCT signals changed significantly (up to 2.8% per 10 mg/dl) with variation of plasma glucose values. The good correlation obtained between the OCT signal slope and blood glucose concentration is due to the coherent detection of backscattered photons, which allows measurements of OCT signal from a specific tissue layer without unwanted signal from other tissue layers. CONCLUSIONS —This pilot study demonstrated the capability of the OCT technique to monitor blood glucose concentration noninvasively in human subjects. Further studies with a larger number of subjects including diabetic subjects are planned to validate these preliminary results.

Journal ArticleDOI
TL;DR: Targets for intervention in SCI toward improved function have been identified using basic research approaches and can be simplified into a list: reduction of edema and free-radical production.
Abstract: Thirty years ago, patients with spinal cord injury (SCI) and their families were told “nothing can be done” to improve function. Since the SCI patient population is reaching normal life expectancy ...

Journal ArticleDOI
TL;DR: Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.
Abstract: Objective . Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. Summary Background Data . Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF- κ B and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF- κ B and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. Conclusion . Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.

Journal ArticleDOI
TL;DR: During the identification period, physicians and medical staff made rapid progress in developing treatment methods to stabilize and sustain patients through the crisis period, thereby substantially improving patient survivorship; nonetheless, the mortality rate fell only to about 40%, where it remains today.
Abstract: I the spring of 1993, a previously undescribed disease emerged in the Southwest, killing 10 people during an 8-week period in May and June. Early during an infection, victims experienced flu-like symptoms for several days, but their condition suddenly and rapidly deteriorated as their lungs filled with fluids; death usually occurred within hours of the onset of this crisis period. There was no cure, no successful medication or treatment, and the disease agent (virus, bacterium, or toxin) was completely unknown. For the first few weeks, the mortality rate was 70%. Researchers from many disciplines immediately focused on the outbreak, attempting to identify the agent and understand the causes and dynamics of the disease. Within weeks, scientists at the Centers for Disease Control and Prevention (CDC) identified the agent as a previously unknown hantavirus (Bunyaviridae), subsequently named Sin Nombre virus, or SNV (Nichol et al. 1993). Because hantaviruses were known to be transmitted by rodents, investigators undertook an intensive small mammal field sampling campaign in the Four Corners region of New Mexico and Arizona. Shortly thereafter, CDC identified the viral reservoir host as a common and widely distributed rodent, the deer mouse, Peromyscus maniculatus (figure 1; Childs et al. 1994). During the identification period, on the medical side, physicians and medical staff made rapid progress in developing treatment methods to stabilize and sustain patients through the crisis period, thereby substantially improving patient survivorship; nonetheless, the mortality rate fell only to about 40%, where it remains today. The emergence of this new disease prompted many questions about its history, causes, and dynamics. Was this a newly Terry L. Yates (e-mail: tyates@unm.edu) is a professor in the Departments of Biology and Pathology at the University of New Mexico, Albuquerque, NM 87131. Cheryl A. Parmenter, Robert R. Parmenter, John R. Vande Castle, Jorge Salazar-Bravo, and Jonathan L. Dunnum are with the Department of Biology and the Museum of Southwestern Biology, University of New Mexico. James N. Mills, Thomas G. Ksiazek, Stuart T. Nichol, and Joni C. Young are with the Centers for Disease Control and Prevention, Atlanta, GA 30333. Charles H. Calisher and Barry J. Beaty are with the Arthropod-borne and Infectious Diseases Laboratory, Foothills Campus, Colorado State University, Fort Collins, CO 80523. Kenneth D. Abbott is with the Department of Biology, Yavapai College, Prescott, AZ 86301. Michael L. Morrison is with the Department of Wildlife and Fisheries Sciences, University of Arizona, Tuscon, AZ 85721. Robert J. Baker is with the Department of Biology and The Museum, Texas Tech University, Lubbock, TX 79409. Clarence J. Peters is with the Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555. © 2002 American Institute of Biological Sciences. The Ecology and Evolutionary History of an Emergent Disease: Hantavirus Pulmonary Syndrome

Journal ArticleDOI
TL;DR: The important findings and major conclusions that have emerged regarding translesion DNA synthesis (TLS) in eukaryotes are highlighted.
Abstract: Cellular DNA is continually damaged by a plethora of extrinsic and intrinsic sources, including UV light from the sun and reactive oxygen species resulting from aerobic respiration. Although cells possess a variety of repair processes to remove DNA lesions, lesions that escape repair can block the replicational machinery, and there has been little understanding of the mechanisms by which eukaryotic cells overcome such blocks and promote the continuity of the newly replicated DNA strand. The past three years, however, have witnessed phenomenal progress in this area of research, and here we highlight the important findings and major conclusions that have emerged regarding translesion DNA synthesis (TLS) in eukaryotes.

Journal ArticleDOI
01 Mar 2002-Lupus
TL;DR: Hispanic and African-American ethnicities and antibodies were shown to be signi” cant predictors of the occurrence of LN, and Sociodemographic,clinical and immunologic/immunogenetic factors seem to be predictive of its occurrence.
Abstract: The purpose of this study was to determine the cumulative incidence of lupus nephritis (LN) and the factors predictive of its occurrence in a multiethnic systemic lupus erythematosus (SLE) cohort. We studied 353 SLE patients as defined by the American College of Rheumatology (ACR) criteria (65 Hispanics, 93 African-Americans and 91 Caucasians). First, we determined the cumulative incidence of LN in all patients. Next, we determined the predictors for LN in those with nephritis occurring after diagnosis. The dependent variable, LN, was defined by: (1) A renal biopsy demonstrating World Health Organization (WHO), class II-V histopathology; and/or (2) proteinuria > or = 0.5 g/24 h or 3+ proteinuria attributable to SLE; and/or (3) one of the following features also attributable to SLE and present on two or more visits, which were performed at least 6 months apart--proteinuria > or = 2+, serum creatinine > or = 1.4 mg/dl, creatinine clearance or = 10 RBCs or WBCs per high power field (hpf), or > or = 3 granular or cellular casts per hpf. Independent variables assessed at diagnosis, and if absent, at baseline, were from four domains: sociodemographic, clinical, immunologic and immunogenetic (including the complete antibody profile and MHC class II alleles), and health habits. Variables with P < 0.05 by chi square analyses were entered into domain-specific stepwise logistic regression analyses controlling for disease duration, with LN as the dependent variable. Significant domain-specific regression variables (P < or = 0.1) were then entered into an overall model. The cumulative incidence of LN was 54.3% in all patients, and 35.3% for those developing LN after diagnosis. LN after diagnosis occurred in 43.1% of 65 Hispanics, 50.5% of 93 African-Americans, and 14.3% of 91 Caucasians, P < 0.0001. The duration of follow-up for those with LN after diagnosis was 5.5+/-2.4 vs 4.0+/-2.9 years for those without LN. Hispanic (odds ratio (OR) = 2.71, 95% confidence limits (CL) = 1.07-6.87, P < 0.04) and African-American ethnicities (OR = 3.13, 95% CL = 1.21-8.09, P < 0.02), not married or living together (OR = 3.45, 95% CL = 1.69-7.69, P < 0.0003), higher SLAM score (OR = 1.11, 95% CL = 1.02-1.19, P < 0.007), anti-dsDNA (OR = 3.14, 95% CL = 1.50-6.57, P < 0.0001) and anti-RNP (OR = 4.24, CL = 1.98-9.07, P < 0.0001) antibodies were shown to be significant predictors of the occurrence of LN. Repeated analyses excluding the patients with missing HLA data showed that absence of HLA-DQB1*0201 was also a significant predictor for the occurrence of LN (OR = 2.34, CL = 1.13-5.26, P < 0.04). In conclusion, LN occurred significantly more often in Hispanics and African-Americans with SLE. Sociodemographic, clinical and immunologic/immunogenetic factors seem to be predictive of LN occurring after the diagnosis of SLE has been made.

Journal ArticleDOI
TL;DR: Results suggest that NEIL2 is involved in global genome repair mainly for removing oxidative products of cytosine, which is similar to NEIL1 in having N-terminal Pro as the active site.

Journal ArticleDOI
TL;DR: If HAART is able to prevent spreading of KS, local therapy of KS may become an essential component of patient management and rationales and graduated treatment algorithms for local and systemic therapy in patients with KS are presented to appropriately meet the challenges of this extraordinary neoplasm.
Abstract: Kaposi's sarcoma (KS) is a mesenchymal tumour involving blood and lymphatic vessels. Only recently has the pathogenesis of this extraordinary neoplasm been elucidated. Viral oncogenesis and cytokine-induced growth together with some state of immunocompromise represent important conditions for this tumour to develop. In 1994, a novel virus was discovered and termed human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpes virus, which can be found in all types of KS, whether related to HIV or not. In the era of highly active antiretroviral therapy (HAART), the incidence of AIDS-KS has considerably declined, probably due to enhanced immune reconstitution and anti-HHV8-specific immune responses. If HAART is able to prevent spreading of KS, local therapy of KS may become an essential component of patient management. Part 1 of the review covers the epidemiology, environmental predispositions, clinical manifestations, and therapy of KS. Newer treatments such as pegylated liposomal anthracyclines and experimental strategies are discussed. We also present rationales and graduated treatment algorithms for local and systemic therapy in patients with KS to appropriately meet the challenges of this extraordinary neoplasm. Part 2, to be published next month, will summarise recent insights in the pathogenesis of KS and will discuss other HHV8-related diseases such as Castleman's disease and primary effusion lymphoma.

Journal ArticleDOI
TL;DR: The results show that the summary performance measure has excellent reliability and is highly sensitive to change.

Journal ArticleDOI
TL;DR: It is explained that septal rupture has become less common with reperfusion therapy but that rapid diagnosis remains crucial and doppler echocardiography is usually diagnostic and used to estimate the size of the left-to-right shunt.
Abstract: When ventricular septal rupture complicates acute myocardial infarction, the mortality rate is high and immediate operative intervention is indicated. This review explains that septal rupture has become less common with reperfusion therapy but that rapid diagnosis remains crucial. Doppler echocardiography is usually diagnostic and can be used to estimate the size of the left-to-right shunt.

Journal ArticleDOI
TL;DR: Using a panel of neutralizing monoclonal antibodies, epitopes in domain III of the envelope protein of the New York strain of West Nile virus are mapped and epitopes located on the upper surface of domain III at residues E307, E330, and E332.
Abstract: Using a panel of neutralizing monoclonal antibodies, we have mapped epitopes in domain III of the envelope protein of the New York strain of West Nile virus. The ability of monoclonal antibodies that recognize these epitopes to neutralize virus appeared to differ between lineage I and II West Nile virus strains, and epitopes were located on the upper surface of domain III at residues E307, E330, and E332.

Journal ArticleDOI
TL;DR: Human metapneumovirus is a clinically important causative agent of acute wheezing in young children and regulated upon activation.

Journal ArticleDOI
TL;DR: This study probed cross-talk between cAMP signaling and the phosphatidylinositol 3-kinase/PKB pathways by monitoring the specific roles that Epac and PKA play individually in regulating PKB activity and suggests a complex regulatory scheme in which Epacand PKA mediate the opposing effects of cAMP on PKB regulation.