Showing papers by "University of Alabama at Birmingham published in 2004"
TL;DR: The higher-order PV taxonomy is described following the general criteria established by the International Committee on the Taxonomy of Viruses (ICTV), reviews the literature of the lower order taxa, lists all known "PV types", and interprets their phylogenetic relationship.
2,970 citations
TL;DR: Data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States.
Abstract: Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estimates regarding its prevalence are limited and unclear. Between July 1998 and October 1999, 400 unselected consecutive premenopausal women (18-45 yr of age) seeking a preemployment physical at the University of Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races). Evaluation included a history and physical examination, a modified Ferriman-Gallwey hirsutism score, and serum screening for hyperandrogenemia, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia. PCOS was diagnosed by the presence of the following: 1) oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey score > or = 6), and 3) the exclusion of related disorders. Confirmed PCOS was established in those individuals whose evaluation was complete and indicative of PCOS, and possible PCOS was established when the hormonal evaluation was not complete or was unavailable, but the clinical phenotype was otherwise suggestive of the disorder. The individual probability of PCOS in women with possible PCOS was assigned a weight based on the findings in similar subjects whose evaluation was complete, and the total number of PCOS cases arising from these individuals was calculated (i.e. individual probability of PCOS x total number of subjects in the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for Black and White women were 8.0 and 4.8%, respectively, not significantly different. These data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States.
2,391 citations
TL;DR: Allan R. Tunkel, Barry J. Hartman, Sheldon L. Kaplan, Bruce A. Kaufman, Karen L. Roos, W. Michael Scheld, and Richard J. Scheld are the authors of this study, which aims to contribute to the understanding of central nervous system disorders and its role in disease.
Abstract: Allan R. Tunkel, Barry J. Hartman, Sheldon L. Kaplan, Bruce A. Kaufman, Karen L. Roos, W. Michael Scheld, and Richard J. Whitley Drexel University College of Medicine, Philadelphia, Pennsylvania; Weill Cornell Medical Center, New York, New York; Baylor College of Medicine, Houston, Texas; Medical College of Wisconsin, Milwaukee; Indiana University School of Medicine, Indianapolis; University of Virginia School of Medicine, Charlottesville; and University of Alabama at Birmingham
1,835 citations
TL;DR: Much effort is currently directed towards understanding the functions and control of GSK3, and identifying methods capable of diminishing the deleterious impact of G SK3 in pathological conditions.
1,486 citations
TL;DR: This work presents a novel and scalable approach that allows for real-time decision-making about whether or not to vaccinate children against infection by a single infectious agent.
Abstract: Peter G. Pappas, John H. Rex, Jack D. Sobel, Scott G. Filler, William E. Dismukes, Thomas J. Walsh, and John E. Edwards Division of Infectious Diseases, University of Alabama at Birmingham, Alabama; AstraZeneca Pharmaceuticals, Manchester, Great Britain; Wayne State University School of Medicine, Detroit, Michigan; Harbor–University of California-Los Angeles Medical Center, Torrance, California; and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
1,378 citations
TL;DR: Age-, sex-, and ethnicity-specific WC percentiles are available for US children and adolescents and can be used as an assessment tool that could impact public health recommendations and suggest concern with respect to high WC values among certain ethnic groups.
1,350 citations
TL;DR: In this paper, HDL has been shown to have anti-atherogenic properties, which may explain the ability of HDL to promote the efflux of cholesterol from cells in the artery wall.
Abstract: There are several well-documented functions of high-density lipoprotein (HDL) that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDL to promote the efflux of cholesterol from cells. This process may minimize the accumulation of foam cells in the artery wall. However, HDL has additional properties that may also be antiatherogenic. For example, HDL is an effective antioxidants. The major proteins of HDL, apoA-I and apoA-II, as well as other proteins such as paraoxonase that cotransport with HDL in plasma, are well-known to have antioxidant properties. As a consequence, HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis.
1,241 citations
TL;DR: Mycoplasma pneumoniae is a unique bacterium that does not always receive the attention it merits considering the number of illnesses it causes and the degree of morbidity associated with it in both children and adults.
Abstract: Mycoplasma pneumoniae is a unique bacterium that does not always receive the attention it merits considering the number of illnesses it causes and the degree of morbidity associated with it in both children and adults. Serious infections requiring hospitalization, while rare, occur in both adults and children and may involve multiple organ systems. The severity of disease appears to be related to the degree to which the host immune response reacts to the infection. Extrapulmonary complications involving all of the major organ systems can occur in association with M. pneumoniae infection as a result of direct invasion and/or autoimmune response. The extrapulmonary manifestations are sometimes of greater severity and clinical importance than the primary respiratory infection. Evidence for this organism's contributory role in chronic lung conditions such as asthma is accumulating. Effective management of M. pneumoniae infections can usually be achieved with macrolides, tetracyclines, or fluoroquinolones. As more is learned about the pathogenesis and immune response elicited by M. pneumoniae, improvement in methods for diagnosis and prevention of disease due to this organism may occur.
1,120 citations
TL;DR: These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system and further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a range of diseases.
Abstract: ▪ Abstract The Class 2 α-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-α, -β, -ɛ, -κ, -ω, -δ, -τ, and -γ) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for ...
1,106 citations
Vanderbilt University1, University of Southern California2, University of Texas MD Anderson Cancer Center3, University of Wisconsin-Madison4, University of California, Los Angeles5, National Center for Genome Resources6, Portland VA Medical Center7, University of Colorado Boulder8, University of Pennsylvania9, Hannover Medical School10, Johns Hopkins University11, Oregon Health & Science University12, Cornell University13, University of Michigan14, University of Tennessee Health Science Center15, Washington University in St. Louis16, University of Toronto17, University of Memphis18, Medical Research Council19, University of Massachusetts Medical School20, Hebrew University of Jerusalem21, Université de Montréal22, Purdue University23, University of California, Davis24, Academy of Sciences of the Czech Republic25, University at Buffalo26, Emory University27, University of Cincinnati28, University of Texas Southwestern Medical Center29, New York University30, University of Groningen31, Rutgers University32, Stanford University33, Max Planck Society34, National Institutes of Health35, University of Alabama at Birmingham36, International Livestock Research Institute37, Heidelberg University38, Medical College of Wisconsin39, Icahn School of Medicine at Mount Sinai40, Oak Ridge National Laboratory41, Charité42, University of Antwerp43, RWTH Aachen University44, Paul Sabatier University45, University of California, San Francisco46, McGill University47, Pasteur Institute48, University of Western Australia49, Yale University50, University of Oxford51, Case Western Reserve University52, Roswell Park Cancer Institute53, University of Kentucky54, University of Helsinki55, University of Nebraska–Lincoln56, Harvard University57, Merck & Co.58, King's College London59, Northwestern University60, Shriners Hospitals for Children61, Thomas Jefferson University62, Novartis63, University of North Carolina at Chapel Hill64, Southern Illinois University Carbondale65, University of Rochester66
TL;DR: The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way the authors approach human health and disease.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
1,040 citations
TL;DR: Specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder.
Abstract: The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinically evident androgen excess and to document the degree of long-term success of suppressive and/or antiandrogen hormonal therapy in a large consecutive population of patients. All patients presenting for evaluation of symptoms potentially related to androgen excess between October 1987 and June 2002 were evaluated, and the data were maintained prospectively in a computerized database. For the assessment of therapeutic response, a retrospective review of the medical chart was performed, after the exclusion of those patients seeking fertility therapy only, or with inadequate follow-up or poor compliance. A total of 1281 consecutive patients were seen during the study period. Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status, determine ovulatory status, or find any evidence of androgen excess. In the remaining population of 873 patients, the unbiased prevalence of androgen-secreting neoplasms was 0.2%, 21-hydroxylase-deficient classic adrenal hyperplasia (CAH) was 0.6%, 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) was 1.6%, hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome was 3.1%, idiopathic hirsutism was 4.7%, and polycystic ovary syndrome (PCOS) was 82.0%. Fifty-nine (6.75%) patients had elevated androgen levels and hirsutism but normal ovulation. A total of 257 patients were included in the assessment of the response to hormonal therapy. The mean duration of follow-up was 33.5 months (range, 6-155). Hirsutism improved in 86%, menstrual dysfunction in 80%, acne in 81%, and hair loss in 33% of patients. The major side effects noted were irregular vaginal bleeding (16.1%), nausea (13.0%), and headaches (12.6%); only 36.6% of patients never complained of side effects. In this large study of consecutive patients presenting with clinically evident androgen excess, specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder. Hirsutism, menstrual dysfunction, or acne, but not alopecia, improved in the majority of patients treated with a combination suppressive therapy; although more than 60% experienced side effects.
Ohio State University1, University of Alabama at Birmingham2, University of Texas Southwestern Medical Center3, National Institutes of Health4, George Washington University5, University of Utah6, University of Chicago7, University of Pittsburgh8, Wake Forest University9, Thomas Jefferson University10, Wayne State University11, Columbia University12, University of Cincinnati13, Brown University14, Northwestern University15, University of Miami16, University of Tennessee Health Science Center17, University of Texas at San Antonio18, University of North Carolina at Chapel Hill19, University of Texas at Austin20, Case Western Reserve University21, Vanderbilt University22
TL;DR: The proportion of women who attempt vaginal delivery after prior cesarean delivery has decreased largely because of concern about safety, and the absolute and relative risks associated with a trial of labor in women with a history of cesAREan delivery are uncertain.
Abstract: background The proportion of women who attempt vaginal delivery after prior cesarean delivery has decreased largely because of concern about safety The absolute and relative risks associated with a trial of labor in women with a history of cesarean delivery, as compared with elective repeated cesarean delivery without labor, are uncertain
TL;DR: The Human Genome Organisation (HUGO) Nomenclature Committee Database provides a list of transporter families of the solute carrier (SLC) gene series, which includes 43 families and 298 transporter genes.
Abstract: The Human Genome Organisation (HUGO) Nomenclature Committee Database provides a list of transporter families of the solute carrier (SLC) gene series (see http://www.gene.ucl.ac.uk/nomenclature/). Currently, it includes 43 families and 298 transporter genes. This special issue features mini-reviews on each of these SLC families written by the experts in each field. A WEB site has been established (http://www.pharmaconference.org/slctable.asp) that gives the latest updates for the SLC families and their members as well as relevant links to gene databases and reviews in the literature. A list of all currently known SLC families, a discussion of additional SLC families and family members as well as a brief summary of non-SLC transporter genes is included in this introduction.
University of California, San Diego1, Mayo Clinic2, New York University3, Georgetown University4, Rush University Medical Center5, University of Michigan6, Baylor College of Medicine7, Oregon Health & Science University8, Columbia University9, Eli Lilly and Company10, McGill University11, University of California, Irvine12, Yale University13, Medical University of South Carolina14, University of Alabama at Birmingham15, Brown University16
TL;DR: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings.
Abstract: Background Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. Objective To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. Design Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. Setting Memory disorder centers in the United States and Canada. Patients A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. Main Outcome Measures Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. Results Mean ± SD Alzheimer's Disease Assessment Scale–Cognitive Subscale scores were 5.6 ± 3.3 for controls, 11.3 ± 4.4 for patients with MCI, 18.0 ± 6.2 for the AD CDR 0.5 group, and 25.2 ± 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E ϵ4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. Conclusions Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.
TL;DR: Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease and is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.
Abstract: background Crohn’s disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. methods This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti–interleukin-12) in 79 patients with active Crohn’s disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti–interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn’s Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points. results
TL;DR: This work identifies the transcription factor ATF4 as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoplast-specific gene expression and indicates that lack of ATF4 phosphorylation by R SK2 may contribute to the skeletal phenotype of CLS.
TL;DR: BBS5, a novel gene for Bardet-Biedl syndrome is identified and it is shown that this novel protein localizes to basal bodies in mouse and C. elegans, is under the regulatory control of daf-19, and is necessary for the generation of both cilia and flagella.
TL;DR: Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.
Abstract: Objective Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease has not been well defined. The purpose of this study was to evaluate the association of dietary and supplemental vitamin D intake with rheumatoid arthritis (RA) incidence. Methods We analyzed data from a prospective cohort study of 29,368 women of ages 55-69 years without a history of RA at study baseline in 1986. Diet was ascertained using a self-administered, 127-item validated food frequency questionnaire that included supplemental vitamin D use. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression, adjusting for potential confounders. Results Through 11 years of followup, 152 cases of RA were validated against medical records. Greater intake (highest versus lowest tertile) of vitamin D was inversely associated with risk of RA (RR 0.67, 95% CI 0.44-1.00, P for trend = 0.05). Inverse associations were apparent for both dietary (RR 0.72, 95% CI 0.46-1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43-1.00, P for trend = 0.03) vitamin D. No individual food item high in vitamin D content and/or calcium was strongly associated with RA risk, but a composite measure of milk products was suggestive of an inverse association with risk of RA (RR 0.66, 95% CI 0.42-1.01, P for trend = 0.06). Conclusion Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.
TL;DR: Mössbauer spectra measured by the Opportunity rover revealed four mineralogical components in Meridiani Planum at Eagle crater: jarosite- and hematite-rich outcrop, hematITE-rich soil, olivine-bearing basaltic soil, and a pyroxene-bearing Basaltic rock (Bounce rock).
Abstract: Mossbauer spectra measured by the Opportunity rover revealed four mineralogical components in Meridiani Planum at Eagle crater: jarosite- and hematite-rich outcrop, hematite-rich soil, olivine-bearing basaltic soil, and a pyroxene-bearing basaltic rock (Bounce rock). Spherules, interpreted to be concretions, are hematite-rich and dispersed throughout the outcrop. Hematitic soils both within and outside Eagle crater are dominated by spherules and their fragments. Olivine-bearing basaltic soil is present throughout the region. Bounce rock is probably an impact erratic. Because jarosite is a hydroxide sulfate mineral, its presence at Meridiani Planum is mineralogical evidence for aqueous processes on Mars, probably under acid-sulfate conditions.
TL;DR: A number of alterations, both directly and indirectly related to hepatic injury and portal hypertension, result in the production or release of mediators into the venous circulation, where they influence the pulmonary microcirculation in experimental hepatopulmonary syndrome.
Abstract: ⇓“The tantalizing problem of the connective link in cirrhotic patients between oxygen unsaturation and possible arteriovenous shunting in the lungs remains unsolved, and any relation between arterial unsaturation and pulmonary vasodilation remains obscure.”
Fig. 1.—
Working model of molecular alterations in the pulmonary microcirculation in experimental hepatopulmonary syndrome (HPS). a) In the normal microvasculature, a balance of vasoconstrictive and vasodilatory factors, including paracrine endothelin (ET)-1-mediated vasoconstriction through the ETA receptor (▪) on smooth muscle cells (SMCs) and ET-1-mediated vasodilatation mediated through the ETB receptor (□) linked to endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs), maintain tone. b) During the development of HPS, a number of alterations, both directly and indirectly related to hepatic injury and portal hypertension, result in the production or release of mediators into the venous circulation, where they influence the pulmonary microcirculation. Increased expression of pulmonary endothelial ETB receptors and increased hepatic production and release of ET-1 contribute to an increase in eNOS expression and enhanced nitric oxide (NO) production in the microvascular endothelium during the initiation of HPS. Tumour necrosis factor (TNF)-α-mediated accumulation of intravascular macrophage-like cells also occurs after chronic common bile duct ligation. Haem oxygenase (HO)-1 and inducible nitric oxide synthase (iNOS) expression increase in these cells and contribute to the progression of HPS. CO: carbon monoxide.
Fig. 2.—
Algorithm for screening and therapeutic decisions in hepatopulmonary syndrome (HPS). OLT: orthotopic liver transplantation; P a,O2: arterial oxygen tension; P A–a,O2: alveolar–arterial oxygen tension difference; CEE: contrast-enhanced echocardiography; PFT: pulmonary function test; MAA: macroaggregated albumin. #: high-resolution thoracic computed tomographic scanning is highly recommended in order to exclude chronic respiratory comorbid conditions; ¶: high risk for post-operative OLT mortality. 1 mmHg=0.133 kPa.
Fig. 3.—
Plot demonstrating the relationship between cardiac output ( Q ') and transpulmonary pressure gradient (TPG; mean pulmonary arterial …
Columbia University1, University of Oxford2, Indiana University – Purdue University Indianapolis3, Harvard University4, Massachusetts Institute of Technology5, University of Zulia6, University of California, Los Angeles7, University of Texas Health Science Center at Houston8, University of South Florida9, University of Rochester10, Boston Children's Hospital11, North Shore-LIJ Health System12, University of Southern California13, Mount Sinai Hospital14, University of California, Berkeley15, New York University16, National Institutes of Health17, University of California, Irvine18, University of Alabama at Birmingham19, Thomas Jefferson University20, University of Iowa21, City University of New York22, Oregon Health & Science University23, Albany Medical College24, University of Ulm25
TL;DR: A model estimated the components of additive genetic, shared environment, and nonshared environment variances confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
TL;DR: Serological expression cloning was used to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD and identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts.
Abstract: Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.
TL;DR: The results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation.
Abstract: Herein, we demonstrate that the ubiquitin-associated (UBA) domain of sequestosome 1/p62 displays a preference for binding K63-polyubiquitinated substrates. Furthermore, the UBA domain of p62 was necessary for aggregate sequestration and cell survival. However, the inhibition of proteasome function compromised survival in cells with aggregates. Mutational analysis of the UBA domain reveals that the conserved hydrophobic patch MGF as well as the conserved leucine in helix 2 are necessary for binding polyubiquitinated proteins and for sequestration-aggregate formation. We report that p62 interacts with the proteasome by pull-down assay, coimmunoprecipitation, and colocalization. Depletion of p62 levels results in an inhibition of ubiquitin proteasome-mediated degradation and an accumulation of ubiquitinated proteins. Altogether, our results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation.
TL;DR: The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia and will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.
Abstract: Objectives. The precise epidemiology of childhood pneumonia remains poorly defined. Accurate and prompt etiologic diagnosis is limited by inadequate clinical, radiologic, and laboratory diagnostic methods. The objective of this study was to determine as precisely as possible the epidemiology and morbidity of community-acquired pneumonia in hospitalized children. Methods. Consecutive immunocompetent children hospitalized with radiographically confirmed lower respiratory infections (LRIs) were evaluated prospectively from January 1999 through March 2000. Positive blood or pleural fluid cultures or pneumolysin-based polymerase chain reaction assays, viral direct fluorescent antibody tests, or viral, mycoplasmal, or chlamydial serologic tests were considered indicative of infection by those organisms. Methods for diagnosis of pneumococcal pneumonia among study subjects were published by us previously. Selected clinical characteristics, indices of inflammation (white blood cell and differential counts and procalcitonin values), and clinical outcome measures (time to defervescence and duration of oxygen supplementation and hospitalization) were compared among groups of children. Results. One hundred fifty-four hospitalized children with LRIs were enrolled. Median age was 33 months (range: 2 months to 17 years). A pathogen was identified in 79% of children. Typical respiratory bacteria were identified in 60% (of which 73% were Streptococcus pneumoniae), viruses in 45%, Mycoplasma pneumoniae in 14%, Chlamydia pneumoniae in 9%, and mixed bacterial/viral infections in 23%. Preschool-aged children had as many episodes of atypical bacterial LRIs as older children. Children with typical bacterial or mixed bacterial/viral infections had the greatest inflammation and disease severity. Multivariate logistic-regression analyses revealed that high temperature (≥38.4°C) within 72 hours after admission (odds ratio: 2.2; 95% confidence interval: 1.4–3.5) and the presence of pleural effusion (odds ratio: 6.6; 95% confidence interval: 2.1–21.2) were significantly associated with bacterial pneumonia. Conclusions. This study used an expanded diagnostic armamentarium to define the broad spectrum of pathogens that cause pneumonia in hospitalized children. The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia. These findings will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.
University of Minnesota1, University of Michigan2, Oregon Health & Science University3, Johns Hopkins University4, Medical College of Wisconsin5, University of Pennsylvania6, Washington University in St. Louis7, Georgia Regents University8, Astellas Pharma9, University of Alabama at Birmingham10, National Institutes of Health11
TL;DR: The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT and this randomized trial demonstrates the efficacy of an echinocandin for antifundal proplylaxis in neutropenia patients.
Abstract: 5 for the National Institute of Allergy and Infectious Diseases Mycoses Study Group a We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing !50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing !50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm (difference, 6.5%); 95% confidence interval, 0.9%-12%; ). This randomized trial demonstrates the efficacy of an P p .03
TL;DR: Preliminary data suggest that the oxidation hypothesis of atherogenesis and the reverse cholesterol transport hypothesis of Atherogenesis may have a common biological basis and Apolipoprotein A-I and apoA-I mimetic peptides may both promote a reduction in oxidized lipids and enhancereverse cholesterol transport and therefore may have therapeutic potential.
TL;DR: For eight heterosexual transmission pairs, it is shown that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins, and that these viruses were uniquely sensitive to neutralization by antibody from the transmitting partner.
Abstract: Heterosexual transmission accounts for the majority of human immunodeficiency virus–1 (HIV-1) infections worldwide, yet the viral properties that determine transmission fitness or outgrowth have not been elucidated Here we show, for eight heterosexual transmission pairs, that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins These viruses were also uniquely sensitive to neutralization by antibody from the transmitting partner Thus, the exposure of neutralizing epitopes, which are lost in chronic infection because of immune escape, appears to be favored in the newly infected host This reveals characteristics of the envelope glycoprotein that influence HIV-1 transmission and may have implications for vaccine design
TL;DR: The search for the phylogenetic roots of adaptive immunity in the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs.
Abstract: Although jawless vertebrates are apparently capable of adaptive immune responses, they have not been found to possess the recombinatorial antigen receptors shared by all jawed vertebrates. Our search for the phylogenetic roots of adaptive immunity in the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs. An invariant stalk region tethers the VLRs to the cell surface by means of a glycosyl-phosphatidyl-inositol anchor. To generate rearranged VLR genes of the diversity necessary for an anticipatory immune system, the single lamprey VLR locus contains a large bank of diverse LRR cassettes, available for insertion into an incomplete germline VLR gene. Individual lymphocytes express a uniquely rearranged VLR gene in monoallelic fashion. Different evolutionary strategies were thus used to generate highly diverse lymphocyte receptors through rearrangement of LRR modules in agnathans (jawless fish) and of immunoglobulin gene segments in gnathostomes (jawed vertebrates).
TL;DR: CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested, and PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties, it may better test the therapeutic potential of MEK inhibition in cancer.
Abstract: Purpose This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. Patients and Methods Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. Results Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18...
University of Pennsylvania1, Rush University Medical Center2, Cleveland Clinic3, Vanderbilt University4, Boston University5, Cornell University6, National Institutes of Health7, Columbia University8, Harvard University9, Boston Children's Hospital10, University of Wisconsin-Madison11, University of California, San Francisco12, Nemours Foundation13, University of Illinois at Chicago14, University of Alabama at Birmingham15, Rutgers University16, University of Michigan17, Cincinnati Children's Hospital Medical Center18
TL;DR: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.
Abstract: Objective: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide—reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. Methods: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. Results: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. Conclusions: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.