Showing papers by "Oregon Health & Science University published in 2004"
Journal Article•
TL;DR: The authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.
1,960 citations
TL;DR: The data suggest that efforts to reduce mortality in this population should be focused on treatment and prevention of coronary artery disease, congestive heart failure, diabetes mellitus, and anemia.
Abstract: Background Chronic kidney disease is the primary cause of end-stage renal disease in the United States. The purpose of this study was to understand the natural history of chronic kidney disease with regard to progression to renal replacement therapy (transplant or dialysis) and death in a representative patient population. Methods In 1996 we identified 27 998 patients in our health plan who had estimated glomerular filtration rates of less than 90 mL/min per 1.73 m 2 on 2 separate measurements at least 90 days apart. We followed up patients from the index date of the first glomerular filtration rates of less than 90 mL/min per 1.73 m 2 until renal replacement therapy, death, disenrollment from the health plan, or June 30, 2001. We extracted from the computerized medical records the prevalence of the following comorbidities at the index date and end point: hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, hyperlipidemia, and renal anemia. Results Our data showed that the rate of renal replacement therapy over the 5-year observation period was 1.1%, 1.3%, and 19.9%, respectively, for the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) stages 2, 3, and 4, but that the mortality rate was 19.5%, 24.3%, and 45.7%. Thus, death was far more common than dialysis at all stages. In addition, congestive heart failure, coronary artery disease, diabetes, and anemia were more prevalent in the patients who died but hypertension prevalence was similar across all stages. Conclusion Our data suggest that efforts to reduce mortality in this population should be focused on treatment and prevention of coronary artery disease, congestive heart failure, diabetes mellitus, and anemia.
1,580 citations
National Institutes of Health1, University of Würzburg2, University of British Columbia3, University of Nebraska Medical Center4, University of Rochester5, Oregon Health & Science University6, University of Arizona7, Fred Hutchinson Cancer Research Center8, University of Oslo9, St Bartholomew's Hospital10, University of Barcelona11
TL;DR: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
Abstract: background Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. methods Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. results Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. conclusions The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
1,336 citations
TL;DR: The purpose of this technical review is to evaluate the evidence relating to the management of hyperglycemia in hospitals, with particular focus on the issue of glycemic control and its possible impact on hospital outcomes.
Abstract: Diabetes increases the risk for disorders that predispose individuals to hospitalization, including coronary artery, cerebrovascular and peripheral vascular disease, nephropathy, infection, and lower-extremity amputations. The management of diabetes in the hospital is generally considered secondary in importance compared with the condition that prompted admission. Recent studies (1,2) have focused attention to the possibility that hyperglycemia in the hospital is not necessarily a benign condition and that aggressive treatment of diabetes and hyperglycemia results in reduced mortality and morbidity. The purpose of this technical review is to evaluate the evidence relating to the management of hyperglycemia in hospitals, with particular focus on the issue of glycemic control and its possible impact on hospital outcomes. The scope of this review encompasses adult nonpregnant patients who do not have diabetic ketoacidosis or hyperglycemic crises.
For the purposes of this review, the following terms are defined (adapted from the American Diabetes Association [ADA] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus) (3):
The prevalence of diabetes in hospitalized adult patients is not known. In the year 2000, 12.4% of hospital discharges in the U.S. listed diabetes as a diagnosis. The average length of stay was 5.4 days (4). Diabetes was the principal diagnosis in only 8% of these hospitalizations. The accuracy of using hospital discharge diagnosis codes for identifying patients with …
1,193 citations
Journal Article•
Tufts University1, Wake Forest University2, Oregon Health & Science University3, Indiana University4, Albany College of Pharmacy and Health Sciences5, Rush University Medical Center6, Vanderbilt University7, East Carolina University8, University of Illinois at Chicago9, Beaumont Hospital10, Johns Hopkins University11, Cleveland Clinic12, University of Wisconsin-Madison13, University of Texas at Austin14, University of Pittsburgh15, Virginia Commonwealth University16, Texas Tech University Health Sciences Center17, National Institutes of Health18, University of Virginia19
TL;DR: The purpose of the Executive Summary is to provide a "stand-alone" summary of the background, scope, methods, and key recommendations, as well as the complete text of the guideline statements.
1,145 citations
TL;DR: The rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis is charted and a molecular-based classification of GIST is proposed.
Abstract: Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.
1,129 citations
01 Jan 2004
TL;DR: This work has consistently shown that there are large performance benefits to be gained by applying Sigma-Point Kalman filters to areas where EKFs have been used as the de facto standard in the past, as well as in new areas where the use of the EKF is impossible.
Abstract: Probabilistic inference is the problem of estimating the hidden variables (states or parameters) of a system in an optimal and consistent fashion as a set of noisy or incomplete observations of the system becomes available online. The optimal solution to this problem is given by the recursive Bayesian estimation algorithm which recursively updates the posterior density of the system state as new observations arrive. This posterior density constitutes the complete solution to the probabilistic inference problem, and allows us to calculate any “optimal” estimate of the state. Unfortunately, for most real-world problems, the optimal Bayesian recursion is intractable and approximate solutions must be used. Within the space of approximate solutions, the extended Kalman filter (EKF) has become one of the most widely used algorithms with applications in state, parameter and dual estimation. Unfortunately, the EKF is based on a sub-optimal implementation of the recursive Bayesian estimation framework applied to Gaussian random variables. This can seriously affect the accuracy or even lead to divergence of any inference system that is based on the EKF or that uses the EKF as a component part. Recently a number of related novel, more accurate and theoretically better motivated algorithmic alternatives to the EKF have surfaced in the literature, with specific application to state estimation for automatic control. We have extended these algorithms, all based on derivativeless deterministic sampling based approximations of the relevant Gaussian statistics, to a family of algorithms called Sigma-Point Kalman Filters (SPKF). Furthermore, we successfully expanded the use of this group of algorithms (SPKFs) within the general field of probabilistic inference and machine learning, both as stand-alone filters and as subcomponents of more powerful sequential Monte Carlo methods (particle filters). We have consistently shown that there are large performance benefits to be gained by applying Sigma-Point Kalman filters to areas where EKFs have been used as the de facto standard in the past, as well as in new areas where the use of the EKF is impossible.
1,116 citations
University of Tennessee Health Science Center1, University of Washington2, Creighton University3, George Mason University4, Semmelweis University5, University of Arkansas System6, University of Murcia7, Neuroscience Research Australia8, University of South Florida9, University of California, Irvine10, University of Auckland11, Johns Hopkins University12, City University of New York13, Ruhr University Bochum14, California State University, Long Beach15, Oregon Health & Science University16, St. John's University17, University of California, Los Angeles18, Bowling Green State University19, Duke University20, Newcastle University21, University of Chicago22
TL;DR: The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is reviewed, with a rationale for each name change and evidence for any homologies implied by the new names.
Abstract: The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is based on flawed assumptions of homology to mammals. In particular, the outdated terminology implies that most of the avian telencephalon is a hypertrophied basal ganglia, when it is now clear that most of the avian telencephalon is neurochemically, hodologically, and functionally comparable to the mammalian neocortex, claustrum, and pallial amygdala (all of which derive from the pallial sector of the developing telencephalon). Recognizing that this promotes misunderstanding of the functional organization of avian brains and their evolutionary relationship to mammalian brains, avian brain specialists began discussions to rectify this problem, culminating in the Avian Brain Nomenclature Forum held at Duke University in July 2002, which approved a new terminology for avian telencephalon and some allied brainstem cell groups. Details of this new terminology are presented here, as is a rationale for each name change and evidence for any homologies implied by the new names. Revisions for the brainstem focused on vocal control, catecholaminergic, cholinergic, and basal ganglia-related nuclei. For example, the Forum recognized that the hypoglossal nucleus had been incorrectly identified as the nucleus intermedius in the Karten and Hodos (1967) pigeon brain atlas, and what was identified as the hypoglossal nucleus in that atlas should instead be called the supraspinal nucleus. The locus ceruleus of this and other avian atlases was noted to consist of a caudal noradrenergic part homologous to the mammalian locus coeruleus and a rostral region corresponding to the mammalian A8 dopaminergic cell group. The midbrain dopaminergic cell group in birds known as the nucleus tegmenti pedunculopontinus pars compacta was recognized as homologous to the mammalian substantia nigra pars compacta and was renamed accordingly; a group of gamma-aminobutyric acid (GABA)ergic neurons at the lateral edge of this region was identified as homologous to the mammalian substantia nigra pars reticulata and was also renamed accordingly. A field of cholinergic neurons in the rostral avian hindbrain was named the nucleus pedunculopontinus tegmenti, whereas the anterior nucleus of the ansa lenticularis in the avian diencephalon was renamed the subthalamic nucleus, both for their evident mammalian homologues. For the basal (i.e., subpallial) telencephalon, the actual parts of the basal ganglia were given names reflecting their now evident homologues. For example, the lobus parolfactorius and paleostriatum augmentatum were acknowledged to make up the dorsal subdivision of the striatal part of the basal ganglia and were renamed as the medial and lateral striatum. The paleostriatum primitivum was recognized as homologous to the mammalian globus pallidus and renamed as such. Additionally, the rostroventral part of what was called the lobus parolfactorius was acknowledged as comparable to the mammalian nucleus accumbens, which, together with the olfactory tubercle, was noted to be part of the ventral striatum in birds. A ventral pallidum, a basal cholinergic cell group, and medial and lateral bed nuclei of the stria terminalis were also recognized. The dorsal (i.e., pallial) telencephalic regions that had been erroneously named to reflect presumed homology to striatal parts of mammalian basal ganglia were renamed as part of the pallium, using prefixes that retain most established abbreviations, to maintain continuity with the outdated nomenclature. We concluded, however, that one-to-one (i.e., discrete) homologies with mammals are still uncertain for most of the telencephalic pallium in birds and thus the new pallial terminology is largely devoid of assumptions of one-to-one homologies with mammals. The sectors of the hyperstriatum composing the Wulst (i.e., the hyperstriatum accessorium intermedium, and dorsale), the hyperstriatum ventrale, the neostriatum, and the archistriatum have been renamed (respectively) the hyperpallium (hypertrophied pallium), the mesopallium (middle pallium), the nidopallium (nest pallium), and the arcopallium (arched pallium). The posterior part of the archistriatum has been renamed the posterior pallial amygdala, the nucleus taeniae recognized as part of the avian amygdala, and a region inferior to the posterior paleostriatum primitivum included as a subpallial part of the avian amygdala. The names of some of the laminae and fiber tracts were also changed to reflect current understanding of the location of pallial and subpallial sectors of the avian telencephalon. Notably, the lamina medularis dorsalis has been renamed the pallial-subpallial lamina. We urge all to use this new terminology, because we believe it will promote better communication among neuroscientists. Further information is available at http://avianbrain.org
1,061 citations
TL;DR: A-kinase anchoring proteins are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers that provide a molecular framework that orients these enzymes towards selected substrates.
Abstract: Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.
1,061 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: A side-by-side comparison of this new fluorescence assay and a standard radioisotopic method suggest that it may be an ideal method for high-throughput antimalarial drug screening.
Abstract: Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC(50)) after 48 h of parasite growth in the presence of each drug. The EC(50)s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-epsilon-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.
TL;DR: It is shown that acidosis activates Ca2+ -permeable acid-sensing ion channels (ASICs), inducing glutamate receptor-independent, Ca2-dependent, neuronal injury inhibited by ASIC blockers, and disclosing new potential therapeutic targets for stroke.
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: The D1-like and D2-like classes of dopamine receptors each has shared signaling properties that contribute to the definition of the receptor class, although some differences among subtypes within a class have been identified.
Abstract: The D1-like (D1, D5) and D2-like (D2, D3, D4) classes of dopamine receptors each has shared signaling properties that contribute to the definition of the receptor class, although some differences among subtypes within a class have been identified. D1-like receptor signaling is mediated chiefly by the heterotrimeric G proteins Gαs and Gαolf, which cause sequential activation of adenylate cyclase, cylic AMP-dependent protein kinase, and the protein phosphatase-1 inhibitor DARPP-32. The increased phosphorylation that results from the combined effects of activating cyclic AMP-dependent protein kinase and inhibiting protein phosphatase 1 regulates the activity of many receptors, enzymes, ion channels, and transcription factors. D1 or a novel D1-like receptor also signals via phospholipase C-dependent and cyclic AMP-independent mobilization of intracellular calcium. D2-like receptor signaling is mediated by the heterotrimeric G proteins Gαi and Gαo. These pertussis toxin-sensitive G proteins regulate some effec...
TL;DR: In this article, the authors provide up-to-date evidence-based guidelines for the optimal treatment of fibromyalgia syndrome (FMS) using a search of all human trials (randomized controlled trials and meta-analyses of randomized controlled trials) of FMS.
Abstract: ContextThe optimal management of fibromyalgia syndrome (FMS) is unclear and
comprehensive evidence-based guidelines have not been reported.ObjectiveTo provide up-to-date evidence-based guidelines for the optimal treatment
of FMS.Data Sources, Selection, and ExtractionA search of all human trials (randomized controlled trials and meta-analyses
of randomized controlled trials) of FMS was made using Cochrane Collaboration
Reviews (1993-2004), MEDLINE (1966-2004), CINAHL (1982-2004), EMBASE (1988-2004),
PubMed (1966-2004), Healthstar (1975-2000), Current Contents (2000-2004),
Web of Science (1980-2004), PsychInfo (1887-2004), and Science Citation Indexes
(1996-2004). The literature review was performed by an interdisciplinary panel,
composed of 13 experts in various pain management disciplines, selected by
the American Pain Society (APS), and supplemented by selected literature reviews
by APS staff members and the Utah Drug Information Service. A total of 505
articles were reviewed.Data SynthesisThere are major limitations to the FMS literature, with many treatment
trials compromised by short duration and lack of masking. There are no medical
therapies that have been specifically approved by the US Food and Drug Administration
for management of FMS. Nonetheless, current evidence suggests efficacy of
low-dose tricyclic antidepressants, cardiovascular exercise, cognitive behavioral
therapy, and patient education. A number of other commonly used FMS therapies,
such as trigger point injections, have not been adequately evaluated.ConclusionsDespite the chronicity and complexity of FMS, there are pharmacological
and nonpharmacological interventions available that have clinical benefit.
Based on current evidence, a stepwise program emphasizing education, certain
medications, exercise, cognitive therapy, or all 4 should be recommended.
TL;DR: It is shown that Ser 62 is dephosphorylated by protein phosphatase 2A (PP2A) before ubiquitination of c-Myc, and that PP2A activity is regulated by the Pin1 prolyl isomerase, resulting in c- myc stabilization.
Abstract: The stability of c-Myc is regulated by multiple Ras effector pathways. Phosphorylation at Ser 62 stabilizes c-Myc, whereas subsequent phosphorylation at Thr 58 is required for its degradation. Here we show that Ser 62 is dephosphorylated by protein phosphatase 2A (PP2A) before ubiquitination of c-Myc, and that PP2A activity is regulated by the Pin1 prolyl isomerase. Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc. A stable c-Myc(T58A) mutant that cannot bind Pin1 or be dephosphorylated by PP2A replaces SV40 small T antigen in human cell transformation and tumorigenesis assays. Therefore, small T antigen, which inactivates PP2A, exerts its oncogenic potential by preventing dephosphorylation of c-Myc, resulting in c-Myc stabilization. Thus, Ras-dependent signalling cascades ensure transient and self-limiting accumulation of c-Myc, disruption of which contributes to human cell oncogenesis.
TL;DR: This study represents the most comprehensive definition of transcription factor binding sites in a metazoan species.
TL;DR: Sudden cardiac death accounts for 5.6% of annual mortality, and prospective evaluation in the general population appears to be feasible, and the use of multiple sources of ascertainment and information significantly enhances phenotyping of SCD cases.
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: The assumption underlying brief behavioral counseling interventions in primary care is that, for identified risky or harmful drinkers, reducing overall alcohol consumption or adopting safer drinking patterns will reduce the risk for medical, social, and psychological problems, and little experimental evidence supports this assumption.
Abstract: Behavioral counseling interventions are effective and could be part of a public health approach to reducing harmful use of alcohol by adult primary care patients. Future research should test strate...
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: Evidence is provided that irradiation of young animals induces a long-term impairment of dentate subgranular zone neurogenesis that is associated with hippocampal-dependent memory deficits.
TL;DR: It is shown that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice and the significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation -induced cognitive impairments.
Abstract: During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.
University of California, Riverside1, California State Polytechnic University, Pomona2, Hebrew University of Jerusalem3, University of Oregon4, University of California, Los Angeles5, University of Edinburgh6, University of Göttingen7, Wright State University8, University of Minnesota9, University of Missouri–Kansas City10, Bio-Rad Laboratories11, University of Düsseldorf12, Technische Universität München13, University of Alberta14, University of Leeds15, Massachusetts Institute of Technology16, Dartmouth College17, Flinders University18, Saitama University19, Oregon Health & Science University20, Ohio State University21, University of California, Irvine22, Texas A&M University23, Anschutz Medical Campus24
TL;DR: An analysis of over 1,100 of the ∼10,000 predicted proteins encoded by the genome sequence of the filamentous fungus Neurospora crassa reveals potential new targets for antifungals as well as loci implicated in human and plant physiology and disease.
Abstract: We present an analysis of over 1,100 of the approximately 10,000 predicted proteins encoded by the genome sequence of the filamentous fungus Neurospora crassa. Seven major areas of Neurospora genomics and biology are covered. First, the basic features of the genome, including the automated assembly, gene calls, and global gene analyses are summarized. The second section covers components of the centromere and kinetochore complexes, chromatin assembly and modification, and transcription and translation initiation factors. The third area discusses genome defense mechanisms, including repeat induced point mutation, quelling and meiotic silencing, and DNA repair and recombination. In the fourth section, topics relevant to metabolism and transport include extracellular digestion; membrane transporters; aspects of carbon, sulfur, nitrogen, and lipid metabolism; the mitochondrion and energy metabolism; the proteasome; and protein glycosylation, secretion, and endocytosis. Environmental sensing is the focus of the fifth section with a treatment of two-component systems; GTP-binding proteins; mitogen-activated protein, p21-activated, and germinal center kinases; calcium signaling; protein phosphatases; photobiology; circadian rhythms; and heat shock and stress responses. The sixth area of analysis is growth and development; it encompasses cell wall synthesis, proteins important for hyphal polarity, cytoskeletal components, the cyclin/cyclin-dependent kinase machinery, macroconidiation, meiosis, and the sexual cycle. The seventh section covers topics relevant to animal and plant pathogenesis and human disease. The results demonstrate that a large proportion of Neurospora genes do not have homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. The group of unshared genes includes potential new targets for antifungals as well as loci implicated in human and plant physiology and disease.
TL;DR: Several recent advances are focused on that address the required diversity for the generation of an optimal immune response in the thymus.
Abstract: In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-αβ gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response.
TL;DR: Reactivity for DOG1 may aid in the diagnosis of GISTs, including PDGFRA mutants that fail to express KIT antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.
Abstract: We recently characterized gene expression patterns in gastrointestinal stromal tumors (GISTs) using cDNA microarrays, and found that the gene FLJ10261 (DOG1, discovered on GIST-1), encoding a hypothetical protein, was specifically expressed in GISTs. The immunoreactivity of a rabbit antiserum to synthetic DOG1 peptides was assessed on two soft tissue tumor microarrays. The tissue microarrays included 587 soft tissue tumors, with 149 GISTs, including 127 GIST cases for which the KIT and PDGFRA mutation status was known. Immunoreactivity for DOG1 was found in 136 of 139 (97.8%) of scorable GISTs. All seven GIST cases with a PDGFRA mutation were DOG1-positive, while most of these failed to react for KIT. The immunohistochemical findings were confirmed with in situ hybridization probes for DOG1, KIT, and PDGFRA. Other neoplasms in the differential diagnosis of GIST, including desmoid fibromatosis (0 of 17) and Schwannoma (0 of 3), were immunonegative for DOG1. Only 4 of 438 non-GIST cases were immunoreactive for DOG1. DOG1, a protein of unknown function, is expressed strongly on the cell surface of GISTs and is rarely expressed in other soft tissue tumors. Reactivity for DOG1 may aid in the diagnosis of GISTs, including PDGFRA mutants that fail to express KIT antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.
TL;DR: 71 HCMV-encoded proteins that included 12 proteins encoded by known viral open reading frames previously not associated with virions and 12 proteins from novel viral ORFs are identified.
Abstract: Human cytomegalovirus (HCMV), a member of the herpesvirus family, is a large complex enveloped virus composed of both viral and cellular gene products. While the sequence of the HCMV genome has been known for over a decade, the full set of viral and cellular proteins that compose the HCMV virion are unknown. To approach this problem we have utilized gel-free two-dimensional capillary liquid chromatography-tandem mass spectrometry (MS/MS) and Fourier transform ion cyclotron resonance MS to identify and determine the relative abundances of viral and cellular proteins in purified HCMV AD169 virions and dense bodies. Analysis of the proteins from purified HCMV virion preparations has indicated that the particle contains significantly more viral proteins than previously known. In this study, we identified 71 HCMV-encoded proteins that included 12 proteins encoded by known viral open reading frames (ORFs) previously not associated with virions and 12 proteins from novel viral ORFs. Analysis of the relative abundance of HCMV proteins indicated that the predominant virion protein was the pp65 tegument protein and that gM rather than gB was the most abundant glycoprotein. We have also identified over 70 host cellular proteins in HCMV virions, which include cellular structural proteins, enzymes, and chaperones. In addition, analysis of HCMV dense bodies indicated that these viral particles are composed of 29 viral proteins with a reduced quantity of cellular proteins in comparison to HCMV virions. This study provides the first comprehensive quantitative analysis of the viral and cellular proteins that compose infectious particles of a large complex virus.
TL;DR: Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up, and previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance to than lack of disease progression.
Abstract: ContextAmong individuals with lower-extremity peripheral arterial disease (PAD),
specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally
related to the degree of functional impairment. However, relations between
these clinical characteristics and objectively measured functional decline
are unknown.ObjectiveTo define whether PAD, ABI, and specific leg symptoms predict functional
decline at 2-year follow-up.Design, Setting, and ParticipantsProspective cohort study among 676 consecutively identified individuals
(aged ≥55 years) with and without PAD (n = 417 and n = 259, respectively),
with baseline functional assessments occurring between October 1, 1998, and
January 31, 2000, and follow-up assessments scheduled 1 and 2 years thereafter.
PAD was defined as ABI less than 0.90, and participants with PAD were categorized
at baseline into 1 of 5 mutually exclusive symptom groups.Main Outcome MeasuresMean annual changes in 6-minute walk performance and in usual-paced
and fast-paced 4-m walking velocity, adjusted for age, sex, race, prior-year
functioning, comorbid diseases, body mass index, pack-years of cigarette smoking,
and patterns of missing data.ResultsLower baseline ABI values were associated with greater mean (95% confidence
interval) annual decline in 6-minute walk performance (−73.0 [−142
to −4.2] ft for ABI <0.50 vs −58.8 [−83.5 to −34.0]
ft for ABI 0.50 to <0.90 vs −12.6 [−40.3 to 15.1] ft for ABI
0.90-1.50, P = .02). Compared with participants without
PAD, PAD participants with leg pain on exertion and rest at baseline had greater
mean annual decline in 6-minute walk performance (−111 [−173 to
−50.0] ft vs −8.67 [−36.9 to 19.5] ft, P = .004), usual-pace 4-meter walking velocity (−0.06 [−0.09
to −0.02] m/sec vs −0.01 (−0.03 to 0.003] m/sec, P = .02), and fastest-pace 4-meter walking velocity (−0.07 [−0.11
to −0.03] m/sec vs −0.02 [−0.04 to −0.006] m/sec, P = .046). Compared with participants without PAD, asymptomatic
PAD was associated with greater mean annual decline in 6-minute walk performance
(−76.8 (−135 to −18.6] ft vs −8.67 (−36.9 to
19.5] ft, P = .04) and an increased odds ratio for
becoming unable to walk for 6 minutes continuously (3.63; 95% confidence interval,
1.58-8.36; P = .002).ConclusionsBaseline ABI and the nature of leg symptoms predict the degree of functional
decline at 2-year follow-up. Previously reported lack of worsening in claudication
symptoms over time in patients with PAD may be more related to declining functional
performance to than lack of disease progression.
Cedars-Sinai Medical Center1, NewYork–Presbyterian Hospital2, University of California, Los Angeles3, University of North Carolina at Chapel Hill4, University of Alabama at Birmingham5, University of California, San Francisco6, University of Hamburg7, Université catholique de Louvain8, Mayo Clinic9, Rush University Medical Center10, University of Duisburg-Essen11, University of Padua12, University of Barcelona13, Oregon Health & Science University14, Erasmus University Rotterdam15, Tufts University16, University of Córdoba (Spain)17, University of Toledo18, University of Colorado Denver19
TL;DR: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.
Abstract: Objective: The HepatAssist liver support system is an extracorpo-real porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective. random-ized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL Versus 59% for control (it = 147; P= 0.12). When Survival was analyzed accounting for confounding factors. in the entire patient Population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio 0.56: P = 0.048). Conclusions: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.
TL;DR: In this article, the effect of yoga and aerobic exercise on cognitive function, fatigue, mood, and quality of life in multiple sclerosis (MS) patients was evaluated by a 6-month study.
Abstract: Objective: To determine the effect of yoga and of aerobic exercise on cognitive function, fatigue, mood, and quality of life in multiple sclerosis (MS). Methods: Subjects with clinically definite MS and Expanded Disability Status Score less than or equal to 6.0 were randomly assigned to one of three groups lasting 6 months: weekly Iyengar yoga class along with home practice, weekly exercise class using a stationary bicycle along with home exercise, or a waiting-list control group. Outcome assessments performed at baseline and at the end of the 6-month period included a battery of cognitive measures focused on attention, physiologic measures of alertness, Profile of Mood States, State-Trait Anxiety Inventory, Multi-Dimensional Fatigue Inventory (MFI), and Short Form (SF)-36 health-related quality of life. Results: Sixty-nine subjects were recruited and randomized. Twelve subjects did not finish the 6-month intervention. There were no adverse events related to the intervention. There were no effects from either of the active interventions on either of the primary outcome measures of attention or alertness. Both active interventions produced improvement in secondary measures of fatigue compared to the control group: Energy and Fatigue (Vitality) on the SF-36 and general fatigue on the MFI. There were no clear changes in mood related to yoga or exercise. Conclusion: Subjects with MS participating in either a 6-month yoga class or exercise class showed significant improvement in measures of fatigue compared to a waiting-list control group. There was no relative improvement of cognitive function in either of the intervention groups.