Showing papers by "University of Tennessee Health Science Center published in 2007"
University of California, Los Angeles1, United States Department of Energy2, University of Paris3, Duke University4, University of Massachusetts Medical School5, University of California, Berkeley6, Centre national de la recherche scientifique7, University of California, San Francisco8, Sun Yat-sen University9, University of Tennessee Health Science Center10, University of Minnesota11, Iowa State University12, Genetic Information Research Institute13, Salk Institute for Biological Studies14, Stanford University15, University of Liège16, University of Nebraska–Lincoln17, University of Cambridge18, Washington University in St. Louis19, University of Córdoba (Spain)20, Kyoto University21, Carnegie Institution for Science22, National Autonomous University of Mexico23, University of Münster24, École Normale Supérieure25, University of Melbourne26, University of Paris-Sud27, University of Mainz28, Scripps Research Institute29, Ohio State University30, University of Chicago31, University of Jena32, University of Arizona33, Louisiana State University34, University of New Brunswick35, University College London36, University of Potsdam37, Delaware Biotechnology Institute38, Boyce Thompson Institute for Plant Research39, Macquarie University40, Oklahoma State University Center for Health Sciences41, İzmir University of Economics42, Academy of Sciences of the Czech Republic43, Charles University in Prague44, St. Edward's University45, University of Puget Sound46, Hokkaido University47, Tsinghua University48, Washington State University49, Appalachian State University50, Marquette University51
TL;DR: Analyses of the Chlamydomonas genome advance the understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.
Abstract: Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the approximately 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.
2,554 citations
Wake Forest University1, Mount Sinai St. Luke's and Mount Sinai Roosevelt2, Harvard University3, Johns Hopkins University4, Pennington Biomedical Research Center5, Miriam Hospital6, American Indian Center7, Baylor College of Medicine8, University of Southern California9, University of Texas Health Science Center at San Antonio10, University of Colorado Denver11, University of Tennessee Health Science Center12, University of Pittsburgh13, University of Alabama at Birmingham14, University of Pennsylvania15
TL;DR: At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes and was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE.
Abstract: Objective: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes one-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. Research Design and Methods: A multi-centered randomized controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with body mass index >25 kg/m2 (>27 kg/m2 if taking insulin). An Intensive Lifestyle Intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared to a Diabetes Support and Education (DSE) condition. Results: Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (p Conclusions: At 1 year, ILI resulted in clinically significant weight loss in persons with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk. Trial Registration: clinicaltrials.gov Identifier: NCT00017953
1,487 citations
Case Western Reserve University1, Emory University2, National Institutes of Health3, University of Alabama at Birmingham4, Yale University5, Harvard University6, University of Miami7, University of Cincinnati8, University of Tennessee Health Science Center9, University of Texas Southwestern Medical Center10, Indiana University – Purdue University Indianapolis11, Brown University12, University of New Mexico13, Wayne State University14, Stanford University15, University of Texas Health Science Center at Houston16, Research Triangle Park17
TL;DR: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002, and it is speculated that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.
1,135 citations
TL;DR: This protocol describes the steps necessary for acquisition, handling and preparation of CII, as well as selection of mouse strains, proper immunization technique and evaluation of the arthritis incidence and severity in the collagen-induced arthritis mouse model.
Abstract: The collagen-induced arthritis (CIA) mouse model is the most commonly studied autoimmune model of rheumatoid arthritis. Autoimmune arthritis is induced in this model by immunization with an emulsion of complete Freund's adjuvant and type II collagen (CII). This protocol describes the steps necessary for acquisition, handling and preparation of CII, as well as selection of mouse strains, proper immunization technique and evaluation of the arthritis incidence and severity. Typically, the first signs of arthritis appear in this model 21–28 days after immunization, and identification of the arthritic limbs is not difficult. Using the protocol described, the investigator should be able to reproducibly induce a high incidence of CIA in various strains of genetically susceptible mice as well as learn how to critically evaluate the pathology of the disease. The total time for the preparation of reagents and the immunization of ten mice is about 1.5 h.
1,000 citations
TL;DR: LKB1 is established as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis in lung cancer, and expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes as targets of LKB1 repression.
Abstract: Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.
969 citations
TL;DR: The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation and may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.
Abstract: MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate about 30% of the encoding genes of the human genome. However, the role of miRNAs in vascular disease is currently completely unknown. Using microarray analysis, we demonstrated for the first time that miRNAs are aberrantly expressed in the vascular walls after balloon injury. The aberrantly expressed miRNAs were further confirmed by Northern blot and quantitative real-time polymerase chain reaction. Modulating an aberrantly overexpressed miRNA, miR-21, via antisense-mediated depletion (knock-down) had a significant negative effect on neointimal lesion formation. In vitro, the expression level of miR-21 in dedifferentiated vascular smooth muscle cells was significantly higher than that in fresh isolated differentiated cells. Depletion of miR-21 resulted in decreased cell proliferation and increased cell apoptosis in a dose-dependent manner. MiR-21-mediated cellular effects were further confirmed in vivo in balloon-injured rat carotid arteries. Western blot analysis demonstrated that PTEN and Bcl-2 were involved in miR-21-mediated cellular effects. The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation. MiRNAs may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.
891 citations
Massachusetts Institute of Technology1, Purdue University2, Michigan State University3, Cornell University4, University of Córdoba (Spain)5, Broad Institute6, Pacific Northwest National Laboratory7, University of Amsterdam8, University of Natural Resources and Life Sciences, Vienna9, Rothamsted Research10, University of Minnesota11, University of Ottawa12, United States Department of Agriculture13, Saint Louis University14, University of Arizona15, University of Tennessee Health Science Center16, National Center for Agricultural Utilization Research17, National Academy of Sciences of Ukraine18, Wageningen University and Research Centre19
TL;DR: The genome of the filamentous fungus Fusarium graminearum, a major pathogen of cultivated cereals, was sequenced and annotated and many highly polymorphic regions contained sets of genes implicated in plant-fungus interactions and were unusually divergent, with higher rates of recombination.
Abstract: We sequenced and annotated the genome of the filamentous fungus Fusarium graminearum, a major pathogen of cultivated cereals. Very few repetitive sequences were detected, and the process of repeat-induced point mutation, in which duplicated sequences are subject to extensive mutation, may partially account for the reduced repeat content and apparent low number of paralogous (ancestrally duplicated) genes. A second strain of F. graminearum contained more than 10,000 single-nucleotide polymorphisms, which were frequently located near telomeres and within other discrete chromosomal segments. Many highly polymorphic regions contained sets of genes implicated in plant-fungus interactions and were unusually divergent, with higher rates of recombination. These regions of genome innovation may result from selection due to interactions of F. graminearum with its plant hosts.
822 citations
TL;DR: In this paper, the authors discuss the anatomy, physiology, and pathophysiology of epicardial adipose tissue and its relationship to coronary atherosclerosis, and they find that the fat around atheromatous coronary arteries secretes several proinflammatory cytokines and is infiltrated by macrophages, lymphocytes, and basophils.
805 citations
TL;DR: It is shown that mitochondrial clearance in reticulocytes requires the BCL2-related protein NIX (BNIP3L) and a BAX- and BAK-independent role for a BCL3-relatedprotein in development, indicating that NIX does not function through established proapoptotic pathways.
Abstract: The regulated clearance of mitochondria is a well recognized but poorly understood aspect of cellular homeostasis, and defects in this process have been linked to aging, degenerative diseases, and cancer. Mitochondria are recycled through an autophagy-related process, and reticulocytes, which completely eliminate their mitochondria during maturation, provide a physiological model to study this phenomenon. Here, we show that mitochondrial clearance in reticulocytes requires the BCL2-related protein NIX (BNIP3L). Mitochondrial clearance does not require BAX, BAK, BCL-XL, BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. Similarly, NIX is not required for the induction of autophagy during terminal erythroid differentiation. NIX is required for the selective elimination of mitochondria, however, because mitochondrial clearance, in the absence of NIX, is arrested at the stage of mitochondrial incorporation into autophagosomes and autophagosome maturation. These results yield insight into the mechanism of mitochondrial clearance in higher eukaryotes. Furthermore, they show a BAX- and BAK-independent role for a BCL2-related protein in development.
777 citations
University of Tennessee Health Science Center1, University of Dundee2, University of California, San Francisco3, Ohio State University4, Georgia Regents University5, University of Pittsburgh6, University of California, San Diego7, University of Colorado Boulder8, Virginia Commonwealth University9, President University10, Anschutz Medical Campus11, Duke University12, Barrow Neurological Institute13, Yale University14, King's College London15, University of Toronto16
TL;DR: A new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses is provided.
Abstract: Rationale
This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.
766 citations
TL;DR: It is shown it is possible to treat insomnia that is comorbid with select psychiatric (depression) and medical (eg, pain and cancer) disorders, which in turn increases the quality of life and functioning of patients, indicating a need for future treatment research.
Abstract: Study Objectives: Determine the comorbidity of insomnia with medical problems. Design: Cross-sectional and retrospective. Participants: Community-based population of 772 men and women, aged 20 to 98 years old. Measurements: Self-report measures of sleep, health, depression, and anxiety. Results: People with chronic insomnia reported more of the following than did people without insomnia: heart disease (21.9% vs 9.5%), high blood pressure (43.1% vs 18.7%), neurologic disease (7.3% vs 1.2%), breathing problems (24.8% vs 5.7%), urinary problems (19.7% vs 9.5%), chronic pain (50.4% vs 18.2%), and gastrointestinal problems (33.6% vs 9.2%). Conversely, people with the following medical problems reported more chronic insomnia than did those without those medical problems: heart disease (44.1% vs 22.8%), cancer (41.4% vs 24.6%), high blood pressure (44.0% vs 19.3%), neurologic disease (66.7% vs 24.3%), breathing problems (59.6% vs 21.4%), urinary problems (41.5% vs 23.3%), chronic pain (48.6% vs 17.2%), and gastrointestinal problems (55.4% vs 20.0%). When all medical problems were considered together, only patients with high blood pressure, breathing problems, urinary problems, chronic pain, and gastrointestinal problems continued to have statistically higher levels of insomnia than those without these medical disorders. Conclusion: This study demonstrates significant overlap between insomnia and multiple medical problems. Some research has shown it is possible to treat insomnia that is comorbid with select psychiatric (depression) and medical (eg, pain and cancer) disorders, which in turn increases the quality of life and functioning of these patients. The efficacy of treating insomnia in many of the above comorbid disorders has not been tested, indicating a need for future treatment research.
George Washington University1, University of North Carolina at Chapel Hill2, Fred Hutchinson Cancer Research Center3, University of California, San Diego4, Northwestern University5, University of Washington6, University of Tennessee Health Science Center7, Harvard University8, Kaiser Permanente9, University at Buffalo10
TL;DR: Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.
Abstract: Background— Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women’s Health Initiative randomized trial of calcium plus vitamin D supplementation. Methods and Results— We randomized 36 282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, wom...
TL;DR: The drug burden index demonstrates that anticholinergic and sedative drug exposure is associated with poorer function in community-dwelling older people and provides a useful evidence-based tool for assessing the functional effect of exposure to medications in this population.
Abstract: Background Older people carry a high burden of illness for which medications are indicated, along with increased risk of adverse drug reactions. We developed an index to determine drug burden based on pharmacologic principles. We evaluated the relationship of this index to physical and cognitive performance apart from disease indication. Methods Data from the Health, Aging, and Body Composition Study on 3075 well-functioning community-dwelling persons aged 70 to 79 years were analyzed by multiple linear regression to assess the cross-sectional association of drug burden index with a validated composite continuous measure for physical function, and with the Digit Symbol Substitution Test for cognitive performance. Results Use of anticholinergic and sedative medications was associated with poorer physical performance score (anticholinergic exposure, 2.08 vs 2.21, P P P = .045; sedative exposure, 34.0 vs 35.5, P = .01). Associations were strengthened when exposure was calculated by principles of dose response. An increase of 1 U in drug burden index was associated with a deficit of 0.15 point ( P P = .01) on the Digit Symbol Substitution Test. These values were more than 3 times those associated with a single comorbid illness. Conclusions The drug burden index demonstrates that anticholinergic and sedative drug exposure is associated with poorer function in community-dwelling older people. This pharmacologic approach provides a useful evidence-based tool for assessing the functional effect of exposure to medications in this population.
TL;DR: It is demonstrated that miRNAs are aberrantly expressed in hypertrophic mouse hearts, and modulating miR-21 expression via antisense-mediated depletion (knockdown) had a significant negative effect on cardiomyocyte hypertrophy.
Abstract: MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate gene expression. Although miRNAs are highly expressed in the heart, their roles in heart diseases are currently unclear. Using microarray analysis designed to detect the majority of mammalian miRNAs identified thus far, we demonstrated that miRNAs are aberrantly expressed in hypertrophic mouse hearts. The time course of the aberrant miRNA expression was further identified in mouse hearts at 7, 14, and 21 days after aortic banding. Nineteen of the most significantly dysregulated miRNAs were further confirmed by Northern blot and/or real-time polymerase chain reaction, in which miR-21 was striking because of its more than fourfold increase when compared with the sham surgical group. Similar aberrant expression of the most up-regulated miRNA, miR-21, was also found in cultured neonatal hypertrophic cardiomyocytes stimulated by angiotensin II or phenylephrine. Modulating miR-21 expression via antisense-mediated depletion (knockdown) had a significant negative effect on cardiomyocyte hypertrophy. The results suggest that miRNAs are involved in cardiac hypertrophy formation. miRNAs might be a new therapeutic target for cardiovascular diseases involving cardiac hypertrophy such as hypertension, ischemic heart disease, valvular diseases, and endocrine disorders.
TL;DR: Accumulating experience suggests that patients with extremely poor lung function who are deemed inoperable by conventional criteria might tolerate combined LVRS and curative-intent resection of lung cancer with an acceptable mortality rate and good postoperative outcomes.
TL;DR: While alloimmunities initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.
Abstract: Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture’s syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-α and IL-1β. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.
TL;DR: The association of ECF with gait speed decline is attenuated by comorbid conditions, particularly depression, and may point to new pathways for the treatment of physical decline associated with diminished cognitive function.
Abstract: BACKGROUND Emerging evidence indicates an association between cognitive function and physical performance in late life. This study examines the relationship between cognitive function and subsequent gait speed decline among high-functioning older adults. METHODS Measures of global cognitive function (Modified Mini Mental State Examination [3MS]) and executive control function (ECF) (a clock drawing task [CLOX 1] and the 15-item Executive Interview [EXIT 15]) were obtained in the Health, Aging, and Body Composition Study in 1999-2000. Gait-speed (meters/second) was assessed over 20 meters at usual pace. Using a mixed model, we assessed the relationship between baseline cognitive function and gait-speed change over 3 years. RESULTS Two thousand, three hundred forty-nine older adults (mean age 75.6 +/- 2.9 years) completed the assessments. After adjustment for baseline gait speed, a 1-standard-deviation (SD) lower performance on each cognitive test was associated with greater gait-speed decline over 3 years: 0.016 m/s for the 3MS (SD = 8.1), 0.009 m/s for CLOX 1 (SD = 2.4), and 0.012 m/s for EXIT 15 (SD = 4.1) (p <.0005 for all). After adjustment for comorbidities, the effect size was attenuated for 3MS and CLOX 1, and the association for EXIT 15 was no longer significant. Depression score was most strongly associated with the EXIT 15 effect reduction. CONCLUSION Global and executive cognitive functions predict declines in gait speed. The association of ECF with gait speed decline is attenuated by comorbid conditions, particularly depression. Elucidation of the mechanisms underlying these associations may point to new pathways for the treatment of physical decline associated with diminished cognitive function.
TL;DR: The simulation study indicates that RERI is the best choice of measures of additivity using a proportional hazards model, and the method has broader application for any regression models with a rate as the dependent variable.
TL;DR: It is shown that Alum activates caspase-1 and induce secretion of mature IL-1β and IL-18, and a mechanism for the adjuvanticity of Alum is suggested.
Abstract: Aluminum hydroxide (Alum) is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. In this study, we show that Alum activates caspase-1 and induce secretion of mature IL-1beta and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1beta or IL-18, despite the fact that the IL-1beta mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1beta and IL-18. Alum-induced IL-1beta and IL-18 production was not due to enhancement of TLR signaling but rather reflected caspase-1 activation and in mouse dendritic cells occurred in a MyD88-independent fashion. Secretion of other proinflammatory cytokines such as IL-8 was not affected by Alum treatments. However, TLR-induced production of IL-10 was increased and that of IFN-gamma-inducible protein decreased by Alum cotreatment. Considering the immunostimulatory activities of these cytokines and the ability of IL-1beta to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.
TL;DR: A full-QTL model is presented with which to explore the genetic architecture of complex trait in multiple environments, which includes the effects of multiple QTLs, epistasis, QTL- by-environment interactions and epistasis-by- Environment interactions.
Abstract: Summary: Understanding how interactions among set of genes affect diverse phenotypes is having a greater impact on biomedical research, agriculture and evolutionary biology. Mapping and characterizing the isolated effects of single quantitative trait locus (QTL) is a first step, but we also need to assemble networks of QTLs and define non-additive interactions (epistasis) together with a host of potential environmental modulators. In this article, we present a full-QTL model with which to explore the genetic architecture of complex trait in multiple environments. Our model includes the effects of multiple QTLs, epistasis, QTL-by-environment interactions and epistasis-by-environment interactions. A new mapping strategy, including marker interval selection, detection of marker interval interactions and genome scans, is used to evaluate putative locations of multiple QTLs and their interactions. All the mapping procedures are performed in the framework of mixed linear model that are flexible to model environmental factors regardless of fix or random effects being assumed. An F-statistic based on Henderson method III is used for hypothesis tests. This method is less computationally greedy than corresponding likelihood ratio test. In each of the mapping procedures, permutation testing is exploited to control for genome-wide false positive rate, and model selection is used to reduce ghost peaks in F-statistic profile. Parameters of the full-QTL model are estimated using a Bayesian method via Gibbs sampling. Monte Carlo simulations help define the reliability and efficiency of the method. Two real-world phenotypes (BXD mouse olfactory bulb weight data and rice yield data) are used as exemplars to demonstrate our methods.
Availability: A software package is freely available at http://ibi.zju.edu.cn/software/qtlnetwork
Contact: [email protected]
Supplementary information: Supplementary data are available at Bioinformatics online.
TL;DR: The identification of MRR1 as the central regulator of the MDR1 efflux pump and the elucidation of the mutations that have occurred in fluconazole-resistant, clinical C. albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen.
Abstract: Constitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has not been resolved. By genome-wide gene expression analysis we have identified a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately upregulated with MDR1 in drug-resistant, clinical C. albicans isolates. Inactivation of MRR1 in two such drug-resistant isolates abolished both MDR1 expression and multidrug resistance. Sequence analysis of the MRR1 alleles of two matched drug-sensitive and drug-resistant C. albicans isolate pairs showed that the resistant isolates had become homozygous for MRR1 alleles that contained single nucleotide substitutions, resulting in a P683S exchange in one isolate and a G997V substitution in the other isolate. Introduction of these mutated alleles into a drug-susceptible C. albicans strain resulted in constitutive MDR1 overexpression and multidrug resistance. By comparing the transcriptional profiles of drug-resistant C. albicans isolates and mrr1Δ mutants derived from them and of C. albicans strains carrying wild-type and mutated MRR1 alleles, we defined the target genes that are controlled by Mrr1p. Many of the Mrr1p target genes encode oxidoreductases, whose upregulation in fluconazole-resistant isolates may help to prevent cell damage resulting from the generation of toxic molecules in the presence of fluconazole and thereby contribute to drug resistance. The identification of MRR1 as the central regulator of the MDR1 efflux pump and the elucidation of the mutations that have occurred in fluconazole-resistant, clinical C. albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen.
TL;DR: It is demonstrated that protein and drug delivery rates from chitosan microspheres may be controlled and extended by controlling the degree of cross-linking with genipin.
TL;DR: The reader should be able to describe the varied appearance of bowel endometriosis, recall that it is difficult to diagnose preoperatively, and explain that surgical treatment offers the best treatment in symptomatic patients through a variety of surgical techniques which is best accomplished with a team approach.
Abstract: Bowel endometriosis opens a new frontier for the gynecologist, as it forces the understanding of a new anatomy, a new physiology, and a new pathology. Although some women with bowel endometriosis may be asymptomatic, the majority of them develop a variety of gastrointestinal complains. No clear guid
TL;DR: The results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development and the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population.
Abstract: ContextLittle is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia.ObjectivesTo investigate the cumulative incidence of secondary neoplasms in pediatric patients treated for acute lymphoblastic leukemia over 30 years and to characterize late-occurring tumors.Design, Setting, and PatientsRetrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St Jude Children's Research Hospital, Memphis, Tenn, who achieved complete remission and had a median follow-up time of 18.7 years (range, 2.4-41.3 years).Main Outcome MeasuresCumulative incidences of secondary neoplasms in first remission and standard incidence ratios of observed rates compared with rates of cancer development in the general US population.ResultsSecondary neoplasms developed as the first event in 123 patients and comprised 46 myeloid malignancies, 3 lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16 meningiomas, and 22 other brain tumors. The cumulative incidence of secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increased substantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years. When meningiomas and basal cell carcinomas were excluded, the overall cumulative incidence was 3.99% (SE, 0.44%) at 15 years and 6.27% (SE, 0.83%) at 30 years, representing a 13.5-fold increase in overall risk compared with the general population. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma.ConclusionsThe cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population. These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development.
Harvard University1, University of California, Davis2, Baylor College of Medicine3, University of California, San Diego4, University of Missouri–Kansas City5, University of Pennsylvania6, George Washington University7, Children's Hospital Oakland Research Institute8, Alfred I. duPont Hospital for Children9, Northwestern University10, Georgia Regents University11, University of Arizona12, Boston Children's Hospital13, University of Washington14, University of Tennessee Health Science Center15, Children's Hospital of Wisconsin16, Columbia University17, University of Southern California18, Ohio State University19
TL;DR: A large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool for management of children presenting to emergency departments with CSF pleocytosis.
Abstract: ContextChildren with cerebrospinal fluid (CSF) pleocytosis are routinely admitted to the hospital and treated with parenteral antibiotics, although few have bacterial meningitis. We previously developed a clinical prediction rule, the Bacterial Meningitis Score, that classifies patients at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/μL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10 000 cells/μL, and a history of seizure before or at the time of presentation.ObjectiveTo validate the Bacterial Meningitis Score in the era of widespread pneumococcal conjugate vaccination.Design, Setting, and PatientsA multicenter, retrospective cohort study conducted in emergency departments of 20 US academic medical centers through the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. All children aged 29 days to 19 years who presented at participating emergency departments between January 1, 2001, and June 30, 2004, with CSF pleocytosis (CSF white blood cells ≥10 cells/μL) and who had not received antibiotic treatment before lumbar puncture.Main Outcome MeasureThe sensitivity and negative predictive value of the Bacterial Meningitis Score.ResultsAmong 3295 patients with CSF pleocytosis, 121 (3.7%; 95% confidence interval [CI], 3.1%-4.4%) had bacterial meningitis and 3174 (96.3%; 95% CI, 95.5%-96.9%) had aseptic meningitis. Of the 1714 patients categorized as very low risk for bacterial meningitis by the Bacterial Meningitis Score, only 2 had bacterial meningitis (sensitivity, 98.3%; 95% CI, 94.2%-99.8%; negative predictive value, 99.9%; 95% CI, 99.6%-100%), and both were younger than 2 months old. A total of 2518 patients (80%) with aseptic meningitis were hospitalized.ConclusionsThis large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.
TL;DR: Within the limits of expert opinion and with the understanding that new research data may take precedence, the experts' recommendations provide helpful guidance in situations where the medical literature is scant or lacking.
Abstract: Background. Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria and management and have dramatically different outcomes. Despite increasing data on treatment of epilepsy, research findings on childhood epilepsy are more limited and many clinical questions remain unanswered, so that clinicians must often rely on clinical judgment. In such clinical situations, expert opinion can be especially helpful. Methods. A survey on pediatric epilepsy and seizures (33 questions and approximately 650 treatment options) was sent to 57 European physicians specializing in pediatric epilepsy, 42 (74%) of whom completed it. In some questions, the experts were asked to recommend overall treatment approaches for specific syndromes (the order in which they would use certain strategies). Most of the questions asked the experts to rate options using a modified version of the RAND 9-point scale for medical appropriateness. Consensus was defined as a non-random distribution of scores by chi-square test, with ratings used to assign a categorical rank (first line/usually appropriate, second line/equivocal, and third line/usually not appropriate) to each option. Results. Valproate was treatment of choice for symptomatic myoclonic and generalized tonic-clonic seizures. For initial monotherapy for complex partial seizures, carbamazepine and oxcarbazepine were treatments of choice, with valproate also first line. As initial therapy for infantile spasms caused by tuberous sclerosis, viagabatrin was treatment of choice. As initial therapy for infantile spasms that are symptomatic in etiology, vigabatrin was also treatment of choice, with adrenocorticotropic hormone (ACTH) and prednisone other first-line options. As initial therapy for Lennox-Gastaut syndrome, valproate was treatment of choice. For acute treatment of a prolonged febrile seizure or cluster of seizures, rectal diazepam was treatment of choice. Valproate was treatment of choice as preventive therapy for febrile seizures. For benign childhood epilepsy with centro-temporal spikes, valproate was treatment of choice. For childhood and juvenile absence epilepsy, valproate was treatment of choice, with lamotrigine another first-line option (ethosuximide was another first-line option for childhood absence epilepsy). For juvenile myoclonic epilepsy in adolescent males, valproate was treatment of choice, with lamotrigine another first-line option; for juvenile myoclonic epilepsy in adolescent females, lamotrigine was treatment of choice, with valproate another firstline option. As initial therapy for neonatal status epilepticus, intravenous (IV) phenobarbital was treatment of choice. As initial therapy for all types of pediatric status epilepticus, IV diazepam was treatment of choice. For generalized tonic-clonic status epilepticus, rectal diazepam and IV lorazepam were also treatments of choice; for complex partial status epilepticus, IV lorazepam was another first-line option. Conclusion. The expert panel reached consensus on many treatment options. Within the limits of expert opinion and with the understanding that new research data may take precedence, the experts’ recommendations provide helpful guidance in situations where the medical literature is scant or lacking. The information in this report should be evaluated in conjunction with evidence-based findings.
TL;DR: The evaluation begins with an extensive history and physical, followed by a diagnostic screening protocol, which may be warranted earlier if a prior miscarriage was found to be euploid, or if there is concomitant infertility and/or advancing maternal age.
Abstract: Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation classically begins after 3 consecutive miscarriages of less than 10 weeks of gestation but may be warranted earlier if a prior miscarriage was found to be euploid, or if there is concomitant infertility and/or advancing maternal age. The evaluation begins with an extensive history and physical, followed by a diagnostic screening protocol. Management must be evidence-based; unproven treatments should be avoided. If no factor is identified, many couples will still eventually have a successful pregnancy outcome with supportive therapy alone.
TL;DR: This paper reports results for the automatic detection of the optic nerve and localization of the macula using digital red-free fundus photography and relies on the accurate segmentation of the vasculature of the retina followed by the determination of spatial features describing the density, average thickness, and average orientation of the Vasculature in relation to the position of the fibre optic nerve.
Abstract: The widespread availability of electronic imaging devices throughout the medical community is leading to a growing body of research on image processing and analysis to diagnose retinal disease such as diabetic retinopathy (DR). Productive computer-based screening of large, at-risk populations at low cost requires robust, automated image analysis. In this paper we present results for the automatic detection of the optic nerve and localization of the macula using digital red-free fundus photography. Our method relies on the accurate segmentation of the vasculature of the retina followed by the determination of spatial features describing the density, average thickness, and average orientation of the vasculature in relation to the position of the optic nerve. Localization of the macula follows using knowledge of the optic nerve location to detect the horizontal raphe of the retina using a geometric model of the vasculature. We report 90.4% detection performance for the optic nerve and 92.5% localization performance for the macula for red-free fundus images representing a population of 345 images corresponding to 269 patients with 18 different pathologies associated with DR and other common retinal diseases such as age-related macular degeneration.
Translational Genomics Research Institute1, Muscular Dystrophy Association2, Washington University in St. Louis3, University of Tennessee Health Science Center4, University of California, Los Angeles5, University of California, Irvine6, University of Texas at San Antonio7, Mayo Clinic8, University of Kansas9, University of California, San Francisco10, Carolinas Medical Center11, University of California, San Diego12, University of Pittsburgh13, California Pacific Medical Center14, Columbia University15
TL;DR: Variants of FLJ10986 may confer susceptibility to sporadic ALS and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.
Abstract: Background Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. Methods We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. Results We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compa...
TL;DR: Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy, and the presence of a dicentric chromosome, monosomy 7, or both predicted a worse EFS but similar OS.