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Showing papers by "University of Tennessee Health Science Center published in 2008"


Journal ArticleDOI
TL;DR: A fully automated service for annotating bacterial and archaeal genomes that identifies protein-encoding, rRNA and tRNA genes, assigns functions to the genes, predicts which subsystems are represented in the genome, uses this information to reconstruct the metabolic network and makes the output easily downloadable for the user.
Abstract: The number of prokaryotic genome sequences becoming available is growing steadily and is growing faster than our ability to accurately annotate them. We describe a fully automated service for annotating bacterial and archaeal genomes. The service identifies protein-encoding, rRNA and tRNA genes, assigns functions to the genes, predicts which subsystems are represented in the genome, uses this information to reconstruct the metabolic network and makes the output easily downloadable for the user. In addition, the annotated genome can be browsed in an environment that supports comparative analysis with the annotated genomes maintained in the SEED environment. The service normally makes the annotated genome available within 12–24 hours of submission, but ultimately the quality of such a service will be judged in terms of accuracy, consistency, and completeness of the produced annotations. We summarize our attempts to address these issues and discuss plans for incrementally enhancing the service. By providing accurate, rapid annotation freely to the community we have created an important community resource. The service has now been utilized by over 120 external users annotating over 350 distinct genomes.

9,397 citations


Journal ArticleDOI
Jean Bousquet, N. Khaltaev, Alvaro A. Cruz1, Judah A. Denburg2, W. J. Fokkens3, Alkis Togias4, T. Zuberbier5, Carlos E. Baena-Cagnani6, Giorgio Walter Canonica7, C. van Weel8, Ioana Agache9, Nadia Aït-Khaled, Claus Bachert10, Michael S. Blaiss11, Sergio Bonini12, L.-P. Boulet13, Philippe-Jean Bousquet, Paulo Augusto Moreira Camargos14, K-H. Carlsen15, Y. Z. Chen, Adnan Custovic16, Ronald Dahl17, Pascal Demoly, H. Douagui, Stephen R. Durham18, R. Gerth van Wijk19, O. Kalayci19, Michael A. Kaliner20, You Young Kim21, Marek L. Kowalski, Piotr Kuna22, L. T. T. Le23, Catherine Lemière24, Jing Li25, Richard F. Lockey26, S. Mavale-Manuel26, Eli O. Meltzer27, Y. Mohammad28, J Mullol, Robert M. Naclerio29, Robyn E O'Hehir30, K. Ohta31, S. Ouedraogo31, S. Palkonen, Nikolaos G. Papadopoulos32, Gianni Passalacqua7, Ruby Pawankar33, Todor A. Popov34, Klaus F. Rabe35, J Rosado-Pinto36, G. K. Scadding37, F. E. R. Simons38, Elina Toskala39, E. Valovirta40, P. Van Cauwenberge10, De Yun Wang41, Magnus Wickman42, Barbara P. Yawn43, Arzu Yorgancioglu44, Osman M. Yusuf, H. J. Zar45, Isabella Annesi-Maesano46, E.D. Bateman45, A. Ben Kheder47, Daniel A. Boakye48, J. Bouchard, Peter Burney18, William W. Busse49, Moira Chan-Yeung50, Niels H. Chavannes35, A.G. Chuchalin, William K. Dolen51, R. Emuzyte52, Lawrence Grouse53, Marc Humbert, C. M. Jackson54, Sebastian L. Johnston18, Paul K. Keith2, James P. Kemp27, J. M. Klossek55, Désirée Larenas-Linnemann55, Brian J. Lipworth54, Jean-Luc Malo24, Gailen D. Marshall56, Charles K. Naspitz57, K. Nekam, Bodo Niggemann58, Ewa Nizankowska-Mogilnicka59, Yoshitaka Okamoto60, M. P. Orru61, Paul Potter45, David Price62, Stuart W. Stoloff63, Olivier Vandenplas, Giovanni Viegi, Dennis M. Williams64 
Federal University of Bahia1, McMaster University2, University of Amsterdam3, National Institutes of Health4, Charité5, Catholic University of Cordoba6, University of Genoa7, Radboud University Nijmegen8, Transilvania University of Brașov9, Ghent University10, University of Tennessee Health Science Center11, University of Naples Federico II12, Laval University13, Universidade Federal de Minas Gerais14, University of Oslo15, University of Manchester16, Aarhus University17, Imperial College London18, Erasmus University Rotterdam19, George Washington University20, Seoul National University21, Medical University of Łódź22, Hai phong University Of Medicine and Pharmacy23, Université de Montréal24, Guangzhou Medical University25, University of South Florida26, University of California, San Diego27, University of California28, University of Chicago29, Monash University30, Teikyo University31, National and Kapodistrian University of Athens32, Nippon Medical School33, Sofia Medical University34, Leiden University35, Leiden University Medical Center36, University College London37, University of Manitoba38, University of Helsinki39, Finnish Institute of Occupational Health40, National University of Singapore41, Karolinska Institutet42, University of Minnesota43, Celal Bayar University44, University of Cape Town45, Pierre-and-Marie-Curie University46, Tunis University47, University of Ghana48, University of Wisconsin-Madison49, University of British Columbia50, Georgia Regents University51, Vilnius University52, University of Washington53, University of Dundee54, University of Poitiers55, University of Mississippi56, Federal University of São Paulo57, German Red Cross58, Jagiellonian University Medical College59, Chiba University60, American Pharmacists Association61, University of Aberdeen62, University of Nevada, Reno63, University of North Carolina at Chapel Hill64
01 Apr 2008-Allergy
TL;DR: The ARIA guidelines for the management of allergic rhinitis and asthma are similar in both the 1999 ARIA workshop report and the 2008 Update as discussed by the authors, but the GRADE approach is not yet available.
Abstract: Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations. In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease. This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work. The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available. Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed. The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.

3,769 citations


Journal ArticleDOI
04 Jan 2008-Science
TL;DR: This comparison reveals genomic changes concomitant with the evolutionary movement to land, including a general increase in gene family complexity; loss of genes associated with aquatic environments; acquisition of genes for tolerating terrestrial stresses; and the development of the auxin and abscisic acid signaling pathways for coordinating multicellular growth and dehydration response.
Abstract: We report the draft genome sequence of the model moss Physcomitrella patens and compare its features with those of flowering plants, from which it is separated by more than 400 million years, and unicellular aquatic algae. This comparison reveals genomic changes concomitant with the evolutionary movement to land, including a general increase in gene family complexity; loss of genes associated with aquatic environments (e.g., flagellar arms); acquisition of genes for tolerating terrestrial stresses (e.g., variation in temperature and water availability); and the development of the auxin and abscisic acid signaling pathways for coordinating multicellular growth and dehydration response. The Physcomitrella genome provides a resource for phylogenetic inferences about gene function and for experimental analysis of plant processes through this plant's unique facility for reverse genetics.

1,749 citations


Journal ArticleDOI
TL;DR: Advances in understanding of the pathobiology of acute lymphoblastic leukaemia, fuelled by emerging molecular technologies, suggest that drugs specifically targeting the genetic defects of leukaemic cells could revolutionise management of this disease.

1,362 citations


Journal ArticleDOI
24 Apr 2008-Nature
TL;DR: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products.
Abstract: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

1,248 citations


Journal ArticleDOI
24 Apr 2008-Nature
TL;DR: Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica’s distinguishing morpho-physiological, medicinal and nutritional properties.
Abstract: Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties.

1,028 citations


Journal ArticleDOI
TL;DR: It is demonstrated that autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies, suggesting a mechanism by which IL- 17 drives autoimmune responses by promoting the formation of spontaneous GCs.
Abstract: Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

671 citations


Journal ArticleDOI
TL;DR: It is shown that alum-induced secretion of IL-1β, IL-18, and IL-33 is mediated by the NLR (nucleotide-binding domain leucine-rich repeat-containing) protein NLRP3 and its adaptor ASC, but not by NLRC4, suggesting that activation of theNLRP3-inflammasome may be a common mechanism of action of particulate adjuvants.
Abstract: Alum is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. We have recently shown that alum activates caspase-1 and induces secretion of mature IL-1β and IL-18. In this study we show that, in human and mouse macrophages, alum-induced secretion of IL-1β, IL-18, and IL-33 is mediated by the NLR (nucleotide-binding domain leucine-rich repeat-containing) protein NLRP3 and its adaptor ASC, but not by NLRC4. Other particulate adjuvants, such as QuilA and chitosan, induce inflammasome activation in a NLRP3-dependent fashion, suggesting that activation of the NLRP3-inflammasome may be a common mechanism of action of particulate adjuvants. Importantly, we demonstrate that Ag-specific Ab production elicited by vaccines that contain alum is significantly impaired in NLRP3-deficient mice. Our results demonstrate for the first time a role for the NLRP3-inflammasome during development of the immune response elicited by alum-enhanced vaccination and suggest that therapeutic intervention aimed at NLRP3 may improve adjuvant efficacy.

636 citations


Journal ArticleDOI
TL;DR: Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsies was reduced among survivors.
Abstract: BACKGROUND Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy METHODS In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age RESULTS A total of 2241 women underwent randomization The baseline characteristics were similar in the two groups Follow-up was achieved for 956% of the children The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (113% and 117%, respectively; relative risk, 097; 95% confidence interval [CI], 077 to 123) However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (19% vs 35%; relative risk, 055; 95% CI, 032 to 095) The risk of death did not differ significantly between the groups (95% vs 85%; relative risk, 112; 95% CI, 085 to 147) No woman had a life-threatening event CONCLUSIONS Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors (ClinicalTrialsgov number, NCT00014989)

553 citations


Journal ArticleDOI
TL;DR: The adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs.
Abstract: When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. 'Disease' is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of 'cross-talk' and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk.

495 citations


Journal ArticleDOI
TL;DR: It is suggested that deiminated histone H3, a covalently modified form of a prominent nuclear autoantigen, is released to the extracellular space as part of the neutrophil response to infections.
Abstract: Posttranslational modifications, such as the deimination of arginine to citrulline by peptidyl arginine deiminase (PAD4), change protein structure and function. For autoantigens, covalent modifications represent a mechanism to sidestep tolerance and stimulate autoimmunity. To examine conditions leading to histone deimination in neutrophils, we used Abs that detect citrullines in the N terminus of histone H3. Deimination was investigated in human neutrophils and HL-60 cells differentiated into granulocytes. We observed rapid and robust H3 deimination in HL-60 cells exposed to LPS, TNF, lipoteichoic acid, f-MLP, or hydrogen peroxide, which are stimuli that activate neutrophils. Importantly, we also observed H3 deimination in human neutrophils exposed to these stimuli. Citrullinated histones were identified as components of extracellular chromatin traps (NETs) produced by degranulating neutrophils. In contrast, apoptosis proceeded without detectable H3 deimination in HL-60 cells exposed to staurosporine or camptothecin. We conclude that histone deimination in neutrophils is induced in response to inflammatory stimuli and not by treatments that induce apoptosis. Our results further suggest that deiminated histone H3, a covalently modified form of a prominent nuclear autoantigen, is released to the extracellular space as part of the neutrophil response to infections. The possible association of a modified autoantigen with microbial components could, in predisposed individuals, increase the risk of autoimmunity.

Journal ArticleDOI
TL;DR: It is shown that common genetic variation influences levels of clinically relevant proteins in human serum and plasma and the identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving the understanding of disease pathways.
Abstract: There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

Journal ArticleDOI
TL;DR: Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women and a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk was not supported.
Abstract: Results Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case – control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) ( r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity ( P trend = .20).


Journal ArticleDOI
TL;DR: Patients receiving face-to-face M TM services provided by pharmacists in collaboration with prescribers experienced improved clinical outcomes and lower total health expenditures, and economic outcomes support inclusion of MTM services in health plan design.
Abstract: Objectives To (1) provide medication therapy management (MTM) services to patients, (2) measure the clinical effects associated with the provision of MTM services, (3) measure the percent of patients achieving Healthcare Effectiveness Data and Information Set (HEDIS) goals for hypertension and hyperlipidemia in the MTM services intervention group in relationship to a comparison group who did not receive MTM services, and (4) compare patients' total health expenditures for the year before and after receiving MTM services. Design Prospective study. Setting Six ambulatory clinics in Minnesota from August 1, 2001, to July 31, 2002. Patients 285 intervention group patients with at least 1 of 12 medical conditions using prestudy health claims; 126 comparison group patients with hypertension and 126 patients with hyperlipidemia were selected among 9 clinics without MTM services for HEDIS analysis. Intervention MTM services provided by pharmacists to BlueCross BlueShield health plan beneficiaries in collaboration with primary care providers. Main outcome measures Drug therapy problems resolved; percentage of patients goals of therapy achieved and meeting HEDIS measures for hypertension and hypercholesterolemia. Total health expenditures per person were measured for a 1-year period before and after enrolling patients in MTM services. Results 637 drug therapy problems were resolved among 285 intervention patients, and the percentage of patients' goals of therapy achieved increased from 76% to 90%. HEDIS measures improved in the intervention group compared with the comparison group for hypertension (71% versus 59%) and cholesterol management (52% versus 30%). Total health expenditures decreased from $11,965 to $8,197 per person (n = 186, P Conclusion Patients receiving face-to-face MTM services provided by pharmacists in collaboration with prescribers experienced improved clinical outcomes and lower total health expenditures. Clinical outcomes of MTM services have chronic care improvement and value-based purchasing implications, and economic outcomes support inclusion of MTM services in health plan design.

Journal ArticleDOI
TL;DR: Naturally occurring dominant STAT‐C resistance mutations are common in treatment‐naïve patients infected with HCV genotype 1, and their influence on treatment outcome should be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Journal ArticleDOI
TL;DR: These studies demonstrate that probiotic-secretory proteins protect the intestinal epithelial tight junctions and the barrier function from hydrogen peroxide-induced insult by a PKC- and MAP kinase-dependent mechanism.
Abstract: Probiotics promote intestinal epithelial integrity and reduce infection and diarrhea. We evaluated the effect of Lactobacillus rhamnosus GG-produced soluble proteins (p40 and p75) on the hydrogen p...

Journal ArticleDOI
TL;DR: Recovery biomarker data were used in regression equations to calibrate self- Reports and the potential application of these equations to disease risk modeling is presented; the authors confirm the existence of systematic bias in dietary self-reports and provide methods of correcting for measurement error.
Abstract: Underreporting of energy consumption by self-report is well-recognized, but previous studies using recovery biomarkers have not been sufficiently large to establish whether participant characteristics predict misreporting. In 2004-2005, 544 participants in the Women's Health Initiative Dietary Modification Trial completed a doubly labeled water protocol (energy biomarker), 24-hour urine collection (protein biomarker), and self-reports of diet (assessed by food frequency questionnaire (FFQ)), exercise, and lifestyle habits; 111 women repeated all procedures after 6 months. Using linear regression, the authors estimated associations of participant characteristics with misreporting, defined as the extent to which the log ratio (self-reported FFQ/nutritional biomarker) was less than zero. Intervention women in the trial underreported energy intake by 32% (vs. 27% in the comparison arm) and protein intake by 15% (vs. 10%). Younger women had more underreporting of energy (p = 0.02) and protein (p = 0.001), while increasing body mass index predicted increased underreporting of energy and overreporting of percentage of energy derived from protein (p = 0.001 and p = 0.004, respectively). Blacks and Hispanics underreported more than did Caucasians. Correlations of initial measures with repeat measures (n = 111) were 0.72, 0.70, 0.46, and 0.64 for biomarker energy, FFQ energy, biomarker protein, and FFQ protein, respectively. Recovery biomarker data were used in regression equations to calibrate self-reports; the potential application of these equations to disease risk modeling is presented. The authors confirm the existence of systematic bias in dietary self-reports and provide methods of correcting for measurement error.

Journal ArticleDOI
TL;DR: Effective retrieval treatment is needed for patients with relapsed or refractory CNS leukaemia, and intrathecal treatment with improved efficacy and reduced side-effects remains a long-term objective.
Abstract: Summary With 5-year event-free survival of 80% now commonplace for paediatric acute lymphoblastic leukaemia (ALL), and 50% for paediatric acute myeloid leukaemia (AML), recent efforts have focused on optimum risk-directed treatment. Because cranial irradiation can cause many acute and late complications (eg, second cancers, neurocognitive deficits, endocrine disorders, and growth impairment), it has been largely replaced by intensive intrathecal treatment and systemic chemotherapy. Prophylactic cranial irradiation (12–18 Gy) is given to 2–20% of patients with ALL who have an increased risk of CNS relapse (such as T-cell immunophenotype, overt CNS disease, high-risk cytogenetic features, or poor response to remission induction treatment), and for the estimated 2% of patients with AML who have overt CNS disease at diagnosis. Although this strategy restricts CNS relapse to 3–8% of patients, several challenges remain. Methods need to eliminate relapse without the use of cranial irradiation in very high-risk patients. Effective retrieval treatment is needed for patients with relapsed or refractory CNS leukaemia, and intrathecal treatment with improved efficacy and reduced side-effects remains a long-term objective. Perhaps the most formidable challenge is to treat children with CNS relapse after a short initial remission or cranial irradiation.

Journal ArticleDOI
TL;DR: The Women9s Health Initiative calcium/vitamin D trial randomly assigned postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion as discussed by the authors.
Abstract: Objective: Experimental and epidemiologic studies suggest that calcium and vitamin D may reduce the risk of developing diabetes mellitus. We examined the effect of calcium plus vitamin D supplementation on the incidence of drug-treated diabetes in postmenopausal women. Research Design And Methods: The Women9s Health Initiative calcium/vitamin D trial randomly assigned postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion. Among 33,951 participants without self-reported diabetes at baseline, we ascertained by treatment assignment new diagnoses of diabetes treated with oral hypoglycemic agents or insulin. Effects of the intervention on fasting measurements of glucose, insulin, and insulin resistance were examined among a subset of participants. Results: Over a median follow-up time of 7 years, 2,291 women were newly diagnosed with diabetes. The hazard ratio for incident diabetes associated with calcium/vitamin D treatment was 1.01 (95% confidence interval 0.94, 1.10) based on intention to treat. This null result was robust in subgroup analyses, efficacy analyses accounting for nonadherence, and analyses examining change in laboratory measurements. Conclusions: Calcium plus vitamin D3 supplementation did not reduce the risk of developing diabetes over seven years of follow-up in this randomized, placebo-controlled trial. Higher doses of vitamin D may be required to affect diabetes risk, and/or associations of calcium and vitamin D intake with improved glucose metabolism observed in nonrandomized studies may be the result of confounding or of other components of foods containing these nutrients.

Journal ArticleDOI
TL;DR: The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: End‐stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient ≥ 10 mm Hg.

Journal ArticleDOI
TL;DR: This review traces the history of one of the most effective treatments for childhood epilepsy, the ketogenic diet, which was introduced by modern physicians as a treatment for epilepsy in the 1920s and declined dramatically with the modern era of antiepileptic drug treatment.
Abstract: Fasting and other dietary regimens have been used to treat epilepsy since at least 500 BC. To mimic the metabolism of fasting, the ketogenic diet (KD) was introduced by modern physicians as a treatment for epilepsy in the 1920s. For two decades this therapy was widely used, but with the modern era of antiepileptic drug treatment its use declined dramatically. By the end of the twentieth century this therapy was available in only a small number of children's hospitals. Over the past 15 years, there has been an explosion in the use, and scientific interest in the KD. This review traces the history of one of the most effective treatments for childhood epilepsy.

Journal ArticleDOI
TL;DR: The treatment cornerstone remains securing the airway, providing efficient drainage and appropriate antibiotics, and improving immunologic status, and a prolonged hospital stay should be anticipated.

Journal ArticleDOI
TL;DR: The possible involvement of gangliosides in the development of AD and the therapeutic potentials of Ganglioside metabolism are described, as well as the involvement of these microdomains in certain neurodegenerative diseases, such as AD.

Journal ArticleDOI
TL;DR: Recent studies elucidating the transcriptional and post-transcriptional regulation of SREBP-1c through nutrition and the action of hormones, particularly insulin, and the resulting implications for dyslipidemia of obesity, metabolic syndrome and type 2 diabetes are summarized.
Abstract: The uptake, biosynthesis and metabolism of cholesterol and other lipids are exquisitely regulated by feedback and feed-forward pathways in organisms ranging from Caenorhabditis elegans to humans. As endoplasmic reticulum (ER) membrane-embedded transcription factors that are activated in the Golgi apparatus, sterol regulatory element-binding proteins (SREBPs) are central to the intracellular surveillance of lipid catabolism and de novo biogenesis. The biosynthesis of SREBP proteins, their migration from the ER to the Golgi compartment, intra-membrane proteolysis, nuclear translocation and trans-activation potential are tightly controlled in vivo. Here we summarize recent studies elucidating the transcriptional and post-transcriptional regulation of SREBP-1c through nutrition and the action of hormones, particularly insulin, and the resulting implications for dyslipidemia of obesity, metabolic syndrome and type 2 diabetes.

Journal ArticleDOI
TL;DR: The role of oxidative stress and locally produced angiotensin II in the pathogenesis of myocardial repair/remodelling after MI is discussed.
Abstract: Heart failure is a global health problem, appearing most commonly in patients with previous myocardial infarction (MI). Cardiac remodelling, particularly fibrosis, seen in both the infarcted and non-infarcted myocardium is recognized to be a major determinant of the development of impaired ventricular function, leading to a poor prognosis. Elucidating cellular and molecular mechanisms responsible for the accumulation of extracellular matrix is essential for designing cardioprotective and reparative strategies that could regress fibrosis after infarction. Multiple factors contribute to left ventricular remodelling at different stages post-MI. This review will discuss the role of oxidative stress and locally produced angiotensin II in the pathogenesis of myocardial repair/remodelling after MI.


Journal ArticleDOI
TL;DR: A progress report of the Collaborative Cross breeding program at ORNL is presented and a description of the kinds of investigations that this resource will support is presented.
Abstract: Complex traits and disease comorbidity in humans and in model organisms are the result of naturally occurring polymorphisms that interact with each other and with the environment. To ensure the availability of resources needed to investigate biomolecular networks and systems-level phenotypes underlying complex traits, we have initiated breeding of a new genetic reference population of mice, the Collaborative Cross. This population has been designed to optimally support systems genetics analysis. Its novel and important features include a high level of genetic diversity, a large population size to ensure sufficient power in high-dimensional studies, and high mapping precision through accumulation of independent recombination events. Implementation of the Collaborative Cross has been ongoing at the Oak Ridge National Laboratory (ORNL) since May 2005. Production has been systematically managed using a software-assisted breeding program with fully traceable lineages, performed in a controlled environment. Currently, there are 650 lines in production, and close to 200 lines are now beyond their seventh generation of inbreeding. Retired breeders enter a high-throughput phenotyping protocol and DNA samples are banked for analyses of recombination history, allele drift and loss, and population structure. Herein we present a progress report of the Collaborative Cross breeding program at ORNL and a description of the kinds of investigations that this resource will support.

Journal ArticleDOI
01 Mar 2008-Obesity
TL;DR: This study evaluated to what extent dual‐energy X‐ray absorptiometry (DXA) and two types of bioimpedance analysis (BIA) yield similar results for body fat mass in men and women with different levels of obesity and physical activity.
Abstract: Objective: This study evaluated to what extent dual-energy X-ray absorptiometry (DXA) and two types of bioimpedance analysis (BIA) yield similar results for body fat mass (FM) in men and women with different levels of obesity and physical activity (PA). Methods and Procedures: The study population consisted of 37–81-year-old Finnish people (82 men and 86 women). FM% was estimated using DXA (GE Lunar Prodigy) and two BIA devices (InBody (720) and Tanita BC 418 MA). Subjects were divided into normal, overweight, and obese groups on the basis of clinical cutoff points of BMI, and into low PA (LPA) and high PA (HPA) groups. Agreement between the devices was calculated by using the Bland–Altman analysis. Results: Compared to DXA, both BIA devices provided on average 2–6% lower values for FM% in normal BMI men, in women in all BMI categories, and in both genders in both HPA and LPA groups. In obese men, the differences were smaller. The two BIA devices provided similar means for groups. Differences between the two BIA devices with increasing FM% were a result of the InBody (720) not including age in their algorithm for estimating body composition. Discussion: BIA methods provided systematically lower values for FM than DXA. However, the differences depend on gender and body weight status pointing out the importance of considering these when identifying people with excess FM.

Journal ArticleDOI
TL;DR: In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.
Abstract: Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI: -0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI: -0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI: 0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.