Showing papers by "University of Basel published in 2010"
TL;DR: In this article, a biennial review summarizes much of particle physics using data from previous editions, plus 2158 new measurements from 551 papers, they list, evaluate and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.
2,788 citations
TL;DR: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.
Abstract: BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)
2,040 citations
TL;DR: It is shown that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR), which uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity.
1,611 citations
TL;DR: High-resolution mass spectrometry–based proteomics was applied to investigate the proteome and phosphoproteome of the human cell cycle on a global scale and quantified 6027 proteins and 20,443 unique phosphorylation sites and their dynamics, finding that nuclear proteins and proteins involved in regulating metabolic processes have high phosphorylated site occupancy in mitosis, suggesting that these proteins may be inactivated by phosphorylate in mitotic cells.
Abstract: Eukaryotic cells replicate by a complex series of evolutionarily conserved events that are tightly regulated at defined stages of the cell division cycle. Progression through this cycle involves a large number of dedicated protein complexes and signaling pathways, and deregulation of this process is implicated in tumorigenesis. We applied high-resolution mass spectrometry-based proteomics to investigate the proteome and phosphoproteome of the human cell cycle on a global scale and quantified 6027 proteins and 20,443 unique phosphorylation sites and their dynamics. Co-regulated proteins and phosphorylation sites were grouped according to their cell cycle kinetics and compared to publicly available messenger RNA microarray data. Most detected phosphorylation sites and more than 20% of all quantified proteins showed substantial regulation, mainly in mitotic cells. Kinase-motif analysis revealed global activation during S phase of the DNA damage response network, which was mediated by phosphorylation by ATM or ATR or DNA-dependent protein kinases. We determined site-specific stoichiometry of more than 5000 sites and found that most of the up-regulated sites phosphorylated by cyclin-dependent kinase 1 (CDK1) or CDK2 were almost fully phosphorylated in mitotic cells. In particular, nuclear proteins and proteins involved in regulating metabolic processes have high phosphorylation site occupancy in mitosis. This suggests that these proteins may be inactivated by phosphorylation in mitotic cells.
1,447 citations
TL;DR: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy, but in the meantime, carotin artery stent should remain the treatment of choice for patients suitable for surgery.
1,115 citations
TL;DR: In this paper, the authors present the first calculations of the optical transients from compact object mergers that self-consistently determine the radioactive heating by means of a nuclear reaction network; using this heating rate, they model the light curve with a one-dimensional Monte Carlo radiation transfer calculation.
Abstract: The most promising astrophysical sources of kHz gravitational waves (GWs) are the inspiral and merger of binary neutron star(NS)/black hole systems. Maximizing the scientific return of a GW detection will require identifying a coincident electromagnetic (EM) counterpart. One of the most likely sources of isotropic EM emission from compact object mergers is a supernova-like transient powered by the radioactive decay of heavy elements synthesized in ejecta from the merger. We present the first calculations of the optical transients from compact object mergers that self-consistently determine the radioactive heating by means of a nuclear reaction network; using this heating rate, we model the light curve with a one-dimensional Monte Carlo radiation transfer calculation. For an ejecta mass ~ 10 -2 M ⊙ (10 -3 M ⊙ ) the resulting light-curve peaks on a time-scale ~1 d at a V-band luminosity vL v ~ 3 x 10 41 (10 41 )erg s -1 [M V = -15(-14)]; this corresponds to an effective 'f' parameter ~3 × 10- 6 in the Li-Paczynski toy model. We argue that these results are relatively insensitive to uncertainties in the relevant nuclear physics and to the precise early-time dynamics and ejecta composition. Since NS merger transients peak at a luminosity that is a factor of ~10 3 higher than a typical nova, we propose naming these events 'kilo-novae'. Because of the rapid evolution and low luminosity of NS merger transients, EM counterpart searches triggered by GW detections will require close collaboration between the GW and astronomical communities. NS merger transients may also be detectable following a short-duration gamma-ray burst or 'blindly' with present or upcoming optical transient surveys. Because the emission produced by NS merger ejecta is powered by the formation of rare r-process elements, current optical transient surveys can directly constrain the unknown origin of the heaviest elements in the Universe.
1,021 citations
TL;DR: This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
Abstract: Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
1,021 citations
University of Basel1, Radboud University Nijmegen2, University of Padua3, Complutense University of Madrid4, University of Paris5, University of Zurich6, University of Bari7, Lithuanian University of Health Sciences8, University of Florence9, Russian Academy10, Rambam Health Care Campus11, University of Regensburg12, Charité13, University of the Witwatersrand14, Johns Hopkins University15, University of Coimbra16, University of Verona17, Lund University18, University of Ljubljana19, Utrecht University20, University of Pécs21, Medical University of Vienna22, University of Debrecen23, Sapienza University of Rome24, University of Geneva25, University of Silesia in Katowice26, University College London27, University of Tübingen28, Military Medical Academy29, Lille University of Science and Technology30, University of Michigan31, Iuliu Hațieganu University of Medicine and Pharmacy32, Charles University in Prague33, University of Zagreb34
TL;DR: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
Abstract: Objectives To determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
1,010 citations
TL;DR: The preclinical profile for an optimized spiroindolone drug candidate, NITD609, shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
Abstract: Recent reports of increased tolerance to artemisinin derivatives—the most recently adopted class of antimalarials—have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
990 citations
TL;DR: The JINA REACLIB project as mentioned in this paper maintains a library of thermonuclear reaction rates for astrophysical applications, which are transparently documented and version tracked, and any set of rates is publicly available and can be downloaded via a web interface at http://groups.nscl.msu.edu/jina/reaclib/db/.
Abstract: We present results from the JINA REACLIB project, an ongoing effort to maintain a current and accurate library of thermonuclear reaction rates for astrophysical applications. Ongoing updates are transparently documented and version tracked, and any set of rates is publicly available and can be downloaded via a Web interface at http://groups.nscl.msu.edu/jina/reaclib/db/. We discuss here our library V1.0, a snapshot of recommended rates for stable and explosive hydrogen and helium burning. We show that the updated reaction rates lead to modest but significant changes in full network, one-dimensional X-ray burst model calculations, compared with calculations with previously used reaction rate sets. The late time behavior of X-ray burst light curves shows significant changes, suggesting that the previously found small discrepancies between model calculations and observations may be solved with a better understanding of the nuclear input. Our X-ray burst model calculations are intended to serve as a benchmark for future model comparisons and sensitivity studies, as the complete underlying nuclear physics is fully documented and publicly available.
840 citations
TL;DR: In most temperate tree species, phenological events such as flowering and autumnal cessation of growth are not primarily controlled by temperature, so how will it affect the arrival of spring and the length of the growing season?
Abstract: Phenological events such as bud burst, flowering, and senescence have received increased interest in the light of global warming ( 1 – 3 ) Spring events at temperate latitudes have advanced by 25 days per decade since 1971 ( 4 ) As global warming progresses, how will it affect the arrival of spring and the length of the growing season?
TL;DR: In this paper, a new reconstruction of Alpine Tethys combines plate-kinematic modeling with a wealth of geological data and seismic tomography to shed light on its evolution, from sea-floor spreading through subduction to collision in the Alps.
University of Freiburg1, Johns Hopkins University2, University of Lübeck3, University of Regensburg4, University of Washington5, University of Maryland, Baltimore6, Washington University in St. Louis7, Boston University8, University of Iceland9, Memorial Hospital of South Bend10, National Institutes of Health11, Erasmus University Rotterdam12, University of Greifswald13, McMaster University14, Mayo Clinic15, University of Mainz16, Wake Forest University17, Harvard University18, University of Basel19, Swiss Tropical and Public Health Institute20, Innsbruck Medical University21, Leipzig University22, Western General Hospital23, University of Texas Health Science Center at Houston24, Cedars-Sinai Medical Center25, University of Pittsburgh26, Ludwig Maximilian University of Munich27, University of Ulm28, University of Edinburgh29, University of Split30, University of Zagreb31, Uppsala University32, University of Kiel33, University of London34, University of Oxford35, Amgen36, University of Michigan37, University of Geneva38, Capital Medical University39, University of California, San Francisco40, Heidelberg University41
TL;DR: The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry to identify new susceptibility loci for reduced renal function as estimated by serum creatinine, serum cystatin c and CKD.
Abstract: Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
TL;DR: Intracranial aneurysm treatment with the PED is technically feasible and can be achieved with a safety profile analogous to that reported for stent-supported coil embolization, as presented in the first prospective multicenter trial of a flow-diverting construct for the treatment of intracranialAneurysms.
Abstract: BACKGROUND AND PURPOSE: Endoluminal reconstruction with flow diverting devices represents a novel constructive technique for the treatment of cerebral aneurysms. We present the results of the first prospective multicenter trial of a flow-diverting construct for the treatment of intracranial aneurysms. MATERIALS AND METHODS: Patients with unruptured aneurysms that were wide-necked (>4 mm), had unfavorable dome/neck ratios ( RESULTS: Thirty-one patients with 31 intracranial aneurysms (6 men; 42–76 years of age; average age, 54.6 years) were treated during the study period. Twenty-eight aneurysms arose from the ICA (5 cavernous, 15 parophthalmic, 4 superior hypophyseal, and 4 posterior communicating segments), 1 from the MCA, 1 from the vertebral artery, and 1 from the vertebrobasilar junction. Mean aneurysm size was 11.5 mm, and mean neck size was 5.8 mm. Twelve (38.7%) aneurysms had failed (or recurred after) a previous endovascular treatment. PED placement was technically successful in 30 of 31 patients (96.8%). Most aneurysms were treated with either 1 (n = 18) or 2 (n = 11) PEDs. Fifteen aneurysms (48.4%) were treated with a PED alone, while 16 were treated with both PED and embolization coils. Two patients experienced major periprocedural stroke. Follow-up angiography demonstrated complete aneurysm occlusion in 28 (93.3%) of the 30 patients who underwent angiographic follow-up. No significant in-construct stenosis (≥50%) was identified at follow-up angiography. CONCLUSIONS: Intracranial aneurysm treatment with the PED is technically feasible and can be achieved with a safety profile analogous to that reported for stent-supported coil embolization. PED treatment elicited a very high rate (93%) of complete angiographic occlusion at 6 months in a population of the most challenging anatomic subtypes of cerebral aneurysms.
TL;DR: It is demonstrated that Rab conversion is the mechanism by which proteins pass from early to late endosomes in Caenorhabditis elegans coelomocytes and identified SAND-1/Mon1 as the critical switch for Rab conversion in metazoa.
TL;DR: The Theriak/Domino software as discussed by the authors uses a unique algorithm of scanning and bookkeeping, which allows to compute completely and automatically a great variety of diagrams: phase diagrams, pseudo-binary, pseudoternary, isopleths, modal amounts, molar properties of single phases or bulk-rock properties like total Δ G, volume of solids, etc.
Abstract: In this paper, the term “equilibrium assemblage diagrams” refers to diagrams strictly based on assemblages predicted by Gibbs free energy minimization. The presented Theriak/Domino software uses a unique algorithm of scanning and bookkeeping, which allows to compute completely and automatically a great variety of diagrams: phase diagrams, pseudo-binary, pseudo-ternary, isopleths, modal amounts, molar properties of single phases or bulk-rock properties like total Δ G , volume of solids, etc. The speed and easiness of use makes thermodynamic modeling accessible to any student of Earth sciences and offers a powerful tool to check the consistency of thermodynamic databases, develop new solution models, plan experimental work, and to understand natural systems. The examples described in this paper demonstrate the capacity of the software, but also to show the usefulness and limitations of computed equilibrium assemblage diagrams. For most illustrations, a metapelite (TN205) from the eastern Lepontine Alps is used. The applications include the interpretation of complex diagrams, mineral reactions, the effect of Al content on the equilibrium assemblages, the interpretation of Si per formula unit in white mica, understanding some features of garnet growth, dehydration and isothermal compressibility, a broadening of the concept of AFM diagrams, combining equilibrium assemblage diagram information with thermobarometry, and comparing the results produced with different databases. Equilibrium assemblage diagrams do not always provide straightforward answers, but mostly stimulate further thought.
TL;DR: A genome-wide phylogeny based on genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes.
Abstract: Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. We sequenced the genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) at 40- to 90-fold coverage using Illumina next-generation DNA sequencing. We constructed a genome-wide phylogeny based on these genome sequences. Comparative analyses of the sequences showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes. Notably, however, most of the 491 experimentally confirmed human T cell epitopes showed little sequence variation and had a lower ratio of nonsynonymous to synonymous changes than seen in essential and nonessential genes. We confirmed these findings in an additional data set consisting of 16 antigens in 99 MTBC strains. These findings are consistent with strong purifying selection acting on these epitopes, implying that MTBC might benefit from recognition by human T cells.
TL;DR: Using adoptive transfer of genetically tagged LTi-like cells, it is demonstrated that NKR⁻RORγt(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)RORγT(+) cells in vivo.
TL;DR: Disruption of function of left, but not right, lateral prefrontal cortex with low-frequency repetitive transcranial magnetic stimulation increased choices of immediate rewards over larger delayed rewards, providing causal evidence for a neural lateral-prefrontal cortex–based self-control mechanism in intertemporal choice.
Abstract: Disruption of function of left, but not right, lateral prefrontal cortex (LPFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) increased choices of immediate rewards over larger delayed rewards. rTMS did not change choices involving only delayed rewards or valuation judgments of immediate and delayed rewards, providing causal evidence for a neural lateral-prefrontal cortex-based self-control mechanism in intertemporal choice.
TL;DR: Hematopoietic stem cell transplantation is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities.
Abstract: Context Hematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known about HSCT use and the factors associated with it on a global level. Objectives To determine current use of HSCT to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level. Design, Setting, and Patients Retrospective survey study of patients receiving allogeneic and autologous HSCTs for 2006 collected by 1327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation. The regional areas used herein are (1) the Americas (the corresponding World Health Organization regions are North and South America); (2) Asia (Southeast Asia and the Western Pacific Region, which includes Australia and New Zealand); (3) Europe (includes Turkey and Israel); and (4) the Eastern Mediterranean and Africa. Main Outcome Measures Transplant rates (number of HSCTs per 10 million inhabitants) by indication, donor type, and country; description of main differences in HSCT use; and macroeconomic factors of reporting countries associated with HSCT rates. Results There were 50 417 first HSCTs; 21 516 allogeneic (43%) and 28 901 autologous (57%). The median HSCT rates varied between regions and countries from 48.5 (range, 2.5-505.4) in the Americas, 184 (range, 0.6-488.5) in Asia, 268.9 (range, 5.7-792.1) in Europe, and 47.7 (range, 2.8-95.3) in the Eastern Mediterranean and Africa. No HSCTs were performed in countries with less than 300 000 inhabitants, smaller than 960 km 2 , or having less than US $680 gross national income per capita. Use of allogeneic or autologous HSCT, unrelated or family donors for allogeneic HSCT, and proportions of disease indications varied significantly between countries and regions. In linear regression analyses, government health care expenditures (r 2 = 77.33), HSCT team density (indicates the number of transplant teams per 1 million inhabitants; r 2 = 76.28), human development index (r 2 = 74.36), and gross national income per capita (r 2 = 74.04) showed the highest associations with HSCT rates. Conclusion Hematopoietic stem cell transplantation is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities.
TL;DR: The results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
Abstract: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
University of Leicester1, University of Nottingham2, Queen Mary University of London3, Medical Research Council4, Imperial College London5, King's College London6, Western General Hospital7, Uppsala University8, Wellcome Trust Sanger Institute9, University of Bristol10, St George's, University of London11, University of Helsinki12, University of Jyväskylä13, National Institutes of Health14, University of Zurich15, University of Split16, University of Zagreb17, University of Edinburgh18, University of Greifswald19, University of Gothenburg20, University of Western Australia21, Sir Charles Gairdner Hospital22, University College London23, University of London24, Glenfield Hospital25, University of Dundee26, National Institute for Health Research27, Southampton General Hospital28, Pasteur Institute29, University of Basel30, AstraZeneca31, University of Tampere32, University of St Andrews33, Health Protection Agency34
TL;DR: Genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium offers mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Abstract: Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
TL;DR: In view of the available pharmacological data and the long tradition of use in the traditional Chinese medicine, L. barbarum and L. chinense certainly deserve further investigation, but clinical evidences and rigorous procedures for quality control are indispensable before any recommendation of use can be made for Goji products.
Abstract: Since the beginning of this century, Goji berries and juice are being sold as health food products in western countries and praised in advertisements and in the media for well-being and as an anti-aging remedy. The popularity of Goji products has rapidly grown over the last years thanks to efficient marketing strategies. Goji is a relatively new name given to Lycium barbarum and L. chinense, two close species with a long tradition of use as medicinal and food plants in East Asia, in particular in China. While only L. barbarum is officinal, the fruit (fructus Lycii) and the root bark (cortex Lycii radicis) of both species are used in the folk medicine. We review here the constituents, pharmacology, safety, and uses of L. barbarum and L. chinense with consideration to the different parts of the plant. Investigations of the fruit have focused on proteoglycans, known as " Lycium barbarum polysaccharides", which showed antioxidative properties and some interesting pharmacological activities in the context of age related diseases such as atherosclerosis and diabetes. As to the root bark, several compounds have demonstrated a hepatoprotective action as well as inhibitory effects on the rennin/angiotensin system which may support the traditional use for the treatment of hypertension. While there are no signs of toxicity of this plant, two cases of possible interaction with warfarin point to a potential risk of drug interaction. In view of the available pharmacological data and the long tradition of use in the traditional Chinese medicine, L. barbarum and L. chinense certainly deserve further investigation. However, clinical evidences and rigorous procedures for quality control are indispensable before any recommendation of use can be made for Goji products.
University of California, San Diego1, University of Basel2, Henry Ford Health System3, Cleveland Clinic4, Wrocław Medical University5, Charité6, Virginia Commonwealth University7, University of California, San Francisco8, University of Otago9, Veterans Health Administration10, National and Kapodistrian University of Athens11, University of Leicester12, University of Maryland, Baltimore13
TL;DR: MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret, and MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP.
TL;DR: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesphageal remodelling were reversed.
Abstract: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated.
TL;DR: In this paper, a spherically symmetric general relativistic radiation hydrodynamics using spectral three-flavor Boltzmann neutrino transport is used to simulate the collapse, bounce, explosion, and the neutrini-driven wind phases consistently over more than 20 s.
Abstract: Massive stars end their lives in explosions with kinetic energies on the order of 10 51 erg. Immediately after the explosion has been launched, a region of low density and high entropy forms behind the ejecta, which is continuously subject to neutrino heating. The neutrinos emitted from the remnant at the center, the protoneutron star (PNS), heat the material above the PNS surface. This heat is partly converted into kinetic energy, and the material accelerates to an outflow that is known as the neutrino-driven wind. For the first time we simulate the collapse, bounce, explosion, and the neutrino-driven wind phases consistently over more than 20 s. Our numerical model is based on spherically symmetric general relativistic radiation hydrodynamics using spectral three-flavor Boltzmann neutrino transport. In simulations where no explosions are obtained naturally, we model neutrino-driven explosions for low- and intermediatemass Fe-core progenitor stars by enhancing the charged current reaction rates. In the case of a special progenitor star, the 8. 8M � O-Ne-Mg-core, the explosion in spherical symmetry was obtained without enhanced opacities. The post-explosion evolution is in qualitative agreement with static steady-state and parametrized dynamic models of the neutrino-driven wind. On the other hand, we generally find lower neutrino luminosities and mean neutrino energies, as well as a different evolutionary behavior of the neutrino luminosities and mean neutrino energies. The neutrino-driven wind is proton-rich for more than 10 s and the contraction of the PNS differs from the assumptions made for the conditions at the inner boundary in previous neutrino-driven wind studies. Despite the moderately high entropies of about 100 kB/baryon and the fast expansion timescales, the conditions found in our models are unlikely to favor r-process nucleosynthesis. The simulations are carried out until the neutrino-driven wind settles down to a quasi-stationary state. About 5 s after the bounce, the peak temperature inside the PNS already starts to decrease because of the continued deleptonization. This moment determines the beginning of a cooling phase dominated by the emission of neutrinos. We discuss the physical conditions of the quasi-static PNS evolution and take the effects of deleptonization and mass accretion from early fallback into account.
TL;DR: A school based multi-component physical activity intervention including compulsory elements improved physical activity and fitness and reduced adiposity in children.
Abstract: Objective To assess the effectiveness of a school based physical activity programme during one school year on physical and psychological health in young schoolchildren. Design Cluster randomised controlled trial. Setting 28 classes from 15 elementary schools in Switzerland randomly selected and assigned in a 4:3 ratio to an intervention (n=16) or control arm (n=12) after stratification for grade (first and fifth grade), from August 2005 to June 2006. Participants 540 children, of whom 502 consented and presented at baseline. Intervention Children in the intervention arm (n=297) received a multi-component physical activity programme that included structuring the three existing physical education lessons each week and adding two additional lessons a week, daily short activity breaks, and physical activity homework. Children (n=205) and parents in the control group were not informed of an intervention group. For most outcome measures, the assessors were blinded. Main outcome measures Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). Secondary outcome measures included body mass index and cardiovascular risk score (average z score of waist circumference, mean blood pressure, blood glucose, inverted high density lipoprotein cholesterol, and triglycerides). Results 498 children completed the baseline and follow-up assessments (mean age 6.9 (SD 0.3) years for first grade, 11.1 (0.5) years for fifth grade). After adjustment for grade, sex, baseline values, and clustering within classes, children in the intervention arm compared with controls showed more negative changes in the z score of the sum of four skinfolds (−0.12, 95 % confidence interval −0.21 to −0.03; P=0.009). Likewise, their z scores for aerobic fitness increased more favourably (0.17, 0.01 to 0.32; P=0.04), as did those for moderate-vigorous physical activity in school (1.19, 0.78 to 1.60; P Conclusions A school based multi-component physical activity intervention including compulsory elements improved physical activity and fitness and reduced adiposity in children. Trial registration Current Controlled Trials ISRCTN15360785.
TL;DR: Urine and blood cultures reveal multidrug-resistant, extendedspectrum β-lactamase–producing Escherichia coli susceptible to imipenem.
Abstract: Copyright © 2010 Massachusetts Medical Society. A 57-year-old man presents with fever, chills, and new lumbar back pain 2 weeks after undergoing a prostate biopsy because of an increased prostate-specific antigen level. His temperature is 39.7°C; he has an enlarged, tender prostate and lumbar spine tenderness. His white-cell count is 9100 per cubic millimeter, and the C-reactive protein level is 343 mg per liter. Urine and blood cultures reveal multidrug-resistant, extendedspectrum β-lactamase–producing Escherichia coli susceptible to imipenem. How should he be evaluated and treated?
Harvard University1, Broad Institute2, QIMR Berghofer Medical Research Institute3, King's College London4, Radboud University Nijmegen Medical Centre5, University of Würzburg6, State University of New York Upstate Medical University7, University of Marburg8, Cardiff University9, Aarhus University Hospital10, University of Zurich11, University of Basel12, Goethe University Frankfurt13, University of Trier14, Trinity College, Dublin15, University of St Andrews16, VU University Amsterdam17, Ghent University18, Semel Institute for Neuroscience and Human Behavior19, University of Pennsylvania20, Children's Hospital of Philadelphia21, Washington University in St. Louis22, University of Valencia23, Hebrew University of Jerusalem24, University of Göttingen25, University of Duisburg-Essen26, University of Southampton27, New York University28, Eli Lilly and Company29, Pfizer30, University of California, Los Angeles31
TL;DR: This paper conducted a meta-analysis of existing studies to boost statistical power and found no genome-wide significant associations, although an analysis of candidate genes suggests that they may be involved in the disorder.
Abstract: Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.