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Showing papers by "Heidelberg University published in 2006"


Journal ArticleDOI
TL;DR: In this article, a 7-item anxiety scale (GAD-7) had good reliability, as well as criterion, construct, factorial, and procedural validity, and increasing scores on the scale were strongly associated with multiple domains of functional impairment.
Abstract: Background Generalized anxiety disorder (GAD) is one of the most common mental disorders; however, there is no brief clinical measure for assessing GAD. The objective of this study was to develop a brief self-report scale to identify probable cases of GAD and evaluate its reliability and validity. Methods A criterion-standard study was performed in 15 primary care clinics in the United States from November 2004 through June 2005. Of a total of 2740 adult patients completing a study questionnaire, 965 patients had a telephone interview with a mental health professional within 1 week. For criterion and construct validity, GAD self-report scale diagnoses were compared with independent diagnoses made by mental health professionals; functional status measures; disability days; and health care use. Results A 7-item anxiety scale (GAD-7) had good reliability, as well as criterion, construct, factorial, and procedural validity. A cut point was identified that optimized sensitivity (89%) and specificity (82%). Increasing scores on the scale were strongly associated with multiple domains of functional impairment (all 6 Medical Outcomes Study Short-Form General Health Survey scales and disability days). Although GAD and depression symptoms frequently co-occurred, factor analysis confirmed them as distinct dimensions. Moreover, GAD and depression symptoms had differing but independent effects on functional impairment and disability. There was good agreement between self-report and interviewer-administered versions of the scale. Conclusion The GAD-7 is a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research.

15,911 citations


Journal ArticleDOI
TL;DR: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients.
Abstract: BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa ...

3,351 citations


Journal ArticleDOI
TL;DR: Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.
Abstract: Mesenchymal stem cells (MSCs) represent a promising tool for new clinical concepts in supporting cellular therapy. Bone marrow (BM) was the first source reported to contain MSCs. However, for clinical use, BM may be detrimental due to the highly invasive donation procedure and the decline in MSC number and differentiation potential with increasing age. More recently, umbilical cord blood (UCB), attainable by a less invasive method, was introduced as an alternative source for MSCs. Another promising source is adipose tissue (AT). We compared MSCs derived from these sources regarding morphology, the success rate of isolating MSCs, colony frequency, expansion potential, multiple differentiation capacity, and immune phenotype. No significant differences concerning the morphology and immune phenotype of the MSCs derived from these sources were obvious. Differences could be observed concerning the success rate of isolating MSCs, which was 100% for BM and AT, but only 63% for UCB. The colony frequency was lowest in UCB, whereas it was highest in AT. However, UCB-MSCs could be cultured longest and showed the highest proliferation capacity, whereas BM-MSCs possessed the shortest culture period and the lowest proliferation capacity. Most strikingly, UCB-MSCs showed no adipogenic differentiation capacity, in contrast to BM- and AT-MSCs. Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.

3,057 citations


Journal ArticleDOI
TL;DR: In this article, the authors compared the effect of clopidogrel and low-dose aspirin on the rate of myocardial infarction, stroke, or death from cardiovascular causes.
Abstract: Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P = 0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P = 0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P = 0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P = 0.046). Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.)

2,464 citations


Journal ArticleDOI
TL;DR: In this article, the authors presented the final report from a series of precision measurements of the muon anomalous magnetic moment, a(mu)=(g-2)/2.54 ppm, which represents a 14-fold improvement compared to previous measurements at CERN.
Abstract: We present the final report from a series of precision measurements of the muon anomalous magnetic moment, a(mu)=(g-2)/2. The details of the experimental method, apparatus, data taking, and analysis are summarized. Data obtained at Brookhaven National Laboratory, using nearly equal samples of positive and negative muons, were used to deduce a(mu)(Expt)=11659208.0(5.4)(3.3)x10(-10), where the statistical and systematic uncertainties are given, respectively. The combined uncertainty of 0.54 ppm represents a 14-fold improvement compared to previous measurements at CERN. The standard model value for a(mu) includes contributions from virtual QED, weak, and hadronic processes. While the QED processes account for most of the anomaly, the largest theoretical uncertainty, approximate to 0.55 ppm, is associated with first-order hadronic vacuum polarization. Present standard model evaluations, based on e(+)e(-) hadronic cross sections, lie 2.2-2.7 standard deviations below the experimental result.

2,207 citations


Journal ArticleDOI
17 Nov 2006-Cell
TL;DR: A model has been constructed that integrates all quantitative data and includes structural models of abundant proteins and, with the exception of the V-ATPase, contains numerous copies of proteins essential for membrane traffic and neurotransmitter uptake.

2,030 citations


Journal ArticleDOI
05 May 2006-Cell
TL;DR: Recent reports describe the removal of aggregates from the cytosol; reveal mechanisms for protein quality control in the endoplasmic reticulum; and provide new insight into two classes of molecular chaperones, the Hsp70 system and the AAA+ (Hsp100) unfoldases.

1,467 citations


Journal ArticleDOI
TL;DR: In this paper, an introduction to the physics of ultracold bosonic atoms in optical lattices is given and an overview of the theoretical and experimental advances to date is provided.
Abstract: Matter waves inside periodic potentials are well known from solid-state physics, where electrons interacting with a crystal lattice are considered. Atomic Bose-Einstein condensates inside light-induced periodic potentials (optical lattices) share many features with electrons in solids, but also with light waves in nonlinear materials and other nonlinear systems. Generally, atom-atom interactions in Bose-Einstein condensates lead to rich and interesting nonlinear effects. Furthermore, the experimental control over the parameters of the periodic potential and the condensate make it possible to enter regimes inaccessible in other systems. In this review, an introduction to the physics of ultracold bosonic atoms in optical lattices is given and an overview of the theoretical and experimental advances to date.

1,346 citations


Journal ArticleDOI
TL;DR: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML, and common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes.
Abstract: Background Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML) Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50 Methods In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily Results Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission Conclusions Nilotinib has a relatively favorable safety profil

1,300 citations


Journal ArticleDOI
TL;DR: Hepatic platelet-endothelial interaction is an early event during endotoxemia, which underlines the probable involvement of platelets in leukocyte recruitment and makes the existence of autoregulatory liver mechanisms likely.
Abstract: Introduction Liver microcirculation disturbances are a cause of hepatic failure in sepsis. Increased leukocyte-endothelial interaction, platelet adherence and impaired microperfusion cause hepatocellular damage. The time course and reciprocal influences of ongoing microcirculatory events during endotoxemia have not been clarified.

1,214 citations


Journal ArticleDOI
TL;DR: TURP still represents the gold standard for managing benign prostatic hyperplasia with decreasing complication rates and technological improvements such as microprocessor-controlled units, better armamentarium such as video TUR, and training helped to reduce perioperative complications.

Journal ArticleDOI
TL;DR: Current research concentrates on the identification of common targets for future analgesic and antipruritic therapy, and there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors.
Abstract: Itch and pain are distinct sensations processed by different but overlapping neural pathways. Ikomaet al. review recent evidence on the molecular mechanisms that underlie itch sensation, highlighting the complex interaction with pain processing, and discuss the therapeutic implications. The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.

Journal ArticleDOI
TL;DR: In this paper, the authors present new analytical data of major and trace elements for the geological MPI-DING glasses KL2-G, ML3B-G and ATHO-G.
Abstract: We present new analytical data of major and trace elements for the geological MPI-DING glasses KL2-G, ML3B-G, StHs6/80-G, GOR128-G, GOR132-G, BM90/21-G, T1-G, and ATHO-G. Different analytical methods were used to obtain a large spectrum of major and trace element data, in particular, EPMA, SIMS, LA-ICPMS, and isotope dilution by TIMS and ICPMS. Altogether, more than 60 qualified geochemical laboratories worldwide contributed to the analyses, allowing us to present new reference and information values and their uncertainties (at 95% confidence level) for up to 74 elements. We complied with the recommendations for the certification of geological reference materials by the International Association of Geoanalysts (IAG). The reference values were derived from the results of 16 independent techniques, including definitive (isotope dilution) and comparative bulk (e.g., INAA, ICPMS, SSMS) and microanalytical (e.g., LA-ICPMS, SIMS, EPMA) methods. Agreement between two or more independent methods and the use of definitive methods provided traceability to the fullest extent possible. We also present new and recently published data for the isotopic compositions of H, B, Li, O, Ca, Sr, Nd, Hf, and Pb. The results were mainly obtained by high-precision bulk techniques, such as TIMS and MC-ICPMS. In addition, LA-ICPMS and SIMS isotope data of B, Li, and Pb are presented.

Journal ArticleDOI
TL;DR: It is shown that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus–induced peritonitis, or in the dorsal skinfold chamber model.
Abstract: The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

Journal ArticleDOI
TL;DR: Evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes is discussed and suggestions for innovative interventions aimed at alleviating phantom pain are derived.
Abstract: Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.

Journal ArticleDOI
TL;DR: A series of further chimeric genomes allowing production of infectious genotype (GT) 1a, 1b, 2a, and 3a particles are created, suggesting that determinants within the structural proteins govern kinetic and efficiency of virus assembly and release and an E1-specific antiserum capable of neutralizing infectivity of all HCV chimeras is described.
Abstract: Chronic liver disease caused by infection with hepatitis C virus (HCV) is an important global health problem that currently affects 170 million people. A major impediment in HCV research and drug development has been the lack of culture systems supporting virus production. This obstacle was recently overcome by using JFH1-based full-length genomes that allow production of viruses infectious both in vitro and in vivo. Although this improvement was important, because of the restriction to the JFH1 isolate and a single chimera consisting of J6CF and JFH1-derived sequences, broadly based comparative studies between different HCV strains were not possible. Therefore, in this study we created a series of further chimeric genomes allowing production of infectious genotype (GT) 1a, 1b, 2a, and 3a particles. With the exception of the GT3a/JFH1 chimera, efficient virus production was obtained when the genome fragments were fused via a site located right after the first transmembrane domain of NS2. The most efficient construct is a GT2a/2a chimera consisting of J6CF- and JFH1-derived sequences connected via this junction. This hybrid, designated Jc1, yielded infectious titers 100- to 1,000-fold higher than the parental isolate and all other chimeras, suggesting that determinants within the structural proteins govern kinetic and efficiency of virus assembly and release. Finally, we describe an E1-specific antiserum capable of neutralizing infectivity of all HCV chimeras.

Journal ArticleDOI
TL;DR: The role of PPARalpha, which is highly activated in PEX5-/- mice with the absence of functional peroxisomes severe abnormalities of mitochondria in different organs are observed which resemble closely those in respiratory chain disorders associated with oxidative stress.

Journal ArticleDOI
TL;DR: In this paper, the experimental hadron yield ratios for central nucleus-nucleus collisions were analyzed in terms of thermal model calculations over a broad energy range, s N N = 27 − 200 GeV, and fits of the experimental data with the model calculations provided the thermal parameters, temperature and baryo-chemical potential at chemical freezeout.

Journal ArticleDOI
Felix Aharonian1, A. G. Akhperjanian1, A. R. Bazer-Bachi, M. Beilicke1, Wystan Benbow1, David Berge1, Konrad Bernlöhr, Catherine Boisson2, O. Bolz1, V. Borrel, Ilana M. Braun1, F. Breitling, A. M. Brown3, Rolf Bühler1, I. Büsching4, Svenja Carrigan1, P. M. Chadwick3, L.-M. Chounet, R. Cornils1, Luigi Costamante1, B. Degrange, Hugh Dickinson3, A. Djannati-Ataï, L. O'c. Drury5, Guillaume Dubus, Kathrin Egberts1, Dimitrios Emmanoulopoulos6, P. Espigat, F. Feinstein, E. Ferrero6, A. Fiasson, G. Fontaine, Seb. Funk, Stefan Funk1, Y. A. Gallant, B. Giebels, J.F. Glicenstein, P. Goret, C. Hadjichristidis3, D. Hauser1, M. Hauser6, G. Heinzelmann7, Gilles Henri, German Hermann1, Jim Hinton1, Werner Hofmann1, M. Holleran4, Dieter Horns1, A. Jacholkowska, O. C. de Jager4, B. Khélifi, Nu. Komin, A. Konopelko, Karl Kosack1, I. J. Latham3, R. Le Gallou3, Anne Lemiere, M. Lemoine-Goumard, Thomas Lohse, Jean Michel Martin2, Olivier Martineau-Huynh, A. Marcowith, Conor Masterson1, T. J. L. McComb3, M. de Naurois, D. Nedbal1, S. J. Nolan3, A. Noutsos3, K. J. Orford1, J. L. Osborne1, M. Ouchrif, M. Panter1, G. Pelletier, S. Pita, G. Pühlhofer1, Michael Punch, B. C. Raubenheimer4, M. Raue1, S. M. Rayner3, A. Reimer8, Olaf Reimer8, J. Ripken7, L. Rob9, L. Rolland, Gavin Rowell1, V. Sahakian10, L. Saugé, S. Schlenker, Reinhard Schlickeiser8, U. Schwanke, Helene Sol2, D. Spangler3, Felix Spanier8, R. Steenkamp11, C. Stegmann, G. Superina, J.-P. Tavernet, Regis Terrier, C. G. Théoret, M. Tluczykont, C. van Eldik1, G. Vasileiadis, Christo Venter4, P. Vincent, Heinrich J. Völk1, S. J. Wagnern6, Martin Ward3 
TL;DR: In this paper, the Crab nebula was observed with the H.E.S. stereoscopic Cherenkov-telescope array between 2003 and 2005 for a total of 22.9 hours (after data quality selection).
Abstract: The Crab nebula was observed with the H.E.S.S. stereoscopic Cherenkov-telescope array between October 2003 and January 2005 for a total of 22.9 hours (after data quality selection). Observations were made with three operational telescopes in late 2003 and with the complete 4 telescope array in January - February 2004 and October 2004 - January 2005. The observations are discussed and used as an example to detail the flux and spectral analysis procedures of H.E.S.S., and to evaluate the systematic uncertainties in H.E.S.S. flux measurements. The flux and spectrum of gamma-rays from the source are calculated on run-by-run and monthly time-scales, and a correction is applied for long-term variations in the detector sensitivity. Comparisons of the measured flux and spectrum over the observation period, along with the results from a number of different analysis procedures are used to estimate systematic uncertainties in the measurements. The energy spectrum is found to follow a power law with an exponential cutoff, with photon index $\Gamma = 2.39 \pm 0.03\stat$ and cutoff energy $E_{c} = (14.3 \pm 2.1\stat) \textrm{TeV}$ between 440 GeV and 40 TeV. The observed integral flux above 1 TeV is $(2.26 \pm 0.08\stat) \times 10^{-11} cm^{-2} s^{-1}$. The estimated systematic error on the flux measurement is estimated to be 20%, while the estimated systematic error on the spectral slope is 0.1.

Journal ArticleDOI
TL;DR: Intriguingly, the overall lipid composition of native HIV membranes resembles detergent-resistant membrane microdomains and is strikingly different from that of host cell membranes, providing strong evidence for the existence of lipid rafts in living cells.
Abstract: The lipids of enveloped viruses play critical roles in viral morphogenesis and infectivity. They are derived from the host membranes from which virus budding occurs, but the precise lipid composition has not been determined for any virus. Employing mass spectrometry, this study provides a quantitative analysis of the lipid constituents of HIV and a comprehensive comparison with its host membranes. Both a substantial enrichment of the unusual sphingolipid dihydrosphingomyelin and a loss of viral infectivity upon inhibition of sphingolipid biosynthesis in host cells are reported, establishing a critical role for this lipid class in the HIV replication cycle. Intriguingly, the overall lipid composition of native HIV membranes resembles detergent-resistant membrane microdomains and is strikingly different from that of host cell membranes. With this composition, the HIV lipidome provides strong evidence for the existence of lipid rafts in living cells.

Journal ArticleDOI
TL;DR: It is indicated that respiratory and physical training could be a promising adjunct to medical treatment in severe PH and the effects add to the beneficial results of modern medical treatment.
Abstract: Background—Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. Methods and Results—Thirty patients with PH (21 women; mean age, 5013 years; mean pulmonary artery pressure, 5015 mm Hg; mean World Health Organization [WHO] class, 2.90.5; pulmonary arterial hypertension, n23; chronic thromboembolic PH, n7) on stable disease-targeted medication were randomly assigned to a control (n15) and a primary training (n15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 6118 to 5418 mm Hg) within the training group. Conclusions—This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment. (Circulation. 2006;114:1482-1489.)

Journal ArticleDOI
26 Jan 2006-Nature
TL;DR: The detection of a cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory, and is suggested to name OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.
Abstract: Over 170 extrasolar planets have so far been discovered, with a wide range of masses and orbital periods, but until last July no planet of Neptune's mass or less had been detected any more than 0.15 astronomical units (AU) from a normal star. (That's close — Earth is one AU from the Sun). On 11 July 2005 the OGLE Early Warning System recorded a notable event: gravitational lensing of light from a distant object by a foreground star revealed a small planet of about 5.5 Earth masses, orbiting at about 2.6 AU from the foreground star. This is the lowest known mass for an extrasolar planet orbiting a main sequence star, and its detection suggests that cool, sub-Neptune mass planets are more common than gas giants, as predicted by the favoured core accretion theory of planet formation. In the favoured core-accretion model of formation of planetary systems, solid planetesimals accumulate to build up planetary cores, which then accrete nebular gas if they are sufficiently massive. Around M-dwarf stars (the most common stars in our Galaxy), this model favours the formation of Earth-mass (M⊕) to Neptune-mass planets with orbital radii of 1 to 10 astronomical units (au), which is consistent with the small number of gas giant planets known to orbit M-dwarf host stars1,2,3,4. More than 170 extrasolar planets have been discovered with a wide range of masses and orbital periods, but planets of Neptune's mass or less have not hitherto been detected at separations of more than 0.15 au from normal stars. Here we report the discovery of a M⊕ planetary companion at a separation of au from a M⊙ M-dwarf star, where M⊙ refers to a solar mass. (We propose to name it OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.) The mass is lower than that of GJ876d (ref. 5), although the error bars overlap. Our detection suggests that such cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory.

Journal ArticleDOI
TL;DR: The CEP290 mutations represent one of the most frequent causes of LCA identified so far and are localized in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290).
Abstract: Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for ∼45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A→G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.

Journal ArticleDOI
Pietro Cortese, G. Dellacasa, Luciano Ramello, M. Sitta  +975 moreInstitutions (78)
TL;DR: The ALICE Collaboration as mentioned in this paper is a general-purpose heavy-ion experiment designed to study the physics of strongly interacting matter and the quark-gluon plasma in nucleus-nucleus collisions at the LHC.
Abstract: ALICE is a general-purpose heavy-ion experiment designed to study the physics of strongly interacting matter and the quark–gluon plasma in nucleus–nucleus collisions at the LHC. It currently involves more than 900 physicists and senior engineers, from both the nuclear and high-energy physics sectors, from over 90 institutions in about 30 countries.The ALICE detector is designed to cope with the highest particle multiplicities above those anticipated for Pb–Pb collisions (dNch/dy up to 8000) and it will be operational at the start-up of the LHC. In addition to heavy systems, the ALICE Collaboration will study collisions of lower-mass ions, which are a means of varying the energy density, and protons (both pp and pA), which primarily provide reference data for the nucleus–nucleus collisions. In addition, the pp data will allow for a number of genuine pp physics studies.The detailed design of the different detector systems has been laid down in a number of Technical Design Reports issued between mid-1998 and the end of 2004. The experiment is currently under construction and will be ready for data taking with both proton and heavy-ion beams at the start-up of the LHC.Since the comprehensive information on detector and physics performance was last published in the ALICE Technical Proposal in 1996, the detector, as well as simulation, reconstruction and analysis software have undergone significant development. The Physics Performance Report (PPR) provides an updated and comprehensive summary of the performance of the various ALICE subsystems, including updates to the Technical Design Reports, as appropriate.The PPR is divided into two volumes. Volume I, published in 2004 (CERN/LHCC 2003-049, ALICE Collaboration 2004 J. Phys. G: Nucl. Part. Phys. 30 1517–1763), contains in four chapters a short theoretical overview and an extensive reference list concerning the physics topics of interest to ALICE, the experimental conditions at the LHC, a short summary and update of the subsystem designs, and a description of the offline framework and Monte Carlo event generators.The present volume, Volume II, contains the majority of the information relevant to the physics performance in proton–proton, proton–nucleus, and nucleus–nucleus collisions. Following an introductory overview, Chapter 5 describes the combined detector performance and the event reconstruction procedures, based on detailed simulations of the individual subsystems. Chapter 6 describes the analysis and physics reach for a representative sample of physics observables, from global event characteristics to hard processes.

Journal ArticleDOI
TL;DR: This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein–mediated signaling pathways.
Abstract: Because of their ability to become rapidly activated at places of vascular injury, platelets are important players in primary hemostasis as well as in arterial thrombosis. In addition, they are also involved in chronic pathological processes including the atherosclerotic remodeling of the vascular system. Although primary adhesion of platelets to the vessel wall is largely independent of G protein–mediated signaling, the subsequent recruitment of additional platelets into a growing platelet thrombus requires mediators such as ADP, thromboxane A2, or thrombin, which act through G protein–coupled receptors. Platelet activation via G protein–coupled receptors involves 3 major G protein–mediated signaling pathways that are initiated by the activation of the G proteins Gq, G13, and Gi. This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein–mediated signaling pathways.

Journal ArticleDOI
03 Nov 2006-Science
TL;DR: It is found that phenylalanine-mediated inter-repeat interactions indeed cross-link FG-repeat domains into elastic and reversible hydrogels and obtained evidence that such hydrogel formation is required for viability in yeast.
Abstract: Nuclear pore complexes permit rapid passage of cargoes bound to nuclear transport receptors, but otherwise suppress nucleocytoplasmic fluxes of inert macromolecules ≥30 kilodaltons. To explain this selectivity, a sieve structure of the permeability barrier has been proposed that is created through reversible cross-linking between Phe and Gly (FG)–rich nucleoporin repeats. According to this model, nuclear transport receptors overcome the size limit of the sieve and catalyze their own nuclear pore-passage by a competitive disruption of adjacent inter-repeat contacts, which transiently opens adjoining meshes. Here, we found that phenylalanine-mediated inter-repeat interactions indeed cross-link FG-repeat domains into elastic and reversible hydrogels. Furthermore, we obtained evidence that such hydrogel formation is required for viability in yeast.

Journal ArticleDOI
TL;DR: It is shown that only a proportion of the parasites enter blood capillaries, whereas others are drained by lymphatics, andymph sporozoites stop at the proximal lymph node, where most are degraded inside dendritic leucocytes, but some can partially differentiate into exoerythrocytic stages.
Abstract: Plasmodium, the parasite that causes malaria, is transmitted by a mosquito into the dermis and must reach the liver before infecting erythrocytes and causing disease. We present here a quantitative, real-time analysis of the fate of parasites transmitted in a rodent system. We show that only a proportion of the parasites enter blood capillaries, whereas others are drained by lymphatics. Lymph sporozoites stop at the proximal lymph node, where most are degraded inside dendritic leucocytes, but some can partially differentiate into exoerythrocytic stages. This previously unrecognized step of the parasite life cycle could influence the immune response of the host, and may have implications for vaccination strategies against the preerythrocytic stages of the parasite.

Journal ArticleDOI
01 May 2006-Stroke
TL;DR: The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS), and at a dose of 125 &mgr;g/kg desmotesplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria.
Abstract: Background and Purpose— Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke. Methods— DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 μg/kg and 125 μg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined. Results— Thirty-seven patients were randomized and received ...

Journal ArticleDOI
TL;DR: The most frequent cause of low vision and blindness in adult Chinese is cataract, followed by degenerativeMyopia and glaucomatous optic neuropathy, with degenerative myopia dominating in younger groups andCataract dominating in elder groups.

Journal ArticleDOI
TL;DR: Future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ.
Abstract: Long-term function of three-dimensional (3D) tissue constructs depends on adequate vascularization after implantation. Accordingly, research in tissue engineering has focused on the analysis of angiogenesis. For this purpose, 2 sophisticated in vivo models (the chorioallantoic membrane and the dorsal skinfold chamber) have recently been introduced in tissue engineering research, allowing a more detailed analysis of angiogenic dysfunction and engraftment failure. To achieve vascularization of tissue constructs, several approaches are currently under investigation. These include the modification of biomaterial properties of scaffolds and the stimulation of blood vessel development and maturation by different growth factors using slow-release devices through pre-encapsulated microspheres. Moreover, new microvascular networks in tissue substitutes can be engineered by using endothelial cells and stem cells or by creating arteriovenous shunt loops. Nonetheless, the currently used techniques are not sufficient to induce the rapid vascularization necessary for an adequate cellular oxygen supply. Thus, future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ.