Showing papers by "Charles University in Prague published in 2008"

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

Abstract: The time to progression among patients receiving bortezomib plus melphalan– prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions Bortezomib plus melphalan–prednisone was superior to melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Abstract: Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Grasping at the routes of biological invasions: a framework for integrating pathways into policy

Abstract: Summary 1. Pathways describe the processes that result in the introduction of alien species from one location to another. A framework is proposed to facilitate the comparative analysis of invasion pathways by a wide range of taxa in both terrestrial and aquatic ecosystems. Comparisons with a range of data helped identify existing gaps in current knowledge of pathways and highlight the limitations of existing legislation to manage introductions of alien species. The scheme aims for universality but uses the European Union as a case study for the regulatory perspectives. 2. Alien species may arrive and enter a new region through three broad mechanisms: importation of a commodity, arrival of a transport vector, and/or natural spread from a neighbouring region where the species is itself alien. These three mechanisms result in six principal pathways: release, escape, contaminant, stowaway, corridor and unaided. 3. Alien species transported as commodities may be introduced as a deliberate release or as an escape from captivity. Many species are not intentionally transported but arrive as a contaminant of a commodity, for example pathogens and pests. Stowaways are directly associated with human transport but arrive independently of a specific commodity, for example organisms transported in ballast water, cargo and airfreight. The corridor pathway highlights the role transport infrastructures play in the introduction of alien species. The unaided pathway describes situations where natural spread results in alien species arriving into a new region from a donor region where it is also alien. 4. Vertebrate pathways tend to be characterized as deliberate releases, invertebrates as contaminants and plants as escapes. Pathogenic micro-organisms and fungi are generally introduced as contaminants of their hosts. The corridor and unaided pathways are often ignored in pathway assessments but warrant further detailed consideration. 5. Synthesis and applications. Intentional releases and escapes should be straightforward to monitor and regulate but, in practice, developing legislation has proved difficult. New introductions continue to occur through contaminant, stowaway, corridor and unaided pathways. These pathways represent special challenges for management and legislation. The present framework should enable these trends to be monitored more clearly and hopefully lead to the development of appropriate regulations or codes of practice to stem the number of future introductions.

Definition, assessment and treatment of wheezing disorders in preschool children: An evidence-based approach

Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Energy Spectrum of Cosmic-Ray Electrons at TeV Energies

Abstract: The very large collection area of ground-based gamma-ray telescopes gives them a substantial advantage over balloon/satellite based instruments in the detection of very-high-energy (>600 GeV) cosmic-ray electrons. Here we present the electron spectrum derived from data taken with the H.E.S.S. system of imaging atmospheric Cherenkov telescopes. In this measurement, the first of this type, we are able to extend the measurement of the electron spectrum beyond the range accessible to direct measurements. We find evidence for a substantial steepening in the energy spectrum above 600 GeV compared to lower energies.

Geographical and taxonomic biases in invasion ecology

Abstract: Invasive alien species come from most taxonomic groups, and invasion biology is searching for robust cross-taxon generalizations and principles. An analysis of 2670 papers dealing with 892 invasive species showed that all major groups of invaders are well studied, but that most information on the mechanisms of invasion has emerged from work on a limited number of the most harmful invaders. A strong geographical bias, with Africa and Asia understudied, inhibits a balanced understanding of invasion, because we might be lacking knowledge of specific invasion mechanisms from poorly studied, regionally specific habitats. International cooperation is required to achieve a more geographically balanced picture of biological invasions. Invasive species with the greatest impact are best studied, but more studies of species that are naturalized but not (yet) invasive are needed to improve understanding of the mechanisms acting during the naturalization phase of invasions and leading to successful invasion.

Observation of the suppression of the flux of cosmic rays above 4x10(19) eV

Abstract: The energy spectrum of cosmic rays above 2.5 x 10;{18} eV, derived from 20,000 events recorded at the Pierre Auger Observatory, is described. The spectral index gamma of the particle flux, J proportional, variantE;{-gamma}, at energies between 4 x 10;{18} eV and 4 x 10;{19} eV is 2.69+/-0.02(stat)+/-0.06(syst), steepening to 4.2+/-0.4(stat)+/-0.06(syst) at higher energies. The hypothesis of a single power law is rejected with a significance greater than 6 standard deviations. The data are consistent with the prediction by Greisen and by Zatsepin and Kuz'min.

Facilitated PCI in patients with ST-elevation myocardial infarction.

Abstract: In this international, double-blind, placebo-controlled study, we randomly assigned patients with ST-segment elevation myocardial infarction who presented 6 hours or less after the onset of symptoms to receive combination-facilitated PCI, abciximabfacilitated PCI, or primary PCI. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary end point was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. Results A total of 2452 patients were randomly assigned to a treatment group. Significantly more patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; P = 0.01 and P = 0.003, respectively). The primary end point occurred in 9.8%, 10.5%, and 10.7% of the patients in the combination-facilitated PCI group, abciximab-facilitated PCI group, and primary-PCI group, respectively (P = 0.55); 90-day mortality rates were 5.2%, 5.5%, and 4.5%, respectively (P = 0.49). Conclusions Neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab alone significantly improved the clinical outcomes, as compared with abciximab given at the time of PCI, in patients with ST-segment elevation myocardial infarction. (ClinicalTrials.gov number, NCT00046228.)

Non-shivering thermogenesis and its thermoregulatory significance.

Abstract: Summary 1. Non-shivering thermogenesis (NST) is a heat-production mechanism participating in the chemical thermoregulation of mammals. 2. NST is additional to shivering and takes place at temperatures close to the thermoneutral zone. 3. NST occurs in newborn mammals and in those that hibernate. In some adult mammals it can be induced by adaptation to cold. 4. In small mammals NST produces approximately the same amount of heat as shivering. It becomes less important with increasing body weight of the animals. 5. NST is regulated by the hypothalamus and it is based predominantly on the calorigenic action of noradrenaline released from sympathetic nerve-endings. Participation of other calorigenic substances and of the specific dynamic action of food cannot be excluded. 6. NST is localized mainly in skeletal muscles and in brown adipose tissue. Small amounts of NST may come from liver, intestine, heart and brain. 7. The biochemical basis of the calorigenic action of noradrenaline has not yet been fully elucidated.

Approaching the dirac point in high-mobility multilayer epitaxial graphene.

Abstract: Multilayer epitaxial graphene is investigated using far infrared transmission experiments in the different limits of low magnetic fields and high temperatures. The cyclotron-resonance-like absorption is observed at low temperature in magnetic fields below 50 mT, probing the nearest vicinity of the Dirac point. The carrier mobility is found to exceed 250,000 cm2/(V x s). In the limit of high temperatures, the well-defined Landau level quantization is observed up to room temperature at magnetic fields below 1 T, a phenomenon unusual in solid state systems. A negligible increase in the width of the cyclotron resonance lines with increasing temperature indicates that no important scattering mechanism is thermally activated.

Lung cancer susceptibility locus at 5p15.33

Abstract: We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis

Abstract: Background Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. Methods Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. Results Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for d...

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies.

Abstract: Aims/hypothesis The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders.

Classifications of Atmospheric Circulation Patterns

Abstract: We review recent advances in classifications of circulation patterns as a specific research area within synoptic climatology. The review starts with a general description of goals of classification and the historical development in the field. We put circulation classifications into a broader context within climatology and systematize the varied methodologies and approaches. We characterize three basic groups of classifications: subjective (also called manual), mixed (hybrid), and objective (computer-assisted, automated). The roles of cluster analysis and principal component analysis in the classification process are clarified. Several recent methodological developments in circulation classifications are identified and briefly described: the introduction of nonlinear methods, objectivization of subjective catalogs, efforts to optimize classifications, the need for intercomparisons of classifications, and the progress toward an optimum, if possible unified, classification method. Among the recent tendencies in the applications of circulation classifications, we mention a more extensive use in climate studies, both of past, present, and future climates, innovative applications in the ensemble forecasting, increasing variety of synoptic-climatological investigations, and steps above from the troposphere. After introducing the international activity within the field of circulation classifications, the COST733 Action, we briefly describe outputs of the inventory of classifications in Europe, which was carried out within the Action. Approaches to the evaluation of classifications and their mutual comparisons are also reviewed. A considerable part of the review is devoted to three examples of applications of circulation classifications: in historical climatology, in analyses of recent climate variations, and in analyses of outputs from global climate models.

Effects of the Direct Lipoprotein-Associated Phospholipase A 2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque

Abstract: Background - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results - This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL; P=0.37). In contrast, Lp-PLA2 activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm; P=0.009), whereas darapladib halted this increase (-0.5±13.9 mm; P=0.71), resulting in a significant treatment difference of -5.2 mm (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95). Conclusions - Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA2 inhibition may represent a novel therapeutic approach.

Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors

Abstract: Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau ( VHL ) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.

Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes

Abstract: Magnetic resonance imaging is a commonly used diagnostic method in medicinal practice as well as in biological and preclinical research. Contrast agents (CAs), which are often applied are mostly based on Gd(III) complexes. In this paper, the ligand types and structures of their complexes on one side and a set of the physico-chemical parameters governing properties of the CAs on the other side are discussed. The solid-state structures of lanthanide(III) complexes of open-chain and macrocyclic ligands and their structural features are compared. Examples of tuning of ligand structures to alter the relaxometric properties of gadolinium(III) complexes as a number of coordinated water molecules, their residence time (exchange rate) or reorientation time of the complexes are given. Influence of the structural changes of the ligands on thermodynamic stability and kinetic inertness/lability of their lanthanide(III) complexes is discussed.

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders

Abstract: The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases.

Aging, Disability and Frailty

Abstract: Despite multiple and often overlapping definitions of disability and frailty, both are common clinical characteristics of aged individuals though not identical. The geriatric syndrome of frailty is de

Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy

Abstract: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease.