Showing papers by "Charles University in Prague published in 2006"

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group

Abstract: Summary Background The role of rituximab in combination with diff erent CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diff use large-B-cell lymphoma remains to be defi ned. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. Methods 824 patients who were from 18 countries; aged 18–60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II–IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic eff ects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. Findings After a median follow-up of 34 months (range 0·03–61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75–83] vs 59% [54–64]; diff erence between groups 20% [13–27], log-rank p<0·0001), and had increased 3-year overall survival (93% [90–95] vs 84% [80–88]; diff erence between groups 9% [3–13], log-rank p=0·0001). Event-free survival was aff ected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defi ned from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not diff er in the frequency of adverse events.

Celecoxib for the Prevention of Colorectal Adenomatous Polyps

Abstract: Background Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention. Methods The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel–Cox test. Results Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62). Conclusions The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193.)

Observations of the Crab nebula with HESS

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.

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Abstract: In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

A low level of extragalactic background light as revealed by gamma-rays from blazars.

Abstract: The diffuse Extragalactic Background Light (EBL) contains unique information about the epochs of formation and the history of evolution of galaxies. Unfortunately, direct measurements are subject to large systematic uncertainties due to the difficulties in the accurate model-based subtraction of the bright foregrounds. An alternative approach is based on the detection and identification of EBL absorption features in high-energy spectra of objects of known redshift. Here we exploit this method on the blazars H 2356-309 (z=0.165) and 1ES 1101-232 (z=0.186), newly discovered at TeV energies by the H.E.S.S. Collaboration. They are the most distant sources with measured spectra known so far at these energies. Their hard spectra provide the most stringent upper limit to date on the EBL in the Opt--NIR band, which appears significantly lower than expected from the current "direct" estimates and very close to the absolute lower limit represented by the integrated light of resolved galaxies. In addition to important cosmological implications, this result shows that the intergalactic space is more transparent to gamma-rays than previously thought, expanding the horizon of the TeV Universe.

The MLL recombinome of acute leukemias.

Abstract: Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

The H.E.S.S. Survey of the Inner Galaxy in Very High Energy Gamma Rays

Abstract: We report on a survey of the inner part of the Galactic plane in very high energy gamma rays with the H.E.S.S. Cerenkov telescope system. The Galactic plane between +/-30° in longitude and +/-3° in latitude relative to the Galactic center was observed in 500 pointings for a total of 230 hr, reaching an average flux sensitivity of 2% of the Crab Nebula at energies above 200 GeV. Fourteen previously unknown sources were detected at a significance level greater than 4 σ after accounting for all trials involved in the search. Initial results on the eight most significant of these sources were already reported elsewhere (Aharonian and coworkers). Here we present detailed spectral and morphological information for all the new sources, along with a discussion on possible counterparts in other wavelength bands. The distribution in Galactic latitude of the detected sources appears to be consistent with a scale height in the Galactic disk for the parent population smaller than 100 pc, consistent with expectations for supernova remnants and/or pulsar wind nebulae.

Discovery of very-high-energy |[gamma]|-rays from the Galactic Centre ridge

Abstract: Events at the centre of our Galaxy are key to our understanding of high-energy processes in the Universe, since it contains examples of virtually every type of exotic object known to astronomers. The very-high-energy γ-ray emission from the Galactic Centre region has now been measured using HESS, the High Energy Stereoscopic System recently constructed in Namibia, South West Africa. HESS operates at energies above the regime accessible to satellite-based detectors, taking γ-ray astronomy into new territory. The results show that these clouds are glowing in very high energy γ-rays. The glow is caused by constant bombardment of the clouds by cosmic rays — probably protons and nuclei — produced close to the central black hole or in the expanding blast waves of supernova explosions. The source of Galactic cosmic rays (with energies up to 1015 eV) remains unclear, although it is widely believed that they originate in the shock waves of expanding supernova remnants1,2. At present the best way to investigate their acceleration and propagation is by observing the γ-rays produced when cosmic rays interact with interstellar gas3. Here we report observations of an extended region of very-high-energy (> 1011 eV) γ-ray emission correlated spatially with a complex of giant molecular clouds in the central 200 parsecs of the Milky Way. The hardness of the γ-ray spectrum and the conditions in those molecular clouds indicate that the cosmic rays giving rise to the γ-rays are likely to be protons and nuclei rather than electrons. The energy associated with the cosmic rays could have come from a single supernova explosion around 104 years ago.

Evolution of the molecular machines for protein import into mitochondria.

Abstract: In creating mitochondria some 2 billion years ago, the first eukaryotes needed to establish protein import machinery in the membranes of what was a bacterial endosymbiont. Some of the preexisting protein translocation apparatus of the endosymbiont appears to have been commandeered, including molecular chaperones, the signal peptidase, and some components of the protein-targeting machinery. However, the protein translocases that drive protein import into mitochondria have no obvious counterparts in bacteria, making it likely that these machines were created de novo. The presence of similar translocase subunits in all eukaryotic genomes sequenced to date suggests that all eukaryotes can be considered descendants of a single ancestor species that carried an ancestral "protomitochondria."

Search for neutral MSSM Higgs bosons at LEP

Abstract: The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of “benchmark” models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter cosβ and, in some scenarios, on the masses of neutral Higgs bosons.

Serum Thyrotropin Concentration as a Novel Predictor of Malignancy in Thyroid Nodules Investigated by Fine-Needle Aspiration

Abstract: Context: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. Objective: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. Design: The design was a prospective cohort. Setting: The study was conducted at a single secondary/tertiary care clinic. Participants: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. Intervention(s): There were no interventions. Main Outcome Measures: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting afte...

Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia

Abstract: Atypical antipsychotics have greatly enhanced the treatment of schizophrenia The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophreniaWhen considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors Balancing presynaptic and postsynaptic D(2) receptor antagonism (eg induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors Serotonergic modulation is associated with a beneficial increase in striatal dopamine release Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (eg by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia

The upgraded DØ detector

Abstract: The D0 experiment enjoyed a very successful data-collection run at the Fermilab Tevatron collider between 1992 and 1996. Since then, the detector has been upgraded to take advantage of improvements to the Tevatron and to enhance its physics capabilities. We describe the new elements of the detector, including the silicon microstrip tracker, central fiber tracker, solenoidal magnet, preshower detectors, forward muon detector, and forward proton detector. The uranium/liquid-argon calorimeters and central muon detector, remaining from Run I, are discussed briefly. We also present the associated electronics, triggering, and data acquisition systems, along with the design and implementation of software specific to D0.

Self-medication with antimicrobial drugs in Europe.

Abstract: We surveyed the populations of 19 European countries to compare the prevalence of antimicrobial drug self-medication in the previous 12 months and intended self-medication and storage and to identify the associated demographic characteristics. By using a multistage sampling design, 1,000-3,000 adults in each country were randomly selected. The prevalence of actual self-medication varied from 1 to 210 per 1,000 and intended self-medication from 73 to 449 per 1,000; both rates were high in eastern and southern Europe and low in northern and western Europe. The most common reasons for self-medication were throat symptoms (e.g., dry, inflamed, red, or sore throat, inflamed tonsils, tonsil pain). The main medication sources were pharmacies and medication leftover from previous prescriptions. Younger age, higher education, and presence of a chronic disease were associated with higher rates of self-medication. Attempts to reduce inappropriate self-medication should target prescribers, pharmacists, and the general public.

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Abstract: Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Fast variability of tera-electron volt gamma rays from the radio galaxy M87.

Abstract: The detection of fast variations of the TeV (10^12 eV) gamma-ray flux, on time-scales of days, from the nearby radio galaxy M 87 is reported. These variations are ~10 times faster than that observed in any other waveband and imply a very compact emission region with a dimension similar to the Schwarzschild radius of the central black hole. We thus can exclude several other sites and processes of the gamma-ray production. The observations confirm that TeV gamma-rays are emitted by extragalactic sources other than blazars, where jets are not relativistically beamed towards the observer.

Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study

Abstract: Background: Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem. Objective: To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis. Methods: MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo. Results: 1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p Conclusions: Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.

A detailed spectral and morphological study of the gamma-ray supernova remnant RX J1713.7-3946 with HESS

Abstract: We present results from deep observations of the Galactic shell-type supernova remnant (SNR) RX J1713.7-3946 (also known as G347.3-0.5) conducted with the complete H.E.S.S. array in 2004. Detailed morphological and spatially resolved spectral studies reveal the very-high-energy (VHE -- Energies E > 100 GeV) gamma-ray aspects of this object with unprecedented precision. Since this is the first in-depth analysis of an extended VHE gamma-ray source, we present a thorough discussion of our methodology and investigations of possible sources of systematic errors. Gamma rays are detected throughout the whole SNR. The emission is found to resemble a shell structure with increased fluxes from the western and northwestern parts. The differential gamma-ray spectrum of the whole SNR is measured over more than two orders of magnitude, from 190 GeV to 40 TeV, and is rather hard with indications for a deviation from a pure power law at high energies. Spectra have also been determined for spatially separated regions of RX J1713.7-3946. The flux values vary by more than a factor of two, but no significant change in spectral shape is found. There is a striking correlation between the X-ray and the gamma-ray image. Radial profiles in both wavelength regimes reveal the same shape almost everywhere in the region of the SNR. The VHE gamma-ray emission of RX J1713.7-3946 is phenomenologically discussed for two scenarios, one where the gamma rays are produced by VHE electrons via Inverse Compton scattering and one where the gamma rays are due to neutral pion decay from proton-proton interactions. In conjunction with multi-wavelength considerations, the latter case is favoured. However, no decisive conclusions can yet be drawn regarding the parent particle population dominantly responsible for the gamma-ray emission from RX J1713.7-3946.

3.9 day orbital modulation in the TeV gamma-ray flux and spectrum from the X-ray binary LS 5039

Abstract: New observations of LS 5039, a High Mass X-ray Binary comprising a massive star and compact object, were carried out with the High Energy Stereoscopic System of Cherenkov Telescopes (H.E.S.S.) in 2005 at very high energy (VHE) gamma-ray energies. These observations reveal that its flux and energy spectrum are modulated with the 3.9 day orbital period of the binary system. This is the first time in gamma-ray astronomy that orbital modulation has been observed, and periodicity clearly established using ground-based gamma-ray detectors. The VHE gamma-ray emission is largely confined to half of the orbit, peaking around the inferior conjunction epoch of the compact object. For this epoch, there is also a hardening of the energy spectrum in the energy range between 0.2 TeV and a few TeV. The flux vs. orbital phase profile provides the first clear indication of gamma-ray absorption via pair production within an astrophysical source, a process which is expected to occur if the gamma-ray production site is situated within ~1 AU of the compact object. Moreover the production region size must be not significantly greater than the binary separation (~0.15 AU). Notably, these constraints are also considerably smaller than the collimated outflows or jets (extending out to ~1000 AU) observed in LS 5039. The spectral hardening could arise from variations with phase in the maximum electron energies, and/or the dominant VHE gamma-ray production mechanism.

A Randomized, Blinded, Multicenter Trial of Lipid-Associated Amphotericin B Alone versus in Combination with an Antibody-Based Inhibitor of Heat Shock Protein 90 in Patients with Invasive Candidiasis

Abstract: BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.