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Find video protocols related to scientific articles indexed in Pubmed.
Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 09-19-2014
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Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection.
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Structural growth trajectories and rates of change in the first 3 months of infant brain development.
JAMA Neurol
PUBLISHED: 08-12-2014
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The very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders.
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SENSE and simultaneous multislice imaging.
Magn Reson Med
PUBLISHED: 08-07-2014
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Simultaneous multislice (SMS) acquisitions play an important role in the challenge of increasing single-shot imaging speed. We show that sensitivity encoding in two spatial dimensions (two-dimensional sensitivity encoding [2D-SENSE]) can be used to reconstruct SMS acquisitions with periodic but otherwise arbitrary undersampling patterns.
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Simulation training for geriatric medicine.
Clin Teach
PUBLISHED: 07-22-2014
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Geriatric medicine encompasses a diverse nature of medical, social and ethical challenges, and requires a multidimensional, interdisciplinary approach. Recent reports have highlighted failings in the care of the elderly, and it is therefore vital that specialist trainees in geriatric medicine are afforded opportunities to develop their skills in managing this complex patient population. Simulation has been widely adopted as a teaching tool in medicine; however, its use in geriatric medicine to date has involved primarily role-play or discrete clinical skills training. This article outlines the development of a bespoke, multimodal, simulation course for specialist trainees in geriatric medicine.
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Effects of APOE ?4, age, and HIV on glial metabolites and cognitive deficits.
Neurology
PUBLISHED: 05-21-2014
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We aimed to evaluate the combined effects of HIV and APOE ?4 allele(s) on glial metabolite levels, and on known cognitive deficits associated with either condition, across the ages.
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Importin-?7 is required for enhanced influenza A virus replication in the alveolar epithelium and severe lung damage in mice.
J. Virol.
PUBLISHED: 05-14-2014
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Influenza A viruses recruit components of the nuclear import pathway to enter the host cell nucleus and promote viral replication. Here, we analyzed the role of the nuclear import factor importin-?7 in H1N1 influenza virus pulmonary tropism by using various ex vivo imaging techniques (magnetic resonance imaging, confocal laser scanning microscopy, and correlative light-electron microscopy). We infected importin-?7 gene-deficient (?7(-/-)) mice with a recombinant H1N1 influenza virus and compared the in vivo viral kinetics with those in wild-type (WT) mice. In WT mice, influenza virus replication in the bronchial and alveolar epithelium already occurred a few days after infection. Accordingly, extensive mononuclear infiltration and alveolar destruction were present in the lungs of infected WT mice, followed by 100% lethality. Conversely, in ?7(-/-) mice, virus replication was restricted mostly to the bronchial epithelium with marginal alveolar infection, resulting in significantly reduced lung damage and enhanced animal survival. To investigate the host immune response during alveolar virus replication, we studied the role of primary macrophages in virus propagation and clearance. The ability of macrophages to support or clear the virus infection, as well as the host cellular immune responses, did not significantly differ between WT and ?7(-/-) mice. However, cytokine and chemokine responses were generally elevated in WT mice, likely reflective of increased viral replication in the lung. In summary, these data show that a cellular factor, importin-?7, is required for enhanced virus replication in the alveolar epithelium, resulting in elevated cytokine and chemokine levels, extensive mononuclear infiltration, and thus, severe pneumonia and enhanced virulence in mice. Importance: Influenza A viruses are respiratory pathogens that may cause pneumonia in humans. Viral infection and replication in the alveoli of the respiratory tract are believed to be crucial for the development of the acute respiratory distress syndrome associated with fatal outcomes in influenza virus-infected patients. Here, we report the requirement of a cellular factor, importin-?7, for efficient virus replication in the alveolar epithelium of mice. Using complementary ex vivo imaging approaches, we show that influenza virus replication is restricted to the bronchial epithelium, followed by enhanced survival in importin-?7-deficient mice. In contrast, the presence of this gene results in enhanced virus replication in the alveoli, elevated cytokine and chemokine responses, mononuclear infiltration, alveolar destruction, and 100% lethality in wild-type mice. Taken together, our results show that importin-?7 is particularly required for virus replication in the alveolar epithelium in association with severe pneumonia and death in mice.
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A Bayesian approach to the creation of a study-customized neonatal brain atlas.
Neuroimage
PUBLISHED: 05-06-2014
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Atlas-based image analysis (ABA), in which an anatomical "parcellation map" is used for parcel-by-parcel image quantification, is widely used to analyze anatomical and functional changes related to brain development, aging, and various diseases. The parcellation maps are often created based on common MRI templates, which allow users to transform the template to target images, or vice versa, to perform parcel-by-parcel statistics, and report the scientific findings based on common anatomical parcels. The use of a study-specific template, which represents the anatomical features of the study population better than common templates, is preferable for accurate anatomical labeling; however, the creation of a parcellation map for a study-specific template is extremely labor intensive, and the definitions of anatomical boundaries are not necessarily compatible with those of the common template. In this study, we employed a volume-based template estimation (VTE) method to create a neonatal brain template customized to a study population, while keeping the anatomical parcellation identical to that of a common MRI atlas. The VTE was used to morph the standardized parcellation map of the JHU-neonate-SS atlas to capture the anatomical features of a study population. The resultant "study-customized" T1-weighted and diffusion tensor imaging (DTI) template, with three-dimensional anatomical parcellation that defined 122 brain regions, was compared with the JHU-neonate-SS atlas, in terms of the registration accuracy. A pronounced increase in the accuracy of cortical parcellation and superior tensor alignment were observed when the customized template was used. With the customized atlas-based analysis, the fractional anisotropy (FA) detected closely approximated the manual measurements. This tool provides a solution for achieving normalization-based measurements with increased accuracy, while reporting scientific findings in a consistent framework.
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Contributions of ambient assisted living for health and quality of life in the elderly and care services - a qualitative analysis from the experts' perspective of care service professionals.
BMC Geriatr
PUBLISHED: 04-29-2014
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Because of the demographic change in industrial countries new technical solutions for the independent living of elderly will become important in the next years. Ambient Assisted Living seeks to address the upcoming challenges by providing technical aids for elderly and care givers. Therefore it is crucial to understand how those socio-technical solutions can address their needs and quality of life (QOL). The aim of this study was to analyse the main needs of dependent elderly and to investigate how different solutions can contribute to health and quality of life.
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[Public health education in Austria. An overview].
Wien Med Wochenschr
PUBLISHED: 03-26-2014
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The future challenges for the Austrian health care system require an increasing number of public health experts of different professions in all fields of public health. In this article the offer of public health education in Austrian universities and universities for applied sciences was searched based on the predominantly online available information on web platforms of the schools. Currently (2013), there are three postgraduate public health university courses and two public health doctoral programs in Austria. Additionally, 34 degree programmes could be identified, in which parts of public health are covered. But also in medical curricula at Austrian medical schools, public health contents have found their place. In Austria, there is already a multifaceted offer for public health education. However, to build an appropriate public health work force, capable to manage the public health challenges in all its dimensions in terms of health in all policies, this offer should still be intensified.
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Comparison of optical and MR-based tracking.
Magn Reson Med
PUBLISHED: 02-12-2014
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The goal of this study was to compare the accuracy of two real-time motion tracking systems in the MR environment: MR-based prospective motion correction (PROMO) and optical moiré phase tracking (MPT).
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Preventive medicine: self-assessment of knowledge, skills and attitudes of medical students at the Medical University of Vienna.
Wien Med Wochenschr
PUBLISHED: 01-28-2014
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Prevention and health promotion are gaining importance in modern medical curricula. Aim of this study was to evaluate the self-assessment of knowledge, skills and attitudes of medical students towards health promotion and prevention. In 2012, at the Medical University of Vienna, 27% of the 633 fourth-year medical students (50.3% male and 49.7% female; mean age: 24 years) completed a questionnaire. Results show a high assessment of prevention in most respondents. Knowledge gaps were detected on occupational health and mother-child pass examinations. However, almost all students reported sufficient knowledge on screening and risk assessment of developing cardiovascular diseases. Almost all respondents estimated to be able to identify risky behaviours. Overall, estimation towards prevention of tomorrow's physicians is very positive. However, only 40% believed to have been adequately trained on preventive medicine so far. Relevant preventive aspects were added to the medical curriculum in 2012-2013 with the new block 'Public Health'.
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MRI default mode network connectivity is associated with functional outcome after cardiopulmonary arrest.
Neurocrit Care
PUBLISHED: 01-28-2014
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We hypothesized that the degree of preserved functional connectivity within the DMN during the first week after cardiopulmonary arrest (CPA) would be associated with functional outcome at hospital discharge.
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Differences in access points to the ambulatory health care system across Austrian federal states.
Wien Med Wochenschr
PUBLISHED: 01-27-2014
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The nine Austrian regions differ according to demographic parameter, health status, and health care structure. It was the aim of this study to analyse whether there are also differences in access points towards the level of ambulatory care.
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Simultaneous Multi-Slice fMRI using spiral trajectories.
Neuroimage
PUBLISHED: 01-22-2014
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Parallel imaging methods using multi-coil receiver arrays have been shown to be effective for increasing MRI acquisition speed. However parallel imaging methods for fMRI with 2D sequences show only limited improvements in temporal resolution because of the long echo times needed for BOLD contrast. Recently, Simultaneous Multi-Slice (SMS) imaging techniques have been shown to increase fMRI temporal resolution by factors of four and higher. In SMS fMRI multiple slices can be acquired simultaneously using Echo Planar Imaging (EPI) and the overlapping slices are un-aliased using a parallel imaging reconstruction with multiple receivers. The slice separation can be further improved using the "blipped-CAIPI" EPI sequence that provides a more efficient sampling of the SMS 3D k-space. In this paper a blipped-spiral SMS sequence for ultra-fast fMRI is presented. The blipped-spiral sequence combines the sampling efficiency of spiral trajectories with the SMS encoding concept used in blipped-CAIPI EPI. We show that blipped spiral acquisition can achieve almost whole brain coverage at 3mm isotropic resolution in 168 ms. It is also demonstrated that the high temporal resolution allows for dynamic BOLD lag time measurement using visual/motor and retinotopic mapping paradigms. The local BOLD lag time within the visual cortex following the retinotopic mapping stimulation of expanding flickering rings is directly measured and easily translated into an eccentricity map of the cortex.
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Health care utilisation in subjects with osteoarthritis, chronic back pain and osteoporosis aged 65 years and more: mediating effects of limitations in activities of daily living, pain intensity and mental diseases.
Wien Med Wochenschr
PUBLISHED: 01-07-2014
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Musculoskeletal diseases (MDs) have major consequences for the individual, and also for society and may thus lead to increased use of health care. It was the aim of this study to explore health care utilisation in patients with self-reported osteoarthritis, chronic back pain or osteoporosis compared with people of the same age without those diseases, based on data of the Austrian health interview survey including 3,097 subjects aged ? 65 years. Patients with MDs in our study visited a general practitioner (GP) and were hospitalised significantly more often compared with persons without the respective diseases. Problems in the activities of daily living (ADLs), pain intensity and anxiety/depression influenced GP consultations. Complex factors explain the higher health care utilisation in subjects with MDs in our study. Our results indicate that integrated strategies are needed to manage those patients, which should focus on management of ADL problems, pain and mental health.
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Smoking prevalence, readiness to quit and smoking cessation in HIV+ patients in Germany and Austria.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Due to the interaction between smoking and the virus and the antiretroviral therapy, the excess health hazard due to smoking is higher in HIV+ patients than in the general population. International studies suggest a higher prevalence of smoking in HIV+ subjects compared to the general population. It was the aim of the study to assess prevalence of smoking, to analyze determinants of smoking, and to evaluate readiness to quit in HIV+ patients in Germany and Austria.
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Involvement of HIV patients in treatment-related decisions.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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The improvement of antiretroviral therapy in the past decades has had a major impact on life expectancy and quality of life of people living with HIV, and also on the relationship between patients and their physicians. What used to be an acute treatment for life threatening complications, and an end-of-life therapy in the beginning of the epidemic, turned over the time into a lifelong care. The good relationship between patients and physicians represents the cornerstone of an optimal long-term therapy. Shared decision making between patients and physicians is a crucial prerequisite for the success of this approach. Several Austrian patient organizations developed an online survey together with MSD (the so-called "PAB-test") aimed to evaluate how people living with HIV perceive the level of care in Austria.
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Health literacy, source of information and impact on adherence to therapy in people living with HIV.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Adequate information and health literacy (HL) has a high impact on patients understanding on the causes and consequences of many chronic diseases, including HIV, and is a crucial prerequisite to ensure adherence to therapy regimens. Several Austrian patient organizations developed an online survey together with MSD (the so-called "PAB-test") aimed to evaluate how people living with HIV perceive the level of care in Austria.
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The NIH Toolbox Cognition Battery: Results from a large normative developmental sample (PING).
Neuropsychology
PUBLISHED: 11-11-2013
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Objective: The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance. Method: The NTCB was administered to a sample of 1,020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States. Results: General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores. Conclusions: The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
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The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis.
Ann. Hematol.
PUBLISHED: 10-15-2013
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The activating KIT D816V mutation plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). For improved and reliable identification of KIT D816V, we have developed an allele-specific quantitative real-time PCR (RQ-PCR) with an enhanced sensitivity of 0.01-0.1 %, which was superior to denaturing high-performance liquid chromatography (0.5-1 %) or conventional sequencing (10-20 %). Overall, KIT D816 mutations were identified in 146/147 (99 %) of patients (D816V, n?=?142; D816H, n?=?2; D816Y, n?=?2) with SM, including indolent SM (ISM, n?=?63, 43 %), smoldering SM (n?=?8, 5 %), SM with associated hematological non-mast cell lineage disease (SM-AHNMD, n?=?16, 11 %), and aggressive SM/mast cell leukemia?±?AHNMD (ASM/MCL, n?=?60, 41 %). If positive in BM, the KIT D816V mutation was found in PB of all patients with advanced SM (SM-AHNMD, ASM, and MCL) and in 46 % (23/50) of patients with ISM. There was a strong correlation between the KIT D816V expressed allele burden (KIT D816V EAB) with results obtained from DNA by genomic allele-specific PCR and also with disease activity (e.g., serum tryptase level), disease subtype (e.g., indolent vs. advanced SM) and survival. In terms of monitoring of residual disease, qualitative and quantitative assessment of KIT D816V and KIT D816V EAB was successfully used for sequential analysis after chemotherapy or allogeneic stem cell transplantation. We therefore conclude that RQ-PCR assays for KIT D816V are useful complimentary tools for diagnosis, disease monitoring, and evaluation of prognosis in patients with SM.
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Comprehensive mutational profiling in advanced systemic mastocytosis.
Blood
PUBLISHED: 08-19-2013
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To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ?3 mutations, and 11/27 patients (41%) exhibited ?5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.
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Impact of methamphetamine on regional metabolism and cerebral blood flow after traumatic brain injury.
Neurocrit Care
PUBLISHED: 07-10-2013
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Substance abuse is a frequent comorbid condition among patients with traumatic brain injury (TBI), but little is known about its potential additive or interactive effects on tissue injury or recovery from TBI. This study aims to evaluate changes in regional metabolism and cerebral perfusion in subjects who used methamphetamine (METH) prior to sustaining a TBI. We hypothesized that METH use would decrease pericontusional cerebral perfusion and markers of neuronal metabolism, in TBI patients compared to those without METH use.
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Imaging of the murine biliopancreatic tract at 7 tesla: Technique and results in a model of primary sclerosing cholangitis.
J Magn Reson Imaging
PUBLISHED: 07-02-2013
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To assess the feasibility of a 7 Tesla (T) MR cholangiopancreatography (MRCP) protocol to image the morphology and detect and intraindividually monitor pathological changes of the biliopancreatic tract in a mouse model of primary sclerosing cholangitis (PSC).
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Predictors of participation in preventive health examinations in Austria.
BMC Public Health
PUBLISHED: 06-11-2013
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Preventive health check-ups in Austria are offered free of charge to all insured adults (98% of the population) and focus on early detection of chronic diseases, primary prevention, and health counseling. The study aims to explore predictors of compliance with the recommended interval of preventive health check-up performance.
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Propagation of calibration errors in prospective motion correction using external tracking.
Magn Reson Med
PUBLISHED: 05-29-2013
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Prospective motion correction of MRI scans using an external tracking device (such as a camera) is becoming increasingly popular, especially for imaging of the head. In order for external tracking data to be transformed into the MR scanner reference frame, the pose (i.e., position and orientation) of the camera relative to the scanner-or cross-calibration-must be accurate. In this study, we investigated how errors in cross-calibration affect the accuracy of motion correction feedback in MRI.
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Three-dimensional Fourier encoding of simultaneously excited slices: Generalized acquisition and reconstruction framework.
Magn Reson Med
PUBLISHED: 05-24-2013
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Simultaneous multislice (SMS) acquisitions have recently received much attention as a means of increasing single-shot imaging speed. SMS acquisitions combine the advantages of single-shot sampling and acceleration along the slice dimension which was previously limited to three-dimensional (3D) volumetric acquisitions. A two-dimensional description of SMS sampling and reconstruction has become established in the literature. Here, we present a more general 3D Fourier encoding and reconstruction formalism for SMS acquisitions that can easily be applied to non-Cartesian SMS acquisitions.
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Genotyping of 25 leukemia-associated genes in a single work flow by next-generation sequencing technology with low amounts of input template DNA.
Clin. Chem.
PUBLISHED: 04-16-2013
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We sought to establish a convenient, sensitive next-generation sequencing (NGS) method for genotyping the 26 most commonly mutated leukemia-associated genes in a single work flow and to optimize this method for low amounts of input template DNA.
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Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain.
J Neuroimmune Pharmacol
PUBLISHED: 04-11-2013
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Proton magnetic resonance spectroscopy ((1)H MRS) has been applied to numerous clinical studies, especially for neurological disorders. This technique can non-invasively evaluate brain metabolites and neurochemicals in selected brain regions and is particularly useful for assessing neuroinflammatory disorders. Neurometabolites assessed with MRS include the neuronal markers N-acetylaspartate (NAA) and glutamate (Glu), as well as the glial marker myo-inositol (MI). Therefore, the concentrations of these metabolites typically correspond to disease severity and often correlate well with clinical variables in the various brain disorders. Neuroinflammation with activated astrocytes and microglia in brain disorders are often associated with elevated MI, and to a lesser extent elevated total creatine (tCr) and choline containing compounds (Cho), which are found in higher concentrations in glia than neurons, while neuronal injury is indicated by lower than normal levels of NAA and Glu. This review summarizes the neurometabolite abnormalities found in MRS studies performed in patients with neuroinflammatory disorders or neuropathic pain, which also may be associated with neuroinflammation. These brain disorders include multiple sclerosis, neuroviral infections (including Human Immunodeficiency virus and Hepatitis C), degenerative brain disorders (including Alzheimers disease and Parkinsons disease), stimulant abuse (including methamphetamine and cocaine) as well as several chronic pain syndromes.
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Fast noniterative calibration of an external motion tracking device.
Magn Reson Med
PUBLISHED: 03-14-2013
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Prospective motion correction of magnetic resonance (MR) scans commonly uses an external device, such as a camera, to track the pose of the organ of interest. However, in order for external tracking data to be translated into the MR scanner reference frame, the pose of the camera relative to the MR scanner must be known accurately. Here, we describe a fast, accurate, non-iterative technique to determine the position of an external tracking device de novo relative to the MR reference frame.
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Quantification and correction of respiration induced dynamic field map changes in fMRI using 3D single shot techniques.
Magn Reson Med
PUBLISHED: 01-15-2013
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PURPOSE: Respiration induced dynamic field map changes in the brain are quantified and the influence on the magnitude signal (physiological noise) is investigated. Dynamic off-resonance correction allows to reduce the signal fluctuations overlaying the blood oxygenation level dependent signal in T2*-weighted functional imaging. THEORY AND METHODS: A single-shot whole brain imaging technique with 100 ms temporal resolution was used to measure dynamic off-resonance maps that were calculated from the incremental changes of the image phase. These off-resonance maps are then used to dynamically update the off-resonance corrected reconstruction. RESULTS: A global resonance offset and a pronounced gradient in head-foot direction were identified as the main components of the change during a respiration cycle. On average, correction for these fluctuations decreases the magnitude fluctuations by around 30%. CONCLUSION: Single shot 3D imaging allows for a robust quantification of dynamic off-resonance changes in the brain. Correction for these fluctuations removes the physiological noise component associated with dynamic point spread function changes.
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Prevention of motion-induced signal loss in diffusion-weighted echo-planar imaging by dynamic restoration of gradient moments.
Magn Reson Med
PUBLISHED: 01-03-2013
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Head motion is a significant problem in diffusion-weighted imaging as it may cause signal attenuation due to residual dephasing during strong diffusion encoding gradients even in single-shot acquisitions. Here, we present a new real-time method to prevent motion-induced signal loss in DWI of the brain.
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TNF?-mediated liver destruction by Kupffer cells and Ly6Chi monocytes during Entamoeba histolytica infection.
PLoS Pathog.
PUBLISHED: 01-03-2013
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Amebic liver abscess (ALA) is a focal destruction of liver tissue due to infection by the protozoan parasite Entamoeba histolytica (E. histolytica). Host tissue damage is attributed mainly to parasite pathogenicity factors, but massive early accumulation of mononuclear cells, including neutrophils, inflammatory monocytes and macrophages, at the site of infection raises the question of whether these cells also contribute to tissue damage. Using highly selective depletion strategies and cell-specific knockout mice, the relative contribution of innate immune cell populations to liver destruction during amebic infection was investigated. Neutrophils were not required for amebic infection nor did they appear to be substantially involved in tissue damage. In contrast, Kupffer cells and inflammatory monocytes contributed substantially to liver destruction during ALA, and tissue damage was mediated primarily by TNF?. These data indicate that besides direct antiparasitic drugs, modulating innate immune responses may potentially be beneficial in limiting ALA pathogenesis.
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Prevalence and status quo of osteoarthritis in Austria. Analysis of epidemiological and social determinants of health in a representative cross-sectional survey.
Wien Med Wochenschr
PUBLISHED: 01-02-2013
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Osteoarthritis has a major impact on mobility and functioning leading to impairment in activities of daily living and quality of life. The aim of our analysis was to reveal the prevalence of self-reported, doctor-diagnosed osteoarthritis with a representative population based survey, including data for 15,474 subjects. Prevalence of osteoarthritis was 11.9 % in men and 18.6 % in women. A total of 73.4 % of men and 74.9 % of women with osteoarthritis reported to have had severe pain in the last 12 months; 60.3 % of male and 67.0 % of female patients reported that the disease was treated within the last 12 months. Age, socio-economic parameters, overweight and obesity, as well as living in a rural area were significant predictors of osteoarthritis. Even if the onset of osteoarthritis may not be averted, public health and prevention programmes may improve quality of life significantly if they are adequately tuned to sex, age and personal capabilities.
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Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels.
J. Neurosci.
PUBLISHED: 12-14-2011
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Cannabis is the most abused illegal substance in the United States. Alterations in brain function and motor behavior have been reported in chronic cannabis users, but the results have been variable. The current study aimed to determine whether chronic active cannabis use in humans may alter psychomotor function, brain activation, and hypothalamic-pituitary-axis (HPA) function in men and women. Thirty cannabis users (16 men, 14 women, 18-45 years old) and 30 nondrug user controls (16 men, 14 women, 19-44 years old) were evaluated with neuropsychological tests designed to assess motor behavior and with fMRI using a 3 Tesla scanner during a visually paced finger-sequencing task, cued by a flashing checkerboard (at 2 or 4 Hz). Salivary cortisol was measured to assess HPA function. Male, but not female, cannabis users had significantly slower performance on psychomotor speed tests. As a group, cannabis users had greater activation in BA 6 than controls, while controls had greater activation in the visual area BA 17 than cannabis users. Cannabis users also had higher salivary cortisol levels than controls (p = 0.002). Chronic active cannabis use is associated with slower and less efficient psychomotor function, especially in male users, as indicated by a shift from regions involved with automated visually guided responses to more executive or attentional control areas. The greater but altered brain activities may be mediated by the higher cortisol levels in the cannabis users, which in turn may lead to less efficient visual-motor function.
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BCR-ABL mutations in chronic myeloid leukemia.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 11-08-2011
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The advent of imatinib has been a major breakthrough in chronic myeloid leukemia (CML) treatment. A few patients treated with imatinib are either refractory to imatinib or eventually relapse. Resistance is frequently associated with mutations in the kinase domain of BCR-ABL. Over 100 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. Most reported mutants are rare, whereas 7 mutated residues comprise two-thirds of all mutations detected. BCR-ABL mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecularly based treatment decisions.
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Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.
Blood
PUBLISHED: 11-03-2011
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The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
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EZH2 mutational status predicts poor survival in myelofibrosis.
Blood
PUBLISHED: 09-14-2011
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We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.
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Predictors of short-term success in smoking cessation in relation to attendance at a smoking cessation program.
Nicotine Tob. Res.
PUBLISHED: 08-10-2011
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The identification of individual characteristics that predict success in smoking cessation is necessary to improve the effectiveness of smoking cessation efforts. The aim of this study was to identify the factors that predict success in smoking cessation in people who attended 2, 3, 4, or 5 sessions of a smoking cessation program.
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Lower glial metabolite levels in brains of young children with prenatal nicotine exposure.
J Neuroimmune Pharmacol
PUBLISHED: 07-08-2011
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Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3-4 years old) children, using proton magnetic resonance spectroscopy ((1)H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/(1)H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA-p?=?0.03) and tCr levels (repeated measures ANOVA-p?=?0.003), especially in the basal ganglia of the girls (-19.3%, p?=?0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p?=?0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r?=?-0.67; p?
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Age and sex effects levels of choline compounds in the anterior cingulate cortex of adolescent methamphetamine users.
Drug Alcohol Depend
PUBLISHED: 06-18-2011
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Methamphetamine can be neurotoxic to the adult brain; however, many individuals first use methamphetamine during adolescence, and the drugs impact on this period of brain development is unknown. Therefore, we evaluated young methamphetamine users for possible abnormalities in brain metabolite concentrations.
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Methamphetamine users show greater than normal age-related cortical gray matter loss.
Addiction
PUBLISHED: 05-12-2011
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Methamphetamine (Meth) abuse continues to be a major illicit drug of abuse. Neuroimaging findings suggest that Meth is neurotoxic and may alter various brain structures, but the effect of Meth on the aging brain has not been studied.
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BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet.
Blood
PUBLISHED: 05-11-2011
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Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.
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A novel phase and frequency navigator for proton magnetic resonance spectroscopy using water-suppression cycling.
Magn Reson Med
PUBLISHED: 04-16-2011
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Magnetic resonance spectroscopy is sensitive to movements, in part, because of motion-induced phase and frequency variations that lead to incoherent averaging. For in vivo proton magnetic resonance spectroscopy, the unsuppressed or under-suppressed water signal can be used to restore coherent averaging; however, this approach results in baseline distortions due to the large water peak. Therefore, a novel water-suppression cycling scheme was developed that alternates between positive and negative residual water signal. Using the residual water signal, the method allows for shot-to-shot phase and frequency correction of individual free induction decays and restoration of signal losses due to incoherent averaging, yet near-complete elimination of residual water. It is demonstrated that the residual water signal can be used to restore metabolite peaks in a brain spectrum from a subject who performed intentional head movements. The ability to correct phase and frequency fluctuations during subject motion is vital for use with adaptive motion correction approaches that ensure proper voxel positioning during head movements.
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Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia.
Br. J. Haematol.
PUBLISHED: 02-01-2011
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We have identified two novel ABL1 fusion genes in two patients with B-cell acute lymphoblastic leukaemia (ALL) associated with a t(3;9)(p12;q34) and a t(5;9)(q23;q34), respectively. Molecular analysis revealed a FOXP1-ABL1 fusion for the t(3;9) and a SNX2-ABL1 fusion for the t(5;9). The fusions were confirmed by specific amplification of the genomic breakpoints using reverse transcription polymerase chain reaction. The identification of ALL with rare ABL1 fusion partners is important because the leukaemia may respond to tyrosine kinase inhibitors in the same way as ALL patients with a classical BCR-ABL1 fusion gene.
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Prospective motion correction for magnetic resonance spectroscopy using single camera Retro-Grate reflector optical tracking.
J Magn Reson Imaging
PUBLISHED: 01-29-2011
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To introduce and evaluate a method of prospective motion correction for localized proton magnetic resonance spectroscopy (1H-MRS) using a single-camera optical tracking system.
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Coverage of recommended vaccinations in subjects with diabetes mellitus and ischemic heart disease: results for women and men.
Wien Med Wochenschr
PUBLISHED: 01-25-2011
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Vaccination is an important public health strategy to prevent adverse health outcomes in the general population and in subjects with chronic diseases. It was the aim of this study to compare data on coverage of recommended vaccinations in men and women with diabetes mellitus and after myocardial infarction (MI) and to analyse trends in three different interview surveys: 1991, 1999 and 2006-07. The data show a rise in influenza vaccination coverage rate in men and women in the general population and in high-risk groups. However, coverage rates in all analysed groups were still strikingly low. Although in soft reported earlier surveys women were vaccinated more often than men, there was a reverse trend observed in the most recent survey. In the survey of 2006-07, men with diabetes or after MI had a higher chance of being vaccinated against influenza when compared to men without these diseases (age adjusted OR: 1.61; 95% CI: 1.29-1.99 and 1.61; 95% CI: 1.21-2.15, respectively). This was, however, not the case in women (OR: 1.10; 95% CI: 0.89-1.35 and 0.87; 95% CI: 0.58-1.33, respectively). Neither men nor women with diabetes mellitus or MI had a significantly higher chance of having pneumococcal vaccination when compared to subjects without these diseases. The observed sex-specific differences demand more research regarding the underlying causes. Strategies to reach higher vaccination coverage in men and women are needed.
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Multi-contrast human neonatal brain atlas: application to normal neonate development analysis.
Neuroimage
PUBLISHED: 01-20-2011
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MRI is a sensitive method for detecting subtle anatomic abnormalities in the neonatal brain. To optimize the usefulness for neonatal and pediatric care, systematic research, based on quantitative image analysis and functional correlation, is required. Normalization-based image analysis is one of the most effective methods for image quantification and statistical comparison. However, the application of this methodology to neonatal brain MRI scans is rare. Some of the difficulties are the rapid changes in T1 and T2 contrasts and the lack of contrast between brain structures, which prohibits accurate cross-subject image registration. Diffusion tensor imaging (DTI), which provides rich and quantitative anatomical contrast in neonate brains, is an ideal technology for normalization-based neonatal brain analysis. In this paper, we report the development of neonatal brain atlases with detailed anatomic information derived from DTI and co-registered anatomical MRI. Combined with a diffeomorphic transformation, we were able to normalize neonatal brain images to the atlas space and three-dimensionally parcellate images into 122 regions. The accuracy of the normalization was comparable to the reliability of human raters. This method was then applied to babies of 37-53 post-conceptional weeks to characterize developmental changes of the white matter, which indicated a posterior-to-anterior and a central-to-peripheral direction of maturation. We expect that future applications of this atlas will include investigations of the effect of prenatal events and the effects of preterm birth or low birth weights, as well as clinical applications, such as determining imaging biomarkers for various neurological disorders.
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Impact of BCR-ABL mutations on patients with chronic myeloid leukemia.
Cell Cycle
PUBLISHED: 01-15-2011
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Therapies that target BCR-ABL in chronic myeloid leukemia, including imatinib, dasatinib and nilotinib, have dramatically improved patient outcome. BCR-ABL mutations, however, contribute to treatment resistance by disrupting drug contact sites or causing conformational changes thus making contact sites inaccessible. Clinical data indicate that developing BCR-ABL mutations during imatinib treatment is predictive for shorter progression-free survival, and that outcomes may depend on mutation type or location. In vitro, dasatinib and nilotinib inhibit most imatinib-resistant BCR-ABL mutations, except for T315I. In clinical studies, other mutations associated with treatment resistance include V299L, T315A, and F317I/L for dasatinib and Y253F/H, E255K/V, and F359C/V for nilotinib. Evaluating patients with clinical signs of resistance for BCR-ABL mutations is an important component of disease monitoring, potentially facilitating selection of subsequent therapy. First-line treatment with dasatinib or nilotinib instead of imatinib may reduce emergence of resistance but novel agents are needed to overcome the problematic T315I mutation.
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Phase contrast imaging in neonates.
Neuroimage
PUBLISHED: 01-11-2011
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Magnetic resonance phase images can yield superior gray and white matter contrast compared to conventional magnitude images. However, the underlying contrast mechanisms are not yet fully understood. Previous studies have been limited to high field acquisitions in adult volunteers and patients. In this study, phase imaging in the neonatal brain is demonstrated for the first time. Compared to adults, phase differences between gray and white matter are significantly reduced but not inverted in neonates with little myelination and iron deposits in their brains. The remaining phase difference between the neonatal and adult brains may be due to a different macromolecule concentration in the unmyelinated brain of the neonates and thus a different frequency due to water macromolecule exchange. Additionally, the susceptibility contrast from brain myelination can be separately studied in neonates during brain development. Therefore, magnetic resonance phase imaging is suggested as a novel tool to study neonatal brain development and pathologies in neonates.
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Dynamics of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor therapy.
Haematologica
PUBLISHED: 12-06-2010
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Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon.
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Lower brain glutamate is associated with cognitive deficits in HIV patients: a new mechanism for HIV-associated neurocognitive disorder.
J Magn Reson Imaging
PUBLISHED: 10-30-2010
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To determine whether subjects with human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) show altered concentrations of brain glutamate (GLU), and whether lower GLU levels correlate with cognitive deficits.
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Prospective motion correction for single-voxel 1H MR spectroscopy.
Magn Reson Med
PUBLISHED: 09-01-2010
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Head motion during (1)H MR spectroscopy acquisitions may compromise the quality and reliability of in vivo metabolite measurements. Therefore, a three-plane image-based motion-tracking module was integrated into a single-voxel (1)H MR spectroscopy (point-resolved spectroscopy) sequence. A series of three orthogonal spiral navigator images was acquired immediately prior to the MR spectroscopy water suppression module in order to estimate head motion. By applying the appropriate rotations and translations, the MR spectroscopy voxel position can be updated such that it remains stationary with respect to the brain. Frequency and phase corrections were applied during postprocessing to reduce line width and restore coherent averaging. Spectra acquired during intentional head motion in 11 volunteers demonstrate reduced lipid contamination and increased spectral reproducibility when motion correction is applied.
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Clinical, laboratory, and neuroimaging characteristics of fatigue in HIV-infected individuals.
J. Neurovirol.
PUBLISHED: 08-31-2010
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Fatigue is among the most common symptoms reported by HIV-infected individuals. Previous reports suggest that the prevalence of fatigue varies by disease status with rates close to 80% in patients with AIDS. However, most studies have not been conducted in the setting of a controlled trial and have not assessed the association of fatigue with cellular markers of brain activity. Data for this study were derived from baseline and longitudinal evaluations in ACTG A5090, a randomized, double-blind, placebo-controlled trial of the Selegiline Transdermal System for the treatment of HIV-associated cognitive impairment. Fatigue was assessed using the Fatigue Severity Scale with scores of >4 considered "fatigued". Participants in a substudy underwent brain magnetic resonance spectroscopy (MRS) imaging, an in vivo method for assessing brain metabolites associated with neuronal and glia activity. Differences between fatigued and non-fatigued participants were evaluated with respect to demographics and clinical characteristics, plasma and CSF HIV-1 RNA concentration, CD4 counts, and brain metabolites. One hundred and twenty-eight participants were enrolled (88% male, median age?=?45 years) and 82 participants (64%, 95% confidence interval 55%, 72%) were fatigued at baseline. MRS was conducted in 62 of the 128 participants. Fatigued participants were significantly younger (p?=?0.011), had lower Karnofsky scores (p?=?0.032), and had higher levels of depressive symptoms on the Center for Epidemiologic Studies Depression (CES-D) scale (p?
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Neurometabolite abnormalities in simian immunodeficiency virus-infected macaques with chronic morphine administration.
J Neuroimmune Pharmacol
PUBLISHED: 06-26-2010
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Opiate abuse increases the risk for human immunodeficiency virus (HIV) infection, while both opiates and HIV may impact the immune and nervous systems. To model potential interactions between opiate drugs and HIV on the brain, neurometabolite levels were evaluated in simian immunodeficiency virus (SIV)-infected macaques with or without chronic morphine administration. Over the course of the study, 58% of these SIV-infected animals progressed to acquired immune deficiency syndrome (AIDS). Brain extracts from four brain regions were evaluated with proton magnetic resonance spectroscopy. Animals with AIDS had lower N-acetyl-aspartate in all four brain regions (p???0.05) as well as lower frontal gray matter total creatine (p=?0.03), lower frontal white matter (p=?0.003) and caudate (p?=?0.002) glutamate, and higher frontal white matter myo-inositol (p=?0.05) than the healthier non-AIDS macaques. Morphine-dependent animals had higher levels of myo-inositol in the putamen (p?=?0.003), especially those with AIDS. In the animals with AIDS, those with morphine dependence had higher total creatine in the frontal white matter (p=?0.04) than those treated with saline, which in turn had lower creatine than saline-injected animals without AIDS (p?=?0.04), leading to an interaction between the effects of morphine and AIDS on total creatine in this brain region (ANOVA p?=?0.02). The majority of these brain metabolites correlated with viral counts indicating more severe metabolite abnormalities in animals with higher viral loads or set points. Collectively, these findings suggest that chronic morphine may protect against the neurotoxic effect of AIDS and reinforce the importance of maintaining a low viral load in AIDS.
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Removal of asymmetric dimethylarginine during artificial liver support using fractionated plasma separation and adsorption.
Scand. J. Gastroenterol.
PUBLISHED: 05-06-2010
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Asymmetric dimethylarginine (ADMA) is the most potent endogenous nitric oxide synthase inhibitor. Elevated ADMA levels have been linked to increased mortality in different patient populations. Key regulation of ADMA levels mainly takes place in the liver. Hence, ADMA is elevated in liver disease. There is no specific pharmacological treatment to lower the elevated ADMA levels. Hemodialysis is of limited efficiency in removing ADMA as it is highly protein bound. Prometheus is an extracorporeal liver support system which allows the removal of protein-bound toxins. We assessed the efficiency of the Prometheus system in reducing high ADMA levels in patients with liver failure.
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Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms.
Haematologica
PUBLISHED: 04-26-2010
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Aberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms.
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Efficacy and safety of capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated pancreatic, gallbladder, and bile duct carcinoma.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 02-15-2010
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Preclinical data indicate the improvement of the antitumor activity of capecitabine by mitomycin C and docetaxel through upregulation of thymidine phosphorylase activity. Therefore, we have established a combination regimen of these drugs (DocMitoCape), which demonstrated preliminary activity especially in bile duct and pancreatic carcinoma.
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Screening for diverse PDGFRA or PDGFRB fusion genes is facilitated by generic quantitative reverse transcriptase polymerase chain reaction analysis.
Haematologica
PUBLISHED: 01-27-2010
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Rapid identification of diverse fusion genes with involvement of PDGFRA or PDGFRB in eosinophilia-associated myeloproliferative neoplasms is essential for adequate clinical management but is complicated by the multitude and heterogeneity of partner genes and breakpoints.
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Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders.
Nat. Genet.
PUBLISHED: 01-13-2010
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Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.
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A polymorphism associated with STAT3 expression and response of chronic myeloid leukemia to interferon ?.
Haematologica
PUBLISHED: 01-13-2010
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Interferon alpha (IFN) induces variable responses in chronic myeloid leukemia (CML), with 8-30% of early chronic phase cases achieving a complete cytogenetic response. We hypothesized that polymorphic differences in genes encoding IFN signal transduction components might account for different patient responses. We studied 174 IFN-treated patients, of whom 79 achieved less than 35% Philadelphia-chromosome (Ph) positive metaphases (responders) and 95 failed to show any cytogenetic response (more than 95% Ph-positive metaphases; non-responders). We compared 17 single nucleotide polymorphisms (SNPs) at IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT3 and STAT5a/b between the two groups and found a significant difference for rs6503691, a SNP tightly linked to STAT5a, STAT5b and STAT3 (minor allele frequency 0.16 for non-responders; 0.06 for responders, P=0.007). Levels of STAT3 mRNA correlated with rs6503691 genotype (P<0.001) as assessed by real time quantitative PCR and therefore we conclude that rs6503691 is associated with the STAT3 expression levels and response of CML patients to IFN.
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Detection of drug-resistant clones in chronic myelogenous leukemia patients during dasatinib and nilotinib treatment.
Clin. Chem.
PUBLISHED: 12-29-2009
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Imatinib effectively inhibits the tyrosine kinase activity conferred by the BCR-ABL gene [fusion gene of BCR (breakpoint cluster region) and ABL1 (c-abl oncogene 1, receptor tyrosine kinase)] and thereby appreciably improves outcomes for chronic myelogenous leukemia (CML). A small percentage of patients relapse because of the proliferation of escape clones; such relapses can be treated with second-generation drugs. Early detection and monitoring of resistant clones may provide clinical benefit. We describe the development and testing of a new approach for quantitative monitoring of CML resistance.
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Cause and management of therapy resistance.
Best Pract Res Clin Haematol
PUBLISHED: 12-05-2009
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A minority of patients treated with imatinib are either refractory to imatinib or eventually relapse. Relapse frequently depends on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression. Over 90 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. These mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecular-based treatment decisions. Therapeutic strategies of imatinib resistant disease include novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, dose escalation to optimise imatinib levels, treatment interruption to stop selection of resistant cells and allogeneic stem cell transplantation in eligible patients.
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Changes in plasma amino acids during extracorporeal liver support by fractionated plasma separation and adsorption.
Artif Organs
PUBLISHED: 10-10-2009
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In patients with liver failure, amino acid dysbalance is common and associated with hepatic encephalopathy. Prometheus is a newly designed extracorporeal liver support system based upon fractionated plasma separation and adsorption (FPSA). We evaluated the influence of FPSA on plasma amino acid patterns in patients with liver failure and hepatic encephalopathy. We studied nine patients with acute-on-chronic liver failure, hepatic encephalopathy, and concomitant renal failure. A single session of FPSA therapy for 5 +/- 1 h was performed in all patients. Twenty-six different plasma amino acids were measured by high-performance liquid chromatography before and after FPSA treatment. Total amino acids as well as Fischer index were calculated. Additionally, a variety of clinical and biochemical parameters were assessed. Before FPSA was started, plasma levels of most amino acids were elevated. Plasma ammonia levels correlated with glutamine levels (P < 0.04). During FPSA, plasma levels of nearly all amino acids significantly decreased except for branched-chain amino acids. The Fischer index improved without reaching statistical significance. FPSA therapy tends to normalize plasma amino acids in patients with combined liver and renal failure. This may contribute to positive pathophysiologic effects, especially on hepatic encephalopathy. However, the clinical significance of these findings needs to be further evaluated.
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TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals.
Haematologica
PUBLISHED: 10-01-2009
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The formation of fusion genes plays roles in both oncogenesis and evolution by facilitating the acquisition of novel functions. Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant.
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Efficacy and safety of anticoagulation with heparin versus heparin plus epoprostenol in patients undergoing extracorporeal liver support with Prometheus.
Artif Organs
PUBLISHED: 08-07-2009
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Anticoagulation for extracorporeal liver support is delicate due to underlying coagulation disorders in patients with liver failure and to the associated elevated bleeding risk. To date, there has been no detailed report on anticoagulation issues in patients treated with Prometheus, a device based on the principle of fractionated plasma separation and adsorption. We studied 17 patients from two centers treated with Prometheus, comparing standard anticoagulation with heparin (15 treatments) and a combination of heparin and the synthetic prostacyclin epoprostenol (22 treatments). Standard coagulation tests, proteins C and S, and thrombin-antithrombin (TAT) complex were determined, and adverse events were recorded. All but two treatments could be completed as scheduled, although filter exchange due to filter clotting was required in 24% of the treatments. Three out of 17 patients developed severe bleeding complications within 24 h of treatment. There were no overt thrombotic events. Addition of epoprostenol neither reduced coagulation-related adverse events nor improved standard coagulation parameters. Protein C, but not protein S, showed a significant reduction (23 +/- 18%) after Prometheus treatments, but levels rebounded to baseline within 18 h. TAT levels--a measure for activation of coagulation--were only altered by Prometheus in patients where TAT was already elevated before treatment. In conclusion, anticoagulation of Prometheus with heparin is feasible but still associated with a relatively high frequency of filter clotting and a considerable risk of severe bleeding in this high-risk patient population. As addition of epoprostenol did not prove beneficial, other strategies, such as regional anticoagulation with citrate, should be further evaluated.
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A co-operative evaluation of different methods of detecting BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on second-line dasatinib or nilotinib therapy after failure of imatinib.
Haematologica
PUBLISHED: 07-16-2009
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Various techniques have been employed to detect BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia who are resistant to imatinib. This has led to different reported frequencies of mutations and the finding of a heterogeneous pattern of individual mutations.
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Design, synthesis and evaluation of monovalent ligands for the asialoglycoprotein receptor (ASGP-R).
Bioorg. Med. Chem.
PUBLISHED: 07-14-2009
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A series of novel aryl-substituted triazolyl D-galactosamine derivatives was synthesized as ligands for the carbohydrate recognition domain of the major subunit H1 (H1-CRD) of the human asialoglycoprotein receptor (ASGP-R). The compounds were biologically evaluated with a newly developed competitive binding assay, surface plasmon resonance and by a competitive NMR binding experiment. With compound 1b, a new ligand with a twofold improved affinity to the best so far known D-GalNAc was identified. This small, drug-like ligand can be used as targeting device for drug delivery to hepatocytes.
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Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention.
PLoS ONE
PUBLISHED: 06-07-2009
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Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task.
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Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.
Blood
PUBLISHED: 04-22-2009
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Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.