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- D-1221-2009 (1)
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Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb\(^{−1}\) of \(\sqrt {s}\) = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between E\(^{miss}_{T}\) > 150 GeV and E\(^{miss}_{T}\) > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presented.
Many extensions of the Standard Model predict the existence of charged heavy long-lived particles, such as R-hadrons or charginos. These particles, if produced at the Large Hadron Collider, should be moving non-relativistically and are therefore identifiable through the measurement of an anomalously large specific energy loss in the ATLAS pixel detector. Measuring heavy long-lived particles through their track parameters in the vicinity of the interaction vertex provides sensitivity to metastable particles with lifetimes from 0.6 ns to 30 ns. A search for such particles with the ATLAS detector at the Large Hadron Collider is presented, based on a data sample corresponding to an integrated luminosity of 18.4 fb\(^{−1}\) of pp collisions at \(\sqrt {s}\) = 8 TeV. No significant deviation from the Standard Model background expectation is observed, and lifetime-dependent upper limits on R-hadrons and chargino production are set. Gluino R-hadrons with 10 ns lifetime and masses up to 1185 GeV are excluded at 95 % confidence level, and so are charginos with 15 ns lifetime and masses up to 482 GeV.
A search for the production of single-top-quarks in association with missing energy is performed in proton–proton collisions at a centre-of-mass energy of \(\sqrt {s}\) =8 TeV with the ATLAS experiment at the large hadron collider using data collected in 2012, corresponding to an integrated luminosity of 20.3 fb\(^{−1}\). In this search, the W boson from the top quark is required to decay into an electron or a muon and a neutrino. No deviation from the standard model prediction is observed, and upper limits are set on the production cross-section for resonant and non-resonant production of an invisible exotic state in association with a right-handed top quark. In the case of resonant production, for a spin-0 resonance with a mass of 500 GeV, an effective coupling strength above 0.15 is excluded at 95 % confidence level for the top quark and an invisible spin-1/2 state with mass between 0 and 100 GeV. In the case of non-resonant production, an effective coupling strength above 0.2 is excluded at 95 % confidence level for the top quark and an invisible spin-1 state with mass between 0 and 657 GeV.
A search for Higgs boson decays to invisible particles is performed using 20.3 fb\(^{−1}\) of pp collision data at a centre-of-mass energy of 8 TeV recorded by the ATLAS detector at the Large Hadron Collider. The process considered is Higgs boson production in association with a vector boson (V = W or Z) that decays hadronically, resulting in events with two or more jets and large missing transverse momentum. No excess of candidates is observed in the data over the background expectation. The results are used to constrain VH production followed by H decaying to invisible particles for the Higgs boson mass range 115 < m\(_{H}\) < 300 GeV. The 95 % confidence-level observed upper limit on σ\(_{VH}\) × BR(H → inv.) varies from 1.6 pb at 115 GeV to 0.13 pb at 300 GeV. Assuming Standard Model production and including the gg → H contribution as signal, the results also lead to an observed upper limit of 78 % at 95 % confidence level on the branching ratio of Higgs bosons decays to invisible particles at a mass of 125 GeV.
A search for Higgs boson pair production pp → hh is performed with 19.5 fb\(^{−1}\) of proton–proton collision data at \(\sqrt {s}\) = 8 TeV, which were recorded by the ATLAS detector at the Large Hadron Collider in 2012. The decay products of each Higgs boson are reconstructed as a high-momentum b\(\overline{b}\) system with either a pair of small-radius jets or a single large-radius jet, the latter exploiting jet substructure techniques and associated b-tagged track-jets. No evidence for resonant or non-resonant Higgs boson pair production is observed. The data are interpreted in the context of the Randall–Sundrum model with a warped extra dimension as well as the two-Higgs-doublet model. An upper limit on the cross-section for pp → G\(^{*}_{KK}\) → hh → b\(\overline{b}\)b\(\overline{b}\) of 3.2(2.3) fb is set for a Kaluza–Klein graviton G\(^{*}_{KK}\) mass of 1.0(1.5) TeV, at the 95 % confidence level. The search for non-resonant Standard Model hh production sets an observed 95 % confidence level upper limit on the production cross-section σ(pp → hh → b\(\overline{b}\)b\(\overline{b}\)) of 202 fb, compared to a Standard Model prediction of σ(pp → hh → b\(\overline{b}\)b\(\overline{b}\)) = 3.6±0.5 fb.
A search for heavy long-lived multi-charged particles is performed using the ATLAS detector at the LHC. Data collected in 2012 at \(\sqrt {s}\) = 8 TeV from pp collisions corresponding to an integrated luminosity of 20.3 fb\(^{−1}\) are examined. Particles producing anomalously high ionisation, consistent with long-lived massive particles with electric charges from |q| = 2e to |q| = 6e are searched for. No signal candidate events are observed, and 95 % confidence level cross-section upper limits are interpreted as lower mass limits for a Drell–Yan production model. The mass limits range between 660 and 785 GeV.
A search is presented for the direct pair production of a chargino and a neutralino pp → \(\tilde{χ}\)\(^{±}_{1}\)\(\tilde{χ}\)\(^{0}_{2}\), where the chargino decays to the lightest neutralino and the W boson, \(\tilde{χ}\)\(^{±}_{1}\)→\(\tilde{χ}\)\(^{0}_{1}\)(W\(^{±}\)→ℓ\(^{±}\)ν), while the neutralino decays to the lightest neutralino and the 125 GeV Higgs boson, \(\tilde{χ}\)\(^{0}_{2}\)→\(\tilde{χ}\)\(^{0}_{1}\)(h→bb/γγ/ℓ\(^{±}\)νqq). The final states considered for the search have large missing transverse momentum, an isolated electron or muon, and one of the following: either two jets identified as originating from bottom quarks, or two photons, or a second electron or muon with the same electric charge. The analysis is based on 20.3 fb\(^{-1}\) of \(\sqrt {s}\) = 8 TeV proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with the Standard Model expectations, and limits are set in the context of a simplified supersymmetric model.
This article reports on a search for dark matter pair production in association with bottom or top quarks in 20.3 fb\(^{−1}\) of pp collisions collected at \(\sqrt {s}\) = 8 TeV by the ATLAS detector at the LHC. Events with large missing transverse momentum are selected when produced in association with high-momentum jets of which one or more are identified as jets containing b-quarks. Final states with top quarks are selected by requiring a high jet multiplicity and in some cases a single lepton. The data are found to be consistent with the Standard Model expectations and limits are set on the mass scale of effective field theories that describe scalar and tensor interactions between dark matter and Standard Model particles. Limits on the dark-matter–nucleon cross-section for spin-independent and spin-dependent interactions are also provided. These limits are particularly strong for low-mass dark matter. Using a simplified model, constraints are set on the mass of dark matter and of a coloured mediator suitable to explain a possible signal of annihilating dark matter.
A search for a new resonance decaying to a W or Z boson and a Higgs boson in the ℓℓ/ℓν/νν+b\(\overline{b}\) final states is performed using 20.3 fb\(^{−1}\) of pp collision data recorded at \(\sqrt {s}\) = 8 TeV with the ATLAS detector at the Large Hadron Collider. The search is conducted by examining the WH / ZH invariant mass distribution for a localized excess. No significant deviation from the Standard Model background prediction is observed. The results are interpreted in terms of constraints on the Minimal Walking Technicolor model and on a simplified approach based on a phenomenological Lagrangian of Heavy Vector Triplets.
Search for W' → tb → qqbb decays in pp collisions at \(\sqrt {s}\) = 8 TeV with the ATLAS detector
(2015)
A search for a massive W′ gauge boson decaying to a top quark and a bottom quark is performed with the ATLAS detector in pp collisions at the LHC. The dataset was taken at a centre-of-mass energy of \(\sqrt {s}\) = 8 TeV and corresponds to 20.3 fb\(^{−1}\) of integrated luminosity. This analysis is done in the hadronic decay mode of the top quark, where novel jet substructure techniques are used to identify jets from high-momentum top quarks. This allows for a search for high-mass W′ bosons in the range 1.5–3.0 TeV. b-tagging is used to identify jets originating from b-quarks. The data are consistent with Standard Model background-only expectations, and upper limits at 95 % confidence level are set on the W′ → tb cross section times branching ratio ranging from 0.16 pb to 0.33 pb for left-handed W′ bosons, and ranging from 0.10 pb to 0.21 pb for W′ bosons with purely right-handed couplings. Upper limits at 95 % confidence level are set on the W′-boson coupling to tb as a function of the W′ mass using an effective field theory approach, which is independent of details of particular models predicting a W′ boson.
The performance of the ATLAS muon trigger system is evaluated with proton–proton collision data collected in 2012 at the Large Hadron Collider at a centre-of-mass energy of 8 TeV. It is primarily evaluated using events containing a pair of muons from the decay of Z bosons. The efficiency of the single-muon trigger is measured for muons with transverse momentum 25 < p\(_{T}\) < 100GeV, with a statistical uncertainty of less than 0.01 % and a systematic uncertainty of 0.6 %. The pT range for efficiency determination is extended by using muons from decays of J/ψ mesons, W bosons, and top quarks. The muon trigger shows highly uniform and stable performance. The performance is compared to the prediction of a detailed simulation.
The production of a Z boson in association with a J/ψ meson in proton–proton collisions probes the production mechanisms of quarkonium and heavy flavour in association with vector bosons, and allows studies of multiple parton scattering. Using 20.3fb\(^{−1}\) of data collected with the ATLAS experiment at the LHC in pp collisions at \(\sqrt {s}\) = 8 TeV, the first measurement of associated Z+J/ψ production is presented for both prompt and non-prompt J/ψ production, with both signatures having a significance in excess of 5σ. The inclusive production cross-sections for Z boson production (analysed in μ\(^{+}\)μ\(^{−}\) or e\(^{+}\)e\(^{−}\) decay modes) in association with prompt and non-prompt J/ψ(→μ\(^{+}\)μ\(^{−}\)) are measured relative to the inclusive production rate of Z bosons in the same fiducial volume to be (36.8±6.7±2.5)×10\(^{−7}\) and (65.8±9.2±4.2)×10\(^{−7}\) respectively. Normalised differential production cross-section ratios are also determined as a function of the J/ψ transverse momentum. The fraction of signal events arising from single and double parton scattering is estimated, and a lower limit of 5.3 (3.7)mb at 68 (95)% confidence level is placed on the effective cross-section regulating double parton interactions.
Measurements of the W production cross sections in association with jets with the ATLAS detector
(2015)
This paper presents cross sections for the production of a W boson in association with jets, measured in proton–proton collisions at \(\sqrt {s}\) = 7 TeV with the ATLAS experiment at the large hadron collider. With an integrated luminosity of 4.6 fb\(^{−1}\), this data set allows for an exploration of a large kinematic range, including jet production up to a transverse momentum of 1 TeV and multiplicities up to seven associated jets. The production cross sections for W bosons are measured in both the electron and muon decay channels. Differential cross sections for many observables are also presented including measurements of the jet observables such as the rapidities and the transverse momenta as well as measurements of event observables such as the scalar sums of the transverse momenta of the jets. The measurements are compared to numerous QCD predictions including next-to-leading-order perturbative calculations, resummation calculations and Monte Carlo generators.
Double-differential three-jet production cross-sections are measured in proton–proton collisions at a centre-of-mass energy of \(\sqrt {s}\) = 7 TeV using the ATLAS detector at the large hadron collider. The measurements are presented as a function of the three-jet mass (m\(_{jjj}\)), in bins of the sum of the absolute rapidity separations between the three leading jets (|Y\(^{*}\)|). Invariant masses extending up to 5 TeV are reached for 8 < |Y\(^{*}\)| < 10. These measurements use a sample of data recorded using the ATLAS detector in 2011, which corresponds to an integrated luminosity of 4.51 fb\(^{-1}\). Jets are identified using the anti-k\(_{t}\) algorithm with two different jet radius parameters, R = 0.4 and R = 0.6. The dominant uncertainty in these measurements comes from the jet energy scale. Next-to-leading-order QCD calculations corrected to account for non-perturbative effects are compared to the measurements. Good agreement is found between the data and the theoretical predictions based on most of the available sets of parton distribution functions, over the full kinematic range, covering almost seven orders of magnitude in the measured cross-section values.
The mass of the top quark is measured in a data set corresponding to 4.6 fb\(^{-1}\) of proton–proton collisions with centre-of-mass energy \(\sqrt {s}\)=7 TeV collected by the ATLAS detector at the LHC. Events consistent with hadronic decays of top–antitop quark pairs with at least six jets in the final state are selected. The substantial background from multijet production is modelled with data-driven methods that utilise the number of identified b-quark jets and the transverse momentum of the sixth leading jet, which have minimal correlation. The top-quark mass is obtained from template fits to the ratio of three-jet to dijet mass. The three-jet mass is calculated from the three jets produced in a top-quark decay. Using these three jets the dijet mass is obtained from the two jets produced in the W boson decay. The top-quark mass obtained from this fit is thus less sensitive to the uncertainty in the energy measurement of the jets. A binned likelihood fit yields a top-quark mass of m\(_{t}\)= 175.1 ± 1.4 (stat.) ± 1.2 (syst.) GeV.
The top quark mass was measured in the channels t\(\overline{t}\) → lepton+jets and t\(\overline{t}\) → dilepton (lepton = e,μ) based on ATLAS data recorded in 2011. The data were taken at the LHC with a proton–proton centre-of-mass energy of \(\sqrt {s}\) = 7 TeV and correspond to an integrated luminosity of 4.6 fb\(^{-1}\). The t\(\overline{t}\) → lepton+jets analysis uses a three-dimensional template technique which determines the top quark mass together with a global jet energy scale factor (JSF), and a relative b-to-light-jet energy scale factor(bJSF), where the terms b-jets and light-jets refer to jets originating from b-quarks and u, d, c, s-quarks or gluons, respectively. The analysis of the t\(\overline{t}\) → dilepton channel exploits a one-dimensional template method using the m\(_{lb}\) observable, defined as the average invariant mass of the two lepton+b-jet pairs in each event. The top quark
mass is measured to be 172.33±0.75(stat + JSF + bJSF)±1.02(syst) GeV, and 173.79 ± 0.54(stat) ± 1.30(syst) GeV in the t\(\overline{t}\) → lepton+jets and t\(\overline{t}\) → dilepton channels, respectively. The combination of the two results yields m\(_{top}\) =172.99 ± 0.48(stat) ± 0.78(syst) GeV, with a total uncertainty of 0.91 GeV.
A measurement of W boson production in lead-lead collisions at \(\sqrt {^{S}NN}\)=2.76 TeV is presented. It is based on the analysis of data collected with the ATLAS detector at the LHC in 2011 corresponding to an integrated luminosity of 0.14 nb\(^{-1}\) and 0.15 nb\(^{-1}\) in the muon and electron decay channels, respectively. The differential production yields and lepton charge asymmetry are each measured as a function of the average number of participating nucleons ⟨N\(_{part}\)⟩ and absolute pseudorapidity of the charged lepton. The results are compared to predictions based on next-to-leading-order QCD calculations. These measurements are, in principle, sensitive to possible nuclear modifications to the parton distribution functions and also provide information on scaling of W boson production in multi-nucleon systems.
The jet energy scale (JES) and its systematic uncertainty are determined for jets measured with the ATLAS detector using proton–proton collision data with a centre-of-mass energy of \(\sqrt {s}\)=7 TeV corresponding to an integrated luminosity of 4.7 fb\(^{-1}\). Jets are reconstructed from energy deposits forming topological clusters of calorimeter cells using the anti-k\(_t\) algorithm with distance parameters R=0.4 or R=0.6, and are calibrated using MC simulations. A residual JES correction is applied to account for differences between data and MC simulations. This correction and its systematic uncertainty are estimated using a combination of in situ techniques exploiting the transverse momentum balance between a jet and a reference object such as a photon or a Z boson, for 20≤p\(^{jet}_{T}\)<1000 GeV and pseudorapidities |η|<4.5. The effect of multiple proton–proton interactions is corrected for, and an uncertainty is evaluated using in situ techniques. The smallest JES uncertainty of less than 1 % is found in the central calorimeter region (|η|<1.2) for jets with 55≤p\(^{jet}_{T}\)<500 GeV. For central jets at lower p\(_{T}\), the uncertainty is about 3 %. A consistent JES estimate is found using measurements of the calorimeter response of single hadrons in proton–proton collisions and test-beam data, which also provide the estimate for p\(^{jet}_{T}\)>1 TeV. The calibration of forward jets is derived from dijet p\(_{T}\) balance measurements. The resulting uncertainty reaches its largest value of 6 % for low-p\(_{T}\) jets at |η|=4.5. Additional JES uncertainties due to specific event topologies, such as close-by jets or selections of event samples with an enhanced content of jets originating from light quarks or gluons, are also discussed. The magnitude of these uncertainties depends on the event sample used in a given physics analysis, but typically amounts to 0.5–3 %.
This paper describes the trigger and offline reconstruction, identification and energy calibration algorithms for hadronic decays of tau leptons employed for the data collected from pp collisions in 2012 with the ATLAS detector at the LHC center-of-mass energy \(\sqrt {s}\)=8 TeV. The performance of these algorithms is measured in most cases with Z decays to tau leptons using the full 2012 dataset, corresponding to an integrated luminosity of 20.3 fb\(^{-1}\). An uncertainty on the offline reconstructed tau energy scale of 2–4 %, depending on transverse energy and pseudorapidity, is achieved using two independent methods. The offline tau identification efficiency is measured with a precision of 2.5 % for hadronically decaying tau leptons with one associated track, and of 4 % for the case of three associated tracks, inclusive in pseudorapidity and for a visible transverse energy greater than 20 GeV. For hadronic tau lepton decays selected by offline algorithms, the tau trigger identification efficiency is measured with a precision of 2–8 %, depending on the transverse energy. The performance of the tau algorithms, both offline and at the trigger level, is found to be stable with respect to the number of concurrent proton–proton interactions and has supported a variety of physics results using hadronically decaying tau leptons at ATLAS.
Studies of the spin and parity quantum numbers of the Higgs boson in the WW\(^{*}\)→eνμν final state are presented, based on proton–proton collision data collected by the ATLAS detector at the Large Hadron Collider, corresponding to an integrated luminosity of 20.3 fb\(^{-1}\) at a centre-of-mass energy of \(\sqrt {s}\)=8 TeV. The Standard Model spin-parity J\(^{CP}\)=0\(^{++}\) hypothesis is compared with alternative hypotheses for both spin and CP. The case where the observed resonance is a mixture of the Standard-Model-like Higgs boson and CP-even (J\(^{CP}\)=0\(^{++}\)) or CP-odd (J\(^{CP}\)=0\(^{+-}\)) Higgs boson in scenarios beyond the Standard Model is also studied. The data are found to be consistent with the Standard Model prediction and limits are placed on alternative spin and CP hypotheses, including CP mixing in different scenarios.
Measurements of the ZZ and WW final states in the mass range above the 2m\(_Z\) and 2m\(_W\) thresholds provide a unique opportunity to measure the off-shell coupling strength of the Higgs boson. This paper presents constraints on the off-shell Higgs boson event yields normalised to the Standard Model prediction (signal strength) in the ZZ→4ℓ, ZZ→2ℓ2ν and WW→eνμν final states. The result is based on pp collision data collected by the ATLAS experiment at the LHC, corresponding to an integrated luminosity of 20.3 fb\(^{-1}\) at a collision energy of \(\sqrt {s}\)=8 TeV. Using the CL\(_S\) method, the observed 95 % confidence level (CL) upper limit on the off-shell signal strength is in the range 5.1–8.6, with an expected range of 6.7–11.0. In each case the range is determined by varying the unknown gg→ZZ and gg→WW background K-factor from higher-order quantum chromodynamics corrections between half and twice the value of the known signal K-factor. Assuming the relevant Higgs boson couplings are independent of the energy scale of the Higgs boson production, a combination with the on-shell measurements yields an observed (expected) 95 % CL upper limit on Γ\(_H\)/Γ\(^{SM}_{H}\) in the range 4.5–7.5 (6.5–11.2) using the same variations of the background K-factor. Assuming that the unknown gg→VV background K-factor is equal to the signal K-factor, this translates into an observed (expected) 95 % CL upper limit on the Higgs boson total width of 22.7 (33.0) MeV.
We describe the case of a 71-year-old Caucasian female with primary disseminated non-small cell cancer of the lung, presented for palliative radiotherapy of metastatic spread to the 9th and 11th thoracic vertebrae without intramedullary growth. Palliative radiotherapy with daily fractions of 3 Gy and a cumulative dose of 36 Gy to thoracic vertebrae 8-12 was performed. The patient received concomitantly 250 mg gefitinib daily. After a latent period of 16 months, the patient developed symptoms of myelitis. Magnetic resonance imaging (MRI) did not reveal any bony or intraspinal tumor progression, but spinal cord signal alteration. No response to steroids was achieved. The neurological symptoms were progressive in August 2013 with the right leg being completely plegic. The left leg was incompletely paralyzed. Deep and superficial sensitivity was also diminished bilaterally. The patient was completely urinary and anally incontinent. Contrary to the clinical findings, a follow-up MRI (July 2013) showed amelioration of the former signal alterations in the spinal cord. The diagnosis of paraneoplastic myelopathy was refuted by a negative test for autologous antibodies. At the last clinical visit in May 2014, the neurological symptoms were stable. The last tumor-specific treatment the patient is receiving is erlotinib 125 mg/d.
We reviewed the literature and found no reported cases of radiation myelopathy after the treatment in such a setting. The calculated probability of such complication after radiotherapy alone is statistically measurable at the level of 0.02%. We suppose that gefitinib could also play a role in the development of this rare complication.
Bone metastasis is a frequent and life-threatening complication of breast cancer. The molecular mechanisms supporting the establishment of breast cancer cells in the skeleton are still not fully understood, which may be attributed to the lack of suitable models that interrogate interactions between human breast cancer cells and the bone microenvironment. Although it is well-known that integrins mediate adhesion of malignant cells to bone extracellular matrix, their role during bone colonization remains unclear. Here, the role of β1 integrins in bone colonization was investigated using tissue-engineered humanized in vitro and in vivo bone models. In vitro, bone-metastatic breast cancer cells with suppressed integrin β1 expression showed reduced attachment, spreading, and migration within human bone matrix compared to control cells. Cell proliferation in vitro was not affected by β1 integrin knockdown, yet tumor growth in vivo within humanized bone microenvironments was significantly inhibited upon β1 integrin suppression, as revealed by quantitative in/ex vivo fluorescence imaging and histological analysis. Tumor cells invaded bone marrow spaces in the humanized bone and formed osteolytic lesions; osteoclastic bone resorption was, however, not reduced by β1 integrin knockdown. Taken together, we demonstrate that β1 integrins have a pivotal role in bone colonization using unique tissue-engineered humanized bone models.
The gene encoding the LIM and SH3 domain protein (LASP1) was cloned two decades ago from a cDNA library of breast cancer metastases. As the first protein of a class comprising one N-terminal LIM and one C-terminal SH3 domain, LASP1 founded a new LIM-protein subfamily of the nebulin group. Since its discovery LASP1 proved to be an extremely versatile protein because of its exceptional structure allowing interaction with various binding partners, its ubiquitous expression in normal tissues, albeit with distinct expression patterns, and its ability to transmit signals from the cytoplasm into the nucleus. As a result, LASP1 plays key roles in cell structure, physiological processes, and cell signaling. Furthermore, LASP1 overexpression contributes to cancer aggressiveness hinting to a potential value of LASP1 as a cancer biomarker. In this review we summarize published data on structure, regulation, function, and expression pattern of LASP1, with a focus on its role in human cancer and as a biomarker protein. In addition, we provide a comprehensive transcriptome analysis of published microarrays (n=2,780) that illustrates the expression profile of LASP1 in normal tissues and its overexpression in a broad range of human cancer entities.
Background:
Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention.
Methods:
All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT.
Results:
In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3% (n=209). A total of 92% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9%; NOAC, 74.8%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence.
Conclusion:
One-year adherence to OAT after stroke is strong (>90%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies.
Models of the outer epithelia of the human body namely the skin, the intestine and the lung have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
Gliomas have been classified according to their histological properties. However, their respective cells of origin are still unknown. Neural progenitor cells (NPC) from the subventricular zone (SVZ) can initiate tumors in murine models of glioma and are likely cells of origin in the human disease. In both, p53 signaling is often functionally impaired which may contribute to tumor formation. Also, TGF-beta, which under physiological conditions exerts a strong control on the proliferation of NPCs in the SVZ, is a potent mitogen on glioma cells. Here, we approach on the crosstalk between p53 and TGF-beta by loss of function experiments using NPCs derived from p53 mutant mice, as well as pharmacological inhibition of TGF-beta signaling using TGF-beta receptor inhibitors. NPC derived from p53 mutant mice showed increased clonogenicity and more rapid proliferation than their wildtype counterparts. Further, NPC derived from p53\(^{mut/mut}\) mice were insensitive to TGF-beta induced growth arrest. Still, the canonical TGF-beta signaling pathway remained functional in the absence of p53 signaling and expression of key proteins as well as phosphorylation and nuclear translocation of SMAD2 were unaltered. TGF-beta-induced p21 expression could, in contrast, only be detected in p53\(^{wt/wt}\) but not in p53\(^{mut/mut}\) NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53\(^{wt/wt}\) but not of p53\(^{mut/mut}\) NPC. In conclusion, our data suggest that the TGF-beta induced growth arrest in NPC depends on functional p53. Mutational inactivation of p53 hence contributes to increased proliferation of NPC and likely to the formation of hyperplasia of the SVZ observed in p53 deficient mice in vivo.
This Letter reports a measurement of the exclusive γγ→ℓ\(^{+}\)ℓ\(^{−}\) (ℓ=e, μℓ=e, μ) cross-section in proton–proton collisions at a centre-of-mass energy of 7 TeV by the ATLAS experiment at the LHC, based on an integrated luminosity of 4.6 fb\(^{−1}\). For the electron or muon pairs satisfying exclusive selection criteria, a fit to the dilepton acoplanarity distribution is used to extract the fiducial cross-sections. The cross-section in the electron channel is determined to be \(^{excl.}_{γγ→e^{+}e^{-}}\)=0.428 ± 0.035 (stat.) ± 0.018 (syst.) pb for a phase–space region with invariant mass of the electron pairs greater than 24 GeV, in which both electrons have transverse momentum p\(_{T}\)>12 GeV and pseudorapidity |η|<2.4. For muon pairs with invariant mass greater than 20 GeV, muon transverse momentum p\(_{T}\)>10 GeV and pseudorapidity |η|<2.4, the cross-section is determined to be \(^{excl.}_{γγ→μ^{+}μ^{-}}\) =0.628 ± 0.032 (stat.) ± 0.021 (syst.) pb. When proton absorptive effects due to the finite size of the proton are taken into account in the theory calculation, the measured cross-sections are found to be consistent with the theory prediction.
A search for the associated production of the Higgs boson with a top quark pair is performed in multilepton final states using 20.3 fb\(^{−1}\) of proton–proton collision data recorded by the ATLAS experiment at \(\sqrt {s}\)=8 TeV at the Large Hadron Collider. Five final states, targeting the decays H→WW\(^{*}\), ττ, and ZZ\(^{*}\), are examined for the presence of the Standard Model (SM) Higgs boson: two same-charge light leptons (e or μ) without a hadronically decaying τ lepton; three light leptons; two same-charge light leptons with a hadronically decaying τ lepton; four light leptons; and one light lepton and two hadronically decaying τ leptons. No significant excess of events is observed above the background expectation. The best fit for the t\(\overline{t}\)H production cross section, assuming a Higgs boson mass of 125 GeV, is 2.1\(^{+1.4}_{-1.2}\) times the SM expectation, and the observed (expected) upper limit at the 95% confidence level is 4.7 (2.4) times the SM rate. The p-value for compatibility with the background-only hypothesis is 1.8σ; the expectation in the presence of a Standard Model signal is 0.9σ.
The distribution and orientation of energy inside jets is predicted to be an experimental handle on colour connections between the hard-scatter quarks and gluons initiating the jets. This Letter presents a measurement of the distribution of one such variable, the jet pull angle. The pull angle is measured for jets produced in t\(\overline{t}\) events with one W boson decaying leptonically and the other decaying to jets using 20.3 fb\(^{−1}\) of data recorded with the ATLAS detector at a centre-of-mass energy of \(\sqrt {s}\)=8 TeV at the LHC. The jet pull angle distribution is corrected for detector resolution and acceptance effects and is compared to various models.
Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2\(^{+}\)-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation". This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.
Introduction:
Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.
Methods:
A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.
Results:
For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m\(^{2}\)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.
Conclusion:
The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.
High transverse momentum jets produced in pp collisions at a centre of mass energy of 7 TeV are used to measure the transverse energy–energy correlation function and its associated azimuthal asymmetry. The data were recorded with the ATLAS detector at the LHC in the year 2011 and correspond to an integrated luminosity of 158 pb\(^{-1}\). The selection criteria demand the average transverse momentum of the two leading jets in an event to be larger than 250 GeV. The data at detector level are well described by Monte Carlo event generators. They are unfolded to the particle level and compared with theoretical calculations at next-to-leading-order accuracy. The agreement between data and theory is good and provides a precision test of perturbative Quantum Chromodynamics at large momentum transfers. From this comparison, the strong coupling constant given at the Z boson mass is determined to be αs(m\(_{Z}\))=0.1173±0.0010 (exp.) \(^{+0.0065}_{−0.0026}\) (theo.).
An observation of the View the Λ\(^0_b\)→ψ(2S)Λ\(^0\) decay and a comparison of its branching fraction with that of the Λ\(^0_b\)→J/ψΛ\(^0\) decay has been made with the ATLAS detector in proton–proton collisions at \(\sqrt {s}\)=8 TeV at the LHC using an integrated luminosity of 20.6 fb\(^{-1}\). The J/ψJ/ψ and ψ(2S) mesons are reconstructed in their decays to a muon pair, while the Λ\(^0\)→pπ\(^-\) decay is exploited for the Λ\(^0\) baryon reconstruction. The Λ\(^0_b\) baryons are reconstructed with transverse momentum p\(_T\)>10 GeV pT>10 GeV and pseudorapidity |η|<2.1. The measured branching ratio of the Λ\(^0_b\)→ψ(2S)Λ\(^0\) and Λ\(^0_b\)→J/ψΛ\(^0\) decays is Γ(Λ\(^0_b\)→ψ(2S)Λ\(^0\))/Γ(Λ\(^0_b\)→J/ψΛ\(^0\))=0.501±0.033(stat)±0.019(syst), lower than the expectation from the covariant quark model.
Myc coordinates transcription and translation to enhance transformation and suppress invasiveness
(2015)
c‐Myc is one of the major human proto‐oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc‐induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript‐specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc‐induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.
As soon as Peripheral Blood Mononuclear Cells (PBMC) are isolated from whole blood, some cells begin dying. The rate of apoptotic cell death is increased when PBMC are shipped, cryopreserved, or stored under suboptimal conditions. Apoptotic cells secrete cytokines that suppress inflammation while promoting phagocytosis. Increased numbers of apoptotic cells in PBMC may modulate T cell functions in antigen-triggered T cell assays. We assessed the effect of apoptotic bystander cells on a T cell ELISPOT assay by selectively inducing B cell apoptosis using α-CD20 mAbs. The presence of large numbers of apoptotic B cells did not affect T cell functionality. In contrast, when PBMC were stored under unfavorable conditions, leading to damage and apoptosis in the T cells as well as bystander cells, T cell functionality was greatly impaired. We observed that measuring the number of apoptotic cells before plating the PBMC into an ELISPOT assay did not reflect the extent of PBMC injury, but measuring apoptotic cell frequencies at the end of the assay did. Our data suggest that measuring the numbers of apoptotic cells prior to and post T cell assays may provide more stringent PBMC quality acceptance criteria than measurements done only prior to the start of the assay.
Background:
Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors.
Project description:
We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns.
Method:
From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling.
Results:
E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility.
Conclusions:
Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs.
Background
This article summarizes the 2012 European Renal Association—European Dialysis and Transplant Association Registry Annual Report (available at www.era-edta-reg.org) with a specific focus on older patients (defined as ≥65 years).
Methods
Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented.
Results
In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients ≥75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients ≥75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients ≥65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3–60.0) which fell to 39.3% (95% CI: 38.7–39.9) in patients 65–74 years and 21.3% (95% CI: 20.8–21.9) in patients ≥75 years.
Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.
In post-dilution online haemodiafiltration (ol-HDF), a relationship has been demonstrated between the magnitude of the convection volume and survival. However, to achieve high convection volumes (>22 L per session) detailed notion of its determining factors is highly desirable. This manuscript summarizes practical problems and pitfalls that were encountered during the quest for high convection volumes. Specifically, it addresses issues such as type of vascular access, needles, blood flow rate, recirculation, filtration fraction, anticoagulation and dialysers. Finally, five of the main HDF systems in Europe are briefly described as far as HDF prescription and optimization of the convection volume is concerned.
Accurate assessment of positive ELISPOT responses for low frequencies of antigen-specific T-cells is controversial. In particular, it is still unknown whether ELISPOT counts within replicate wells follow a theoretical distribution function, and thus whether high power parametric statistics can be used to discriminate between positive and negative wells. We studied experimental distributions of spot counts for up to 120 replicate wells of IFN-γ production by CD8+ T-cell responding to EBV LMP2A (426 – 434) peptide in human PBMC. The cells were tested in serial dilutions covering a wide range of average spot counts per condition, from just a few to hundreds of spots per well. Statistical analysis of the data using diagnostic Q-Q plots and the Shapiro-Wilk normality test showed that in the entire dynamic range of ELISPOT spot counts within replicate wells followed a normal distribution. This result implies that the Student t-Test and ANOVA are suited to identify positive responses. We also show experimentally that borderline responses can be reliably detected by involving more replicate wells, plating higher numbers of PBMC, addition of IL-7, or a combination of these. Furthermore, we have experimentally verified that the number of replicates needed for detection of weak responses can be calculated using parametric statistics.
Background and purpose:
Silent atrial fibrillation (AF) and tachycardia (AT) are considered precursors of ischaemic stroke. Therefore, detection of paroxysmal atrial rhythm disorders is highly relevant, but is clinically challenging. We aimed to evaluate the diagnostic value of natriuretic peptide levels in the detection of paroxysmal AT/AF in a pilot study.
Methods:
Natriuretic peptide levels were analysed in two independent patient cohorts (162 patients with arterial hypertension or other cardiovascular risk factors and 82 patients with retinal vessel disease). N-terminal-pro-brain natriuretic peptide (NT-proBNP) and BNP were measured before the start of a 7-day Holter monitoring period carefully screened for AT/AF.
Results:
244 patients were included; 16 had paroxysmal AT/AF. After excluding patients with a history of AT/AF (n=5), 14 patients had newly diagnosed AT/AF (5.8%) NT-proBNP and BNP levels were higher in patients with paroxysmal AT/AF in both cohorts: (1) 154.4 (IQR 41.7; 303.6) versus 52.8 (30.4; 178.0) pg/mL and 70.0 (31.9; 142.4) versus 43.9 (16.3; 95.2) and (2) 216.9 (201.4; 277.1) versus 90.8 (42.3–141.7) and 96.0 (54.7; 108.2) versus 29.1 (12.0; 58.1). For the detection of AT/AF episodes, NT-proBNP and BNP had an area under the curve in receiver operating characteristic analysis of 0.76 (95% CI, 0.64 to 0.88; p=0.002) and 0.75 (0.61 to 0.89; p=0.004), respectively.
Conclusions:
NT-proBNP and BNP levels are elevated in patients with silent AT/AF as compared with sinus rhythm. Thus, screening for undiagnosed paroxysmal AF using natriuretic peptide level initiated Holter monitoring may be a useful strategy in prevention of stroke or systemic embolism.
Background
Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.
Results
We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias.
Conclusions
Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.
Aims
To survey the perceived indications for magnetic resonance imaging of the small bowel (MRE) by experts, when MR enteroclysis (MREc) or MR enterography (MREg) may be chosen, and to determine how the approach to MRE is modified when general anaesthesia (GA) is required.
Materials and methods
Selected opinion leaders in MRE completed a questionnaire that included clinical indications (MREg or MREc), specifics regarding administration of enteral contrast, and how the technique is altered to accommodate GA.
Results
Fourteen responded. Only the diagnosis and follow-up of Crohn’s disease were considered by over 80 % as a valid MRE indication. The remaining indications ranged between 35.7 % for diagnosis of caeliac disease and unknown sources of gastrointestinal bleeding to 78.6 % for motility disorders. The majority chose MREg over MREc for all indications (from 100 % for follow-up of caeliac disease to 57.7 % for tumour diagnosis). Fifty per cent of responders had needed to consider MRE under GA. The most commonly recommended procedural change was MRI without enteral distention. Three had experience with intubation under GA (MREc modification).
Conclusion
Views were variable. Requests for MRE under GA are not uncommon. Presently most opinion leaders suggest standard abdominal MRI when GA is required.
Thrombocytopenia and pancytopenia, occurring in patients with Fanconi anemia (FA), are interpreted either as progression to bone marrow failure or as developing myelodysplasia. On the other hand, immune thrombocytopenia (ITP) represents an acquired and often self-limiting benign hematologic disorder, associated with peripheral, immune-mediated, platelet destruction requiring different management modalities than those used in congenital bone marrow failure syndromes, including FA. Here, we describe the clinical course of two independent FA patients with atypical – namely immune – thrombocytopenia. While in one patient belonging to complementation group FA-A, the ITP started at 17 months of age and showed a chronically persisting course with severe purpura, responding well to intravenous immunoglobulins (IVIG) and later also danazol, a synthetic androgen, the other patient (of complementation group FA-D2) had a self-limiting course that resolved after one administration of IVIG. No cytogenetic aberrations or bone marrow abnormalities other than FA-typical mild dysplasia were detected. Our data show that acute and chronic ITP may occur in FA patients and impose individual diagnostic and therapeutic challenges in this rare congenital bone marrow failure/tumor predisposition syndrome. The management and a potential context of immune pathogenesis with the underlying marrow disorder are discussed.
High convection volume in online post-dilution haemodiafiltration: relevance, safety and costs
(2015)
Increasing evidence suggests that treatment with online post-dilution haemodiafiltration (HDF) improves clinical outcome in patients with end-stage kidney disease, if compared with haemodialysis (HD). Although the primary analyses of three large randomized controlled trials (RCTs) showed inconclusive results, post hoc analyses of these and previous observational studies comparing online post-dilution HDF with HD showed that the risk of overall and cardiovascular mortality is lowest in patients who are treated with high-volume HDF. As such, the magnitude of the convection volume seems crucial and can be considered as the ‘dose’ of HDF. In this narrative review, the relevance of high convection volume in online post-dilution HDF is discussed. In addition, we briefly touch upon some safety and cost issues.
Each positive well in ELISPOT assays contains spots of variable sizes that can range from tens of micrometers up to a millimeter in diameter. Therefore, when it comes to counting these spots the decision on setting the lower and the upper spot size thresholds to discriminate between non-specific background noise, spots produced by individual T cells, and spots formed by T cell clusters is critical. If the spot sizes follow a known statistical distribution, precise predictions on minimal and maximal spot sizes, belonging to a given T cell population, can be made. We studied the size distributional properties of IFN-γ, IL-2, IL-4, IL-5 and IL-17 spots elicited in ELISPOT assays with PBMC from 172 healthy donors, upon stimulation with 32 individual viral peptides representing defined HLA Class I-restricted epitopes for CD8 cells, and with protein antigens of CMV and EBV activating CD4 cells. A total of 334 CD8 and 80 CD4 positive T cell responses were analyzed. In 99.7% of the test cases, spot size distributions followed Log Normal function. These data formally demonstrate that it is possible to establish objective, statistically validated parameters for counting T cell ELISPOTs.
The title compound, C\(_{12}\)H\(_{9}\)N\(_{3}\)O, is an intermediate in the synthesis of the muscarinic M2 receptor antagonist AFDX-384. The seven-membered ring adopts a boat conformation and the dihedral angle between the planes of the aromatic rings is 41.51 (9)°. In the crystal, molecules are linked into [001] chains of alternating inversion dimers formed by pairs of N-H・・・O hydrogen bonds and pairs of N-H・・・N hydrogen bonds. In both cases, R\(_{2}\)\(^{2}\)(8) loops are generated.
Background
The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal’s sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY).
Methods
Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA.
Results
SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs.
Conclusion
Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia.