855 research outputs found
Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses
Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011.
<p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs).
<p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion.
<p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage
Sisyphus cooling and amplification by a superconducting qubit
Laser cooling of the atomic motion paved the way for remarkable achievements
in the fields of quantum optics and atomic physics, including Bose-Einstein
condensation and the trapping of atoms in optical lattices. More recently
superconducting qubits were shown to act as artificial two-level atoms,
displaying Rabi oscillations, Ramsey fringes, and further quantum effects.
Coupling such qubits to resonators brought the superconducting circuits into
the realm of quantum electrodynamics (circuit QED). It opened the perspective
to use superconducting qubits as micro-coolers or to create a population
inversion in the qubit to induce lasing behavior of the resonator. Furthering
these analogies between quantum optical and superconducting systems we
demonstrate here Sisyphus cooling of a low frequency LC oscillator coupled to a
near-resonantly driven superconducting qubit. In the quantum optics setup the
mechanical degrees of freedom of an atom are cooled by laser driving the atom's
electronic degrees of freedom. Here the roles of the two degrees of freedom are
played by the LC circuit and the qubit's levels, respectively. We also
demonstrate the counterpart of the Sisyphus cooling, namely Sisyphus
amplification. Parallel to the experimental demonstration we analyze the system
theoretically and find quantitative agreement, which supports the
interpretation and allows us to estimate system parameters.Comment: 7 pages, 4 figure
Resolved Sideband Cooling of a Micromechanical Oscillator
Micro- and nanoscale opto-mechanical systems provide radiation pressure
coupling of optical and mechanical degree of freedom and are actively pursued
for their ability to explore quantum mechanical phenomena of macroscopic
objects. Many of these investigations require preparation of the mechanical
system in or close to its quantum ground state. Remarkable progress in ground
state cooling has been achieved for trapped ions and atoms confined in optical
lattices. Imperative to this progress has been the technique of resolved
sideband cooling, which allows overcoming the inherent temperature limit of
Doppler cooling and necessitates a harmonic trapping frequency which exceeds
the atomic species' transition rate. The recent advent of cavity back-action
cooling of mechanical oscillators by radiation pressure has followed a similar
path with Doppler-type cooling being demonstrated, but lacking inherently the
ability to attain ground state cooling as recently predicted. Here we
demonstrate for the first time resolved sideband cooling of a mechanical
oscillator. By pumping the first lower sideband of an optical microcavity,
whose decay rate is more than twenty times smaller than the eigen-frequency of
the associated mechanical oscillator, cooling rates above 1.5 MHz are attained.
Direct spectroscopy of the motional sidebands reveals 40-fold suppression of
motional increasing processes, which could enable reaching phonon occupancies
well below unity (<0.03). Elemental demonstration of resolved sideband cooling
as reported here should find widespread use in opto-mechanical cooling
experiments. Apart from ground state cooling, this regime allows realization of
motion measurement with an accuracy exceeding the standard quantum limit.Comment: 13 pages, 5 figure
Light hadron, Charmonium(-like) and Bottomonium(-like) states
Hadron physics represents the study of strongly interacting matter in all its
manifestations and the understanding of its properties and interactions. The
interest on this field has been revitalized by the discovery of new light
hadrons, charmonium- and bottomonium-like states. I review the most recent
experimental results from different experiments.Comment: Presented at Lepton-Photon 2011, Mumbai, India; 21 pages, 18 figures;
add more references; some correctio
Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery
A cross sectional study of requests for knee radiographs from primary care
<p>Abstract</p> <p>Background</p> <p>Knee pain is the commonest pain complaint amongst older adults in general practice. General Practitioners (GPs) may use x rays when managing knee pain, but little information exists regarding this process. Our objectives, therefore, were to describe the information GPs provide when ordering knee radiographs in older people, to assess the association between a clinical diagnosis of osteoarthritis (OA) and the presence of radiographic knee OA, and to investigate the clinical content of the corresponding radiologists' report.</p> <p>Methods</p> <p>A cross sectional study of GP requests for knee radiographs and their matched radiologists' reports from a local radiology department. Cases, aged over 40, were identified during an 11-week period. The clinical content of the GPs' requests and radiologists' reports was analysed. Associations of radiologists' reporting of i) osteoarthritis, ii) degenerative disease and iii) individual radiographic features of OA, with patient characteristics and clinical details on the GPs' requests, were assessed.</p> <p>Results</p> <p>The study identified 136 cases with x ray requests from 79 GPs and 11 reporting radiologists. OA was identified clinically in 19 (14%) of the requests, and queried in another 31 (23%). The main clinical descriptor was pain in 119 cases (88%). Radiologists' reported OA in 22% of cases, and the features of OA were mentioned in 63%. Variation in reporting existed between radiologists. The commonest description was joint space narrowing in 52 reports (38%). There was an apparent although non significant increase in the reporting of knee OA when the GP had diagnosed or queried it (OR 1.95; 95% CI 0.76, 5.00).</p> <p>Conclusion</p> <p>The features of radiographic OA are commonly reported in those patients over 40 whom GPs send for x ray. If OA is clinically suspected, radiologists appear to be more likely to report its presence. Further research into alternative models of referral and reporting might identify a more appropriate imaging policy in knee disorders for primary care.</p
World Heart Federation Roadmap on Atrial Fibrillation - A 2020 Update
The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world’s population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them.
Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow.
This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great
Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor
<p>Abstract</p> <p>Background</p> <p>Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) β2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance. We tested the hypothesis that CysLTs affect production of Tn and Ln β2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT<sub>1 </sub>or CysLT<sub>2</sub>, mediate this effect.</p> <p>Methods</p> <p>Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D<sub>4 </sub>(LTD<sub>4</sub>) and E<sub>4 </sub>(LTE<sub>4</sub>) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR. CysLT receptors were differentially blocked with use of montelukast or BAY u9773.</p> <p>Results</p> <p>LTD<sub>4 </sub>and LTE<sub>4 </sub>significantly augmented the expression of Tn, whereas LTD<sub>4</sub>, distinctly from LTE<sub>4</sub>, was able to increase also the Ln β2 chain. Although the expression of CysLT<sub>2 </sub>prevailed over that of CysLT<sub>1</sub>, the up-regulation of Tn and Ln β2 chain by CysLTs was completely blocked by the CysLT<sub>1</sub>-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.</p> <p>Conclusion</p> <p>These findings suggest that the CysLT-induced up-regulation of Tn and Ln β2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT<sub>1 </sub>receptor. The results provide a novel aspect to support the use of CysLT<sub>1 </sub>receptor antagonists in the anti-remodeling treatment of asthma.</p
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