Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety

Incremental doses of intravenous labetalol are safe and effective and, at times, such therapy may need to be augmented by a continuous infusion of labetalol to control severe hypertension. Continuous infusions of labetalol may exceed the recommended maximum daily dose of 300 mg on occasion. We report a case in which hypertension occurring after an abdominal aortic aneurysm repair, initially responsive to intermittent intravenous beta-blockade, became resistant to this therapy leading to the choice of an intravenous labetalol infusion as the therapeutic option. The labetalol infusion resulted in a profound cardiovascular compromise in this postoperative critically ill patient. While infusions of labetalol have successfully been used, prolonged administration in the intensive care unit requires vigilance and the establishment of a therapeutic rationale/policy for interventions, such as the ready availability of glucagon, β-agonists, phosphodiesterase inhibitors, insulin, and vasopressin when severe cardiovascular depression occurs

Statistical analysis for plant genetic resources: Clustering and indices in R made simple

This handbook aims to give researchers tools and methods to analyse mathematically complex morphological characterization data. R is a powerful software language and environment for statistical computing and graphics, developed by volunteers from around the world, working together over the Internet. The core development team consists of fewer than twenty programmers who maintain and develop the general R environment, with contributions from many others. A much larger number of contributors write individual statistical packages for R that address specific needs. Statisticians and researchers write many of these statistical packages for their own research purposes, ensuring that R is in the forefront of developments in statistics. Another of R's strengths is the ease with which well-designed publication-quality plots can be produced, including mathematical symbols and formulae where needed. On the down side, if you are used to pointand-click interfaces, you may find that R has a relatively steep learning curve. As one of the developers of R once put it, R is not designed to make easy things simple, but to make difficult things possible. Nonetheless, several projects are working on making R easier to use, and interfaces should improve in the near future. We would not propose R had we not found that it has many facilities useful to the analysis of plant genetic resources data, facilities not commonly found in other statistical packages. We also believe that with a step-by-step guide, providing examples of typical analyses required in plant genetic resources research, most researchers will be able to implement such analyses quite simply on their own data. This tutorial provides such a guide, beginning with simple examples that soon demonstrate the power of R, and allows users to gradually become acquainted with the more complex aspects. Just enough explanation of the statistics is given for readers with a basic understanding of the subject to understand the output of the analyses

Design of Strongly Modulating Pulses to Implement Precise Effective Hamiltonians for Quantum Information Processing

We describe a method for improving coherent control through the use of detailed knowledge of the system's Hamiltonian. Precise unitary transformations were obtained by strongly modulating the system's dynamics to average out unwanted evolution. With the aid of numerical search methods, pulsed irradiation schemes are obtained that perform accurate, arbitrary, selective gates on multi-qubit systems. Compared to low power selective pulses, which cannot average out all unwanted evolution, these pulses are substantially shorter in time, thereby reducing the effects of relaxation. Liquid-state NMR techniques on homonuclear spin systems are used to demonstrate the accuracy of these gates both in simulation and experiment. Simulations of the coherent evolution of a 3-qubit system show that the control sequences faithfully implement the unitary operations, typically yielding gate fidelities on the order of 0.999 and, for some sequences, up to 0.9997. The experimentally determined density matrices resulting from the application of different control sequences on a 3-spin system have overlaps of up to 0.99 with the expected states, confirming the quality of the experimental implementation.Comment: RevTeX3, 11 pages including 2 tables and 5 figures; Journal of Chemical Physics, in pres

Experimental ionization of atomic hydrogen with few-cycle pulses

We present the first experimental data on strong-field ionization of atomic hydrogen by few-cycle laser pulses. We obtain quantitative agreement at the 10% level between the data and an {\it ab initio} simulation over a wide range of laser intensities and electron energies

Diffuse versus square-well confining potentials in modelling AA@C60_{60} atoms

Attention: this version-$2$ of the manuscript differs from its previously uploaded version-$1$ (arXiv:1112.6158v1) and subsequently published in 2012 J. Phys. B \textbf{45} 105102 only by a removed typo in Eq.(2) of version-$1$; there was the erroneous factor "2" in both terms in the right-hand-side of the Eq.(2) of version-$1$. Now that the typo is removed, Eq.(2) is correct. A perceived advantage for the replacement of a discontinuous square-well pseudo-potential, which is often used by various researchers as an approximation to the actual C$_{60}$ cage potential in calculations of endohedral atoms $A$@C$_{60}$, by a more realistic diffuse potential is explored. The photoionization of endohedral H@C$_{60}$ and Xe@C$_{60}$ is chosen as the case study. The diffuse potential is modelled by a combination of two Woods-Saxon potentials. It is demonstrated that photoionization spectra of $A$@C$_{60}$ atoms are largely insensitive to the degree $\eta$ of diffuseness of the potential borders, in a reasonably broad range of $\eta$'s. Alternatively, these spectra are found to be insensitive to discontinuity of the square-well potential either. Both potentials result in practically identical calculated spectra. New numerical values for the set of square-well parameters, which lead to a better agreement between experimental and theoretical data for $A$@C$_{60}$ spectra, are recommended for future studies.Comment: 11 pages, 4 figure

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor that Attenuates Disease Progression in Alzheimer\u27s Disease Mouse Models

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150\u27s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior

Measurement of laser intensities approaching 10 15 W/cm 2 with an accuracy of 1%

Accurate knowledge of the intensity of focused ultrashort laser pulses is crucial to the correct interpretation of experimental results in strong-field physics. We have developed a technique to measure laser intensities approaching 1015W/cm2 with an accu

Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction