Anaesthetic Preconditioning; The Role of ATP-Sensitive K+ Channels

Stroke in general but especially in the postoperative period is a serious clinical problem that warrants new therapeutic approaches. Here neuroprotective strategies and especially preconditioning have recently emerged as promising. Preconditioning was originally demonstrated in the heart but was subsequently also found in other organs. Classically it describes a phenomenon where short periods of ischaemia render tissues less vulnerable to major infarcts. In addition to ischaemia neuronal preconditioning can be achieved pharmacologically as well as through inhalational anaesthetics or drugs that open ATP-sensitive K+(KATP) channels. However, the mechanisms through which anaesthetics produce protection remain elusive and the use of K+ channel openers is hampered by their inability to cross the blood-brain-barrier. This study was conducted to investigate the effects of inhalational anaesthetics on KATP channels and to explore whether their neuronal preconditioning properties were dependent on KATP channel opening. First, in whole-cell and excised patchclamp experiments the effects of inhalational anaesthetics on recombinant wild type neuronal (Kir6.2/SUR1) KATP and related as well as modified channels were evaluated. Secondly, the KATP channel dependence of anaesthetic preconditioning was tested in neuronal-glial co-cultures. Recombinant KATP channels were activated by xenon, but inhibited by halogenated volatiles. Moreover, it was shown that xenon acted directly on the Kir6.2 pore-forming subunit, reduced the ability of ATP to inhibit the channel and had no effect on the ATP-regulated Kir1.1 channel. Functionally both sevoflurane and xenon preconditioned neurons at clinically used concentrations but only the effect of xenon was dependent on KATP channel activation. Thus this study established xenon as a novel KATP channel opener. It interacts with the pore-forming Kir6.2 rather than the regulatory sulphonylurea receptor subunit and disinhibits the channel from the blocking actions of ATP. As a consequence xenon but not sevoflurane is able to precondition neurons in a KATP channel-dependent manner

Gravitation Physics at BGPL

We report progress on a program of gravitational physics experiments using cryogenic torsion pendula undergoing large-amplitude torsion oscillation. This program includes tests of the gravitational inverse square law and of the weak equivalence principle. Here we describe our ongoing search for inverse-square-law violation at a strength down to $10^{-5}$ of standard gravity. The low-vibration environment provided by the Battelle Gravitation Physics Laboratory (BGPL) is uniquely suited to this study.Comment: To be published in The Proceedings of the Francesco Melchiorri Memorial Conference as a special issue of New Astronomy Review

Laboratory Tests of Gravitational Physics Using a Cryogenic Torsion Pendulum

Progress and plans are reported for a program of gravitational physics experiments using cryogenic torsion pendula undergoing large amplitude torsional oscillation. The program includes a UC Irvine project to measure the gravitational constant G and joint UC Irvine - U. Washington projects to test the gravitational inverse square law at a range of about 10 cm and to test the weak equivalence principle.Comment: 17 pages, 11 figures, contribution to the 10th Marcel Grossman Conference Proceedings (Rio de Janeiro, July 20 - 26, 2003) - changed wording in first paragraph of section

Is number sense impaired in chronic pain patients?

BACKGROUND: Recent advances in imaging have improved our understanding of the role of the brain in painful conditions. Discoveries of morphological changes have been made in patients with chronic pain, with little known about the functional consequences when they occur in areas associated with ‘number-sense’; thus, it can be hypothesized that chronic pain impairs this sense. METHODS: First, an audit of the use of numbers in gold-standard pain assessment tools in patients with acute and chronic pain was undertaken. Secondly, experiments were conducted with patients with acute and chronic pain and healthy controls. Participants marked positions of numbers on lines (number marking), before naming numbers on pre-marked lines (number naming). Finally, subjects bisected lines flanked with ‘2’ and ‘9’. Deviations from expected responses were determined for each experiment. RESULTS: Four hundred and ninety-four patients were audited; numeric scores in the ‘moderate’ and ‘severe’ pain categories were significantly higher in chronic compared with acute pain patients. In experiments (n=150), more than one-third of chronic pain patients compared with 1/10th of controls showed greater deviations from the expected in number marking and naming indicating impaired number sense. Line bisection experiments suggest prefrontal and parietal cortical dysfunction as cause of this impairment. CONCLUSIONS: Audit data suggest patients with chronic pain interpret numbers differently from acute pain sufferers. Support is gained by experiments indicating impaired number sense in one-third of chronic pain patients. These results cast doubts on the appropriateness of the use of visual analogue and numeric rating scales in chronic pain in clinics and research

On the equivalence principle and gravitational and inertial mass relation of classical charged particles

We show that the locally constant force necessary to get a stable hyperbolic motion regime for classical charged point particles, actually, is a combination of an applied external force and of the electromagnetic radiation reaction force. It implies, as the strong Equivalence Principle is valid, that the passive gravitational mass of a charged point particle should be slight greater than its inertial mass. An interesting new feature that emerges from the unexpected behavior of the gravitational and inertial mass relation, for classical charged particles, at very strong gravitational field, is the existence of a critical, particle dependent, gravitational field value that signs the validity domain of the strong Equivalence Principle. For electron and proton, these critical field values are $g_{c}\simeq 4.8\times 10^{31}m/s^{2}$ and $g_{c}\simeq 8.8\times 10^{34}m/s^{2}$, respectively

Status of FAA Studies in Thermal Acoustics

As with many aerospace applications, commercial jet engine components are operated in demanding environments, often at extreme temperature and stress conditions. The predominant used surface inspection method used on these components is fluorescent penetrant inspection. Research has been ongoing for a number of years on a new technology using a short burst of low frequency ( ∼ 20 KHz) ultrasound to “heat up” cracks and make them visible in the infrared range. The basic premise of the Thermal Acoustic method is to use an energy source with recent efforts using an ultrasonic horn originally intended for use in ultrasonic welding to excite the component. The energy source causes an increase in local heating, which is detectable with infrared cameras typically used in Thermographic inspection. While considerable research is underway, additional information on the sensitivity and applicability of this technique to engine components and alloys is needed prior to widespread use in the aviation industry. The purpose of this program is to provide additional data to determine applicability of this method to engine components

Camps, not just parties: The dynamic foundations of affective polarization in multi-party systems

Concerns over affective polarization in Western democracies are growing. But which broader political distinctions are also affective demarcations? As inter-party cooperation is the rule in multi-party democracies, explaining affective polarization beyond partisan divisions is crucial. I argue that demarcations between political camps deepen affective polarization, and country-level factors influence the relevance of these affective divides. Based on survey data from 23 Western democracies (1996-2019), I demonstrate that affect is most polarized between Left and Right camps, and between the Radical Right and other camps. Further, these divides are dynamic and depend on different country-level outcomes. The Left/Right divide disappears when Left and Right parties govern together, while the Radical Right divide is fortified with Radical Right electoral success. These findings highlight that affective polarization's group foundations extend beyond partisanship, and that affective polarization could even act as a defence mechanism against radical challengers

Economic liberalization and the antecedents of top management teams: evidence from Turkish 'big' business

There has been an increased interest in the last two decades in top management teams (TMTs) of business firms. Much of the research, however, has been US-based and concerned primarily with TMT effects on organizational outcomes. The present study aims to expand this literature by examining the antecedents of top team composition in the context of macro-level economic change in a late-industrializing country. The post-1980 trade and market reforms in Turkey provided the empirical setting. Drawing upon the literatures on TMT and chief executive characteristics together with punctuated equilibrium models of change and institutional theory, the article develops the argument that which firm-level factors affect which attributes of TMT formations varies across the early and late stages of economic liberalization. Results of the empirical investigation of 71 of the largest industrial firms in Turkey broadly supported the hypotheses derived from this premise. In the early stages of economic liberalization the average age and average organizational tenure of TMTs were related to the export orientation of firms, whereas in later stages, firm performance became a major predictor of these team attributes. Educational background characteristics of teams appeared to be under stronger institutional pressures, altering in different ways in the face of macro-level change

A phase 2, randomized, double‐blind, placebo‐controlled study of GS‐9450 in subjects with nonalcoholic steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 ( P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion : GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (H epatology 2012)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90118/1/24747_ftp.pd