Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

Glen S Patten1,2, Richard J Head1, Mahinda Y Abeywardena1,21CSIRO Preventative Health National Research Flagship, Adelaide, Australia; 2CSIRO Food and Nutritional Sciences, Adelaide, AustraliaBackground and aims: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice.Methods: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques.Results: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC50 [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively) (P < 0.01). The inhibitory influence of opioid agonists (IC50) in electrically driven ileal mouse preparations were DADLE ([D-Ala2, D-Leu5]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly Κ- and δ-opioid receptor activity with a smaller µ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the µ-opioid receptor antagonists, casoxin 4 and lactoferroxin A, applied before and after morphine injection were unable to antagonize morphine inhibition of gut transit.Conclusions: Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route.Keywords: lactoferroxin A, µ-opioid receptor antagonist, opioid agonist

The Effect of Ventricular Assist Devices on Post-Transplant Mortality An Analysis of the United Network for Organ Sharing Thoracic Registry

ObjectivesThis study sought to determine the relationship between pre-transplant ventricular assist device (VAD) support and mortality after heart transplantation.BackgroundIncreasingly, VADs are being used to bridge patients to heart transplantation. The effect of these devices on post-transplant mortality is unclear.MethodsPatients 18 years or older who underwent first-time, single-organ heart transplantation in the U.S. between 1995 and 2004 were included in the analyses. This study compared 1,433 patients bridged with intracorporeal and 448 patients bridged with extracorporeal VADs with 9,455 United Network for Organ Sharing status 1 patients not bridged with a VAD with respect to post-transplant mortality. Because the proportional hazards assumption was not met, hazard ratios (HRs) for different time periods were estimated.ResultsIntracorporeal VADs were associated with an HR of 1.20 (95% confidence interval [CI]: 1.02 to 1.43; p = 0.03) for mortality in the first 6 months after transplant and an HR of 1.99 (95% CI: 1.44 to 2.75; p < 0.0001) beyond 5 years. Between 6 months and 5 years, the HRs were not significantly different from 1. Extracorporeal VADs were associated with an HR of 1.91 (95% CI: 1.53 to 2.37; p < 0.0001) for mortality in the first 6 months and an HR of 2.93 (95% CI: 1.19 to 7.25; p = 0.02) beyond 5 years. The HRs were not significantly different from 1 between 6 months and 5 years, except for an HR of 0.23 (95% CI: 0.06 to 0.91; p = 0.04) between 24 and 36 months.ConclusionsExtracorporeal VADs are associated with higher mortality within 6 months and again beyond 5 years after transplantation. Intracorporeal VADs are associated with a small increase in mortality in the first 6 months and a clinically significant increase in mortality beyond 5 years. These data do not provide evidence supporting VAD implantation in stable United Network for Organ Sharing status I patients awaiting heart transplantation

Graphical programming: A systems approach for telerobotic servicing of space assets

Satellite servicing is in many ways analogous to subsea robotic servicing in the late 1970's. A cost effective, reliable, telerobotic capability had to be demonstrated before the oil companies invested money in deep water robot serviceable production facilities. In the same sense, aeronautic engineers will not design satellites for telerobotic servicing until such a quantifiable capability has been demonstrated. New space servicing systems will be markedly different than existing space robot systems. Past space manipulator systems, including the Space Shuttle's robot arm, have used master/slave technologies with poor fidelity, slow operating speeds and most importantly, in-orbit human operators. In contrast, new systems will be capable of precision operations, conducted at higher rates of speed, and be commanded via ground-control communication links. Challenge presented by this environment include achieving a mandated level of robustness and dependability, radiation hardening, minimum weight and power consumption, and a system which accommodates the inherent communication delay between the ground station and the satellite. There is also a need for a user interface which is easy to use, ensures collision free motions, and is capable of adjusting to an unknown workcell (for repair operations the condition of the satellite may not be known in advance). This paper describes the novel technologies required to deliver such a capability

Reliability of patient responses in pay for performance schemes: analysis of national General Practitioner Patient Survey data in England

Objective To assess the robustness of patient responses to a new national survey of patient experience as a basis for providing financial incentives to doctors

Patterns of Recovery from Severe Mental Illness: A Pilot Study of Outcomes

We performed a pilot study examining the patterns of recovery from severe mental illness in a model integrated service delivery system using measures from the Milestones of Recovery Scale (MORS), a valid and reliable measure of recovery outcomes which ranges from 1 to 8 (8 levels). For purposes of presentation, we constructed an aggregate MORS (6 levels) where the levels are described as follows: (1) extreme risk; (2) unengaged, poorly self-coordinating; (3) engaged, poorly self-coordinating; (4) coping and rehabilitating; (5) early recovery, and (6) self reliant. We analyzed MORS data on individuals followed over time from The Village in Long Beach, California (658 observations). Using Markov Chains, we estimated origin-destination transition probabilities, simulating recovery outcomes for 100 months. Our models suggest that after 12 months only 8% of “extreme risk” clients remain such. Over 40% have moved to “engaged, poorly self-coordinating.” After 2 years, almost half of the initial “extreme Risk” clients are “coping/rehabilitating”, “early recovery” or “Self reliant.” Most gains occur within 2 years

Amyotrophic lateral sclerosis-motor neuron disease, monoclonal gammopathy, hyperparathyroidism, and B12 deficiency: case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Amyotrophic lateral sclerosis (the most common form of motor neuron disease) is a progressive and devastating disease involving both lower and upper motor neurons, typically following a relentless path towards death. Given the gravity of this diagnosis, all efforts must be made by the clinician to exclude alternative and more treatable entities. Frequent serology testing involves searching for treatable disorders, including vitamin B12 deficiency, parathyroid anomalies, and monoclonal gammopathies.</p> <p>Case presentation</p> <p>We present the case of a 78-year-old Caucasian man with all three of the aforementioned commonly searched for disorders during an investigation for amyotrophic lateral sclerosis.</p> <p>Conclusions</p> <p>The clinical utility of these common tests and what they ultimately mean in patients with amyotrophic lateral sclerosis is discussed, along with a review of the literature.</p

Open Access to Geoscience Data for Exploration and Assessment

ABSTRACT The U.S. National Geothermal Data System&apos;s (NGDS -www.geothermaldata.org) provides free open access to millions of data records, maps, and reports, sharing relevant geoscience and land use data to propel geothermal development and production in the U.S. Since the NGDS is built using the Geoscience Information Network data integration framework the system is compliant with international standards and protocols, scalable, extensible, and can be deployed throughout the world. NGDS currently serves information from hundreds of the U.S. Department of Energy&apos;s sponsored development and research projects and geologic data feeds from 60+ data providers in all 50 states, using free and open source software, in a federated system where data owners maintain control of their data. This interactive online system is opening new exploration opportunities and shortening project development by making data easily discoverable, accessible, and interoperable at no cost to users

The Pine Needle, April 1947

Libraries and archives collect materials from different cultures and time periods to preserve and make available the historical record. As a result, materials such as those presented here may reflect sexist, misogynistic, abusive, racist, or discriminatory attitudes or actions that some may find disturbing, harmful, or difficult to view. Both a humor and literary magazine, The Pine Needle was a University of Maine student-produced periodical that began publication in the fall of 1946, the first post-World War II semester that saw GIs returni to campus. The Needle reflected an edginess and rebellion not found in previous UMaine student publications. While past student publications relied on euphemisms for alcohol and dating on campus, The Needle overtly sexualized co-eds and discussed the use of drugs, tobacco, and alcohol by students who experienced war. Cover art for this issue is an unsigned ink illustration of three students seated in a lecture hall taking an exam

Evidence for a fast evolution of the UV luminosity function beyond redshift 6 from a deep HAWK-I survey of the GOODS-S field

We perform a deep search for galaxies in the redshift range 6.5<z<7.5, to measure the evolution of the number density of luminous galaxies in this redshift range and derive useful constraints on the evolution of their Luminosity Function. We present here the first results of an ESO Large Program, that exploits the unique combination of area and sensitivity provided in the near-IR by the camera Hawk-I at the VLT. We have obtained two Hawk-I pointings on the GOODS South field for a total of 32 observing hours, covering ~90 arcmin2. The images reach Y=26.7 mags for the two fields. We have used public ACS images in the z band to select z-dropout galaxies with the colour criteria Z-Y>1, Y-J<1.5 and Y-K<2. The other public data in the UBVRIJHK bands are used to reject possible low redshift interlopers. The output has been compared with extensive Monte Carlo simulations to quantify the observational effects of our selection criteria as well as the effects of photometric errors. We detect 7 high quality candidates in the magnitude range Y=25.5-26.7. This interval samples the critical range for M* at z>6 (M_1500 ~- 19.5 to -21.5). After accounting for the expected incompleteness, we rule out at a 99% confidence level a Luminosity Function constant from z=6 to z=7, even including the effects of cosmic variance. For galaxies brighter than M_1500=-19.0 we derive a luminosity density rho_UV=1.5^{+2.0}_{-0.9} 10^25 erg/s/Hz/Mpc3, implying a decrease by a factor 3.5 from z=6 to z~6.8. On the basis of our findings, we make predictions for the surface densities expected in future surveys surveys, based on ULTRA-VISTA, HST-WFC3 or JWST-NIRCam, evaluating the best observational strategy to maximise their impact.Comment: Accepted for publication in Astronomy & Astrophysic