Physicians who have practiced in both the United States and Canada compare the systems.

OBJECTIVES. The aim of this study was to examine the US and Canadian systems from the unique perspective of physicians who have practiced in both Canada and the United States. METHODS. Questionnaires were sent to 355 Canadian physicians who graduated from US medical schools and 347 US physicians who graduated from Canadian medical schools. RESULTS. The overall response rate was 59% (65% of US-graduated Canadian physicians and 54% of Canadian-graduated US physicians). Thirty-six percent of the respondents were "dual experience" physicians; that is, they had practiced medicine in both countries after completing their medical training. Physicians who left Canada were more likely than those who left the United States to indicate dissatisfaction with the health care system as a reason for leaving. Respondents expressed greater professional satisfaction with their current country of practice, but overall, dual-experience physicians in the United States favored that system only slightly more than the Canadian system, whereas those in Canada rated the Canadian system significantly better than the US system. CONCLUSIONS. The comparatively weak rating of the US system by dual-experience physicians underlines the need for health care reform.     

The role of serotonergic receptors in the effects ofmu opioids in squirrel monkeys responding under a titration procedure

This experiment was conducted to determine whether drugs acting on brain serotonin modulate the effects of themu opioid, morphine, as measured by the squirrel monkey shock titration procedure and, if so, whether serotonergic modulation is mediated via specific 5HT receptor subtypes. Under this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-s shock period terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The intensity below which monkeys maintained shock 50% of the time (median shock level or MSL) and rate of responding (RR) in the presence of shock were determined under control conditions and after administration of morphine alone and in combination with various serotonergic compounds. Morphine increased median shock level and decreased rate of responding in a dose-dependent manner. These effects of morphine were attenuated by the 5HT_1A receptor agonists, 8-OH-DPAT [(+)-8-hydroxy-2(di-n-propylamino tetralin HBr] and ipsapirone. The effects of morphine were not altered by the 5HT_1A receptor antagonist, NAN-190 [1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl] piperazine HBr], the 5HT₂ receptor antagonist, ketanserin, the 5HT₃ receptor antagonist, MDL 72222 [3-tropanyl-3,5-dichlorobenzoate], the alpha₂ adrenergic antagonist, yohimbine, or the alpha₂ adrenergic agonist, clonidine. These results suggest that 5HT_1A receptors may be involved in the effects of morphine in the shock titration procedure, whereas 5HT₂, 5HT₃ and alpha₂ adrenergic receptors do not appear to play a role in morphine's effects in this procedure.This work was supported by US Public Health Service Grants R37 DA 02749 and F31 DA 05537 from the National Institute on Drug Abuse. Animals used in this study were cared for in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of North Carolina and the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services, National Institutes of Health, Publication No. 85–23, revised 1985)Supported by Predoctoral Training Award T32 DA 07244 and recipient of Individual Predoctoral Fellowship Award F31 DA 05537 from the National Institute on Drug AbuseRecipient of Research Scientist Award DA 00033 from the National Institute on Drug Abuse     

Synthesis of HDAC Inhibitor Libraries via Microscale Workflow

An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques. The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation.     

Effects of LY150720 (picenadol), a novel mixed-action opioid, on schedule-controlled responding in the squirrel monkey

The opioid LY150720 is a racemic mixture whose resolution results in a highly stereospecific separation of agonist and antagonist activity. The effects of LY150720 (0.3-3.0 mg/kg), its agonist (dextro) isomer LY136596 (0.3-1.7 mg/kg) and morphine (0.03-1.0 mg/kg) were studied alone and in combination with naloxone (0.001-1.0 mg/kg) in squirrel monkeys whose responding was maintained under a multiple fixed-ratio 30-response fixed-interval 5-minute (mult FR-30 FI 5-min) schedule of food presentation. LY150720, LY136596 and morphine generally decreased responding under both schedule components, although in several instances increases in responding under the FI component were noted, particularly following LY150720 and LY136596. Naloxone (0.1-3.0 mg/kg) generally had little effect on responding, whereas the antagonist (levo) isomer LY136595 (0.3-10.0 mg/kg) decreased responding under both schedule components. The rate-decreasing effects of morphine, LY150720 and LY136596 were reversed by naloxone; doses of naloxone required to reverse the effects of all three drugs were comparable. When combined with morphine, naloxone restored rates and patterns of responding to control values, whereas combinations of LY150720 or LY136596 and naloxone increased responding under the FI component in excess of control values. These increases appear to be due to anticholinergic actions of LY150720 and LY136596, as they are reversed by physostigmine (0.01 mg/kg) and similar increases are produced by scopolamine (0.01-0.1 mg/kg).     

A new species of Tritrichomonas (Sarcomastigophora: Trichomonida) from the domestic cat (Felis catus)

Feline trichomoniasis is an intestinal disease in cats resulting in chronic diarrhea, flatulence, tenesmus, and fecal incontinence. Bovine trichomoniasis is a sexually transmitted disease of cattle infecting the reproductive tract of cows causing pyometra and possible mid- to late-term abortions. The causative agent for both diseases has been reported to be the flagellated protozoan, Tritrichomonas foetus. However, several published reports support significant biological differences between T. foetus isolated from bovines and felines. In the present study, we describe Tritrichomonas blagburni n.sp. from the domestic cat (Felis catus) as the causative agent of feline intestinal trichomoniasis. We support our proposal based on results of experimental cross-infection studies between cats and cattle using both feline and bovine isolates of the parasite, differences in pathogenicity between the two parasites for the respective host species, and molecular gene sequencing differences between parasites obtained from domestic cats and parasites obtained from cattle.     

Three-choice discrimination in pigeons is based on relative efficacy differences among opioids

RATIONALE: Drug discrimination assays can provide important information on receptor selectivity and relative efficacy to guide the classification and characterization of opioid agonists. OBJECTIVES: A three-choice discrimination was established among high efficacy opioid agonist morphine, low efficacy opioid agonist nalbuphine, and saline to examine the conditions under which differences in relative efficacy might serve as a basis for stimulus control. METHODS: Seven White Carneau pigeons were trained to discriminate among 5.6 mg/kg nalbuphine, 3.2 mg/kg morphine, and saline under fixed ratio 30 (FR30) schedules of food reinforcement. Substitution and antagonism experiments were then conducted with mu, kappa, and delta opioids and naltrexone, respectively and the percent responding appropriate to the training stimuli was determined. RESULTS: Low, intermediate, and high doses of morphine produced > or = 80% saline-, > or = 60% nalbuphine-, and > or = 96% morphine-appropriate responding, respectively. Low and high doses of nalbuphine produced > or = 80% saline- and nalbuphine-appropriate responding, respectively. In substitution tests, low doses of fentanyl and etorphine produced partial nalbuphine-appropriate responding (20-60%) and high doses produced > or = 60-80% morphine-appropriate responding. Intermediate doses of buprenorphine and dezocine produced > or = 60-80% nalbuphine-appropriate responding and high doses produced > or = 80% morphine-appropriate responding. The lower efficacy agonists butorphanol, nalorphine, and levallorphan produced > or = 40-80% nalbuphine-appropriate responding. The kappa agonists spiradoline and U50,488 produced approximately > or = 50% nalbuphine-appropriate responding whereas d-amphetamine, saline, and delta agonists BW373U86 and SNC 80 produced > or = 80% saline-appropriate responding. Naltrexone produced > or = 80% saline-appropriate responding and reversed the stimulus effects of morphine and nalbuphine. CONCLUSIONS: The discrimination between morphine and nalbuphine in pigeons is predominantly based on the relative efficacy differences between morphine, a higher-efficacy mu agonist and nalbuphine, a lower-efficacy mu agonist.     

Geographic Differences in Event Rates by Model for End-Stage Liver Disease Score

The ability of the model for end-stage liver disease (MELD) score to accurately predict death among liver transplant candidates allows for evaluation of geographic differences in transplant access for patients with similar death risk. Adjusted models of time to transplant and death for adult liver transplant candidates listed between 2002 and 2003 were developed to test for differences in MELD score among Organ Procurement and Transplantation Network (OPTN) regions and Donation Service Areas (DSA). The average MELD and relative risk (RR) of death varied somewhat by region (from 0.82 to 1.28), with only two regions having significant differences in RRs. Greater variability existed in adjusted transplant rates by region; 7 of 11 regions differed significantly from the national average. Simulation results indicate that an allocation system providing regional priority to candidates at MELD scores > or = 15 would increase the median MELD score at transplant and reduce the total number of deaths across DSA quintiles. Simulation results also indicate that increasing priority to higher MELD candidates would reduce the percentage variation among DSAs of transplants to patients with MELD scores > or = 15. The variation decrease was due to increasing the MELD score at time of transplantation in the DSAs with the lowest MELD scores at transplant.     

Pediatric rehabilitation. 3. Disorders of the spinal cord: spinal cord injury, myelodysplasia

This self-directed learning module provides review and references for the basic concepts of, and highlights new advances in, disorders of the spinal cord in children. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. For spinal cord injury, only data pertinent to the pediatric age group are discussed. Myelodysplasia is presented in detail to include genetic implications, early intervention, long-term management planning, psychosocial impact, and quality-of-life considerations.     

Effects of N-methyl-D-aspartate receptor antagonists on acute morphine-induced and l-methadone-induced antinociception in mice.

Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined. PERSPECTIVE: The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.