The clinical pharmacology of intranasal l-methamphetamine.

BackgroundWe studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.Methods12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.ResultsPlasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.ConclusionInhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant

Occupational Therapy Practice Patterns In Two Rural States: Does The College Experience Influence Rural Employment Choice?

An online survey was conducted of 225 occupational therapy (OT) practitioners living in the rural states of North Dakota and Wyoming to explore practice patterns and the influence of the college experience on employment choice. Findings showed that rural practitioners had greater variability of hours spent working (5.5 more hours per week, p=.028), and one more work location on average (p=.006). Therapists in urban settings spent 15% more time in fieldwork education than their rural counterparts (p=.021). Rural practice choice was influenced by participation in Level I and Level II fieldwork (p=.002) but not by loan debt. Study implications for academic programs include focusing on multiple areas of practice in the curriculum design, and exposure of students to rural practitioners and rural practice examples/experiences. Recommendations were made for rural fieldwork educator training and employer support of rural fieldwork education. Further study of the experience of working within a rural practice context as a student and OT practitioner are recommended, including variables impacting rural practitioner work with fieldwork students, and student interest in rural fieldwork placement

Ethical, legal, and social issues in the Earth BioGenome Project.

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project's technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP's Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not-and cannot-provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP's work

Ethical, legal, and social issues in the Earth BioGenome Project

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project’s technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP’s Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not—and cannot—provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP’s work

Case 27-2011: A 17-Year-Old Boy with Abdominal Pain and Weight Loss

Pr e sen tat ion of C a se Dr. Nina Mayer (Medicine-Pediatrics): A 17-year-old boy was seen in the pediatric gastroenterology clinic of this hospital because of abdominal pain and weight loss. The patient had been well until approximately 6 weeks earlier, when intermittent crampy abdominal pain developed. Approximately 3 weeks later, nonbloody diarrhea developed and lasted for a week, associated with one episode of emesis. Thereafter, abdominal pain occurred daily, was predominantly located in the right lower quadrant, radiated to the right flank, and was associated with lower back discomfort, borborygmi, and constipation. During the fourth week of illness, after the diarrhea had resolved, the patient saw his primary care physician. Serum levels of glucose, alanine aminotransferase, and thyrotropin were normal, as were tests of renal function. Tests for tissue transglutaminase IgA antibodies, hepatitis A virus, hepatitis C virus, and the human immunodeficiency virus (HIV) were negative. Results of tests for serum antibodies to Epstein-Barr virus (EBV) were consistent with past infection; testing was positive for hepatitis B virus surface antibody and negative for hepatitis B surface antigen, indicating immunity or past infection. Other results are shown in Two weeks later, the patient was seen in the pediatric gastroenterology clinic at this hospital. He rated the abdominal pain at 5 on a scale of 0 to 10, with 10 indicating the most severe pain. He reported one bowel movement of hard stool daily, and one episode of blood streaking on the stool after straining, with no mucus. He reported that he had lost 18.2 kg during the previous 2 years. The first 11 to 12 kg was intentional; however, during the 6 weeks before this evaluation, additional weight loss had occurred unintentionally. The body-mass index (the weight in kilograms divided by the square of the height in meters) had reportedly decreased from 27.0 (>95th percentile for his age) to 20.5 (25th to 50th percentile). He reported night sweats with chills but no fever. The patient had visited relatives in Haiti approximately 4 years earlier for 1 week; he reported no exposure to persons with respiratory or gastrointestinal symptoms while there or recently. Skin tests for tuberculosis were reportedly negative befor

The experience of providing young people attending general practice with an online risk assessment tool to assess their own sexual health risk

<p>Abstract</p> <p>Background</p> <p>Targeted chlamydia screening has been advocated to reduce chlamydia associated reproductive sequelae. General practitioners are well positioned to play a major role in chlamydia control. The primary aim of this pilot study was to measure the effect of offering an online sexual health assessment tool, <it>Youth Check Your Risk</it>, on chlamydia testing rates among young people attending general practices. The secondary aim was to test the acceptability of the tool among general practitioners and young people.</p> <p>Methods</p> <p>General practitioners at three practices in Melbourne, Australia, referred patients aged 16 to 24 years to <it>Youth Check Your Risk </it><url>http://www.checkyourrisk.org.au</url> for use post-consultation between March to October 2007. The proportion of young people tested for chlamydia before and during the implementation of the tool was compared. Acceptability was assessed through a structured interviewer-administered questionnaire with general practitioners, and anonymous online data provided by <it>Youth Check Your Risk </it>users.</p> <p>Results</p> <p>The intervention did not result in any significant increases in the proportion of 16 to 24 year old males (2.7% to 3.0%) or females (6.3% to 6.4%) tested for chlamydia. A small increase in the proportion of 16 to 19 year old females tested was seen (4.1% to 7.2%). Of the 2997 patients seen during the intervention phase, 871 (29.1%) were referred to <it>Youth Check Your Risk </it>and 120 used it (13.8%). Major reasons for low referral rates reported by practitioners included lack of time, discomfort with raising the issue of testing, and difficulty in remembering to refer patients.</p> <p>Conclusion</p> <p>Offering an online sexual risk assessment tool in general practice did not significantly increase the proportion of young people tested for chlamydia, with GPs identifying a number of barriers to referring young people to <it>Youth Check Your Risk</it>. Future interventions aimed at increasing chlamydia screening in general practice with the aid of an online risk assessment tool need to identify and overcome barriers to testing.</p

A Phase 1 Trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion

BackgroundThe selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.MethodsTwelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained.ResultsSelegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline.ConclusionNo pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions

Implementation and testing of the first prompt search for gravitational wave transients with electromagnetic counterparts

Aims. A transient astrophysical event observed in both gravitational wave (GW) and electromagnetic (EM) channels would yield rich scientific rewards. A first program initiating EM follow-ups to possible transient GW events has been developed and exercised by the LIGO and Virgo community in association with several partners. In this paper, we describe and evaluate the methods used to promptly identify and localize GW event candidates and to request images of targeted sky locations. Methods. During two observing periods (Dec 17 2009 to Jan 8 2010 and Sep 2 to Oct 20 2010), a low-latency analysis pipeline was used to identify GW event candidates and to reconstruct maps of possible sky locations. A catalog of nearby galaxies and Milky Way globular clusters was used to select the most promising sky positions to be imaged, and this directional information was delivered to EM observatories with time lags of about thirty minutes. A Monte Carlo simulation has been used to evaluate the low-latency GW pipeline's ability to reconstruct source positions correctly. Results. For signals near the detection threshold, our low-latency algorithms often localized simulated GW burst signals to tens of square degrees, while neutron star/neutron star inspirals and neutron star/black hole inspirals were localized to a few hundred square degrees. Localization precision improves for moderately stronger signals. The correct sky location of signals well above threshold and originating from nearby galaxies may be observed with ~50% or better probability with a few pointings of wide-field telescopes.Comment: 17 pages. This version (v2) includes two tables and 1 section not included in v1. Accepted for publication in Astronomy & Astrophysic

Molecular Sites for the Positive Allosteric Modulation of Glycine Receptors by Endocannabinoids

Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α1, α2 and α3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α1 GlyRs but inhibit α2 and α3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine the positive modulation of α1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α1 GlyRs, without affecting inhibition of α2 and α3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain