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

Inverse Protein Folding Using Deep Bayesian Optimization

Inverse protein folding -- the task of predicting a protein sequence from its backbone atom coordinates -- has surfaced as an important problem in the "top down", de novo design of proteins. Contemporary approaches have cast this problem as a conditional generative modelling problem, where a large generative model over protein sequences is conditioned on the backbone. While these generative models very rapidly produce promising sequences, independent draws from generative models may fail to produce sequences that reliably fold to the correct backbone. Furthermore, it is challenging to adapt pure generative approaches to other settings, e.g., when constraints exist. In this paper, we cast the problem of improving generated inverse folds as an optimization problem that we solve using recent advances in "deep" or "latent space" Bayesian optimization. Our approach consistently produces protein sequences with greatly reduced structural error to the target backbone structure as measured by TM score and RMSD while using fewer computational resources. Additionally, we demonstrate other advantages of an optimization-based approach to the problem, such as the ability to handle constraints

Tobacco-specific and combustion pollutants in settled house dust in Malta

Aim: Most of the carcinogenic pollutants coming from tobacco smoking or other combustion processes tend to accumulate in settled house dust (SHD) over time. This study evaluated the load of these pollutants in smokers and non-smokers’ houses from relatively fresh SHD collected in five different districts on the island of Malta. Methods: An improved, efficient extraction method to obtain three fractions from a 200 mg of SHD was developed. It was validated for the analysis of nicotine and polycyclic aromatic hydrocarbons (PAH) by GCMS/ MS and nicotelline and TSNA by LC-MS/MS. Kruskal-Wallis H tests were used to evaluate differences across districts, while a Mann-Whitney U test was used to check differences between smokers and non-smokers’ houses. Diagnostic ratios were used to evaluate the carcinogenicity of PAH in SHD in Malta. Results: For all analytes, no statistical difference was observed across different districts, but, in smokers’ houses, 97.9% of the total concentration of all target analytes found in SHD is nicotine, 0.1% is TSNA, and 2.0% is PAH. In non-smokers’ houses, nicotine represents 16.8% of the load, while 0.4% and 82.8% are TSNA and PAH, respectively. The carcinogenicity of the PAH mixture in Maltese SHD, expressed as the mean benzo(a)pyrene equivalent (BaPeq) is 371 ng/g. Conclusion: Indoor activities, ventilation practices, and infiltration of outdoor pollutants contribute to a complex SHD composition. Although the BaPeq is on the lower end of carcinogenicity, the effects of a mixture including tobacco-related potent carcinogens in SHD are largely unknown. In view of indoor, continuous exposure to SHD through several pathways, further research is warranted.peer-reviewe

Efficient Photon Upconversion Enabled by Strong Coupling Between Organic Molecules and Quantum Dots

Hybrid structures formed between organic molecules and inorganic quantum dots can accomplish unique photophysical transformations by taking advantage of their disparate properties. The electronic coupling between these materials is typically weak, leading photoexcited charge carriers to spatially localize to a dot or a molecule at its surface. However, we show that by converting a chemical linker that covalently binds anthracene molecules to silicon quantum dots from a carbon-carbon single bond to a double bond, we access a strong-coupling regime where excited carriers spatially delocalize across both anthracene and silicon. By pushing the system to delocalize, we design a photon upconversion system with a higher efficiency (17.2%) and lower threshold intensity (0.5 W/cm^2) than that of a corresponding weakly-coupled system. Our results show that strong coupling between molecules and nanostructures achieved through targeted linking chemistry provides a new route for tailoring properties in materials for light-driven applications.Comment: 33 pages (20 in main text, 13 in supporting information), 12 figures (5 in main text, 7 in supporting information

Tantalum versus Titanium Acetabular Shells in Young Active THR Patients: A Radiostereometric Analysis (RSA) Study

Introduction: In the active THR (total hip replacement) population, acetabular component stability is crucial for preventing implant failure. Titanium fiber metal coating is the most common material used in cementless THR. Trabecular metal, composed of porous tantalum, is designed to improve tissue infiltration and limit migration. It is unknown if tantalum offers an advantage over titanium in the biologic fixation of porous-coated acetabular shells. Radiostereometric analysis (RSA) provides highly precise measurements of micromotion that are otherwise not detectable by routine radiographs. Methods: In this IRB approved, prospective, randomized, blinded study, 46 patients received a primary THR by a single surgeon. Each patient was randomized to receive a titanium (23) or tantalum (23) uncemented cup. Tantalum RSA markers were implanted around the polyethylene liner and into the patient’s femur and periacetabular bone. Also, patients received either a highly cross-linked (n=25) or a conventional liner (n=21). RSA examinations, Harris Hip, UCLA, WOMAC, SF-12 scores were obtained at 10 days, 6 months, and annually through 5 years. Results: The randomized groups had comparable mean age, preoperative activity, and average BMI. The tantalum shells demonstrated less median translation than the titanium shells at each time-point, but there was no statistical difference between the two shells. At 6 months median translation of tantalum and titanium was -0.01mm and 0.04mm and remained stable with median translation of -0.02mm and 0.04mm at four years. Mean UCLA, WOMAC, Harris Hip, and SF-12 PCS and MCS scores improved similarly in both groups. Conclusions: After THR, both patient cohorts had excellent clinical outcomes with statistically significant improvements in function and pain relief. Although tantalum porous-coated acetabular shells demonstrated less y-translation and y-rotation at all time points, there was no statistically significant difference in shell migration and both shells demonstrated excellent stability with minimal micromotion at four years

Concert recording 2017-11-28

[Track 1]. Bill Bailey / Hughie Cannon arranged by James Garrett -- [Track 2]. Second suite. I. March [Track 3]. II. Song without words, I\u27ll love my love / Gustav Holst arranged by Cody Hutchison -- [Track 4]. Deutschland uber alles / Franz Joseph Haydn arranged by Eugene Anderson -- [Track 5]. Geleit from Three pieces / Johannes Brahms translated by William R. Lee -- [Track 6]. Belle of Chicago march / John Philip Sousa arranged by Skip Gray -- [Track 7]. Three preludes from op. 34. No. 14 [Track 8]. No. 7 [Track 9]. No. 16 / Dmitri Shostakovich arranged by Rauch -- [Track 10]. Tuba Sunday / traditional arranged by Gerald Sloan -- [Track 11]. Quartet for tubas / Sy Brandon -- [Track 12.] Cherokee / John Schooley -- [Track 13]. Moondance / John Stevens -- [Track 14]. Amazing grace / traditional arranged by David Uber

Ubiquitous atmospheric contamination by tobacco smoke : nicotine and a new marker for tobacco smoke-derived particulate matter, nicotelline

Second Hand Smoke (SHS) has always been primarily linked with indoor pollution. To date nicotine was the favoured marker for SHS alongside measurements of particulate matter (PM) levels. As nicotine is mainly found in the gas-phase and reactive in the outdoor environment it is not ideal as a marker for the SHS-driven particulate component in PM. Nicotelline, a minor tobacco alkaloid that is stable, found almost exclusively in the particle phase and easy to quantify even at low concentrations, is being proposed as a better marker. It is the first study using bisulfate-treated quartz fiber filters to show that airborne nicotine (gas+particle phase) is directly proportional to airborne nicotelline in countries that have different climates. The analytical method developed has been validated to show that the use of untreated filters is suitable for the quantification of nicotelline even at low concentrations. Although nicotelline exhibits a seasonal and geographical variation, this is the first comprehensive study which demonstrates the ubiquitous presence of nicotelline in PM from outdoor air samples collected in the USA (0.1–285.6 pgm-3), UK (2.3–9.1 pgm-3), Hong Kong (3.8–109.3 pgm-3) and Malta (4.2–280.8 pgm-3). From the nicotelline apportionment factor of 1589 ng/mg of tobacco smoke PM we estimate the fraction of outdoor airborne PM derived from SHS to be in the range of 0.03–0.08%. While it is unlikely for tobacco smoke-related toxics in outdoor PM to be considered a major health hazard, in heavily polluted microenvironments this marker would be useful in tracing the presence of SHS and emerging Third Hand Smoke components that form or are found in airborne and settled PM that could induce serious health effects.peer-reviewe