The Role of N-acetyl-L-Cysteine (NAC) as an Adjuvant to Opioid Treatment in Patients with Inadequately Controlled Chronic Neuropathic Pain

Introduction. While opioid medications are commonly prescribed for management of neuropathic pain (NP), long-term use has been associated with increased risk for overdose, drug interactions and addiction. New strategies are necessary to better manage chronic pain, thereby reducing need for opioid medications and their associated adverse consequences. N-acetyl-L-cysteine (NAC), an over-the-counter supplement, has shown promise in the treatment of psychiatric and addictive disorders. In addition, NAC has shown promise for reducing physiological signs of NP in laboratory rat models, prompting this study. Purpose. The present study was an open-label clinical trial of NAC as an adjuvant to opioid treatment for poorly controlled, chronic NP. It examined whether 1200 mg NAC twice daily for 4 weeks was associated with: lower ratings of patient-reported pain; reductions in PRN opioid medication for breakthrough pain; and improvements in physical and mental health quality of life (QoL). The study also examined whether appraisal of pain impacts response to medication. Method. Participants were N=28 chronic NP patients who consented to study participation. This consisted of 2 baseline assessments, 4 weeks of NAC and 1 post-trial follow-up visit. The majority (N=17) dropped out or were excluded during baseline. Of the remaining participants, N = 11 started the study medication and N=10 completed the study, with daily recordings of pain severity ratings and use of PRN opioid medication. Small sample size limited analyses to qualitative case reviews and effect sizes. Results. Over 90% of participants receiving NAC completed the study. Case review found varied results. While 4 of 10 participants showed decrease in average pain ratings during NAC, estimated effect sizes for the whole sample were small, bordering on negligible (ω² from .003 to .027) as were those for PRN opioids (Partial Eta-Squared=.0003). Effect size for mental health QoL was medium (Cohen\u27s d=.421). Conclusions. With N=10, findings must be interpreted with caution. Nonetheless, the study found some albeit small evidence supporting NAC for improving mental health QoL and pain ratings. Several participants reported improvements in pain and mental health domains while taking NAC. NAC was well tolerated with minimal side effects. Lessons from this study will inform design and implementation of future NAC studies

Simulation of the HIV-1 Vpu transmembrane domain as a pentameric bundle

AbstractThe transmembrane domain of oligomeric protein Vpu encoded by HIV-1 has been studied by means of a molecular dynamics simulation. A pentameric bundle of unconstrained helices (residues 6–28 of Vpu) with a water filled pore was initially assembled in a membrane mimetic octane/water system. This system was simulated, using the CHARMm19 and OPLS united atom force fields with no constraints at a temperature of 300 K and a pressure of 1 atm. For these forcefields and the initial conditions tested, the oligomeric bundle expelled most of the pore water molecules. The resulting bundle and residual waters adopt a conical structural motif with some resemblance to a potassium channel

Discriminating Stay-Green Grasses Using Hyperspectral Imaging and Chemometrics

Screening of plant collections for traits can be expensive, in terms of the number of plants to be screened, the duration of the plant lifecycle and the required observations. This study describes the application of a non-invasive method, hyperspectral imaging, combined with multivariate analysis, to distinguish between homozygous wild-type (YY) Lolium multiflorum and Lolium multiflorum F2 back cross plants heterozygous for y, a recessive Festuca pratensis stay-green gene (Thomas et al., 1997)

A search for rapidly pulsating hot subdwarf stars in the GALEX survey

NASA's Galaxy Evolution Explorer (GALEX) provided near- and far-UV observations for approximately 77 percent of the sky over a ten-year period; however, the data reduction pipeline initially only released single NUV and FUV images to the community. The recently released Python module gPhoton changes this, allowing calibrated time-series aperture photometry to be extracted easily from the raw GALEX data set. Here we use gPhoton to generate light curves for all hot subdwarf B (sdB) stars that were observed by GALEX, with the intention of identifying short-period, p-mode pulsations. We find that the spacecraft's short visit durations, uneven gaps between visits, and dither pattern make the detection of hot subdwarf pulsations difficult. Nonetheless, we detect UV variations in four previously known pulsating targets and report their UV pulsation amplitudes and frequencies. Additionally, we find that several other sdB targets not previously known to vary show promising signals in their periodograms. Using optical follow-up photometry with the Skynet Robotic Telescope Network, we confirm p-mode pulsations in one of these targets, LAMOST J082517.99+113106.3, and report it as the most recent addition to the sdBVr class of variable stars.Comment: 11 Pages, 8 Figures, Accepted for publication in the Astrophysical Journa

The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review

The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields

Cold collapse and the core catastrophe

We show that a universe dominated by cold dark matter fails to reproduce the rotation curves of dark matter dominated galaxies, one of the key problems that it was designed to resolve. We perform numerical simulations of the formation of dark matter halos, each containing \gsim 10^6 particles and resolved to 0.003 times the virial radius, allowing an accurate comparison with rotation curve data. A good fit to both galactic and cluster sized halos can be achieved using the density profile rho(r) \propto [(r/r_s)^1.5(1+(r/r_s)^1.5)]^-1, where r_s is a scale radius. This profile has a steeper asymptotic slope, rho(r) \propto r^-1.5, and a sharper turnover than found by lower resolution studies. The central structure of relaxed halos that form within a hierarchical universe has a remarkably small scatter (unrelaxed halos would not host disks). We compare the results with a sample of dark matter dominated, low surface brightness (LSB) galaxies with circular velocities in the range 100-300 km/s. The rotation curves of disks within cold dark matter halos rise too steeply to match these data which require a constant mass density in the central regions. The same conclusion is reached if we compare the scale free shape of observed rotation curves with the simulation data. It is important to confirm these results using stellar rather than HI rotation curves for LSB galaxies. We test the effects of introducing a cut-off in the power spectrum that may occur in a universe dominated by warm dark matter. In this case halos form by a monolithic collapse but the final density profile hardly changes, demonstrating that the merger history does not play a role in determining the halo structure.Comment: Latex 13 pages, 4 figures. Submitted to MNRAS. High resolution colour version of figure 4 and other N-body images here: http://star-www.dur.ac.uk:80/~moore/images

Measurement of gut permeability using fluorescent tracer agent technology

Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use

Clinical diagnosis of symptomatic midfoot osteoarthritis:cross-sectional findings from the Clinical Assessment Study of the Foot

OBJECTIVE: To derive a multivariable diagnostic model for symptomatic midfoot osteoarthritis (OA). METHODS: Information on potential risk factors and clinical manifestations of symptomatic midfoot OA was collected using a health survey and standardised clinical examination of a population-based sample of 274 adults aged ≥50 years with midfoot pain. Following univariable analysis, random intercept multi-level logistic regression modelling that accounted for clustered data was used to identify the presence of midfoot OA independently scored on plain radiographs (dorso-plantar and lateral views), and defined as a score of ≥2 for osteophytes or joint space narrowing in at least one of four joints (first and second cuneometatarsal, navicular-first cuneiform and talonavicular joints). Model performance was summarised using the calibration slope and area under the curve (AUC). Internal validation and sensitivity analyses explored model over-fitting and certain assumptions. RESULTS: Compared to persons with midfoot pain only, symptomatic midfoot OA was associated with measures of static foot posture and range-of-motion at subtalar and ankle joints. Arch Index was the only retained clinical variable in a model containing age, gender and body mass index (BMI). The final model was poorly calibrated (calibration slope, 0.64, 95% CI: 0.39, 0.89) and discrimination was fair-to-poor (AUC, 0.64, 0.58, 0.70). Final model sensitivity and specificity were 29.9% (22.7, 38.0) and 87.5% (82.9, 91.3), respectively. Bootstrapping revealed the model to be over-optimistic and performance was not improved using continuous predictors. CONCLUSIONS: Brief clinical assessments provided only marginal information for identifying the presence of radiographic midfoot OA among community-dwelling persons with midfoot pain