Layered structure of room-temperature ionic liquids in microemulsions by multinuclear NMR spectroscopic studies

Microemulsions form in mixtures of polar, nonpolar, and amphiphilic molecules. Typical microemulsions employ water as the polar phase. However, microemulsions can form with a polar phase other than water, which hold promise to diversify the range of properties, and hence utility, of microemulsions. Here microemulsions formed by using a room-temperature ionic liquid (RTIL) as the polar phase were created and characterized by using multinuclear NMR spectroscopy. 1H, 11B, and 19F NMR spectroscopy was applied to explore differences between microemulsions formed by using 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) as the polar phase with a cationic surfactant, benzylhexadecyldimethylammonium chloride (BHDC), and a nonionic surfactant, Triton X-100 (TX-100). NMR spectroscopy showed distinct differences in the behavior of the RTIL as the charge of the surfactant head group varies in the different microemulsion environments. Minor changes in the chemical shifts were observed for [bmim]+ and [BF 4]- in the presence of TX-100 suggesting that the surfactant and the ionic liquid are separated in the microemulsion. The large changes in spectroscopic parameters observed are consistent with microstructure formation with layering of [bmim]+ and [BF4]- and migration of Cl- within the BHDC microemulsions. Comparisons with NMR results for related ionic compounds in organic and aqueous environments as well as literature studies assisted the development of a simple organizational model for these microstructures. Confining ions: Multinuclear NMR experiments were used to explore two different reverse micelle systems formed by using a cationic and nonionic surfactant with the room-temperature ionic liquid (RTIL) [bmim][BF4] (bmim=1-butyl-3-methylimidazolium) as the polar phase. Microemulsions formed by using a cationic surfactant revealed layering of the RTIL that does not occur in systems formed with the nonionic surfactant (see figure). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Fil: Falcone, Ruben Dario. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; ArgentinaFil: Baruah, Bharat. Kennesaw State University; Estados Unidos. State University of Colorado - Fort Collins; Estados UnidosFil: Gaidamauskas, Ernestas. State University of Colorado - Fort Collins; Estados Unidos. Vilniaus Universitetas; LituaniaFil: Rithner, Christopher D.. State University of Colorado - Fort Collins; Estados UnidosFil: Correa, Nestor Mariano. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; ArgentinaFil: Silber, Juana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; ArgentinaFil: Crans, Debbie C.. State University of Colorado - Fort Collins; Estados UnidosFil: Levinger, Nancy E.. State University of Colorado - Fort Collins; Estados Unido

Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania

Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [3H]-sphingosine and myo-[3H]-inositol, alkaline hydrolysis, HPTLC fractionations and mass spectrometry analyses, we observed a perturbation in the metabolism of inositolphosphorylceramides (IPCs) and phosphatidylinositols (PIs) after treatment of L. amazonensis promastigotes with tamoxifen, with a significant reduction in the biosynthesis of the major IPCs (composed of d16:1/18:0-IPC, t16:0/C18:0-IPC, d18:1/18:0-IPC and t16:0/20:0-IPC) and PIs (sn-1-O-(C18:0)alkyl -2-O-(C18:1)acylglycerol-3-HPO4-inositol and sn-1-O-(C18:0)acyl-2-O-(C18:1)acylglycerol-3-HPO4-inositol) species. Substrate saturation kinetics of myo-inositol uptake analyses indicated that inhibition of inositol transport or availability were not the main reasons for the reduced biosynthesis of IPC and PI observed in tamoxifen treated parasites. An in vitro enzymatic assay was used to show that tamoxifen was able to inhibit the Leishmania IPC synthase with an IC50 value of 8.48 μM (95% CI 7.68–9.37), suggesting that this enzyme is most likely one of the targets for this compound in the parasites

Nanoparticle mediated silencing of DNA repair sensitizes pediatric brain tumor cells to y-irradiation

Medulloblastoma (MB) and ependymoma (EP) are the most common pediatric brain tumors, afflicting 3000 children annually. Radiotherapy (RT) is an integral component in the treatment of these tumors; however, the improvement in survival is often accompanied by radiation-induced adverse developmental and psychosocial sequelae. Therefore, there is an urgent need to develop strategies that can increase the sensitivity of brain tumors cells to RT while sparing adjacent healthy brain tissue. Apurinic endonuclease 1 (Ape1), an enzyme in the base excision repair pathway, has been implicated in radiation resistance in cancer. Pharmacological and specificity limitations inherent to small molecule inhibitors of Ape1 have hindered their clinical development. Here we report on a nanoparticle (NP) based siRNA delivery vehicle for knocking down Ape1 expression and sensitizing pediatric brain tumor cells to RT. The NP comprises a superparamagnetic iron oxide core coated with a biocompatible, biodegradable coating of chitosan, polyethylene glycol (PEG), and polyethyleneimine (PEI) that is able to bind and protect siRNA from degradation and to deliver siRNA to the perinuclear region of target cells. NPs loaded with siRNA against Ape1 (NP:siApe1) knocked down Ape1 expression over 75% in MB and EP cells, and reduced Ape1 activity by 80%. This reduction in Ape1 activity correlated with increased DNA damage post-irradiation, which resulted in decreased cell survival in clonogenic assays. The sensitization was specific to therapies generating abasic lesions as evidenced by NP:siRNA not increasing sensitivity to paclitaxel, a microtubule disrupting agent. Our results indicate NP-mediated delivery of siApe1 is a promising strategy for circumventing pediatric brain tumor resistance to RT

The long-term treatment of restless legs syndrome/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group

AbstractA Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis–Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6months or longer presented at meetings over the past 2years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, “What is the efficacy of this treatment in patients with RLS/WED?” and “What is the safety of this treatment in patients with RLS/WED?”The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5years: gabapentin enacarbil, pramipexole, and ropinirole (1year); levodopa (2years); and rotigotine (5years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient’s severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions

Trial of SAGE-217 in Patients with Major Depressive Disorder

BACKGROUND: Altered neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (+/-SE) change in the HAM-D score from baseline to day 15 was -17.4+/-1.3 points in the SAGE-217 group and -10.3+/-1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P \u3c 0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.)

The Lantern Vol. 74, No. 2, Spring 2007

• La Viuda • The Curb After Light Drizzling • Loose Cream • The Problem of Ants • Streetplay • Avignon, Anno Domini 1348 • Autophagia • Silverette-New Wave Fascist Date Routine • Mint Shavings • Dogtags • Millenials • Rain That Sleeps by Itself at Track Number 5 • Amorphous • I Found a Flashlight • Sippikkul Muthu: Pearl Within Shell • Of Lies • The Complications of a Fish-Only Diet • Ashes • Unto the Fourth Generation • Marooned on Piano Island • Sweethttps://digitalcommons.ursinus.edu/lantern/1170/thumbnail.jp

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Astro2020 APC White Paper: The MegaMapper: a z > 2 spectroscopic instrument for the study of Inflation and Dark Energy

MegaMapper is a proposed ground-based experiment to measure Inflation parameters and Dark Energy from galaxy redshifts at

How to handle mortality when investigating length of hospital stay and time to clinical stability

<p>Abstract</p> <p>Background</p> <p>Hospital length of stay (LOS) and time for a patient to reach clinical stability (TCS) have increasingly become important outcomes when investigating ways in which to combat Community Acquired Pneumonia (CAP). Difficulties arise when deciding how to handle in-hospital mortality. Ad-hoc approaches that are commonly used to handle time to event outcomes with mortality can give disparate results and provide conflicting conclusions based on the same data. To ensure compatibility among studies investigating these outcomes, this type of data should be handled in a consistent and appropriate fashion.</p> <p>Methods</p> <p>Using both simulated data and data from the international Community Acquired Pneumonia Organization (CAPO) database, we evaluate two ad-hoc approaches for handling mortality when estimating the probability of hospital discharge and clinical stability: 1) restricting analysis to those patients who lived, and 2) assigning individuals who die the "worst" outcome (right-censoring them at the longest recorded LOS or TCS). Estimated probability distributions based on these approaches are compared with right-censoring the individuals who died at time of death (the complement of the Kaplan-Meier (KM) estimator), and treating death as a competing risk (the cumulative incidence estimator). Tests for differences in probability distributions based on the four methods are also contrasted.</p> <p>Results</p> <p>The two ad-hoc approaches give different estimates of the probability of discharge and clinical stability. Analysis restricted to patients who survived is conceptually problematic, as estimation is conditioned on events that happen <it>at a future time</it>. Estimation based on assigning those patients who died the worst outcome (longest LOS and TCS) coincides with the complement of the KM estimator based on the subdistribution hazard, which has been previously shown to be equivalent to the cumulative incidence estimator. However, in either case the time to in-hospital mortality is ignored, preventing simultaneous assessment of patient mortality in addition to LOS and/or TCS. The power to detect differences in underlying hazards of discharge between patient populations differs for test statistics based on the four approaches, and depends on the underlying hazard ratio of mortality between the patient groups.</p> <p>Conclusions</p> <p>Treating death as a competing risk gives estimators which address the clinical questions of interest, and allows for simultaneous modelling of both in-hospital mortality and TCS / LOS. This article advocates treating mortality as a competing risk when investigating other time related outcomes.</p

Pivotal Role of Adenosine Neurotransmission in Restless Legs Syndrome

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A1 receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α2δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS