Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels.

Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge.

Biocompatible Glycopolymer-PLA Amphiphilic Hybrid Block Copolymers with Unique Self-Assembly, Uptake, and Degradation Properties.

The self-assembly of Janus-type amphiphilic hybrid block copolymers composed of hydrophilic/hydrophobic layers has shown promise for drug encapsulation and delivery. Saccharides have previously been incorporated to improve the biocompatibility of self-assembled structures; however, glycopolymer block copolymers have been less explored, and their structure-property relationships are not well understood. In this study, novel glycopolymer-branched poly(lactic acid) (PLA) block copolymers were synthesized via thiol-ene coupling and their composition-dependent morphologies were elucidated.

Kainate receptor channel opening and gating mechanism.

Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism. Although structures of kainate receptor domains and subunit assemblies are available, the mechanism of kainate receptor gating remains poorly understood.

The impact of spike timing precision and spike emission reliability on decoding accuracy.

Precisely timed and reliably emitted spikes are hypothesized to serve multiple functions, including improving the accuracy and reproducibility of encoding stimuli, memories, or behaviours across trials. When these spikes occur as a repeating sequence, they can be used to encode and decode a potential time series. Here, we show both analytically and in simulations that the error incurred in approximating a time series with precisely timed and reliably emitted spikes decreases linearly with the number of neurons or spikes used in the decoding.

Management of Hyperhemolysis in β-thalassemia With Multiple Immunosuppressives, Including Complement Blockade.

Hyperhemolysis is a life-threatening condition of exaggerated hemolysis of red blood cells which occurs in patients receiving chronic transfusion therapy. We present a 19-year-old male with the β-thalassemia major with an episode of hyperhemolysis. Hemolysis was initially unresponsive to immunosuppression but responded after the addition of eculizumab.

Promoting Quality in Medicaid Transformation.

North Carolina's upcoming shift to Medicaid managed care will present the opportunity to build on the current quality of services in a system that is focused on whole-person treatment. WellCare of North Carolina, Inc. intends to use innovative approaches that combine aspects of successful programs in other states, tailored to fit North Carolina and improve the quality of care.

Neutronic performance characteristics of different LEU fuels in a proposed NIST research reactor.

As a potential replacement for the National Bureau Standards Reactor (NBSR) at the U.S. National Institute of Standards and Technology (NIST), a conceptual design of a new reactor with a horizontally-split core has recently been studied using low-enriched uranium (LEU) silicide dispersion (USi/Al) fuel.

FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration.

Background And Objectives: The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction.

Comparison of three measurement models of discounting among individuals with methamphetamine use disorder.

Background And Objectives: Delay discounting is associated with numerous clinically significant aspects of substance use disorders (SUDs). Recent studies have demonstrated that different models for assessing discounting may result in disparate conclusions. The current study compared two discounting tasks: money now versus money later (M-M) and methamphetamine now versus money later (MA-M) among non-treatment seeking individuals (N = 59) with methamphetamine use disorder (MAUD).

Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial.

Background: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies.

Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S.

A COMPARISON OF MAZUR'S AND AREA UNDER THE CURVE FOR DESCRIBING STEEP DISCOUNTERS.

Delay discounting describes how a reward loses value as a function of increasing delay to its receipt and has been reliably associated with a variety of vulnerable populations including those with substance use disorders (SUDs). Two commonly used models to assess delay discounting in the field of SUDs include log derived from Mazur's hyperbolic equation and area under the curve (AUC). In the current study, we compared log with AUC on delay discounting data obtained from non-treatment seeking, cocaine- and methamphetamine-dependent volunteers.

The limited impact that cocaine use patterns have on neurocognitive functioning in individuals with cocaine use disorder.

It is well-documented in the literature that cocaine use is associated with neurocognitive impairment. The manner in which patterns of cocaine use, such as years of use, recent use over the past month, and daily amount of cocaine use, moderate neurocognition has been studied in a relatively piecemeal manner. Hence, the purpose of the study was to evaluate whether cocaine use patterns modulate neurocognition in individuals with cocaine use disorder.

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

Objective: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine.

Methods: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion.

Electrocardiographic characteristics in individuals with cocaine use disorder.

Background And Objectives: Chronic cocaine use has been linked to several abnormalities in cardiac functioning. The objective of this study was to further characterize baseline heart rate and electrocardiograph (ECG) profiles of individuals with cocaine use disorder (CUD) by evaluating demographic and drug use variables that may impact cardiovascular profiles.

Methods: Participants with CUD (n = 335, primarily African-American males) provided demographic and drug use data and ECG profiles (eg, heart rate, PR Interval, QRS, and QTc) were obtained via 12-lead ECG.

The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders.

Objective: To determine whether premorbid IQ mediates performance on neurocognitive tests in individuals diagnosed with cocaine use disorder (CUD).

Method: Recently abstinent cocaine users (N = 113) completed measures sensitive to the effects of cocaine on cognition: Conners' Continuous Performance Task-II (CPT-II), n-back working memory test, and Hopkins Verbal Learning Task-Revised (HVLT-R). Premorbid IQ was calculated using the Oklahoma Premorbid Intelligence Estimate, which integrates scores from the Wechsler Adult Intelligence Scale-III and demographic variables.

Treadmill exercise improves fitness and reduces craving and use of cocaine in individuals with concurrent cocaine and tobacco-use disorder.

Exercise may be a useful treatment for substance use disorders. Participants (N=24) included treatment-seeking individuals with concurrent cocaine and tobacco-use disorder (cigarette smokers). Participants were randomized to either running or walking (30min per session, 3 times per week) or sitting (control condition) for 4 consecutive weeks.

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

Background: In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil.

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

Objectives: We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals.

Methods: This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years.

Doxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: a pilot clinical trial.

Background: Serotonin and norepinephrine reuptake inhibitors are effective first-line agents for the treatment of posttraumatic stress disorder (PTSD), but treatment is associated with a range of side effects that limit treatment adherence. Prazosin, an α1-noradrenergic antagonist with a half-life of roughly 2-3 hours, has shown promise in the treatment of sleep disturbance and nightmares. Doxazosin extended release (XL) is also an α1-noradrenergic antagonist but with a half-life of approximately 15-19 hours.

Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

Background: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine.

Next Generation Programmable Bio-Nano-Chip System for On-Site Detection in Oral Fluids.

Current on-site drug of abuse detection methods involve invasive sampling of blood and urine specimens, or collection of oral fluid, followed by qualitative screening tests using immunochromatographic cartridges. Test confirmation and quantitative assessment of a presumptive positive are then provided by remote laboratories, an inefficient and costly process decoupled from the initial sampling. Recently, a new noninvasive oral fluid sampling approach that is integrated with the chip-based Programmable Bio-Nano-Chip (p-BNC) platform has been developed for the rapid (~ 10 minutes), sensitive detection (~ ng/ml) and quantitation of 12 drugs of abuse.

Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder.

Background: Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder.

Methods: The current report describes results from a double-blind, placebo-controlled study in which participants (n=14-17/group) were randomized to huperzine A (0.