Sequential nested assembly at the liquid/solid interface.

Studying the stepwise assembly of a four component hybrid structure on Au(111)/mica, the pores of a hydrogen bonded bimolecular network of 3,4,9,10-perylenetetracarboxylic diimide (PTCDI) and 1,3,5-triazine-2,4,6-triamine (melamine) were partitioned by three and four-armed molecules based on oligo([biphenyl]-4-ylethynyl)benzene, followed by the templated adsorption of either C60 fullerene or adamantane thiol molecules. The characterisation by ambient scanning tunneling microscopy (STM) reveals that the pore modifiers exhibit dynamics which pronouncedly depend on the molecular structure. The three-armed molecule 1,3,5-tris([1,1'-biphenyl]-4-ylethynyl)benzene (3BPEB) switches between two symmetry equivalent configurations on a time scale fast compared to the temporal resolution of the STM. Derivatisation of 3BPEB by hydroxyl groups substantially reduces the switching rate. For the four-armed molecule configurational changes are observed only occasionally. The observation of isolated fullerenes and small clusters of adamantane thiol molecules, which are arranged in a characteristic fashion, reveals the templating effect of the trimolecular supramolecular network. However, the fraction of compartments filled by guest molecules is significantly below one for both the thermodynamically controlled adsorption of C60 and the kinetically controlled adsorption of the thiol with the latter causing partial removal of the pore modifier. The experiments, on the one hand, demonstrate the feasibility of templating by nested assembly but, on the other hand, also pinpoint the requirement for the energy landscape to be tolerant to variations in the assembly process.

Development and preliminary validation of the focused analgesia selection test to identify accurate pain reporters.

Clinical trials of analgesics have been plagued with poor assay sensitivity due, in part, to variability in subjects' pain reporting. Herein, we develop and evaluate the focused analgesia selection test (FAST), a method to measure patients' pain reporting skills. Subjects with osteoarthritis of the hip, knee, and/or ankle with pain intensity of ≥3/10 on a 0-10 numerical rating scale were enrolled. Subjects underwent the FAST procedure, which consists of recording subjects' pain reports in response to repeated administration of thermal noxious stimuli of various intensities applied on the arm with the Medoc® Thermal Sensory Analyzer II. Subjects also rated non-noxious stimuli consisting of visual contrast rating. After performing an exercise task, subjects also rated clinical pain and were asked to report whether their pain had increased, decreased, or stayed the same. Overall, 88 subjects were enrolled, and 83 were included in the analyses. FAST's outcomes including the R2, intraclass correlation coefficient (ICC), and coefficient of variation (CoV) indicated that subjects' pain reporting skills were widely distributed. Higher FAST ICC significantly predicted greater changes in clinical pain following exercise (p=0.017), whereas the visual contrast test did not predict postexercise pain. FAST is the first method that measures subjects' pain reporting skills. Using FAST to enrich clinical trials with "good" pain reporters (with high FAST ICC) could increase assay sensitivity. Further evaluation of FAST is ongoing.

Development of a bedside pain assessment kit for the classification of patients with osteoarthritis.

There are no standardized bedside assessments for subtyping patients with osteoarthritis (OA) based on pain mechanisms. Thus, we developed a bedside sensory testing kit (BSTK) to classify OA patients based on sensory profiles potentially indicative of pain mechanism. After usability and informal reliability testing (n = 22), the kit was tested in a formal reliability study (n = 20). Patients completed questionnaires and sensory testing: pressure algometry to detect hyperalgesia; repeat algometry after heterotopic noxious conditioning stimulation to measure diffuse noxious inhibitory control (DNIC); light touch using Von Frey filaments; and cold allodynia using a brass rod. The procedure was brief and well tolerated. Algometry and filament testing were highly reliable [intra-class correlation coefficients (ICCs) 0.71-0.91]; DNIC was acceptably reliable (ICCs 0.53-0.91); brass rod reliability was inconclusive. Patients were classified empirically into four groups: "All abnormal findings" (primary and secondary hyperalgesia and dysfunctional DNIC); "all normal findings"; and two intermediate groups. The "all abnormal findings" group had more neuropathic pain symptoms, and lower WOMAC total, stiffness, and activity scores than the "all normal findings" group. Simple BSTK procedures, consolidated in a kit, reliably classified OA patients into subgroups based on sensory profile, suggesting that OA patients differ in underlying pain mechanisms. Further research is needed to confirm these subgroups and determine their validity in predicting response to treatment.

Assessment of pain and activity using an electronic pain diary and actigraphy device in a randomized, placebo-controlled crossover trial of celecoxib in osteoarthritis of the knee.

OBJECTIVE: The primary goal was to determine whether a composite measure of pain and activity is a more responsive assessment of analgesic effect than pain alone or activity alone in patients with osteoarthritis (OA) of the knee. DESIGN: We conducted a randomized, double-blind, placebo-controlled, 2-period, crossover study of celecoxib vs. placebo in subjects with chronic pain due to knee OA. Patients with knee OA and baseline pain intensity score ≥4 on a 0-10 numerical rating scale (NRS) before each period were randomized. Pain endpoints included in-clinic pain score (24-hour and 1-week recall), daily paper diary pain score, current pain on an electronic pain diary (each on NRS), and WOMAC pain subscale. Activity measures included WOMAC function subscale and actigraphy using a device. Three composite pain-activity measures were prespecified. RESULTS: Sixty-three patients were randomized and 47 completed the study. The WOMAC pain subscale was the most responsive of all five pain measures. Pain-activity composites resulted in a statistically significant difference between celecoxib and placebo but were not more responsive than pain measures alone. However, a composite responder defined as having 20% improvement in pain or 10% improvement in activity yielded much larger differences between celecoxib and placebo than with pain scores alone. Actigraphy was more responsive than the WOMAC function scale, possibly due to lower placebo responsiveness. CONCLUSION: We have identified composite pain-activity measures that are similarly or more responsive than pain-alone measures in patients with OA. Further research is warranted to determine the optimal method for computing these composites.

Nonmedical Use and Diversion of ADHD Stimulants Among U.S. Adults Ages 18-49: A National Internet Survey.

OBJECTIVE: Evaluate nonmedical use (NMU) of ADHD prescription stimulants (Ritalin(®), Adderall(®), Adderall(®) XR, Concerta(®), and Vyvanse(®)) in a U.S. adult general population sample. METHOD: In all, 10,000 adults (aged 18-49) from an online, opt-in panel, proximity matched to U.S. Census demographics, were surveyed to assess NMU prevalence, routes of administration (ROA), reasons for NMU, and diversion source. RESULTS: Lifetime NMU of any prescription drug was 35.1%, pain medications (24.6%), sedatives/tranquilizers (15.6%), sleep medications (9.9%), and prescription stimulants (8.1%). Within the prescription stimulants, rates of NMU (per 100,000 prescriptions dispensed) were 1.62 for Ritalin and 1.61 for Adderall followed by Adderall XR (0.62), Concerta (0.19), and Vyvanse (0.13). Respondents used stimulants mostly for wakefulness and performance enhancement, obtained the drugs from family/friends, and used oral ROA. CONCLUSION: NMU of ADHD prescription stimulants were low compared with other prescription medications. While prevalence of NMU was higher for immediate-release than extended-release ADHD medications, absolute rates for prescription stimulants were low.

Bestowing structure upon the pores of a supramolecular network.

Trigonal molecules compartmentalise the pores of a honeycomb network of 3,4:9,10-tetracarboxylic diimide (PTCDI) and 1,3,5-triazine-2,4,6-triamine (melamine). Extending the 1,3,5-tri(phenylene-ethynylene)benzene core by a phenyl group allows for a well-defined accommodation of the molecule into two symmetry equivalent positions in the pore. The corresponding styryl or phenylene-ethynylene derivatives exceed the pore size and, thus, impede pore modification.

Nanopatterning by molecular self-assembly on surfaces.

The ability to pattern surfaces down to the nanoscale is of increasing importance in nanoscience research. The use of supramolecular chemistry to drive the formation of self-assembled networks allows for a bottom-up approach to achieve nanopatterned surfaces. This short review highlights some of the recent breakthroughs in achieving long-range order in such molecular based systems, complemented with examples from our own work. The tuning of molecular architectures can exert control on the emergent properties and function of molecules at interfaces. In particular the formation of porous honeycomb networks allows the rational design of highly ordered patterned surface domains and the investigation of molecular dynamics, chirality and templating effects on surfaces.

A brief survey to characterize oxycodone abuse patterns in adolescents enrolled in two substance abuse recovery high schools.

BACKGROUND: Although oxycodone is one of the most widely available and abused opioids, little published information exists on the abuse of immediate-release oxycodone. OBJECTIVE: To obtain information on abuse of oxycodone and the effectiveness of abuse-deterrent strategies, especially for immediate-release oxycodone, we surveyed oxycodone abuse patterns in a population of experienced opioid abusers. METHODS: Students or recent graduates of two substance abuse recovery high schools in Massachusetts were surveyed on abuse behaviors with short-acting single-entity oxycodone (e.g., Roxicodone), short-acting combination oxycodone (e.g., Percocet), and extended-release oxycodone. RESULTS: Twenty-four students completed surveys. Mean age was 17.7 years (range 16-19), and mean age at first abuse of oxycodone was 15 (range 13-18). Overall, 56% of students reported oxycodone as their favorite prescription opioid to abuse. The primary preferred method of abuse of all oxycodone formulations was intranasal administration: 83% of single-entity oxycodone abusers preferred intranasal administration compared with 67% of combination oxycodone abusers and 69% of extended-release oxycodone abusers. Approximately half of our respondents preferred to ingest oxycodone orally, 25-38% of respondents swallowed the pill intact, and another 13-17% chewed the pill before swallowing. Maximum dose ever abused at one time ranged from 15 to 400 mg. Most respondents had abused ≥60 mg of oxycodone at a time. CONCLUSIONS: In this small study, adolescent oxycodone abusers use high quantities of oxycodone at a time, alter routes of administration for not only extended-release but also immediate-release products, and commonly abuse single-entity oxycodone products. Abuse-deterrent formulations may be one strategy for addressing such behaviors.

Determining the clinically important difference in visual analog scale scores in abuse liability studies evaluating novel opioid formulations.

PURPOSE: This study determined how the magnitude of change in positive subjective responses predicts clinical outcome in a treatment setting. Specifically, we attempted to define what constitutes a clinically important difference (CID) in subjective responses. METHODS: A 100-mm visual analog scale (VAS) measured subjective ratings of drug "high," calculated via an anchor-based method with published data from participants receiving sustained-release naltrexone (NTX) and heroin in a laboratory setting. The data were then compared to clinical outcomes in a treatment trial with sustained-release naltrexone. A distribution-based method subsequently analyzed data from participants who received ALO-01 (extended-release morphine with sequestered NTX) to predict its abuse liability. RESULTS: Differences in ratings of drug high of approximately 10 mm on a 100-mm line were clinically significant. By extrapolation, CIDs were also found between crushed or intact ALO-01 and immediate-release morphine sulfate (IRMS). No CIDs were found between intact and crushed ALO-01. CONCLUSIONS: From laboratory and treatment trial data involving naltrexone, calculation of CIDs in subjective ratings of high is possible. Consequently, crushing/swallowing or injecting ALO-01 produces clinically significantly less drug high than oral or intravenous morphine alone, suggesting that ALO-01 has lower abuse liability by those routes than morphine formulations.

Presynaptic induction and expression of timing-dependent long-term depression demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist.

NMDA receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). To help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. We used this method to investigate timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.

Equivalent inter- and intramodality long-term priming: evidence for a common lexicon for words seen and words heard.

Weaker inter- than intramodality long-term priming of words has promoted two hypotheses: (1) separate visual and auditory lexicons and (2) modality dependence of implicit memory. In five experiments, we employed manipulations aimed to minimize study-test asymmetries between the two priming conditions. Activities at visual and auditory study were matched, words were phonologically consistent, and study modality was manipulated between subjects. Equal magnitudes of inter- and intramodality priming were found in experiments with visual and auditory stem completion at test, with visual fragment completion at test, and with visual and auditory perceptual identification at test. A within-subjects experiment yielded the conventional intramodality advantage. The results point to a single amodal lexicon and to modality-independent phonological processing as the basis of implicit word memory.

Vowel duration affects visual word identification: evidence that the mediating phonology is phonetically informed.

What form is the lexical phonology that gives rise to phonological effects in visual lexical decision? The authors explored the hypothesis that beyond phonological contrasts the physical phonetic details of words are included. Three experiments using lexical decision and 1 using naming compared processing times for printed words (e.g., plead and pleat) that differ, when spoken, in vowel length and overall duration. Latencies were longer for long-vowel words than for short-vowel words in lexical decision but not in naming. Further, lexical decision on long-vowel words benefited more from identity priming than lexical decision on short-vowel words, suggesting that representations of long-vowel words achieve activation thresholds more slowly. The discussion focused on phonetically informed phonologies, particularly gestural phonology and its potential for understanding reading acquisition and performance.