A mechanical adapter for installing mission equipment on large space structures

A mechanical attachment adapter was designed, constructed, and tested. The adapter was was included in a simulation program that investigated techniques for assembling erectable structures under simulated zero-g conditions by pressure-suited subjects in a simulated EVA mode. The adapter was utilized as an interface attachment between a simulated equipment module and one node point of a tetrahedral structural cell. The mating performance of the adapter, a self-energized mechanism, was easily and quickly demonstrated and required little effort on the part of the test subjects

Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series

<p>Abstract</p> <p>Introduction</p> <p>The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone.</p> <p>Case presentation</p> <p>We describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations.</p> <p>Conclusions</p> <p>The marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions.</p

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis

Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. Methods This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. Results The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P &lt; 0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. Conclusion Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements

Distinct anterior cingulate neurons drive changes-of-mind and monitor past performance

When choosing between two actions, sensory evidence is accumulated toward one of the choices until a threshold is reached. Sensory neuron spike rate has been shown to track evidence accumulation. However, subjects will occasionally change their mind (switching from one action to the other), which is accompanied by a reversal in sensory neuron activity. It is unknown what neurons activate during a change-of-mind (CoM) potentially driving it. One candidate is anterior cingulate cortex (ACC), which has been shown in human EEG studies to respond around a CoM. Here, we for the first time directly report CoM in a rodent model. Head-fixed rats (N=43) were trained to discriminate stimuli by running on a treadmill past a distance threshold (Go) or remaining immobile (NoGo). On some NoGo stimulus trials, rats began running shortly after NoGo stimulus onset but made a CoM and chose to return to immobility before crossing the threshold. The time of CoM was defined by peak velocity of the treadmill, when the rat stopped running and began slowing down toward immobility. We tested the hypothesis that reversal from a higher velocity Go response to the NoGo response (immobility) would be associated with a larger ACC single unit response during the CoM. We recorded 574 ACC single units. On CoM trials, we found that stimulus-evoked responses of units tuned to the Go stimulus instead responded to the NoGo stimulus, suggesting engagement of the incorrect stimulus-response mapping in ACC. During the subsequent CoM, 20% of units scaled their activity with movement reversal size; moreover, a demixed PCA analysis showed that movement reversal size explained a large amount of variance in the population activity. Separately, 13% of units responded similarly but at the end of the trial and apparently quantified the magnitude of conflict between competing actions occurring earlier in the trial. In addition, whole-cortex 32-electrode EEG translationally linked rat and human CoM by identifying a frontal response during CoM. Our results support current theories that the ACC monitors past conflict between competing actions and significantly broaden the role for ACC by showing that ACC neurons may drive CoM

ACC single unit and neuronal population correlates of response conflict versus and error detection in a novel rodent near mistake paradigm

It is debated whether the anterior cingulate cortex (ACC) detects errors or response conflict because population (EEG) measures support both accounts. One way to disambiguate conflict and errors is to measure near mistakes which, in humans, consist of moving but stopping before a threshold (e.g., pressing a key in response to a NoGo stimulus). Near mistake movement magnitude correlates with conflict magnitude; thus, it is a tool for studying neuronal correlates of conflict, which should scale with movement magnitude. Here, we demonstrate near mistakes in head-fixed rats on a treadmill as they discriminate Go and NoGo visual orientation gratings by remaining immobile (NoGo) or running past a distance threshold (Go). Variable near mistake velocities allowed us to study encoding of conflict and errors at the single cell level. We tested the hypothesis that conflict-encoding single units would scale firing rate with conflict magnitude (i.e., near mistake running velocity), but would not respond to error feedback (noise burst)