Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Analysis of the convergence history of fluid flow through nozzles with shocks

Convergence of iterative methods for the solution of the steady quasi-one-dimensional nozzle problem with shocks is considered. The finite-difference algorithms obtained from implicit schemes are used to approximate both the Euler and Navier-Stokes Equations. These algorithms are investigated for stability and convergence characteristics. The numerical methods are broken down into their matrix-vector components and then analyzed by examining a subset of the eigensystem using a method based on the Arnoldi process. The eigenvalues obtained by this method are accurate to within 5 digits for the largest ones and to within 2 digits for the ones smaller in magnitude compared the elgenvalues obtained using the full Jacobian. In the analysis we examine the functional relationship between the numerical parameters and the rate of convergence of the iterative scheme. Acceleration techniques for iterative methods like Wynn\u27s e-algorithm are also applied to these systems of difference equations in order to accelerate their convergence. This acceleration translates into savings in the total number of iterations and thus the total amount of computer time required to obtain a converged solution. The rate of convergence of the accelerated system is found to agree with the prediction based on the eigenvalues of the original iteration matrix. The ultimate goal of this study is to extend this elgenvalue analysis to multi-dimensional problems and to quantitatively estimate the effects of different parameters on the rate of convergence

Irish Maritime Trade in the Eighteenth Century: a Study in Patterns of Trade, Market Structures, and Merchant Communities

Ireland has a centuries-long history of maritime and economic interaction with Great Britain and other more distant communities on the Atlantic rim. In the last forty years of academic writing on the main themes of Ireland's economic history, very few historians have examined the late-eighteenth century maritime trade data. The original Customs logs or port books are lost but other sources of information remain. This thesis uses a new source of information, Richard Eaton's A Daily and Alphabetical Arrangement of all Imports and Exports at the Port of Dublin, in the Quarter ending the 25th March, 1785, as well as the shipping reports contained in the daily newspapers of the time to create a micro-history of the maritime and mercantile interaction between Ireland and her trading partners. Eaton's "List" not only gives us a complete tally of the goods exported from, and imported into Dublin in the first three months of 1785 but the customs official also recorded the names of each merchant or firm operating in Dublin at that time. This is the first time that such detailed information has been available to scholars and it is unavailable from any other source. The focus is on Dublin in 1785 and a comparison is made with another Irish port city -- Belfast. Change over time is measured by using data for the same focal cities in 1770. Ireland's key market is England and Liverpool is the increasingly popular destination for goods leaving Dublin and the port of lading for goods arriving in Dublin. Using the databases created for the purpose, this thesis analyses the relationship between Dublin/Belfast and Liverpool and discusses the patterns of trade and market structures. Although every export/import sector had a group of leading merchants, no single merchant or small group of merchants were able to wield sufficient market power to exclude competitors. All sectors of the merchant communities of Dublin, Belfast and Liverpool -- regardless of whether they dealt in primary produce, linen products or merchants' goods -- were general merchants, with little evidence of specialisation

Paddlefish buccal flow velocity during ram suspension feeding and ram ventilation

A micro-thermistor probe was inserted into the buccal cavity of freely swimming paddlefish to measure flow velocity during ram ventilation, ram suspension feeding and prey processing. Swimming speed was measured from videotapes recorded simultaneously with the buccal flow velocity measurements. Both swimming velocity and buccal flow velocity were significantly higher during suspension feeding than during ram ventilation. As the paddlefish shifted from ventilation to feeding, buccal flow velocity increased to approximately 60 % of the swimming velocity. During prey processing, buccal flow velocity was significantly higher than the swimming velocity, indicating that prey processing involves the generation of suction. The Reynolds number (Re) for flow at the level of the paddlefish gill rakers during feeding is about 30, an order of magnitude lower than the Re calculated previously for pump suspension-feeding blackfish. These data, combined with data available from the literature, indicate that the gill rakers of ram suspension-feeding teleost fishes may operate at a substantially lower Re than the rakers of pump suspension feeders

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS

Calculation of unsteady flows in curved pipes

Highly unsteady three-dimensional flows in curved pipe

Nanotools for Neuroscience and Brain Activity Mapping

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function

Dynamic changes in accumbens dopamine correlate with learning during intracranial self-stimulation

Dopamine in the nucleus accumbens (NAc) is an important neurotransmitter for reward-seeking behaviors such as intracranial self-stimulation (ICSS), although its precise role remains unclear. Here, dynamic fluctuations in extracellular dopamine were measured during ICSS in the rat NAc shell with fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Rats were trained to press a lever to deliver electrical stimulation to the substantia nigra (SNc)/ventral tegmental area (VTA) after the random onset of a cue that predicted reward availability. Latency to respond after cue onset significantly declined across trials, indicative of learning. Dopamine release was evoked by the stimulation but also developed across trials in a time-locked fashion to the cue. Once established, the cue-evoked dopamine transients continued to grow in amplitude, although they were variable from trial to trial. The emergence of cue-evoked dopamine correlated with a decline in electrically evoked dopamine release. Extinction of ICSS resulted in a significant decline in goal-directed behavior coupled to a significant decrease in cue-evoked phasic dopamine across trials. Subsequent reinstatement of ICSS was correlated with a return to preextinction transient amplitudes in response to the cue and reestablishment of ICSS behavior. The results show the dynamic nature of chemical signaling in the NAc during ICSS and provide new insight into the role of NAc dopamine in reward-related behaviors

Neural encoding of cocaine-seeking behavior is coincident with phasic dopamine release in the accumbens core and shell

Mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are part of a complex circuit mediating cocaine-directed behaviors. However, the precise role of rapid (subsecond) dopamine release within the primary sub-regions of the NAc, the core and shell, and its relationship to NAc cell firing during this behavior remain unknown. Here, using fast-scan cyclic voltammetry (FSCV) we report rapid dopamine signaling in both the core and shell, however, significant differences were observed in the timing of dopamine release events within seconds of the cocaine reinforced response during self-administration sessions. Importantly, simultaneous voltammetric and electrophysiological recordings from the same electrode reveal that, at certain sites within both sub-regions, neurons exhibiting patterned activation were observed at locations where rapid dopamine release was present; the greater the strength of the neural signal the larger the dopamine release event. In addition, it was at those locations that electrically-evoked stimulated release was greatest. No changes in dopamine were observed where nonphasic neurons were recorded. Thus, although differences are evident in dopamine release dynamics relative to cocaine-reinforced responding within the core and shell, dopamine release is heterogeneous within each structure and varies as a function of precise neuronal targets during cocaine-seeking behavior

Feeding Induced by Cannabinoids Is Mediated Independently of the Melanocortin System

Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance