Sensory motor systems of artificial and natural hands

The surgeon Ambroise Paré designed an anthropomorphic hand for wounded soldiers in the 16th century. Since that time, there have been advances in technology through the use of computer-aided design, modern materials, electronic controllers and sensors to realise artificial hands which have good functionality and reliability. Data from touch, object slip, finger position and temperature sensors, mounted in the fingers and on the palm, can be used in feedback loops to automatically hold objects. A study of the natural neuromuscular systems reveals a complexity which can only in part be realised today with technology. Highlights of the parallels and differences between natural and artificial hands are discussed with reference to the Southampton Hand. The anatomical structure of parts of the natural systems can be made artificially such as the antagonist muscles using tendons. Theses solutions look promising as they are based on the natural form but in practice lack the desired physical specification. However, concepts of the lower spinal loops can be mimicked in principle. Some future devices will require greater skills from the surgeon to create the interface between the natural system and an artificial device. Such developments may offer a more natural control with ease of use for the limb deficient person

Electroencephalographic and behavioral convulsant effects of hydrobromide and hydrochloride salts of bupropion in conscious rodents

A novel bromide salt of the antidepressant bupropion (bupropion HBr) has recently been developed and approved for use in the United States. Given previous use of bromides to treat seizures, and that the existing chloride salt of bupropion (HCl) can cause seizures, it is important to determine if the HBr salt may be less likely to cause seizures than the HCl salt. In the present animal studies this was evaluated by means of quantified electroencephalogram (EEG), observation, and the rotarod test in mice and rats. Both bupropion salts were tested at increasing equimolar doses administered intraperitoneally. The results in mice showed that bupropion HCl 125 mg/kg induced a significantly higher ten-fold increase in the mean number of cortical EEG seizures compared to bupropion HBr (7.50 ± 2.56 vs 0.75 ± 0.96; p = 0.045), but neither drug caused any brain injuries. In rats bupropion HBr 100 mg/kg induced single EEG seizure activity in the cortical and hippocampal (depth) electrodes and in significantly (p < 0.05) fewer rats (44%) compared to bupropion HCl, which induced 1 to 4 convulsions per rat in all rats (100%) dosed. The total duration of cortical seizures in bupropion HCl-treated rats was significantly longer than the corresponding values obtained in bupropion HBr-treated rats (424.6 seconds vs 124.5 seconds respectively, p < 0.05). Bupropion HCl consistently induced more severe convulsions at each dose level compared to bupropion HBr. Both treatments demonstrated a similar dose-dependent impairment of rotarod performance in mice. In conclusion, these findings suggest that bupropion HBr may have a significantly lower potential to induce seizures in mice and rats, particularly at higher doses, compared to bupropion HCl. Determination of this potential clinical advantage will require human studies. If confirmed by such studies, it is likely that this potential beneficial clinical benefit would be due to the presence of the bromide salt given the long history of the use of bromide to treat seizure disorders

The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ?

Since 1955, several alkyl‐carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life‐threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ‐aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl‐carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl‐carbamates have been shown to interact with voltage‐gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl‐carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl‐carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno‐bamate's mechanistic profile is unique among the alkyl‐carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate

Do Multi-Paddock Systems Increase Evenness of Grazing at the Paddock Scale?

There is ongoing debate about the benefits of multi-paddock rotationally grazed systems compared to continuous grazing (Briske et al. 2008). One of the purported benefits of high density short duration grazing is more spatially uniform defoliation. A commercial-scale trial in northern Australia (Hunt et al. 2013) compared continuously grazed paddocks to cell grazed and wet season spelled systems in newly developed paddocks. This paper reports the effect of grazing system on defoliation with distance to water through time

Tomographic image of melt storage beneath Askja Volcano, Iceland using local microseismicity

We use P wave and S wave arrivals from microseismic earthquakes to construct 3-D tomographic Vp and Vs images of the magma storage region beneath Askja's central volcano in the Northern Volcanic Zone of Iceland. A distinctive ellipsoidal low-velocity anomaly, with both Vp and Vsvelocities 8-12% below the background, is imaged at 6-11 km depth beneath the caldera. The presence of a shallow magma chamber is corroborated by geodetic and gravity studies. The small Vp/Vs anomaly suggests a lack of pervasive melt. We interpret this anomaly as a region of multiple sills, some frozen but hot, others containing partial melt. A second, smaller low-velocity anomaly beneath the main magma storage region may represent a magma migration pathway. This interpretation is supported by the close proximity to the anomaly of clusters of deep, magmatically induced earthquakes. However, the location and shape of this deep anomaly are poorly constrained by the current data set

Distinct features of seizures induced by cocaine and amphetamine analogs

Abstract Seizure-related emergencies caused by stimulants of abuse have been increasing. To better understand the nature of these drug-induced convulsions, we characterized the seizure patterns associated with high doses of cocaine, and the amphetamine analogs, metham-Ž . phetamine, methylenedioxymethamphetamine MDMA and 4-methylaminorex. The features of the stimulant-induced seizures were Ž . Ž . distinct and included the following: 1 the duration of convulsive activity was shortest for cocaine and longest for methamphetamine, 2 Ž . only MDMA produced a secondary clonic phase after the initial ictal event, and 3 4-methylaminorex manifested a very steep dose-response curve. Differential preventive profiles of anticonvulsant agents on the stimulant-induced seizures also were observed. For example, cocaine-related seizures were most effectively prevented by, while methamphetamine-induced seizures were completely refractory to, phenytoin pretreatment. The only anticonvulsants which appeared to influence methamphetamine-related convulsions were diazepam and valproate. A unique feature of 4-methylaminorex was that related seizures were almost completely blocked by the calcium channel blocker, flunarizine.

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

Objective Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD), in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizure (RISE-SRS) model of temporal lobe epilepsy (TLE). Methods We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure (MES), 6 Hz psychomotor seizure, and pentylenetetrazol (PTZ) acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective (ED50) or behavioral toxic dose (TD50) was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg, single dose) in a rat model of pilocarpine-induced status epilepticus. We defined the effect of chronic CBD administration (200mg/kg, orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE-SRS model of TLE. Results CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD’s acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time-dependent increase in seizure burden and improved TLE-associated motor comorbidities of epileptic rats in the RISE-SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task. Significance The present study illustrates that CBD is a well-tolerated and effective antiseizure agent and illustrates a potential disease-modifying effect of CBD on both reducing seizure burden and associated comorbidities well-after the onset of symptomatic seizures in a model of TLE

Long non-coding RNAs and latent HIV : a search for novel targets for latency reversal

The latent cellular reservoir of HIV is recognized as the major barrier to cure from HIV infection. Long non-coding RNAs (lncRNAs) are more tissue and cell type-specific than protein coding genes, and may represent targets of choice for HIV latency reversal. Using two in vitro primary T-cell models, we identified lncRNAs dysregulated in latency. PVT1 and RP11-347C18.3 were up-regulated in common between the two models, and RP11-539L10.2 was down-regulated. The major component of the latent HIV reservoir, memory CD4+ T-cells, had higher expression of these lncRNAs, compared to naive T-cells. Guilt-by-association analysis demonstrated that lncRNAs dysregulated in latency were associated with several cellular pathways implicated in HIV latency establishment and maintenance: proteasome, spliceosome, p53 signaling, and mammalian target of rapamycin (MTOR). PVT1, RP11-347C18.3, and RP11-539L10.2 were down-regulated by latency reversing agents, suberoylanilide hydroxamic acid and Romidepsin, suggesting that modulation of lncRNAs is a possible secondary mechanism of action of these compounds. These results will facilitate prioritization of lncRNAs for evaluation as targets for HIV latency reversal. Importantly, our study provides insights into regulatory function of lncRNA during latent HIV infection

NESC Peer-Review of the Flight Rationale for Expected Debris Report

Since the loss of Columbia on February 1, 2003, the Space Shuttle Program (SSP) has significantly improved the understanding of launch and ascent debris, implemented hardware modifications to reduce debris, and conducted tests and analyses to understand the risks associated with expected debris. The STS-114 flight rationale for expected debris relies on a combination of all three of these factors. A number of design improvements have been implemented to reduce debris at the source. The External Tank (ET) thermal protection system (TPS) foam has been redesigned and/or process improvements have been implemented in the following locations: the bipod closeout, the first ten feet of the liquid hydrogen (LH2) tank protuberance air load (PAL) ramp, and the LH2 tank-to-intertank flange closeout. In addition, the forward bipod ramp has been eliminated and heaters have been installed on the bipod fittings and the liquid oxygen (LO2) feedline forward bellows to prevent ice formation. The Solid Rocket Booster (SRB) bolt catcher has been redesigned. The Orbiter reaction control system (RCS) thruster cover "butcher paper" has been replaced with a material that sheds at a low velocity. Finally, the pad area has been cleaned to reduce debris during lift-off