Синий маквин мультики

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ПОСМОТРИТЕ ВИДЕО ПО ТЕМЕ: Тачки 3 Киндер Сюрприз Новая Коллекция Машинки Дисней Kinder Surprise Cars 3

#Тачки Молния Маквин Мультик.Гран При 1 Серия #Мультик Про Машинки

Datasets and additional figures supporting this article have been uploaded as electronic supplementary material. To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures MedCM in the event of exposure to VM, VX or VM—VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice.

The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route.

There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

There was a general expectation that it would mark the beginning of a new phase for the Convention—an evolution from the initial period of focus on destruction of existing chemical weapons to a new period of focus on preventing the re-emergence of chemical weapons.

But the expectations turned out to be very premature. Concern was raised over the increasingly frequent and persuasive evidence that chemical weapons had been used in the Syrian Arab Republic by the Assad regime. The decisive event was the use of sarin in Damascus on 21 August , resulting in the deaths of some civilians [ 6 ]. The UN investigation was able to conclude, based on a range of evidence, including analysis of samples, that sarin had been used [ 7 , 8 ].

The world was suddenly faced with a new chemical weapon destruction challenge. But in one respect, this was less than in other cases: most CW possessor states had declared stocks which included filled munitions, often with explosive components, largely comprising actual CW agent.

Destroying these stocks had required the building of specialized new destruction facilities: a complex, time-consuming and expensive process. Implementing such a programme in the Syrian Arab Republic would have been almost impossible. Fortunately, the Syrian Arab Republic stockpile was unique in comprising almost entirely precursor chemicals. This feature made it feasible to remove the chemicals from the Syrian Arab Republic for destruction elsewhere.

The Syrian Arab Republic government declared approximately tonnes of chemical weapons, mostly precursors, and approximately tonnes of raw materials [ 10 ]. The blister agent sulfur mustard was the only complete or unitary chemical warfare agent declared. The nerve agents sarin, VM and VX figure 1 were stockpiled in binary form, meaning two precursors are stored and mixed just before use.

The destruction of these chemicals was a multinational responsibility. The most hazardous—sulfur mustard Around tonnes of an aqueous solution of sodium O -ethyl methylphosphonothioate 1 , the first precursor to VM and VX, were incinerated in Finland.

Approximately tonnes of the second precursors needed to make VM or VX have been incinerated by the British company Veolia [ 12 ]. The VM precursor, N , N -diethylaminoethylchloride hydrochloride 2 , was in aqueous solution and the VX precursor, N , N -diisopropylaminoethylchloride hydrochloride 3 , was stored separately in the solid state and aqueous solution.

Structures of VM, VX and precursor chemicals: mixing 1 with 2 , or 3 , in aqueous solution produces the corresponding nerve agents, which pose a toxic hazard. The separate precursors have relatively low acute toxicity compared with the nerve agents.

VX and VM are highly potent nerve agents that act primarily by inhibiting the nerve agent acetylcholinesterase; V agents are typically much less volatile than G agents, like sarin, therefore absorption through the skin represents a particularly hazardous route of exposure for V agents.

There are no reported studies on VM toxicology or responsiveness to medical countermeasures MedCM , in contrast to VX, which has been shown to be responsive to treatment following poisoning by inhalation or skin contact [ 13 , 14 ]. In response to the international effort to eliminate the Syrian Arab Republic stockpile safely, we conducted complementary in vitro and in vivo studies. Here, we present the first comparison of the percutaneous toxicity of VM and VX, and their mixtures, in a guinea pig model of nerve agent poisoning [ 15 ].

We also report the first study of the responsiveness of animals poisoned by VM to traditional nerve agent MedCM. We measured the percutaneous penetration rate of VM alone and mixed in various proportions with VX, in both guinea pig and pig skin. The collection of data from both species in vitro enables greater confidence in the extrapolation of results from the in vivo experiments to humans. These data, in combination with work conducted by other international partners on the acute toxicity of VM and its responsiveness to MedCM, will inform the hazard to humans from these nerve agents and their mixtures, and suitable medical approaches in case of accidental poisoning by them.

The synthesis of these two nerve agents figure 2 was accomplished using standard organophosphorus chemistry [ 16 ] after successful practice runs with unlabelled starting materials, by chlorination of diethyl [ 14 C]-methylphosphonate 4 to give ethyl [ 14 C]-methylphosphonochloridate 5 , followed by its reaction with lithium N , N -diethyl- or N , N -diisopropylaminoethanethiolate. The unlabelled nerve agents not shown were prepared similarly from unlabelled diethyl methylphosphonate.

Online version in colour. The resulting solution was transferred by cannula to the chloridate solution 0. The chloroform extracts were combined and dried MgSO 4. The drying agent was filtered off and the solvent evaporated under reduced pressure to give a liquid.

This was purified by bulb-to-bulb distillation under vacuum to give 14 C VM 0. Labelled and unlabelled samples of the V-agents were confirmed analytically pure by mass spectrometry techniques that are reported elsewhere [ 19 — 24 ]. Eight Large White pigs were humanely killed, the whole abdominal skin flank close clipped and excised. Skin sections were stored flat and frozen for a period not exceeding six months. Percutaneous absorption experiments were performed with Franz-type glass diffusion cells as previously described [ 26 ].

Donor chambers had an available surface area of 2. The results from the two studies were combined to allow quantification of the combined 14 C VX and 14 C VM penetration rate. Each mixture proportion was repeated using dilute agent in isopropyl alcohol, IPA for comparison with the in vivo guinea pig studies where agent was applied in a carrier solvent due to the extremely small volumes required.

For all dosing conditions, the donor chambers were left unoccluded for the duration of the study. Each sample was replaced with an equivalent volume of fresh receptor fluid. The amount of radioactivity was converted to amount of VX and VM by comparison to standard samples prepared and measured simultaneously. Maximum penetration rates J max were calculated by measuring the gradient of the line obtained by plotting the amount of agent penetrating against time under finite dose conditions.

Maximum penetration rates were expressed as the percentage of applied dose penetration rate in order to perform statistical comparisons between each mixture proportion. The lights were on from Body weight and temperature were recorded daily throughout the experiment. On each experimental day, VM, VX or a mixed solution were diluted to the appropriate concentration in IPA and applied to a clipped area of the dorsal skin at a dose volume of 0.

Guinea pigs were then returned to a laboratory and observed periodically thereafter. Clinical signs of nerve agent poisoning, e. Incapacitation was classified as normal, mild, moderate or substantial [ 27 ]. These doses were selected to align with doses we have previously used in guinea pigs [ 15 ], and the oxime doses were not equimolar to each other or to human autoinjector doses. A probit regression model was used to fit a dose—response curve to the survival data using the generalized linear model in the R statistical software package.

The LD 50 was calculated from the probit regression by rearranging the model formula in terms of dose. Approximate standard errors for fit to this dose estimate were calculated using the transformation method and confidence intervals using the delta method. At the conclusion of the study all LD 50 values were reanalysed using a bias reduced logistic regression fitting method [ 30 , 31 ]. The predicted toxicity of mixtures of VM and VX was calculated from a simple proportional combination [ 32 ] using, for VM, the estimate of the LD 50 derived from analysis of the combined data set of both VM-alone determinations 1.

The times to therapy administration were compared using a two-tailed t -test in Graphpad Prism 5 GraphPad Software Inc. In guinea pig skin, there was no significant difference between the percentage of applied dose penetration rates of 14 C VM or 14 C VX from neat or dilute agent mixtures table 1. The combined penetration of 14 C VM and 14 C VX through guinea pig skin from matched experiments is shown in figure 3.

There was no significant difference between the combined penetration rates of either neat or dilute agent mixtures through guinea pig skin. There was no statistical difference in the per cent of applied dose J max for either VX or VM ratio penetration. The combined J max value gives the penetration rate of both nerve agents present at each ratio. In pig skin, there was no significant difference between the percentage of applied dose penetration rates of 14 C VM or 14 C VX from neat or dilute agent mixtures table 2.

For the dilute study, similar amounts of radioactivity were located in the skin and receptor fluid. There was no significant difference between the combined penetration rates of either neat or dilute agent mixtures through pig skin.

Guinea pig skin was more permeable to either agent than pig skin, in agreement with previous findings [ 26 ]. The toxicity was repeated as part of the mixture series and that determination gave an estimated LD 50 of 1. Re-analysis of the first data set at the conclusion of the study gave a revised estimate of 1. This value is approximately twice that of the LD 50 of VX 0. The toxicity of three mixed solutions of VM was not significantly different from the pure agents figure 5 and was not significantly different from the theoretical predicted toxicity of the mixture.

This implies that there was no interaction between the agents, either on the skin or in the body, which changed their toxicity. None of the observed signs of poisoning and post-mortem findings suggested that VM was different from other anticholinesterase nerve agents recently characterized in this model [ 33 ]. Toxicity determination LD 50 values for VM alone and in three proportions with VX, applied via the percutaneous route in guinea pigs.

IPA was used as the carrier solvent throughout. Divided therapy, administered on the appearance of signs of poisoning and subsequently on worsening signs, prolonged the times to death compared to saline-treated controls figure 6.

Guinea pigs dosed with VM 2. Note that although these doses were equitoxic, a greater mass of agent was applied in the case of VM. Survival in guinea pigs following percutaneous challenge with VM 2. For therapy doses see text. VM is a structural variant of VX with similar physicochemical properties.

The synthesis of 14 C-labelled VM, percutaneous toxicity of VM, the toxicity of mixtures of V-agents, the protection afforded by in-service medical countermeasures against a lethal percutaneous dose of VM and the skin penetration characteristics of VM alone or of mixtures of VM and VX have not been reported previously.

Complementary in vitro and in vivo studies were completed to inform the advice that could be provided to those agencies undertaking the destruction of the precursor chemicals to these agents. This study determined the penetration rate of 14 C VM through pig and guinea pig skin in vitro for the first time.

Guinea pig skin was more permeable than pig skin to both 14 C VM and 14 C VX, either alone or in combination, dilute or neat. This finding agrees with previous results for 14 C VX penetration [ 26 ]. The penetration rate of neat 14 C VM was not significantly different from that of neat 14 C VX through either guinea pig or pig skin.

The presence of VX did not affect the penetration rate of 14 C VM in mixtures of various proportions, and vice versa.


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Синий маквин мультики

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Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX

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Michael J. Spillane, who was called [ by whom? Spillane, along with his twin brother, was born on July 13, , to John Spillane, an Irish immigrant from County Kerry. They were the youngest of seven children.

Mischa Maisky

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Mischa Maisky was born in in Riga [1] and is the younger brother of organist, harpsichordist and musicologist Valery Maisky — He was taught by Mstislav Rostropovich at the Moscow Conservatory from to In he won sixth prize at the International Tchaikovsky Competition in Moscow. He emigrated to Israel in , [3] where he holds citizenship. Maisky first performed in the United States at Carnegie Hall in Maisky has performed with his children Sascha, a violinist, and Lily Maisky , a classical pianist. Part of the public criticizes his extensive and often extreme use of vibrato and his generally loud playing.

Datasets and additional figures supporting this article have been uploaded as electronic supplementary material. To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures MedCM in the event of exposure to VM, VX or VM—VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro.

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  1. Евгеиня

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