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Int. J. Mol. Sci. 2014, 15(6), 9809-9825; doi:10.3390/ijms15069809
Published: 2 June 2014
Abstract: Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.
1. Introduction
Inhibitors of AChE (EC 188.8.131.52.) and BChE (EC 220.127.116.11) are neurotoxic compounds capable of causing central, peripheral or both central and peripheral cholinergic crises. A number of these compounds have also found application as drugs developed for the treatment of Alzheimer's disease (AD) and myasthenia gravis [1,2]. These are based on the premise that increasing the availability of acetylcholine (ACh) at acetylcholine receptors in the brain, results in better neuron to neuron transport that will improve cognitive function. Cholinergic nerves, however, can be found in both the central (CNS) and peripheral (PNS) nervous systems and disparate body tissues [3]. Drugs that cross the blood brain barrier do not have dissociable groups as can be seen in the case of AD drugs [4]. Some of these drugs cannot penetrate the CNS and this property makes them suitable for use in myasthenia gravis [5]. For a long time, regulation of immunity was not considered an effect of AChE inhibitors. However, recent evidence casts new light on the subject. In this review, we explore the link between immunity and the AChE inhibitors as currently available AChE inhibiting drugs for AD.
2. The Cholinergic Anti-Inflammatory Pathway
Ach is a ubiquitous neurotransmitter [6,7] and found even in the roundworm Caenorhabditis elegans, one of the simplest organisms with a nervous system [8,9]. In the roundworm one third of the nervous system is cholinergic [10]. Humans have a large percentage of nervous system that is cholinergic including the CNS. Cholinergic nerves also form a major part of the parasympathetic and sympathetic nervous systems [11,12]. The wider significance of Ach is in understanding the biological effects of tested toxins and/or medical drugs: as any immunological effects of AChE inhibitors can involve both CNS and PNS, this has to be taken into consideration in interpreting any findings. For this reason, vagotomy, used to study the cholinergic anti-inflammatory pathway in animal experiments or selecting compounds that do not cross the blood brain barrier should be considered carefully before drawing any conclusions as to which pathway is involved in the proposed mechanism.
The cholinergic system is tightly associated with the cholinergic anti-inflammatory pathway dominantly located in blood and mucosa. This pathway is a regulatory link between nerve terminations in blood and macrophages expressing the α7 nicotinic acetylcholine receptor (α7 nAChR) on their surface [11,13,14]. For a long time, the mechanisms of inflammatory regulation remained unclear. Discovery of the cholinergic anti-inflammatory pathway, however, allowed us to understand how the CNS is involved in the regulation of innate immunity [15,16,17,18,19,20,21,22,23,24]. AChE bound on erythrocytes plays an important role in termination of cholinergic anti-inflammatory pathway activation [11,25]. AChE activity is typically low in AD patients treated with AChE inhibitors [26]. Compared to AChE, BChE is constituted in the liver and secreted into the plasma where the enzyme is dissolved [27]. Apart from the fact that the conversion rate of Ach by BChE is lower than the conversion by AChE, BChE can substitute for AChE and split the neurotransmitter once they make contact [28,29]. The effect of BChE became relevant once the cholinergic anti-inflammatory pathway was studied as BChE plays a greater role in the blood than in the nervous system.
The cholinergic anti-inflammatory pathway is one-way: the CNS can attenuate inflammation mediated by macrophages or any other immune cells having α7 nAChR. Ach released from the vagus nerve termination, agonizes α7 nAChR, which responds by opening a central channel allowing an influx of Ca2+ into macrophages [11,30,31]. Increased levels of Ca2+ activate the nuclear factor κ B (NF κB) resulting in suppression of inflammatory cytokine production including tumor necrosis factor α (TNFα), high mobility group box of proteins and interleukin 6 (IL-6) [32,33]. These blood AChE and plasma BChE are able to terminate the stimulation of the cholinergic anti-inflammatory pathway due to splitting ACh. The principle of the pathway is depicted in Figure 1.
The primary purpose of using AChE inhibitors in pharmacology is not modulation of immunity related pathologies. However, recent studies indicate that these inhibitors can cause a significant modulation of immunity as a side effect [29,34,35]. As seen from Figure 1, they can modulate the cholinergic anti-inflammatory pathway via protection of Ach from splitting by cholinesterases and thus enhancing the pathway. The mechanism of action is probably less effective than the standard mode but it becomes relevant when someone is using an inhibitor of cholinesterases in large amounts and/or for a long time such as patients suffering from AD.
Apart from the regulation processes, some inhibitors can influence immunity via forming antigens by reaction with e.g., plasma proteins. The immune system is thus activated and the stimulation counteracts the anti-inflammatory action. This effect is, however, very weak but it can play a role in forming antibody proteins modified by nerve agents [36].
3. Division of Inhibitors
The structure of AChE and BChE has been extensively reviewed in the following publications [7,29,37,38]. In brief, AChE has a more developed peripheral anionic site and narrower aromatic gorge than BChE. Aromatic compounds have higher affinity for AChE than BChE. Some aromatic inhibitors of AChE do not inhibit BChE, for example aflatoxins [39,40]. When the role of the cholinesterases is evaluated in humans, their genomic diversity and posttranslational modifications have to be taken into account [41,42].
Organophosphorus compounds are irreversible inhibitors of both AChE and BChE. They bind to the active site of the cholinesterases and easily cross the blood brain barrier [6,43]. Nerve agents, e.g., sarin, soman, tabun, and some highly toxic compounds, formerly used as pesticides (paraoxon, parathion, malaoxon, malathion), are examples [44,45,46,47]. High toxicity characterizes organophosphorus inhibitors that are used in chemical warfare or as pesticides. Their pharmacological importance is relatively small; Metrifonate (trichlorfon) was chosen for AD treatment and became an exception but it was withdrawn because of adverse effects [48,49,50]. Though organophosphorus compounds typically inhibit both AChE and BChE, tetraisopropyl pyrophosphoramide, also known as iso-OMPA, is dissimilar to the other inhibitors. It does not penetrate to the active site of AChE and it inhibits BChE only. It is typically used as a reagent for rapid distinction between AChE and BChE activity in biological samples [51,52].
Carbamate inhibitors bind to the active site of both cholinesterases like organophosphorus inhibitors; however, the covalent bound is not stable and the carbamate moiety is hydrolytically split from the active site after some time [29,53,54]. The mechanism of carbamate binding is sometimes called pseudo-irreversible because of carbamate moiety spontaneous hydrolysis and resurrection of cholinesterase activity. From a pharmacological point of view, there is a big difference between carbamates and organophosphorus inhibitors. Many carbamates do not cross the blood brain barrier and the carbamate moiety has to be modified or encapsulated to cross it [55,56,57]. Quarternary ammonium containing pyridostigmine and neostigmine are examples. On the other hand, the blood brain barrier is not impenetrable by all carbamates e.g., rivastigmine (see further text) and physostigmine easily reach AChE in the brain [58,59,60].
AChE and BChE can be inhibited by a group of secondary metabolites from plants and fungi. Galantamine and huperzine are examples of plant alkaloids used in pharmacology. Alkaloids α-chaconine, α-solanine, tomatine, berberine, palmatine and jatrorrhizine are other metabolites that inhibit cholinesterases [29,61,62,63,64,65]. Aflatoxins too, can be introduced as secondary metabolites from fungi.
Disparate synthetic drugs not belonging to carbamates and organophosphates can be mentioned last but not least. Donepezil is the most relevant compound of this group. (See the next chapter). Tacrine (1,2,3,4-tetrahydroacridin-9-amine) is another synthetic drug which easily crosses the blood brain barrier and is used as a highly effective drug for ameliorating Alzheimer disease manifestation by inhibition AChE and by lower but still effective inhibition of BChE [53,66,67]. It was withdrawn from clinical use because of adverse effects. Hepatotoxicity was the main pathological consequence of tacrine intake [68,69]. The basic facts about groups of inhibitors are summarized in Table 1.
In considering the role of the inhibitors in modulating immunity, other factors such as the environment and genetic disposition should be taken into account. This conclusion is based on blood cholinesterase activity in male volunteers working with pesticides [70]. The activity varied in infected patients with proven bacterial meningitis [71]. The sensitivity of humans to the inhibitors can also significantly be affected because detoxification mechanisms have unequal efficacy. This idea was, e.g., demonstrated by Sonali et al.on AD patients treated with rivastigmine [72]. Variability in inhibitor effects should be considered when conclusions are drawn from animal models and cell lines, extrapolated to humans.
|Table 1. Summarization of facts about cholinesterases' inhibitors.
|Group of Compounds
|Compounds (Examples)
|Mechanism of Inhibition
|Inhibition of AChE and BChE
|Penetration through Blood Brain Barrier
|Importance as Drugs
|sarin, soman, tabun, malaoxon
|equal to AChE and BChE
|pyridostigmine, physostigmine neostigmine, rivastigmine
|equal to AChE and BChE
|low (pyridostigmine, neostigmine), good (physostigmine, rivastigmine)
|AChE > BChE
|former drug, discontinued now
|huperzine A
|AChE >> BChE
|will increase
4. Inhibitors that Cross the Blood Brain Barrier
The following text focuses on galantamine, donepezil, huperzine and rivastigmine. Galantamine (Figure 2) is a drug used for treating AD and related dementias. Currently, galantamine is an alternative to rivastigmine and can be given to patients with similar stages of dementia. On the market, it is sold under the trade names Razadyne™, Razadyne™ER, Reminyl™ER, and Reminyl® The drug was firstly isolated by soviet scientists Mashkovsky and Kruglikova-Lvova from bulbs of Caucasian snowdrops Galanthus sp. in the early 1950s and chemical synthesis was introduced in the following decades [80]. After marketing of the drug, it drove out the more toxic tacrine [81] and has become one of the best drugs for Alzheimer disease treatment [73].
Galantamine is a competitive inhibitor of AChE and an allosteric modulator of nAChR [74]. Its dual action on both AChE and nAChR is an advantage and unlike other marketed drugs that inhibit AChE. It is believed that galantamine may interact with the cholinergic anti-inflammatory pathway via direct modulation of the α7 nAChR [82]. The anti-inflammatory pathway modulation may explain the activation of microglia followed by amyloid beta clearance [83]. In a rat model, galantamine was also approved as effective in reducing circulating TNFα which was, in the past, initiated by administration of bacterial lipopolysaccharide [84]. For this reason, galantamine could act not only as a drug for symptomatic treatment but as a compound for slowing Alzheimer disease progression. This conclusion is not, however, commonly accepted and more detailed evidence of the process is needed.
Donepezil is a selective, noncompetitive inhibitor of AChE. The inhibition is quite effective as the equilibrium constant is reported to be 12.5 nmol/L for AChE from rat erythrocytes [75]. Donepezil is available under the trade name Aricept as a highly effective drug for Alzheimer disease, originally developed by Eisai and Pfizer. The structure of donepezil is depicted in Figure 3. Clinical experience with donepezil is good: it is well tolerated and slowly eliminated so that the drug can be taken over long periods [76]. Compared to other drugs for Alzheimer disease, donepezil works via a simple pathway based on AChE inhibition. It is not involved in other pathways and does not involve BChE inhibition [29].
We can assume that donepezil activates the cholinergic anti-inflammatory pathway via inhibition of AChE and increased availability of ACh. However, Hwang and coworkers found anti-inflammatory effects on microglia cell lines where no AChE was present [85]. These authors showed significant attenuation of TNFα, IL-1, and NF-κB release. From these results, we can infer that donepezil is either able to directly stimulate α7 nAChR and not act as an inhibitor only or it has some other unknown pathway. Beside the anti-inflammatory pathway, donepezil was proven to be able to modulate viral progression and the modulation is probably based on a mechanism other than agonism of α7 nAChR [86,87]. This fact would support the results on the microglia cells. Unfortunately, the antiviral effect of donepezil was not studied further, though the issue deserves greater attention.
Huperzine is a secondary metabolite from the lycopods, Huperzia from which it is isolated for pharmacological purposes. The upper production of huperzine alkaloids can be found in H. serata. More types of huperzine are known. However, huperzine A (Figure 2) is the most likely to be used in Alzeheimer disease [75]. Elaborative isolation of huperzine from plant biomass is the main disadvantage of huperzine as chemical synthesis is problematic due to expensive isolation of the (−) huperzine A from the (+) isomer which is not pharmacologically relevant [88]. Though advanced chemical synthesis protocols [89] and biotechnology processes [90] for the (−) huperzine A production are described, they are far from practical use. Huperzine is used in traditional Chinese medicine and it is available as a supplement in the country. It can be taken as a mechanically milled plant tissue or as an extract prepared by chromatographic isolation [77]. In countries of the European Union and United States, pro-drug ZT-1 derived from huperzine A is clinically tested and introduction for therapy purposes is expected in the near future [91].
Huperzine A is a selective inhibitor of AChE, acting by a non-competitive or mixed mechanism [75]. Huperzine A can bind to the peripheral anionic site of AChE and the effect is reportedly responsible for amelioration of the amyloidogenic process [92]. Besides AChE inhibition, huperzine A is a potent non-competitive inhibitor of the N-methyl-d-aspartate receptor [78,79].
Huperzine A was proven to reduce neuroinflammation in experimental autoimmune encephalomyelitis in mice [93]. The authors reported a decrease in the number of inflammatory cells, interferon gamma (IFNγ), IL-17, MCP-1, RANTES, TWEAK and an increase in IL-4 and IL-10 in the course of treatment. In another experiment, huperzine inhibited activation of NF-κB, inducible nitric oxide synthase and cyclooxygenase 2 in C6 rat glioma cells [94]. Though direct molecular evidence is missing, agonism of α7 nAChR with subsequent activation of the cholinergic anti-inflammatory pathway is presumed to be involved in huperzine's mechanism of action [95].
Rivastigmine (Figure 3) is a carbamate inhibitor of AChE as well as BChE and it easily crosses the blood brain barrier. Rivastigmine is probably the most marketed carbamate in pharmacology. The drug is sold under the trade name Exelon for the treatment of Alzheimer and Parkinson disease in early and mild stages. Currently, it is the only available drug for these diseases, which is not a reversible inhibitor of AChE since it inhibits the cholinesterases in a pseudo-irreversible manner [96]. Slow elimination of rivastigmine because of the covalent bond in the active site of the enzyme is an advantage over other drugs. The effect of rivastigmine can last until the rivastigmine moiety spontaneously splits from the cholinesterase's active site by a decarbonylation process [4,54].
The long-term effects of rivastigmine remain unclear. It was proven that rivastigmine causes significant up-regulation of AChE expression [97]. The molecular mechanism is, however, unrevealed. In clinical tests, rivastigmine was not found to generate inflammation or have any other adverse effect. For this reason, rivastigmine is considered as a quite safe drug [98]. On the contrary, more detailed examination showed that rivastigmine can suppress inflammation [99]. Namely, decreased reactivity of encephalitogenic T lymphocytes and production of pro-inflammatory cytokines was reported [100]. More experiments on this issue will be necessary as the exact mechanism is not clear. It can be assumed that the cholinergic anti-inflammatory pathway can be activated as Ach becomes available for the α7 nAChR on macrophages and microglial cells. Direct proof is, however, missing.
Like rivastigmine, physostigmine (or eserine in some sources) crosses the blood brain barrier and can inhibit AChE and BChE in the both central and peripheral nervous systems. Physostigmine is a carbamate of natural origin that can be found in the seeds from a plant Physostigma venosum known as the Calabar bean. At the current time, cheap and reliable protocols for physostigmine synthesis are available and preferred over isolation from plants [101]. Physostigmine can be used for alleviation of glaucoma manifestation [102] and it is suitable for the treatment of Alzheimer disease [103,104]. As discussed later in the text, physostigmine can inhibit protein kinase C. This ability is not common to other carbamate inhibitors of cholinesterases [105]. Physostigmine was shown to increase the availability of ACh and stimulate the cholinergic anti-inflammatory pathway in experimental endotoxemia by lipopolysaccharide [106]. In another experiment, physostigmine regulated early inflammation and oxidative stress as the superoxide radical in rats with induced forebrain ischemia [107].
5. Peripherally Acting Carbamates-Parasympathomimetics
Most carbamates have limited ability to pass the blood brain barrier. Rivastigmine is an exception from this point of view. The poor ability to cross the blood brain barrier can be an advantage when we need a compound to regulate the PNS and not the CNS. Drugs that do this are used for two main purposes: in the treatment of myasthenia gravis [108] and in anesthesia [109]. Myasthenia gravis is an autoimmune disease where antibodies against acetylcholine receptors are created in the body. The treatment the disease can be based on administration of immunosuppressant and/or an AChE inhibitor [110]. In surgical interventions, there is a necessity to give muscle relaxants such as parasympathomimetics. The parasympathomimetics can act as polarizing agents via direct stimulation of receptors (e.g., succinylcholine) or as non-polarizing agents where the peripherally acting carbamates belong [111,112]. Pyridostigmine and neostigmine are well known examples of carbamates acting as parasympathomimetics [113]. Beside the carbamates, a quaternary nitrogen containing inhibitor edrophonium is also used as a parasympathomimetic [114]. The chemical structures of neostigmine and pyridostigmine are shown in Figure 4. Though the blood brain barrier seems to be impenetrable for compounds like pyridostigmine and neostigmine, the contrary is true. For example, Friedman et al. showed that stress conditions can cause penetrability of blood brain barrier by pyridostigmine [115]. This factor has to be considered in critical evaluation of peripherally acting carbamates. Strong stressogenic conditions can cause peripherally acting carbamates to have the same effect as a centrally acting one.
The peripherally acting carbamates have similar action to rivastigmine. They are pseudo-irreversible inhibitors of both AChE and BChE [29]. Selective effect on the PNS is the main difference between the carbamates such as neostigmine and pyridostigmine and the centrally acting rivastigmine. The inability to cross blood brain barrier discriminates the peripherally acting carbamates from being used for regulation of neuroinflammation and other immunity related disorders within the CNS. On the other hand, they can be expected to be favored in the generalized immunity disorder regulation whenever brain functions should be spared.
Plausible anti-inflammatory effects of the peripherally acting carbamates have been described in some papers. In an example, physostigmine (crossing blood brain barrier) and neostigmine (not crossing) reduced inflammation which was previously initiated by a bacterial lipopolysaccharide [116,117]. Similar results were reported in an experiment where mice were infected with tularemia and treated with neostigmine [118]. In this experiment, neostigmine worsened the tularemia pathology. Sun et al.tested neostigmine effects in mice and Beagle dogs [119]. They showed that neostigmine acts via the cholinergic anti-inflammatory pathway. This conclusion is supported by the fact that mice with knockout gene for α7 nAChR are not sensitive to the immunomodulatory effect. On the other hand, more experiments on the issue will be needed as some did not confirm any significant anti-inflammatory effect of carbamates [120]. Regulation of immunity can be based on pathways far from the cholinergic system. e.g., Bitzinger et al. revealed the ability of physostigmine to inhibit protein kinase C while neostigmine did not have this ability [105].
6. Conclusions
Currently available drugs for inhibiting either AChE alone or in combination with BChE are available for the treatment of AD, myasthenia gravis and other conditions. These drugs however, are not used for immunomodulation purposes at this time. This review highlights the fact that these inhibitors may affect not only the cholinergic anti-inflammatory pathway but also other unknown pathways involved in regulating immunity. A simplified mechanism for how these inhibitors may be involved in regulating immunity is depicted schematically in Figure 5. This issue deserves greater attention due to its pharmacological relevance.
The Ministry of Education, Youth and Sports of the Czech Republic is gratefully acknowledged for project LH11023. A long-term organization development plan 1011 (Faculty of Military Health Sciences, University of Defence, Czech Republic) is acknowledged as well.
Conflicts of Interest
The author declares no conflict of interest.
- Ofek, K.; Soreq, H. Cholinergic involvement and manipulation approaches in multiple system disorders. Chem. Biol. Interact. 2013, 203, 113–119, doi:10.1016/j.cbi.2012.07.007.
- De los Rios, C. Cholinesterase inhibitors: A patent review (2007–2011). Expert Opin. Ther. Pat. 2012, 22, 853–869, doi:10.1517/13543776.2012.701619.
- Silman, I.; Sussman, J.L. Acetylcholinesterase: "Classical" and "non-classical" functions and pharmacology. Curr. Opin. Pharmacol. 2005, 5, 293–302, doi:10.1016/j.coph.2005.01.014.
- Tayeb, H.O.; Yang, H.D.; Price, B.H.; Tarazi, F.I. Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors. Pharmacol. Ther. 2012, 134, 8–25, doi:10.1016/j.pharmthera.2011.12.002. 22198801
- Haines, S.R.; Thurtell, M.J. Treatment of ocular myasthenia gravis. Curr. Treat. Option Neurol. 2012, 14, 103–112, doi:10.1007/s11940-011-0151-8.
- Marrs, T.C.; Maynard, R.L. Neurotranmission systems as targets for toxicants: A review. Cell Biol. Toxicol. 2013, 29, 381–396, doi:10.1007/s10565-013-9259-9.
- Colovic, M.B.; Krstic, D.Z.; Lazarevic-Pasti, T.D.; Bondzic, A.M.; Vasic, V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol. 2013, 11, 315–335, doi:10.2174/1570159X11311030006.
- Rakowski, F.; Srinivasan, J.; Sternberg, P.W.; Karbowski, J. Synaptic polarity of the interneuron circuit controlling c. Elegans locomotion. Front. Comput. Neurosci. 2013, 7, 128. 24106473
- Kosinski, R.A.; Zaremba, M. Dynamics of the model of the caenorhabditis elegans neural network. Acta Phys. Pol. B 2007, 38, 2201–2210.
- Rand, J.B. Acetylcholine. WormBook 2007, doi:10.1895/wormbook1.131.1.
- Pohanka, M. Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology. Int. J. Mol. Sci. 2012, 13, 2219–2238, doi:10.3390/ijms13022219. 22408449
- Bellier, J.P.; Kimura, H. Peripheral type of choline acetyltransferase: Biological and evolutionary implications for novel mechanisms in cholinergic system. J. Chem. Neuroanat. 2011, 42, 225–235, doi:10.1016/j.jchemneu.2011.02.005.
- Wessler, I.; Kirkpatrick, C.J. Acetylcholine beyond neurons: The non-neuronal cholinergic system in humans. Br. J. Pharmacol. 2008, 154, 1558–1571, doi:10.1038/bjp.2008.185.
- Rosas-Ballina, M.; Tracey, K.J. Cholinergic control of inflammation. J. Intern. Med. 2009, 265, 663–679, doi:10.1111/j.1365-2796.2009.02098.x. 19493060
- Bernik, T.R.; Friedman, S.G.; Ochani, M.; DiRaimo, R.; Ulloa, L.; Yang, H.; Sudan, S.; Czura, C.J.; Ivanova, S.M.; Tracey, K.J. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 2002, 195, 781–788, doi:10.1084/jem.20011714.
- Borovikova, L.V.; Ivanova, S.; Zhang, M.H.; Yang, H.; Botchkina, G.I.; Watkins, L.R.; Wang, H.C.; Abumrad, N.; Eaton, J.W.; Tracey, K.J. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000, 405, 458–462, doi:10.1038/35013070.
- Ofek, K.; Krabbe, K.S.; Evron, T.; Debecco, M.; Nielsen, A.R.; Brunnsgaad, H.; Yirmiya, R.; Soreq, H.; Pedersen, B.K. Cholinergic status modulations in human volunteers under acute inflammation. J. Mol. Med. 2007, 85, 1239–1251, doi:10.1007/s00109-007-0226-x. 17657467
- Andersson, U.; Tracey, K.J. Neural reflexes in inflammation and immunity. J. Exp. Med. 2012, 209, 1057–1068, doi:10.1084/jem.20120571.
- Pavlov, V.A.; Ochani, M.; Gallowitsch-Puerta, M.; Ochani, K.; Huston, J.M.; Czura, C.J.; Al-Abed, Y.; Tracey, K.J. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. USA 2006, 103, 5219–5223, doi:10.1073/pnas.0600506103.
- Pavlov, V.A.; Parrish, W.R.; Rosas-Ballina, M.; Ochani, M.; Puerta, M.; Qchani, K.; Chavan, S.; Al-Abed, Y.; Tracey, K.J. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav. Immun. 2009, 23, 41–45, doi:10.1016/j.bbi.2008.06.011.
- Tracey, K.J. The inflammatory reflex. Nature 2002, 420, 853–859, doi:10.1038/nature01321.
- Tracey, K.J. Reflex control of immunity. Nat. Rev. Immunol. 2009, 9, 418–428, doi:10.1038/nri2566.
- Wang, H.; Yu, M.; Ochani, M.; Amella, C.A.; Tanovic, M.; Susarla, S.; Li, J.H.; Wang, H.C.; Yang, H.; Ulloa, L.; et al. Nicotinic acetylcholine receptor alpha 7 subunit is an essential regulator of inflammation. Nature 2003, 421, 384–388, doi:10.1038/nature01339.
- Wang, H.; Liao, H.; Ochani, M.; Justiniani, M.; Lin, X.C.; Yang, L.H.; Al-Abed, Y.; Wang, H.C.; Metz, C.; Miller, E.J.; et al. Cholinergic agonists inhibit hmgb1 release and improve survival in experimental sepsis. Nat. Med. 2004, 10, 1216–1221, doi:10.1038/nm1124.
- Silva-Herdade, A.S.; Saldanha, C. Effects of acetylcholine on an animal mode of inflammation. Clin. Hemorheol. Microcirc. 2013, 53, 209–216. 23187452
- Coin, A.; Perissinotto, E.; Catanzaro, S.; Mosele, M.; de Rui, M.; Girardi, A.; Inelmen, E.M.; Toffanello, E.D.; Manzato, E.; Sergi, G. Effects of 21 months of cholinesterase inhibitors on cognitive and functional decline in demented patients. Aging Clin. Exp. Res. 2012, 24, 14–16. 23160499
- Iwasaki, T.; Yoneda, M.; Nakajima, A.; Terauchi, Y. Serum butyrylcholinesterase is strongly associated with adiposity, the serum lipid profile and insulin resistance. Intern. Med. 2007, 46, 1633–1639, doi:10.2169/internalmedicine.46.0049.
- Karlsson, D.; Fallarero, A.; Brunhofer, G.; Mayer, C.; Prakash, O.; Mohan, C.G.; Vuorela, P.; Erker, T. The exploration of thienothiazines as selective butyrylcholinesterase inhibitors. Eur. J. Pharm. Sci. 2012, 47, 190–205, doi:10.1016/j.ejps.2012.05.014.
- Pohanka, M. Cholinesterases, a target of pharmacology and toxicology. Biomed. Pap. 2011, 155, 219–229, doi:10.5507/bp.2011.036.
- Noelker, C.; Stuckenholz, V.; Reese, J.P.; Alvarez-Fischer, D.; Sankowski, R.; Rausch, T.; Oertel, W.H.; Hartmann, A.; van Patten, S.; Al-Abed, Y.; et al. Cni-1493 attenuates neuroinflammation and dopaminergic neurodegeneration in the acute mptp mouse model of Parkinson's disease. Neurodegener. Dis. 2013, 12, 103–110, doi:10.1159/000342714.
- Lee, L.; Kosuri, P.; Arancio, O. Picomolar amyloid-beta peptides enhance spontaneous astrocyte calcium transients. J. Alzheimers Dis. 2014, 38, 49–62. 23948929
- Sun, P.; Zhou, K.W.; Wang, S.; Li, P.; Chen, S.J.; Lin, G.P.; Zhao, Y.; Wang, T.H. Involvement of mapk/NF-κB signaling in the activation of the cholinergic anti-inflammatory pathway in experimental colitis by chronic vagus nerve stimulation. PLoS One 2013, 8, e69424, doi:10.1371/journal.pone.0069424. 23936328
- De Haan, J.J.; Hadfoune, M.; Lubbers, T.; Hodin, C.; Lenaerts, K.; Ito, A.; Verbaeys, I.; Skynner, M.J.; Cailotto, C.; van der Vliet, J.; et al. Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. Am. J. Physiol.-Gastroint. Liver Physiol. 2013, 305, G383–G391, doi:10.1152/ajpgi.00333.2012.
- Starec, M.; Sinet, M.; Kodym, P.; Rosina, J.; Fiserova, A.; Desforges, B.; Rouveix, B. The effect of drugs on the mortality of mice inoculated with friend leukaemia virus or toxoplasma gondii. Physiol. Res. 1997, 46, 107–111. 9727501
- Pohanka, M. Role of oxidative stress in infectious diseases. A review. Folia Microbiol. 2013, 58, 503–513, doi:10.1007/s12223-013-0239-5.
- Smirnov, I.; Belogurov, A.; Friboulet, A.; Masson, P.; Gabibov, A.; Renard, P.Y. Strategies for the selection of catalytic antibodies against organophosphorus nerve agents. Chem.-Biol. Interact. 2013, 203, 196–201, doi:10.1016/j.cbi.2012.10.011.
- Da Silva, V.B.; de Andrade, P.; Kawano, D.F.; Morais, P.A.B.; de Almeida, J.R.; Carvalho, I.; Taft, C.A.; da Silva, C. In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity. Future Med. Chem. 2011, 3, 947–960, doi:10.4155/fmc.11.67.
- Krall, W.J.; Sramek, J.J.; Cutler, N.R. Cholinesterase inhibitors: A therapeutic strategy for alzheimer disease. Ann. Pharmacother. 1999, 33, 441–450, doi:10.1345/aph.18211.
- Arduini, F.; Errico, I.; Amine, A.; Micheli, L.; Palleschi, G.; Moscone, D. Enzymatic spectrophotometric method for aflatoxin b detection based on acetylcholinesterase inhibition. Anal. Chem. 2007, 79, 3409–3415, doi:10.1021/ac061819j.
- Arduini, F.; Amine, A.; Moscone, D.; Palleschi, G. Biosensors based on cholinesterase inhibition for insecticides, nerve agents and aflatoxin b-1 detection (review). Microchim. Acta 2010, 170, 193–214, doi:10.1007/s00604-010-0317-1.
- Brazzolotto, X.; Wandhammer, M.; Ronco, C.; Trovaslet, M.; Jean, L.; Lockridge, O.; Renard, P.Y.; Nachon, F. Human butyrylcholinesterase produced in insect cells: Huprine-based affinity purification and crystal structure. FEBS J. 2012, 279, 2905–2916, doi:10.1111/j.1742-4658.2012.08672.x.
- Massoulie, J. The origin of the molecular diversity and functional floating of cholinesterases. Neurosignals 2002, 11, 130–143, doi:10.1159/000065054.
- Marrs, T.C. Organophosphate poisoning. Pharmacol. Ther. 1993, 58, 51–66, doi:10.1016/0163-7258(93)90066-M.
- Furtado, M.D.; Rossetti, F.; Chanda, S.; Yourick, D. Exposure to nerve agents: From status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy. Neurotoxicology 2012, 33, 1476–1490, doi:10.1016/j.neuro.2012.09.001.
- Dorandeu, F.; Foquin, A.; Briot, R.; Delacour, C.; Denis, J.; Alonso, A.; Froment, M.T.; Renault, F.; Lallement, G.; Masson, P. An unexpected plasma cholinesterase activity rebound after challenge with a high dose of the nerve agent vx. Toxicology 2008, 248, 151–157, doi:10.1016/j.tox.2008.03.013.
- Raghu, P.; Madhusudana Reddy, T.; Reddaiah, K.; Swamy, B.E.; Sreedhar, M. Acetylcholinesterase based biosensor for monitoring of malathion and acephate in food samples: A voltammetric study. Food Chem. 2014, 142, 188–196, doi:10.1016/j.foodchem.2013.07.047.
- Ahmed, M.; Rocha, J.B.; Mazzanti, C.M.; Morsch, A.L.; Cargnelutti, D.; Correa, M.; Loro, V.; Morsch, V.M.; Schetinger, M.R. Malathion, carbofuran and paraquat inhibit bungarus sindanus (krait) venom acetylcholinesterase and human serum butyrylcholinesterase in vitro. Ecotoxicology 2007, 16, 363–369, doi:10.1007/s10646-007-0137-1.
- Tian, Y.; Zhou, S.F.; Gao, Y.; Zhou, Y.J.; Shi, R.; Heiger-Bernays, W.; Ding, Y.; Wang, P.; Han, S.; Shen, X.M. Effects of repeated maternal oral exposure to low levels of trichlorfon on development and cytogenetic toxicity in 3-day mouse embryos. Food Chem. Toxicol. 2011, 49, 2655–2659, doi:10.1016/j.fct.2011.07.011.
- Becker, R.E.; Unni, L.K.; Greig, N.H. Resurrecting clinical pharmacology as a context for alzheimer disease drug development. Curr. Alzheimer Res. 2009, 6, 79–81, doi:10.2174/156720509787313916.
- López-Arrieta, J.M.; Schneider, L. Metrifonate for Alzheimer's disease. Cochrane Database Syst. Rev. 2006, CD003155.
- Yang, Y.X.; Niu, L.Z.; Li, S.N. Purification and studies on characteristics of cholinesterases from daphnia magna. J. Zhejiang Univ.-Sci. B 2013, 14, 325–335, doi:10.1631/jzus.B1200113.
- Oropesa, A.L.; Gravato, C.; Sanchez, S.; Soler, F. Characterization of plasma cholinesterase from the white stork (ciconia ciconia) and its in vitro inhibition by anticholinesterase pesticides. Ecotoxicol. Environ. Saf. 2013, 97, 131–138, doi:10.1016/j.ecoenv.2013.07.022.
- Zawadzka, A.; Lózinska, I.; Moleda, Z.; Panasiewicz, M.; Czarnocki, Z. Highly selective inhibition of butyrylcholinesterase by a novel melatonin-tacrine heterodimers. J. Pineal Res. 2013, 54, 435–441. 24325732
- Bartolucci, C.; Stojan, J.; Yu, Q.S.; Greig, N.H.; Lamba, D. Kinetics of torpedo californica acetylcholinesterase inhibition by bisnorcymserine and crystal structure of the complex with its leaving group. Biochem. J. 2012, 444, 269–277, doi:10.1042/BJ20111675.
- Jokanovic, M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol. Lett. 2009, 190, 107–115, doi:10.1016/j.toxlet.2009.07.025.
- Ballatore, C.; Zhang, B.; Trojanowski, J.Q.; Lee, V.M.Y.; Smith, A.B. In situ blood-brain barrier permeability of a c-10 paclitaxel carbamate. Bioorg. Med. Chem. Lett. 2008, 18, 6119–6121, doi:10.1016/j.bmcl.2008.10.024.
- Prades, R.; Guerrero, S.; Araya, E.; Molina, C.; Salas, E.; Zurita, E.; Selva, J.; Egea, G.; Lopez-Iglesias, C.; Teixido, M.; et al. Delivery of gold nanoparticles to the brain by conjugation with a peptide that recognizes the transferrin receptor. Biomaterials 2012, 33, 7194–7205, doi:10.1016/j.biomaterials.2012.06.063.
- Lee, N.Y.; Kang, Y.S. The inhibitory effect of rivastigmine and galantamine on choline transport in brain capillary endothelial cells. Biomol. Ther. 2010, 18, 65–70, doi:10.4062/biomolther.2010.18.1.065.
- Di Stefano, A.; Iannitelli, A.; Laserra, S.; Sozio, P. Drug delivery strategies for Alzheimer's disease treatment. Expert Opin. Drug Deliv. 2011, 8, 581–603, doi:10.1517/17425247.2011.561311.
- Beilin, B.; Bessler, H.; Papismedov, L.; Weinstock, M.; Shavit, Y. Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period. Acta Anaesthesiol. Scand. 2005, 49, 78–84, doi:10.1111/j.1399-6576.2004.00548.x.
- Arkypova, V.N.; Dzyadevych, S.V.; Soldatkin, A.P.; El'skaya, A.V.; Martelet, C.; Jaffrezic-Renault, N. Development and optimisation of biosensors based on ph-sensitive field effect transistors and cholinesterases for sensitive detection of solanaceous glycoalkaloids. Biosens. Bioelectron. 2003, 18, 1047–1053, doi:10.1016/S0956-5663(02)00222-1.
- Dzyadevich, S.V.; Arkhypova, V.N.; Soldatkin, A.P.; El'skaya, A.V.; Martelet, C.; Jaffrezic-Renault, N. Enzyme biosensor for tomatine detection in tomatoes. Anal. Lett. 2004, 37, 1611–1624, doi:10.1081/AL-120037591.
- Benilova, I.V.; Arkhypova, V.N.; Dzyadeviych, S.V.; Jaffrezic-Renault, N.; Martelet, C.; Soldatkin, A.P. Kinetics of human and horse sera cholinesterases inhibition with solanaceous glycoalkaloids: Study by potentiometric biosensor. Pest. Biochem. Physiol. 2006, 86, 203–210, doi:10.1016/j.pestbp.2006.04.002.
- Ingkaninan, K.; Phengpa, P.; Yuenyongsawad, S.; Khorana, N. Acetylcholinesterase inhibitors from stephania venosa tuber. J. Pharm. Pharmacol. 2006, 58, 695–700, doi:10.1211/jpp.58.5.0015.
- Xiao, H.T.; Peng, J.; Liang, Y.; Yang, J.; Bai, X.; Hao, X.Y.; Yang, F.M.; Sun, Q.Y. Acetylcholinesterase inhibitors from corydalis yanhusuo. Nat. Prod. Res. 2011, 25, 1418–1422, doi:10.1080/14786410802496911.
- Jann, M.W.; Shirley, K.L.; Small, G.W. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin. Pharmacokinet. 2002, 41, 719–739, doi:10.2165/00003088-200241100-00003.
- Pohanka, M. Acetylcholinesterase inhibitors: A patent review (2008-present). Expert Opin. Ther. Pat. 2012, 22, 871–886, doi:10.1517/13543776.2012.701620.
- Alfirevic, A.; Mills, T.; Carr, D.; Barratt, B.J.; Jawaid, A.; Sherwood, J.; Smith, J.C.; Tugwood, J.; Hartkoorn, R.; Owen, A.; et al. Tacrine-induced liver damage: An analysis of 19 candidate genes. Pharmacogenet. Genomics 2007, 17, 1091–1100, doi:10.1097/FPC.0b013e3282f1f12b. 18004213
- Carr, D.F.; Alfirevic, A.; Tugwood, J.D.; Barratt, B.J.; Sherwood, J.; Smith, J.; Pirmohamed, M.; Park, B.K. Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity. Pharmacogenet. Genomics 2007, 17, 961–972, doi:10.1097/FPC.0b013e3282f00919.
- Pathak, M.K.; Fareed, M.; Srivastava, A.K.; Pangtey, B.S.; Bihari, V.; Kuddus, M.; Kesavachandran, C. Seasonal variations in cholinesterase activity, nerve conduction velocity and lung function among sprayers exposed to mixture of pesticides. Environ. Sci. Pollut. Res. 2013, 20, 7296–7300, doi:10.1007/s11356-013-1743-5.
- Berg, R.M.G.; Ofek, K.; Qvist, T.; Tofteng, F.; Soreq, H.; Moller, K. Cholinesterase modulations in patients with acute bacterial meningitis. Scand. J. Clin. Lab. Investig. 2011, 71, 350–352, doi:10.3109/00365513.2011.558107.
- Sonali, N.; Tripathi, M.; Sagar, R.; Velpandian, T.; Subbiah, V. Clinical effectiveness of rivastigmine monotherapy and combination therapy in Alzheimer's patients. CNS Neurosci. Ther. 2013, 19, 91–97, doi:10.1111/cns.12036.
- Bond, M.; Rogers, G.; Peters, J.; Anderson, R.; Hoyle, M.; Miners, A.; Moxham, T.; Davis, S.; Thokala, P.; Wailoo, A.; et al. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of technology appraisal no. 111): A systematic review and economic model. Health Technol. Asses. 2012, 16, 1–470.
- Lilienfeld, S. Galantamine—A novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease. CNS Drug Rev. 2002, 8, 159–176, doi:10.1111/j.1527-3458.2002.tb00221.x.
- Bai, D.L.; Tang, X.C.; He, X.C. Huperzine a, a potential therapeutic agent for treatment of Alzheimer's disease. Curr. Med. Chem. 2000, 7, 355–374, doi:10.2174/0929867003375281.
- Cheewakriengkrai, L.; Gauthier, S. A 10-year perspective on donepezil. Expert Opin. Pharmacother. 2013, 14, 331–338, doi:10.1517/14656566.2013.760543.
- Zhang, H.C.; Liang, H.; Kuang, P.Q.; Yuan, Q.P.; Wang, Y. Simultaneously preparative purification of huperzine a and huperzine b from huperzia serrata by macroporous resin and preparative high performance liquid chromatography. J. Chromatogr. B 2012, 904, 65–72, doi:10.1016/j.jchromb.2012.07.019.
- Zhang, J.M.; Hu, G.Y. Huperzine a, a nootropic alkaloid, inhibits n-methyl-d-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience 2001, 105, 663–669, doi:10.1016/S0306-4522(01)00206-8.
- Zhang, Y.H.; Zhao, X.Y.; Chen, X.Q.; Wang, Y.; Yang, H.H.; Hu, G.Y. Spermidine antagonizes the inhibitory effect of huperzine a on h-3 dizocilpine (mk-801) binding in synaptic membrane of rat cerebral cortex. Neurosci. Lett. 2002, 319, 107–110, doi:10.1016/S0304-3940(01)02565-4.
- Heinrich, M.; Teoh, H.L. Galanthamine from snowdrop—The development of a modern drug against Alzheimer's disease from local caucasian knowledge. J. Ethnopharmacol. 2004, 92, 147–162, doi:10.1016/j.jep.2004.02.012.
- Rainer, M. Galanthamine in Alzheimer's disease-A new alternative to tacrine? CNS Drugs 1997, 7, 89–97, doi:10.2165/00023210-199707020-00001.
- Pavlov, V.A.; Ochani, M.; Parrish, W.R.; Rosas-Ballina, M.; Ochani, K.; Al-Abed, Y.; Tracey, K.J. The anti-inflammatory efficacy of galantamine is dependent on the integrity of the cholinergic anti-inflammatory pathway. Shock 2007, 27, 23.
- Takata, K.; Kitamura, Y.; Saeki, M.; Terada, M.; Kagitani, S.; Kitamura, R.; Fujikawa, Y.; Maelicke, A.; Tomimoto, H.; Taniguchi, T.; et al. Galantamine-induced amyloid-beta clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J. Biol. Chem. 2010, 285, 40180–40191, doi:10.1074/jbc.M110.142356.
- Liu, Z.H.; Ma, Y.F.; Wu, J.S.; Gan, J.X.; Xu, S.W.; Jiang, G.Y. Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide-induced peritonitis. Chin. Med. J. 2010, 123, 1727–1730. 20819637
- Hwang, J.; Hwang, H.; Lee, H.W.; Suk, K. Microglia signaling as a target of donepezil. Neuropharmacology 2010, 58, 1122–1129, doi:10.1016/j.neuropharm.2010.02.003.
- Sochocka, M.; Zaczynska, E.; Leszek, J.; Siemieniec, W.; Blach-Olszewska, Z. Effect of donepezil on innate antiviral immunity of human leukocytes. J. Neurol. Sci. 2008, 273, 75–80, doi:10.1016/j.jns.2008.06.021. 18662817
- Sochocka, M.; Zaczynska, E.; Tabol, A.; Czarny, A.; Leszek, J.; Sobczynski, M. The influence of donepezil and egb 761 on the innate immunity of human leukocytes effect on the NF-κB system. Int. Immunopharmacol. 2010, 10, 1505–1513, doi:10.1016/j.intimp.2010.08.024.
- Tang, X.C.; Kindel, G.H.; Kozikowski, A.P.; Hanin, I. Comparison of the effects of natural and synthetic huperzine-a on rat brain cholinergic function in vitro and in vivo. J. Enthnopharmacol. 1994, 44, 147–155, doi:10.1016/0378-8741(94)01182-6.
- White, J.D.; Li, Y.; Kim, J.; Terinek, M. A novel synthesis of (−)-huperzine a via tandem intramolecular aza-prins cyclization-cyclobutane fragmentation. Org. Lett. 2013, 15, 882–885, doi:10.1021/ol400012s.
- Ma, X.; Gang, D.R. In vitro production of huperzine a, a promising drug candidate for Alzheimer's disease. Phytochemistry 2008, 69, 2022–2028, doi:10.1016/j.phytochem.2008.04.017. 18538805
- Leman, L.; Kitson, S.L.; Brown, R.T.; Cairns, J.; Watters, W.; McMordie, A.; Murrell, V.L.; Marfurt, J. Synthesis of isotopically labelled c-14 zt-1 (debio-9902), d(3) zt-1 and (−)-d(3) huperzinea, a new generation of acetylcholinesterase inhibitors. J. Labelledc Compd. Rad. 2011, 54, 720–730, doi:10.1002/jlcr.1918.
- Hedberg, M.M.; Clos, M.V.; Ratia, M.; Gonzalez, D.; Lithner, C.U.; Camps, P.; Munoz-Torrero, D.; Badia, A.; Gimenez-Llort, L.; Nordberg, A. Effect of huprine x on beta-amyloid, synaptophysin and alpha 7 neuronal nicotinic acetylcholine receptors in the brain of 3xtg-ad and appswe transgenic mice. Neurodegener. Dis. 2010, 7, 379–388, doi:10.1159/000287954.
- Wang, J.; Chen, F.; Zheng, P.; Deng, W.J.; Yuan, J.; Peng, B.; Wang, R.C.; Liu, W.J.; Zhao, H.; Wang, Y.Q.; et al. Huperzine a ameliorates experimental autoimmune encephalomyelitis via the suppression of t cell-mediated neuronal inflammation in mice. Exp. Neurol. 2012, 236, 79–87, doi:10.1016/j.expneurol.2012.03.024. 22524989
- Wang, Z.F.; Tang, X.C. Huperzine a protects c6 rat glioma cells against oxygen-glucose deprivation-induced injury. FEBS Lett. 2007, 581, 596–602, doi:10.1016/j.febslet.2007.01.016.
- Wang, Z.F.; Wang, J.; Zhang, H.Y.; Tang, X.C. Huperzine a exhibits anti-inflammatory and neuroprotective effects in a rat model of transient focal cerebral ischemia. J. Neurochem. 2008, 106, 1594–1603, doi:10.1111/j.1471-4159.2008.05504.x.
- Darreh-Shori, T.; Soininen, H. Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: A review of recent clinical studies. Curr. Alzheimer Res. 2010, 7, 67–73, doi:10.2174/156720510790274455. 20205672
- Darreh-Shori, T.; Hellstrom-Lindahl, E.; Flores-Flores, C.; Guan, Z.Z.; Soreq, H.; Nordberg, A. Long-lasting acetylcholinesterase splice variations in anticholinesterase-treated Alzheimer's disease patients. J. Neurochem. 2004, 88, 1102–1113, doi:10.1046/j.1471-4159.2003.02230.x.
- Bastiat, G.; Plourde, F.; Motulsky, A.; Furtos, A.; Dumont, Y.; Quirion, R.; Fuhrmann, G.; Leroux, J.C. Tyrosine-based rivastigmine-loaded organogels in the treatment of Alzheimer's disease. Biomaterials 2010, 31, 6031–6038, doi:10.1016/j.biomaterials.2010.04.009.
- Field, R.H.; Gossen, A.; Cunningham, C. Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: Reconciling inflammatory and cholinergic hypotheses of delirium. J. Neurosci. 2012, 32, 6288–6294, doi:10.1523/JNEUROSCI.4673-11.2012.
- Nizri, E.; Irony-Tur-Sinai, M.; Faranesh, N.; Lavon, I.; Lavi, E.; Weinstock, M.; Brenner, T. Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine. J. Neuroimmunol. 2008, 203, 12–22, doi:10.1016/j.jneuroim.2008.06.018.
- Chiou, W.H.; Kao, C.L.; Tsai, J.C.; Chang, Y.M. Domino rh-catalyzed hydroformylation-double cyclization of o-amino cinnamyl derivatives: Applications to the formal total syntheses of physostigmine and physovenine. Chem. Commun. 2013, 49, 8232–8234, doi:10.1039/c3cc43257b.
- Realini, T. A history of glaucoma pharmacology. Optom. Vis. Sci. 2011, 88, 36–38, doi:10.1097/OPX.0b013e3182058ead.
- Greig, N.H.; Becker, R.E.; Yu, Q.; Holloway, H.W.; Tweedie, D.; Luo, W.; Utsuki, T.; Ingram, D.K.; Maccecchini, M.L.; Rogers, J.T.; et al. From natural products to alzheimer experimental therapeutics, eserine based drugs as symptomatic and disease altering agents. Prog. Nutr. 2010, 12, 58–63.
- Russo, P.; Frustaci, A.; del Bufalo, A.; Fini, M.; Cesario, A. Multitarget drugs of plants origin acting on Alzheimer's disease. Curr. Med. Chem. 2013, 20, 1686–1693, doi:10.2174/0929867311320130008.
- Bitzinger, D.I.; Zausig, Y.A.; Paech, C.; Gruber, M.; Busse, H.; Sinner, B.; Graf, B.M.; Trabold, B. Modulation of immune functions in polymorphonuclear neutrophils induced by physostigmine, but not neostigmine, independent of cholinergic neurons. Immunobiology 2013, 218, 1049–1054, doi:10.1016/j.imbio.2013.01.003.
- Peter, C.; Schmidt, K.; Hofer, S.; Stephan, M.; Martin, E.; Weigand, M.A.; Walther, A. Effects of physostigmine on microcirculatory alterations during experimental endotoxemia. Shock 2010, 33, 405–411, doi:10.1097/SHK.0b013e3181b77e82.
- Kutsuna, S.; Tsuruta, R.; Fujita, M.; Todani, M.; Yagi, T.; Ogino, Y.; Igarashi, M.; Takahashi, K.; Izumi, T.; Kasaoka, S.; et al. Cholinergic agonist physostigmine suppresses excessivesuperoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in rats with forebrain ischemia/reperfusion. Brain Res. 2010, 1313, 242–249, doi:10.1016/j.brainres.2009.11.077.
- Benatar, M.; Kaminski, H. Medical and surgical treatment for ocular myasthenia. Cochrane Database Syst. Rev. 2012, 12, CD005081. 23235620
- Chambers, D.; Paulden, M.; Paton, F.; Heirs, M.; Duffy, S.; Craig, D.; Hunter, J.; Wilson, J.; Sculpher, M.; Woolacott, N. Sugammadex for the reversal of muscle relaxation in general anaesthesia: A systematic review and economic assessment. Health Technol. Assess. 2010, 14, 1–211. 21208547
- Cossins, J.; Belaya, K.; Zoltowska, K.; Koneczny, I.; Maxwell, S.; Jacobson, L.; Leite, M.I.; Waters, P.; Vincent, A.; Beeson, D. The search for new antigenic targets in myasthenia gravis. Ann. N. Y. Acad. Sci. 2012, 1275, 123–128, doi:10.1111/j.1749-6632.2012.06833.x.
- Vyskocil, F.; Malomouzh, A.I.; Nikolsky, E.E. Non-quantal acetylcholine release at the neuromuscular junction. Physiol. Res. 2009, 58, 763–784. 20059289
- Walker, S.M.; Yaksh, T.L. Neuraxial analgesia in neonates and infants: A review of clinical and preclinical strategies for the development of safety and efficacy data. Anesth. Analg. 2012, 115, 638–662. 22798528
- Fisher, D.M. Clinical pharmacology of neuromuscular blocking agents. Am. J. Health Syst. Pharm. 1999, 56, S4–S9. 10580734
- Yang, L.P.; Keam, S.J. Sugammadex: A review of its use in anaesthetic practice. Drugs 2009, 69, 919–942, doi:10.2165/00003495-200969070-00008.
- Friedman, A.; Kaufer, D.; Shemer, J.; Hendler, I.; Soreq, H.; TurKaspa, I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat. Med. 1996, 2, 1382–1385, doi:10.1038/nm1296-1382. 8946841
- Kalb, A.; von Haefen, C.; Sifringer, M.; Tegethoff, A.; Paeschke, N.; Kostova, M.; Feldheiser, A.; Spies, C.D. Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model. PLoS One 2013, 8, e62679, doi:10.1371/journal.pone.0062679. 23671623
- Kalb, A.; von Haefen, C.; Sifringer, M.; Tegethoff, A.; Paeschke, N.; Kostova, M.; Feldheiser, A.; Spies, C.D. Physostigmine and neostigmine reduce the increased expression of il-1beta in the hippocampus and cortex after surgery combined with lps-treatment. Eur. J. Neurol. 2012, 19, 756.
- Pohanka, M.; Pavlis, O. Neostigmine modulates tularemia progression in balb/c mice. Afr. J. Pharm. Pharmacol. 2012, 6, 1317–1322.
- Sun, L.; Zhang, G.F.; Zhang, X.; Liu, Q.; Liu, J.G.; Su, D.F.; Liu, C. Combined administration of anisodamine and neostigmine produces anti-shock effects: Involvement of alpha 7 nicotinic acetylcholine receptors. Acta Pharm. Sin. 2012, 33, 761–766, doi:10.1038/aps.2012.26.
- Kox, M.; Pompe, J.C.; Peters, E.; Vaneker, M.; van der Laak, J.W.; van der Hoeven, J.G.; Scheffer, G.J.; Hoedemaekers, C.W.; Pickkers, P. Alpha 7 nicotinic acetylcholine receptor agonist gts-21 attenuates ventilator-induced tumour necrosis factor-alpha production and lung injury. Br. J. Anaesth. 2011, 107, 559–566, doi:10.1093/bja/aer202.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).


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Star Walk 2 App
The original Star Walk was one of the best astronomy apps to come around. Happily, Star Walk 2 only builds on that success.
Nice Weather, Plus Some Exciting Astronomical Events
Not much detail to go into here, because it's yet another stunning summer weekend in the Delaware Valley!
Astronomers Announce Discovery of New 'Dwarf' Planet at Edge of Solar System
It's official designation is 2012 VP113. The "VP" in the name inspired its nickname: Biden.
Meteor Shower Expected To Peak Overnight On Dec. 13-14
Despite the amount of moonlight present in the sky tonight, those who'd like to watch the shower and can find a spot away from city lights can expect to see up to 50 or more meteors per hour.
Solar Walk App
The Solar Walk app lets you learn all about the sky above us, with over 375 images and eight videos.
NASA Visualization Explorer
Odds are you won't get to explore the stars yourself – or even have access to all of NASA's tools. The Visualization Explorer app is the next best thing.
Area Astronomers Hoping For Clear Skies For Rare Venus Event Tonight
Dr. Harry Augensen, professor of physics and astronomy at Widener University, says scientists have been interested in transits of Venus for centuries.
The Night Sky App
Stargazing goes high tech with the Night Sky app – an educational app that makes astronomy accessible to pretty much anyone.
The Second Annual Philadelphia Science Festival Opens
Science is in everything we do, and Director Gerri Trooskin says the point of this festival is to show just how much fun science can be.
Study Shows Students Who Major In Astronomy Have Zero Unemployment
If you have a college age student with an undeclared major, you may want to steer them into astronomy.
Several Philadelphia Observatories Open For Night Of Star Gazing
The Franklin Institute's observatory is just one of a few places where you can take in the view Thursday night.

subset: commoncrawl


text: Common Core Uses SEIU Protest To Teach 3rd Graders About 'Rights and Responsibilities' Print article Send a Tip by Dr. Susan Berry 11 Oct 2013 post a comment A new report from Education Action Group Foundation, Inc. (EAG) indicates that a Common Core-aligned teacher guide encourages third graders to learn about "rights and responsibilities" through a story about a 1985 SEIU-led janitors' strike in Los Angeles. Kyle Olson of EAGnews.org wrote that textbook publisher Zaner-Bloser includes, in its Common Core-aligned third-grade teaching guide, a book entitled "Si Se Puede/Yes We Can!" The book is included in Zaner-Bloser's unit on "Rights and Responsibilities." Olson wrote that the goal of the Zaner-Bloser guide is to have eight and nine year-old children consider the "central question" of "How can we work together as a community to stand up for our rights?" In "Si Se Puede," third-graders learn that in 1985 janitors went on strike "for more money because their wages [were] too low to be fair." In the guide, Olson says teachers "are told to introduce students to the vocabulary word of the week--'protest.'" According to Olson, who reviewed the teaching guide: The book instructs the teacher to "remind students that a protest is an event in which people publicly show their strong disapproval of something. Discuss protest throughout the week. Challenge students to use the word while speaking and writing." After students read the book and learn about underpaid janitors and protests, the guide tells teachers to help students apply these concepts to their lives. They do that by brainstorming about problems they believe exist in their school. In case the kids can't identify any problems worth protesting, the Zaner-Bloser authors helpfully offer an example: "No talking allowed in the lunchroom." The authors even suggest a solution: "Protest by making signs and marching." "So here you have a Common Core-aligned lesson instructing third-graders how to stage a public protest against their adult school leaders," Olson said. "They're essentially being groomed to be future members of labor unions, or at least to sympathize with the organized labor point of view." Olson wrote that nowhere in the "Rights and Responsibilities" teachers' guide is there any mention of the Constitution or the founding of America based on the desire to protect God-given, natural individual rights. Proponents of Common Core often argue that the standards are not a "government takeover" of education because local school districts can decide how they are going to implement the standards and which materials they will use. However, most school districts in states that have adopted Common Core will not be designing their own unique curriculum due to restrictions on time and money. Many are purchasing pre-written, "canned," Common Core-aligned curricula from major textbook companies, like Zaner-Bloser. McGraw-Hill Education, for example, another well-known textbook publisher, urges educators to simply purchase their curriculum materials: McGraw-Hill Education, with its long history of providing the highest quality curriculum materials for educators, offers a seamless solution to schools that are transitioning to the new Common Core State Standards. We have the experts and the expertise in instruction and assessment to help schools implement the standards smoothly and successfully. The result? Teachers will have the tools and students will have the skills they need to meet the expectations of the new standards. We have the knowledge. We have the experience. Partner with us to improve teaching and learning. The implication is that designing a curriculum based on the Common Core standards is a problem that requires a "solution," and, for textbook publishers, the "solution" is for school districts to buy their entire Common Core-aligned curriculum. All the more reason for parents to be watchful of what their children are learning in school and the materials used to teach them.


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Barclays Premier League
Old Trafford
Saturday 23 April 2011
(Hernandez 83)
United: van der Sar; Fabio, Ferdinand, Evans, O'Shea (Evra, 57); Valencia, Gibson (Giggs, 74), Anderson, Nani (Owen, 63); Hernandez, Rooney. Subs not used: Kuszczak, Brown, Rafael, Carrick.
Everton: Howard; Hibbert, Jagielka, Distin, Baines; Coleman (Gueye, 75), Neville, Osman, Rodwell, Bilyaletdinov (Cahill, 46); Beckford (Anichebe, 46). Subs not used: Mucha, Skodran, Mustafi, Duffy, Vellios.
On Saturday 22 April 2000, Manchester United swept aside Southampton at The Dell to claim the club's sixth Premier League crown in eight years - and 13th title in total.
Bouncing back from a midweek Champions League defeat to Real Madrid, the Reds produced a display full of the quick passing and incisive movement that had led to the Treble in the previous year. The champions raced into a three-goal lead by the half-hour mark and never looked in danger from that point on.
A trademark David Beckham free-kick, after a foul on Andy Cole set Sir Alex Ferguson's men on course for victory, and when Francis Benali deflected the ball into his own net following a great surge down the left from Phil Neville, United were in firm control. Shortly afterwards, Roy Keane found Beckham in space on the right and he played a rapier-like ball to Solskjaer. The Norwegian's majestic control and volley into the besieged Southampton net sent the travelling support into raptures and even though the Saints eventually responded with a splendid solo effort from Latvian international Marian Pahars, the result was by then academic. United were champions again, this time with four games to spare.


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Daniel Markham's Pretty Bitchin'
By Kelly Dearmore
Americans Under 30 the Most Cynical Bunch Ever
By Jim Schutze
13 of the Best Female-Fronted Bands in DFW
By Rachel Watts
Your Baseball Season Guide to Pre- and Post-Game Eats...
By Lauren Drewes Daniels
The Bizarre Life and Troubling Death of DarkSide
By Anna Merlan
The Ten Most Badass Band Names in DFW
By Lee Escobedo
By Alice Laussade
In the band's namesake Sydney Pollack film, desperate contestants in a dance marathon push their bodies to the limit in order to capture a cash prize. Drop by the Cavern tonight, and you may just find yourself channeling that kind of energy, bopping and ca-chunking your body to the musical circus onstage before you. More of a spastic carnival than an indie-rock band (even if they have released both of their albums for the Kill Rock Stars label), this frenetic troupe from British Columbia includes a full-on horn section and claims as many as nine members. Known throughout the Pacific Northwest for the dizzying exuberance of their live show, They Shoot Horses have all the juice-loosened pomp of a fun-loving brass band stampeding down Bourbon Street. With that kind of wild racket blaring away, you can either join the parade or get trampled underfoot. With Dutch Treats and Laura Palmer.


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November 29, 2014
RICHMOND, Va. (AP) -- Owners of electric-powered mopeds could be hit with a $100 annual registration fee as a result of legislation passed by the 2013 General Assembly.
The Virginian-Pilot reports that the fee is an unintended consequence of the sweeping transportation funding bill and a separate measure regulating mopeds.
The road funding measure includes a $100 registration surcharge on alternative vehicles such as hybrids. And because mopeds would be classified as state-registered vehicles, those with electric motors would be subject to the fee. That means owners of electric scooters that retail in some places for $800 to $900 would pay more than one-tenth of the purchase price in annual fees.
Republican Sen. Steve Newman of Lynchburg has asked Gov. Bob McDonnell to amend his moped bill to fix the problem.
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text:
Palfinger North America redesigns website
Equipment World Staff
| August 04, 2012 |
The Palfinger North America Group (PNAG), which includes Palfinger North America, Interlift, Omaha Standard Palfinger and Palfinger American Roll-Off, has launched its newly-redesigned website.
The site gives visitors information about PNAG products and provides downloads, technical data, media and company information for customers.
View the website at palfinger.com .
From our partners
Top 4 Construction Hazards
Help keep yourself and your employees safe. Educate yourself on the four…
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small testicle sized lumps on the breasts.
Person 1:OMG DO I HAVE CANCER?
Person 2:Nah they're just breasticles.
Person 2:Nah they're just breasticles.
de RenegadePie 28 Decembrie 2006
saggy boobs that resemble a scrotum
dude that fat chick's got fatass breasticles
de heywud Jablowme 17 Noiembrie 2003
Large natural breasts.
My girlfriend has nice breasticles.
de Anonymous 06 Aprilie 2003
when a guy sticks his large penis in betweens a nice set of man titties then a girl licks the man's meaty nipples.
Breasticles is a great way to get a fat threesome horny.
de Mr. Benton 10 Noiembrie 2007
When girls get uptight cause guyz got testicles. They call their tits breasticles
Girl: "Boy, yo testies got nuttin on my huge breasticles!"
de Joel of Swink 08 Noiembrie 2007
Breasticles: man boobs breast+testicles=breasticles
2:fun way to say man titties
2:fun way to say man titties
1:im so fat i got huge breasticles i need a bra
2:look at the bresticles on that guy
2:look at the bresticles on that guy
de bob ure uncle 19 Februarie 2005
Noun. 1. Boobies
If you go to Hooters, you see Breasticles.
de captain crunch 14 Martie 2003


text:
Nike 6.0 Dirt Jump Shoot 6
British dirt jump goodness from Alex Rankin and Nike 6.0Credit: Nike and/or Rankin?
6 comments
784 Shop Mechanic http://p.vitalmtb.com/photos/users/784/avatar/c50_92723060_1252166248.jpg?1290151596 http://www.vitalmtb.com/community/Shop-Mechanic,784/all 09/05/09 1 4 47 1
Alex Rankin rules. His films have such a natural feel to them. Nothing overly setup or contrived like so many of the other vids these days. You always get a sense of the fun of mountain biking along with the excitement, danger, and beauty. His choice of music always works great with his films too.
747 mxnate http://p.vitalmtb.com/photos/users/747/avatar/c50_88958720_1266680261.jpg?1290151538 http://www.vitalmtb.com/community/mxnate,747/all 09/03/09 7 3 34 66
nike Blows. They systematically ruin everything they touch.
559 Mwood http://p.vitalmtb.com/photos/users/559/avatar/c50_91824930_1254599170.jpg?1290151111 http://www.vitalmtb.com/community/Mwood,559/all 08/19/09 2 12 http://www.vitalmtb.com/community/Mwood,559/setup 16 79
im loven all the work there going to just to get the 'shot'. its siiick
506 alloutprodux http://p.vitalmtb.com/photos/users/506/avatar/c50_89856460_1250093972.jpg?1290150974 http://www.vitalmtb.com/community/alloutprodux,506/all 08/12/09 18 31 8 215
that was sick --
reminded me of that gonz section from the old blind vid
with the groooovy jazz -- spomer & sven
i know you guys remember that one!


text:
November 28, 2014
FRESNO, Calif. (AP) - Authorities in Fresno County are looking for a man who bolted from a courtroom after a witness identified him as a possible robbery suspect.
The Fresno Bee reports that during a preliminary hearing on a home invasion case, a female witness on the stand pointed to a man who was watching Friday's proceedings and said he stole her television.
The man shouted an obscenity and ran from the courtroom.
Fresno Police spokesman Jaime Rios says a sheriff's bailiff was unable to pursue the man because he was watching two suspects.
A Fresno police officer also at the hearing gave chase, but could not catch the man who got away.
Rios says that police have a pretty good idea who the man is. His name has not been released.
Copyright 2014 Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
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Shahil Roy From: Kolkata
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text: 'Atlas Shrugged III' Gets New Cast, Aims at Election-Themed Release Date Print article Send a Tip by Zachary Leeman 24 Jan 2014 post a comment Producers Harmon Kaslow and John Aglialoro will be rounding out their Atlas Shrugged movie trilogy this year with the currently titled Atlas Shrugged Part III: Who Is John Galt? The movie has begun filming and has been awarded an entirely new cast and crew as it preps for a September release. The first two Atlas Shrugged movies were ambitious and underrated, but neither found major box office success, despite rigorous marketing pushes from Kaslow and Aglialoro. However, the films have found better success on video and through merchandising on their website, where a cult following has revealed itself. Like the last movie in the franchise, Atlas III sports an entirely new cast. The two primary protagonists of the story, Dagny Taggart and Hank Rearden, will be portrayed by Laura Regan and Rob Morrow. Taggart was formerly played by Taylor Schilling and Samantha Mathis, while Rearden was previously brought to life onscreen by Grant Bowler and Jason Beghe. Other cast roles include the characters Ragnar Danneskjold and Francisco d'Anconia. Those parts will be played by Eric Allan Kramer and Joaquim de Almeida. The film's director is James Manera, co-creator of Chevy's Like a Rock ad campaign. The producers have stressed that Atlas III will be the best and most faithful in the series, and they have put forth a marketing strategy that includes playing the movie in 500 of the most successful theaters the previous movies played in, as well as premiering shortly before the 2014 mid-term elections. With a fresh cast and a recently very successful kickstarter campaign, Atlas III seems like it may, in fact, be the best of the series. However, the real pressure on the movie is in how it performs at the box office. The original Atlas Shrugged was supposed to be a box office hit, considering the popularity of the book. It was also supposed to mainstream conservative films at the box office, but it failed to do so. In today's world of crowd funding and online streaming, box office means less than before; nonetheless, the first two movies' failures at the box office has given liberals and movie fans alike the ammo to label the Atlas Shrugged films disappointments and failures altogether. That is not true, of course, as both have found success and are very strong movies. However, it would be nice to see Atlas III find the mainstream box office success the first films pined for, paving the way for conservative-themed movies to be mainstreamed in some way and vindicated in the face of criticism. In honor of saving the best news for last, the producers have also cast the important role of John Galt. Considering Ayn Rand's character is the true hero of part three, and is required to convey many big ideas through much dialogue, there's quite a bit of pressure on the actor taking this role. That actor happens to be the young Kristoffer Polaha (TV's Ringer, Life Unexpected). "As soon as Kris walked in the room and said, 'Hello,' we knew we found him. Kris is John Galt," producer Kaslow said. Atlas Shrugged Part III: Who is John Galt? will hit theaters in September.


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I know there is "Wheatwine" so maybe GF "wines" need to be named more ingredient specific? Like Milletwine, Sourghumwine...etc...
Like my snazzy new avatar? Get Sons of Zymurgy swag, here, and brew with the best.Revvy's one of the cool reverends. He has a Harley and a t-shirt that says on the back "If you can read this, the bitch was Raptured. - Madman
I gotta tell ya, just between us girls, that Revvy is HOT. Very tall, gorgeous grey hair and a terrific smile. He's very good looking in person, with a charismatic personality... he drives like a ****ing maniac! - YooperBrew
makes sense, but milletwine just doesn't sound good to me.
Gluten free beer is a marketer's nightmare. None of the ingredients sound good in any way and the word 'gluten' sucks too. As someone who does this professionally, I suggest you stick to names that utilize actual beer terminology and change it to be imitation or fake. Seriously, no one wants to drink anything with the word millet or sorghum in the name.
Also, I think that switching the brown sugar for dark candi will help some, but I feel you still need more.
Also, don't forget yeast nutrient, or not much will happen.
right, yeast nutrient. I have been adding a teaspoon of brags free aminos solution to each one of my beers. Its actually meant for human consumption, but contains a huge amount of free aminos. seems to work for lighter beers but I will get a real nutrient for this HG brew.
thanks for the link Kershner its definitely an interesting idea
If I replaced the brown sugar with Candi sugar, and carmelized the honey that would make for a much fuller beer. Think its enough?
edit: posted this before I saw your last post. so if its to unfermentable can I just caramelized less of it? say, 1 lb caramalized honey, 2 lb not?


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West Elm Fall Preview Collection
10 Instant Favorites From West Elm's Fall Preview
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10 Instant Favorites From West Elm's Fall Preview
West Elm recently offered readers a sneak peek at its Fall collection, and I've already identified several must-have items for my home. You can shop the West Elm Fall preview collection in full here. First, take a look at what I'm loving, and then let me know if you agree with my faves, or if you think I'm missing out on some essentials from the Fall collection sneak peek.
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text:
Stop Being so Damned Hard on Yourself.
Find a Conversation
|Fri, 01-21-2011 - 4:53am
Some interesting advice here,,, we all have areas about ourselves that we are not satisfied with
|Sat, 01-22-2011 - 1:51pm
Negative thinking is annoying and exhausting!
People who self dialogue about their imagined or real flaws need to look around and accept the fact that everyone has them. What they don't think about, too, is that others may be looking at their good points and wishing they could be more like them!
If I'm around a negative person more than a few minutes, it begins to drain me and I have to get away from them!!
There are two ladies up the street from me. They both live alone next door to each other. They're both always complaining about someone or something or whatever all the time and they feed off of each other!! One is worse than the other and I pity her kids having to put up with her crap!! At our neighborhood dinners, I try to steer away from sitting near them.


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Dale's mailbag
A: Both those lakes in southern Cook County started doing well for pike early in the ice-fishing season. But I would suggest the best shot at a big pike through the ice is farther south, just across the state line at Willow Slough in Indiana. But Saavedra touched on one of the stories this winter: good ice fishing for pike across the area, north to south.
Updated: September 24, 2012 6:25AM
BUCK OF the WEEK: UNPLUGGED
Mike Skwira of Burbank sent this photo of two bucks "sauntering around in Resurrection Cemetery last fall.'' That might be the first from Resurrection for BOTW: Unplugged, the weekly celebration of live big bucks around Chicago outdoors. Send nominations to firstname.lastname@example.com.
Illinois deer hunters bagged a preliminary total of 181,936 deer during the 2010-11 seasons. That is down more than 10 percent from the record 201,301 in 2005-06 and down from 189,277 in 2009-10. The gender split (doe/buck) was 50-50.
Hunters harvested 98,700 deer during the seven days of the split 2010 Illinois firearm deer season. During the archery season, which began Oct. 1 and ended last Sunday, hunters bagged 63,584 deer, down from 64,864 in 2009-10. The combined preliminary harvest for the late-winter antlerless-only and the special CWD deer seasons was 14,843, down from 17,826 last season. The muzzleloader-only season dropped to 3,276 deer. The youth season had a harvest of 1,533.
Today: Final day, Hammond Outdoor Sports Show, Jean Shepherd Community Center, Hammond, Ind., sportsshow.gohammond.com.
Wednesday-next Sunday: America's Outdoor Show, Stephens Convention Center, Rosemont, americasoutdoorshow.com.
Thursday-next Sunday: Strictly Sail Chicago, Navy Pier, strictlysailchicago.com,
Friday-next Sunday: Illinois Fish & Feather Expo, Interstate Center, Bloomington, illinoisfishandfeather.com.DALE'S MAILBAG


text:
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text:
Monday, 01 June 2009 07:18
New Experience Wrestling
Episodes 007 and 008
Reviewed by Joe Babinsack
Downtown Bruno in a referee's suit. A classy crowd in the audience, taking in a decidedly Old School version of wrestling, packaged as new. All good things come around again, at some point, but did anyone think it would take a quarter-century for St Louis style wrestling, well, maybe a little older, and a little slower, to appear in a ring in Memphis?
The roster comes from the Nightmare Ken Wayne's School of Wrestling, and it is decidedly different.
New Experience Wrestling is decidedly that. I'm not so sure there are any very many fans outside of Memphis who have experienced this style, this throw-back feel, this utterly antithetical to Sports Entertainment version of what none of us would be ashamed to call professional wrestling.
I'll say this. If you're big into ROH, or the American Indy style that dominates most independent level landscapes, you're in for a major cultural shock. NEW is slow paced. So slow that you are forced to experience the most minute of selling, and the very fundamentals of the sport: working holds, maneuvering in the ring, telling the story of the match, and paying keen attention to the details.
It's a far cry from watching guys rush to hit their high spots, and scramble to get all their spots in.
What fascinated me from minute one was the utter dedication of the promotion, the talent and the announcers in putting it all together. This is a decided effort on the NEW management to put a vision into reality. It's an intensive style that means that the roster must be on the right page. And while the announce crew shows some rough spots, the overall "feel" of the show is more than just excellent.
One thing I'll definitely give props to NEW about is that they format their DVD as two TV shows.
So many indy promotions, and even ROH if you want me to point fingers, are hell bent on making PPV's out of their events, instead of creating a formatting that would bespeak a single or series of TV shows. The constructive criticism here is that if a promotion is already geared to putting together a formatted show, then if and when they get TV, whether local or bigger, then there's practice, focus and a booking mentality already in place.
Instead, so many indies try to cram 10 matches on a DVD, and never once think about the viewer. How many fans sit through a two hour DVD in one sitting? Break it down into true shows, and let the viewer experience the product with a more natural time frame, instead of watching a match or two.
The videos, the intros and the repetition may be called filler by the less informed, but if I may go back to my favorite ECW (original, 1990's version) reference, let's not forget that the most awesome TV show of all time was a whole lot of pitching product, a lot of recapping, and a solid format.
I get the impression that as NEW progresses, it would slip readily into those concepts: strong TV format, self-promotional focus, internally logical style and atmosphere.
But the matches are the product, and the product is very good.
Again, this is a slow style, but it is one that can be grasped and readily appreciated. It's not all about running the ropes and high-octane madness. With NEW, the fundamental base is mat wrestling, and it's that throw-back to working the leg, working the arm; picking a body part and working and selling and setting up the finish…. which seems a long way to go at times.
The concept that everyone is competitive and mostly even in skill only reinforces the concepts. I'm not so sure that will go over well in the star-power oriented mindset of too many fans, but I found it a mere fleeting distraction. Several matches on the two shows seemed to end rather abruptly, which did enhance the concept that wrestling between two talented guys sometimes does end up with a fluky finish or just by the right move being hit at the right time.
The injury aspect turned the concept up a notch for me.
The style screams physical (without punches, that is) and the announcers play it up big time. As a work, it's a great feel, because I'm taken back in time to a point where if an injury occurs in the ring, I'm not in the modern mindset of a referee giving the "X" signal, and the crowd somewhat respectfully, more outwardly dubious, looking on as if it's a surreal situation where you know you should act like you care, but in reality … there's no emotional connection and no one cares.
With NEW, there's a quick immersion into the opposite.
We see some inadvertent blood. We see a really weird looking leapfrog (Ok, hardcores, you know the chant, and you'll call it a botched spot) turning into something that bespeaks an injury angle, but in the way the matches play out , one isn't so sure.
I'm seeing a guy with a knee injury, and the opponent a little concerned, a little hesitant, and then ultimately opportunistic. Someone's got to win the match before the doctor can hit the ring.
There's something quaint about the promos. We get a few minutes of talk before each match, and it's cool to see the talent given the opportunity to get on the mic and show what they've got. A few matches seemed a bit contrived in their promos, responses, and how the announcers worked it into the flow of the match, but again, there's something to the old formulas that make the competition meaningful.
The roster is mostly guys from Nightmare Ken Wayne's school, and also includes Derrick King, and WWE developmental talent Byron Wilcott, and local veteran "Golden Boy" Greg Anthony.
Anthony kicks off the first episode against Greg King Jr. (I guess WWE dictates definitely don't apply here!) Other guys include "3G" Eric Wayne (hmmm, third generation guy named Wayne training at Ken Wayne's school?) plus Matt Justice and Kid Nikels.
I'm doubly hesitant to do a match recap replete with holds, because this is a promotion not about this and that and the other thing, instead, it focuses on an atmosphere – the "New Experience" – and the tremendous Old School values. And of course, I hate revealing match results – what's the use? I want you to want to buy the DVD, not just say you watched it.
But watch it you should.
NEW is decidedly different, and the kind of promotion that would be run-of-the mill forty years ago. But for all you WWE types who don't seem to comprehend that the WWE isn't exactly what pro wrestling was, let alone what it is, let alone what it can be, here's your chance to have your world rocked.
"For more information on New Experience Wrestling and the "Nightmare" Ken Wayne School of Wrestling, visit www.nightmarekenwayne.com or call 901-831-4198."


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COLLIER COUNTY, Fla.- The search continues for an Immokalee mother of four who has been missing since Saturday morning.
Friends and family say 24-year-old Esterlyne Delmas would never leaver her children. And while they're hoping for the best, they're fearing for the worst.
"She's not the type of person that would just leave her baby like that, especially without food. So, she just left the baby, she didn't make a bottle, none of that," said friend Ritza Hilaire.
Family and friends have filed a missing persons report with the Collier County Sheriff's Office, and even reached out to representatives who handle human trafficking.
Anyone with information is asked to call the CCSO at (239) 774-4434.


text:
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Auto Electrical Parts
Home » Automotive PartsAuto Electrical Parts
Auto Electrical Parts
Auto electrical parts are one of the most important things to know for judging any automobile's caliber. The auto electrical parts vary model to model, however the basic electric parts are common in the automobiles. In the market we see numerous publications catering the complete information about the auto electrical parts and automobile sector. These publications including online, pursue several terminologies and jargons for simplifications for the customers so that one can easily understand the complex structures of auto electrical parts. The knowledge about the auto electrical parts is very essential as that makes one select automobiles.
Looking at the market trends, it seems that masses are too zealous to know about the parts and sub parts and other technicalities. One when drives any automobile hardly he realizes that he is not driving a single machine but a machine composed countless spares and cables.
Auto electric parts are in different forms for different purposes; the only commonality is that they depend on the electricity generated by the automobile battery:
Plugs - The usability of the plugs is numerous, as plugs like spark plugs, glow plugs serve important functions.
Cables - The whole body of the automobile depend on these high capacity cables. These are just like nerves as cables like speedometer cables, control cables and others are common in the automobiles.
Lights - lights are the integral part of the automobiles. There are various kinds of lights in the automobiles. The headlights, backlights and indicators are the prime electric parts of any automobile. In case of four wheelers, interior light is too available.
Horns - The alerts and other kinds sounds we here is also the auto electric parts. Nowadays there are many innovative sounds that have adequate pitch and consume less electricity.
Automotive-accessories-parts.com is the land of all the auto electrical parts traders in the international and national market. Automotive-accessories-parts.com along with customer guides, have enlisted all the names in the market of the auto electrical parts. One can select the best suited dealer and send their leads for further business expansions.
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Manufacture and suppliers of auto electrical parts
Rajdhani Diesels & Electricals
Manufacturers,Exporters and Suppliers of auto electrical partsAddress : Opp. Allahabad Bank, Near Bombay Motor Circle, Residency Road, Jodhpur Rajasthan
Phone : +91-291-2771861 / 2750193 / 51 Mobile Phone : +91-9351184111 / 9414127473 /
Website : http://www.rajdhanidiesels.co.in
Visakha Diesel Private Limited
Manufacturers,Exporters and Suppliers of alternatorsAddress : Plot No : 202, Sector 4, MVP Colony Visakhapatnam Andhra Pradesh
Phone : 91-891-2737777 Mobile Phone : 9866681117
Website : http://www.visakhadiesel.in
Sprayking Agro Equipment Pvt. Ltd.
Manufacturers,Exporters and Suppliers of electrical parts, auto electrical partsAddress : 590, GIDC, Phase - 2, Dared, Jamnagar Gujarat
Phone : +91-288-2730750 Mobile Phone : +91-9328377772
Website : http://www.spraykingagro.net
Smd Auto Industries
Manufacturers,Exporters and Suppliers of auto electrical parts, alternator rotorAddress : Rz - 934 B, Street No. - 14 1, Sadh Nagar, Palam Delhi
Mobile Phone : +91-9818389298
Website : http://www.smdautoindustries.co.in
Kanifnath Import Export
Manufacturers,Exporters and Suppliers of automobile electrical parts, vehicles electrical parts, tractor electrical partsAddress : Devendra Nivas, S. No. 94/94, Paud Road, Kothrud Pune Maharashtra
Phone : +91-20-25285180 Mobile Phone : +91-9158054333
Website : http://www.kanifnathimportexportindia.com
Anon Power Solutions
Manufacturers,Exporters and Suppliers of auto batteriesAddress : Plot No.- 312/2 C/4 Hindustan Compuerts , Sandesh Cinemax, Malegaon Maharashtra
Phone : 91-2554-252400 Mobile Phone : +91-9403407920/9420590220
Website : http://www.anonpowersolutions.com
Paras Industries
Manufacturers,Exporters and Suppliers of brass electrical partsAddress : Plot No. 6/a, Haribhai's Wadi, Sanker Tekri, Udyognagar Jamnagar Gujarat
Phone : +91-288-2568178
Website : http://www.parasindustries.com
Paras Auto Industries
Manufacturers,Exporters and Suppliers of automotive alternators, alternator rotorsAddress : 1052/69 Deva Ram Park North Delhi Delhi
Mobile Phone : +91-9891528601/9999251005
Website : http://www.parasautoelectric.com
Vkg Impex
Suppliers of two wheeler electrical parts, automobile cablesAddress : B-71, Nav Kunj, Plot No. 87, I.p. Extension, Patparganj New Delhi
Phone : +91-98713-98644
Website : http://www.vkgimpex.co.in
Universal Components
Manufacturers,Exporters and Suppliers of auto electrical partsAddress : A-811, Dubua Colony Faridabad Haryana
Phone : +91-129-2481099 Mobile Phone : +91-9818462066
Website : http://www.universalcomponents.net
Ayma Electronics
M. M. Enterprises
Manufacturers,Exporters and Suppliers of automotive bulbsAddress : 21, Kewal Park Extn, Azadpur New Delhi
Phone : +91-91362-16411 Mobile Phone : +91-9911946100
Website : http://www.mmautoproducts.com
Cameo Lock Industries
Manufacturers,Exporters and Suppliers of ignition switchesAddress : 5/100 Nagla Masani Khair Road Aligarh Uttar Pradesh India
Phone : 91-571-2522170/ Mobile Phone : +91-9837041062
Website : http://www.cameolockindustries.com
S S Power System
Ariba Power Control
Rishabh Diesel
Exporters and Suppliers of alternatorAddress : Opp. Sant Avenue, In Side SBI, G T Road, Amritsar Punjab
Phone : +91-183-5069380 Mobile Phone : +91-8872733380
Website : http://www.rishabhdiesel.co.in
E Control Devices
Manufacturers,Exporters and Suppliers of automotive relaysAddress : SCF #- 17, 2nd Floor, Hetiram Building, Opp. Satyam Guest House, Near New Anaj Mandi, Sector-16 Faridabad Haryana
Phone : 91-129-4003088/ Mobile Phone : +91-9910650088
Website : http://www.econtroldevices.co.in
Shree Jamna Associates
Manufacturers and Suppliers of automotive electrical partsAddress : 767/11, Chabi Ganj, Kashmere Gate Delhi
Phone : 91-11-23917003 Mobile Phone : +91-9911170625
Website : http://www.jamnaassociates.com
Kds Autoelctrical Parts
Manufacturers,Exporters and Suppliers of automotive alternator, automotive clutch platesAddress : 3066/7, Gali Kalyan Singh, Ram Bazar, Mori Gate / Kashmere Gate Delhi
Mobile Phone : +91-9873500286
Website : http://www.kdsautoelectricals.in
Elak Private Limited
Manufacturers,Exporters and Suppliers of auto battery chargersAddress : 216, Industrial Area, Phase-1 Chandigarh Chandigarh
Phone : +91-172-4673400 / 5078112 / 50
Website : http://www.elakindia.in
Heena Electric Corporation
Manufacturers and Exporters of auto electrical partsAddress : Opp. Vijay Petrol Pump, Kali Nadi Road Bulandshahr Uttar Pradesh
Mobile Phone : +91-9897184431 / 9927142799 /
Website : http://www.heenaelectriccorporation.com
ND Auto Electricals
Manufacturers,Exporters and Suppliers of auto terminalsAddress : Khasra No. 70/1/1, Plot No.-216, Mangol Pur Kalan, Behind Shri Tula Ram Public School New Delhi Delhi
Mobile Phone : +91-9811883735 / 9891485567
Website : http://www.ndautoelectricals.com
Bhandari Enterprises
Manufacturers,Exporters and Suppliers of auto electrical alternator assembly, automotive ignition switches, electronic automotive relays, automotive products, ignition switchesAddress : 336 / 4, Kamal Motor Market, Punja Sharif, Kashmere Gate Delhi
Phone : +91-11-23937148 Mobile Phone : 91^9971158459
Website : http://www.bhandarienterprises.co.in
Chandra Vacuum Tech.
Manufacturers,Exporters and Suppliers of automotive bulbsAddress : D-186 Street, 8/1 Prahlad Vihar, Rohini, Sector-25 New Delhi Delhi
Phone : +91-11-32025180 Mobile Phone : 91^8470838710
Website : http://www.autobulbsindia.in
Tazo Light Industries
Sindhwani Enterprises
Manufacturers,Exporters and Suppliers of auto batteriesAddress : Shop No. 28, Near Jaipur Golden Transport, Behind Rajput Patrol Pump, Oasis Hotel Chowk, Pandharpur Maharashtra India
Phone : 91-240-6004000 Mobile Phone : +91-9860740000/9326074000
Website : http://www.sindhwanienterprises.in
Greatway India
Manufacturers and Exporters of auto alternator parts, auto ignition switches, auto electrical parts, alternator spare parts, automobile alternator parts, self starter electrical parts, auto lighting partsAddress : 307/31, 2nd Floor, Oberai Motor Market, Krishna Gali, Kashmere Gate New Delhi Delhi India
Phone : +91-11-20418828 Mobile Phone : 9350404043/9212184043/98102040
Website : http://www.autoelectrical.co.in
Toyota Dubai Llc
Zahra International
Advance Automobiles India
Harinder Industries Pvt Ltd
Boschasia S & T Co. Ltd
Amit Auto Electrical Parts
Guangzhou Liancheng Technology Co. Ltd.
RST Enterprise Co. Ltd.
Reliables Automobile
Hi-lux Autoelectric Private Limited
Sacred Industries
Ramsays Corporation Private Limited
Sunway Auto Electrical Co. Ltd.
moreland auto parts wreckers
Jay Ushin Ltd.
Agon Industries
Arihant Batteries Pvt. Ltd.
Panwar Power Solutions
Trimurti Automobile & Gen. Suppliers
Naresh Enterprises
Narendra Automobiles
Kareepa Enterprise
Interplex Electronics India
Guangzhou Kungfu Decoration Materials Co., Ltd.
Adarsh Motors
Legend Power Solutions
Golden Auto
Bhagat Motor Store
Bhagat Motor Store
Tyre Shopee Naraina
Sahni Motors
Lal Tyres Pvt. Ltd.
Kamal Auto Stores Bombay Pvt. Ltd.
General Motor Company
Bansal Traders
Anand Tyres
Fullboar4x4 Victoria
Taizhou Dianjing Mold Co. Ltd
Jastron Electronics
Shree Polymers
Anjul Automotives
Empire Automobiles Ltd.
Eagle Auto Links
Minda Acoustic Limited
Pright Autompbile
Chheda Electricals and Electronics Pvt. Ltd.
Neil Motors
Dongguan Nanyue Mould Die Casting Co. Ltd.,
Hebei Jiujiu Mechanical Electrical Co. Ltd
Beta Motors
Arun Electric
Anil Automobiles
Suyash Industries
Neptune Automotive Solution
Shalimer Precision
Sethi Motor Works
Mani International
Slw Automotive
Lucas Indian Service Ltd.
786 Motorcycle Parts


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Reviews for Amber Vanilla Hydrating Hand & Body Lotion
Average rating: 5 out of 5 hearts
1 voted:0 voted:0 voted:0 voted:0 voted:
By Michelle on May 12, 2014
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This hydrating lotion is formulated with organic coconut water for its mineral, electrolyte and superior moisturizing properties.
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