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Carbamazepine and phenytoin, two of the most commonly prescribed antiepileptic drugs, have been proposed to share a similar mechanism of action by use-dependent inhibition of Na+ channels. The proposed similar mechanism of action, however, cannot explain the common clinical experiences that the two drugs are different; in some patients, one drug may be more effective than the other. This may occur even when optimal therapeutic concentrations are reached with both medications in plasma or the cerebrospinal fluid. In this study, we show that the action of the two drugs on Na+ channels are quantitatively very different. The affinity between inactivated Na+ channels and carbamazepine (apparent dissociation constant ∼25 μm) is ∼3 times lower than that of phenytoin, yet the binding rate constant of carbamazepine onto the inactivated Na+ channels is ∼38,000m − 1/sec− 1, or ∼5 times faster than that of phenytoin. It is speculated that carbamazepine may be more effective than phenytoin in treating seizures whose ictal depolarization shift is relatively short, whereas a better response to phenytoin may imply abnormal discharges characterized by more prolonged depolarization.
Epilepsy is a common neurological disorder, and control of seizures relies mostly on appropriate antiepileptic medications. A more sophisticated choice of the available antiepileptics depends on further characterization of the molecular mechanisms underlying anticonvulsant action, together with deliberate correlation of such mechanisms with various possible patterns of seizure discharges. In this approach, an essential consideration is why an anticonvulsant is effective against some neuronal discharges but not against others. For example, why could normal neuronal activities be preserved in the presence of effective inhibition of seizures? Thus far, the experimental finding most relevant to this issue is probably the use-dependent block of neuronal discharges produced by some antiepileptics such as DPH and CBZ (1-3).
DPH and CBZ, two widely prescribed antiepileptics, have been shown to inhibit high-frequency firings but not lower frequency firings. Such a use- or frequency-dependent block is analogous to that obtained with local anesthetics (for review, see ref. 4) and is similarly ascribed to a voltage-dependent inhibitory effect on voltage-gated Na+channels. It has been shown that DPH and CBZ inhibit Na+currents in peripheral axons and cultured neuroblastoma cells and that the inhibition is more potent at more depolarized potentials (5-8). Na+ channels are more likely to adopt the deactivated (resting or closed) conformation at hyperpolarized potentials but tend to be transiently activated (open) and then inactivated at depolarized potentials; therefore, the voltage-dependent inhibition may be explained by the speculation that the inactivated conformation of Na+ channels has a higher affinity to the drug than the resting conformation [the modulated receptor hypothesis (9, 10)], along with a related finding that drug binding slows remarkably the recovery of inactivated channels back to the resting state (11, 12).
The use-dependent inhibition of neuronal discharges, however, cannot be completely understood by the different binding affinities between the drug and different gating conformations of the Na+ channel. For example, after only one action potential, most Na+channels would be in the inactivated state. DPH and CBZ cannot bind to the inactivated channels and inhibit Na+ currents in this situation; otherwise, normal firings would also be blocked by these drugs. The requirement of high-frequency discharges or prolonged depolarization for the inhibition to occur seems to imply that the drug binding onto the inactivated channels is slow. Thus, one probably should consider both the steady state effects and their kinetics to understand the antiepileptic effect of DPH and CBZ through the action on Na+ channels. Recently, Kuo and Bean (13) demonstrated a relatively high affinity [apparent dissociation constant (K app) ∼7 μm] and a slow binding rate constant (∼9,000m − 1/sec− 1 at room temperature and −20 mV) of DPH binding to inactivated Na+channels in hippocampal neurons. The former explains the strong blocking effect of DPH on repetitive discharges superimposed on prolonged depolarization shift, and the latter assures a negligible effect of DPH on normal low-frequency firings or very transient high-frequency bursts.
Although the use-dependent block of repetitive firing and the inhibition of Na+ channels by CBZ and DPH are apparently similar, the two drugs are different. It is not a rare experience that in some seizure patients, one drug may be quite more effective than the other, even when optimal therapeutic concentrations are reached with both medications in plasma or cerebrospinal fluid. It is therefore desirable to investigate the steady state effect and kinetics of CBZ inhibition of neuronal Na+ channels, especially to see whether there are any significant differences between CBZ and DPH. Here we show that the affinity between CBZ and the inactivated Na+ channels in hippocampal neurons (apparent dissociation constant ∼25 μm) is ∼3 times lower than that of DPH. However, the binding rate constant between CBZ and the inactivated Na+ channels is ∼38,000m − 1/sec− 1, or ∼5 times faster than that of DPH. These results could have significant pharmacotherapeutic implications when correlated with various possible ictal cellular discharge patterns (see Discussion).
Materials and Methods
Cell preparation.
Coronal slices of the whole brain were prepared from 7- to 14-day-old Long-Evans rats. The CA1 region was dissec1ted from the slices and cut into small chunks. After treatment for 5–10 min at 37° in dissociation medium (82 mm Na2SO4, 30 mmK2SO4, 3 mm MgCl2, 5 mm HEPES, and 0.001% phenol red indicator, pH 7.4) containing 0.5 mg/ml trypsin (type XI; Sigma, St. Louis, MO), tissue chunks were moved to dissociation medium containing no trypsin but containing 1 mg/ml bovine serum albumin (Sigma) and 1 mg/ml trypsin inhibitor (type II-S; Sigma). Each time the cells were needed, 2–3 chunks were picked and triturated to release single neurons.
Whole-cell recording.
The dissociated neurons were put in a recording chamber containing Tyrode's solution (150 mmNaCl, 4 mm KCl, 2 mm MgCl2, 2 mm CaCl2, and 10 mm HEPES, pH 7.4). Whole-cell voltage clamp recordings were obtained using pipettes pulled from borosilicate micropipettes (absorbance 1.55–1.60 mm; Hilgenberg, Malsfeld, Germany), fire polished, and coated with Sylgard (Dow-Corning, Midland, MI). The pipette resistance was 1–2 MΩ when filled with the internal solution containing 75 mm CsCl, 75 mm CsF, 2.5 mm MgCl2, 5 mm HEPES, 2.5 mm EGTA, pH adjusted to 7.4 by CsOH. A seal was formed, and whole-cell configuration was obtained in Tyrode's solution. The cell was then lifted from the bottom of the chamber and moved in front of an array of flow pipes (microcapillary from Hilgenberg; content 1 μl, length 64 mm) emitting either control- or drug-containing external recording solutions (Tyrode's solution with or without 10–300 μm CBZ and 10–100 μm DPH). CBZ and DPH were dissolved in dimethylsulfoxide to make a 100-mmstock solution, which was then diluted in Tyrode's solution to attain the desired final concentrations. The final concentration of dimethylsulfoxide (0.3% or less) was not found to have detectable effect on Na+ currents. The solubility of DPH is lower than CBZ, and it was not possible to obtain DPH concentrations greater than 100 μm in Tyrode's solution (pH 7.4, 25°). Currents were recorded at room temperature (∼25°) with an Axoclamp 200A amplifier, filtered at 5 kHz with a four-pole Bessel filter, digitized at 20- to 50-μsec intervals, and stored using a Digidata-1200 analog/digital interface along with the pCLAMP software (all from Axon Instruments, Foster City, CA). Residual series resistance is generally smaller than 1 MΩ after partial compensation (typically >90%), and the product of residual series resistance and cell capacitance was generally <20 μsec. All statistics are given as mean ± standard deviation.
Stronger inhibition of Na+ current by carbamazepine at more depolarized holding potentials.
Fig. 1demonstrates the voltage-dependent effect of CBZ on neuronal Na+ currents. At a holding potential of −100 mV, 10 μm CBZ has negligible effect on the Na+currents, and even 100 μm CBZ produces no more than ∼10% inhibition of the Na+ currents. However, at a holding potential of −70 mV, 10 and 100 μm CBZ significantly inhibit the Na+ currents (Fig. 1A). Similar experiments were performed at different holding potentials, and the dose-response curves are plotted in Fig. 1B. The effect of various concentrations of CBZ on Na+ currents could be fit by a simple one-to-one binding curve for each holding potential. CBZ inhibits neuronal Na+ currents with aK app of ∼20 μm at a holding potential of −60 mV. In contrast, the K app at −100 mV is ∼900 μm (a rough estimate, because even 300 μm CBZ could block the current by no more than 30%), which indicates an affinity change of almost 50 times between membrane potentials −60 mV and −100 mV.
As the steady state inactivation curve of Na+ channels also shows a steep change between −60 to −100 mV (see the control curves in Fig. 2A), the above finding is consistent with the notion that CBZ binds to the inactivated channels with high affinity but to the resting channels with low affinity. This point can be illustrated in a more quantitative manner with the following scheme:
in which R and I are the resting and inactivated states of the channel, and RD and ID are the CBZ-bound (and inhibited) resting and inactivated states, respectively. The activated (open) state is omitted because most activated Na+ channels inactivate so quickly that, in a steady state condition, one might consider only the R and I states for simplicity. According to this scheme, at any particular holding potential, the fraction of channels in state R (the channels that may be activated or the current that may be elicited upon membrane depolarization) would be reduced by CBZ with aK app given by (13, 14): in which h is the fraction of channels in stateR in the absence of drug ('fraction available' in the control condition in Fig. 2A), and KR andKI are the dissociation constants for the resting and inactivated states, respectively. This is as if the overall affinity of CBZ to the channel (which may be represented by 1/K app because the dissociation constant is inversely proportional to affinity) is a weighted average of the affinity to each state of the channel (Σ fraction of a state × the affinity toward that state, orh/KR + (1 −h)/ KI ). Thus, a largeK app of ∼900 μm at −100 mV, in which h is >0.95, and a small K appof ∼20 μm at −60 mV, in which h is <0.05 (Figs. 1B and 2A), would clearly indicate thatKR ≫KI . Along with the values of h at these potentials, one may also assume thatKI should be close to 20 μm, whereasKR must be somewhat larger than 900 μm.
Measurement of the affinity between inactivated Na+channels and CBZ by shift of the inactivation curve.
AKI of ∼20 μm for CBZ is significantly larger than the value previously reported for DPH [∼7 μm(13)]. Because the inactivated state is probably the major target of CBZ and DPH, a further comparison ofKI is of great interest. Based on the foregoing scheme, KI can be estimated by another approach. In the control condition, the inactivation curve (the fraction of channels in state R at various membrane potentials) can be approximated by a Boltzmann distribution, 1/[1+exp(V −Vh )/k] (Fig. 2A), in which V is the membrane potential,Vh is the half-inactivated potential (at which half of the channels are in state R and the other half are in state I), and k is the slope factor. When CBZ is added, according to the foregoing scheme, the shape of the curve should remain the same, but the midpoint (Vh ) would be shifted by ΔV, with exp(ΔV/k) equal to [1+(D/KI )]/[1+(D/KR )], in which D is the concentration of CBZ (13, 15). Fig. 2A shows that with 10–300 μm CBZ added, the inactivation curves are indeed shifted to the left. Fig. 2, B and C illustrate that the shift of CBZ is dose-dependent and that the slope of the curves remains unchanged in the presence of CBZ. Cumulative results of ΔV/k in various concentrations of CBZ and DPH are shown in Fig. 3, A and B. Fig. 3C plots the exponentials of the mean values of ΔV/k, which shows that the affinity of CBZ to the inactivated Na+channel (KI ∼25 μm) is ∼3 times lower than that of DPH (KI ∼9 μm).
Slow unbinding rate of CBZ from the inactivated Na+channels.
It has been demonstrated in hippocampal neurons that DPH-bound inactivated Na+ channels recover much slower than the inactivated channel in the control condition (12). Fig.4 shows that CBZ also has a similar effect. From the time course of recovery in Fig. 4A, and especially from the expanded time courses of initial recovery in Fig. 4B, it is clear that CBZ-bound inactivated channels recover much more slowly than normal inactivated channels. Despite the fact that the residual or resting block is more pronounced in higher concentrations of CBZ, the kinetics of recovery in 100 and 300 μm CBZ are similar. The gray bararea in Fig. 4B indicates that after just a few milliseconds at the recovery gap potential, the majority of normal inactivated channels recover, whereas most CBZ-bound channels do not. This would be useful later for studying the binding rate of CBZ.
The binding rate of CBZ is faster than that of DPH.
According to the gray bar area in Fig. 4B, the binding rate of CBZ onto inactivated Na+ channels may be assessed by a voltage protocol similar to that in Fig. 4A, but the prepulse is gradually lengthened with the −120-mV gap fixed at 5 msec in duration. The decrease of the Na+ currents elicited during the subsequent test pulse mostly reflects the increase of the drug-bound inactivated channels, with some contamination from the concomitant increase of the normal inactivated channels, which have not recovered during the 5-msec gap (Fig. 5A). The contamination is corrected by calculating the difference between the Na+ currents in the control and in the presence of drug (Fig. 5B). It is evident that 300 μm CBZ approaches the steady state block faster than 100 μm CBZ, and it is especially interesting to compare the time courses of 100 μm CBZ and of 100 μm DPH. Consistent with the aforementioned conclusion that DPH has a higher binding affinity to the inactivated Na+ channel than CBZ, the steady state block is larger for DPH. However, the binding rate of CBZ is significantly faster than that of DPH because the steady state block is reached much earlier in CBZ. The two time courses thus cross, and for short depolarization, CBZ may actually have a stronger inhibitory effect on Na+ channels than equimolar DPH. Fig. 5C shows that the macroscopic binding rates increase linearly with drug concentration, which supports the presumption in Fig. 1B that CBZ (and DPH) interacts with Na+ channels via a simple one-to-one binding (bimolecular) reaction. It is also demonstrated that the binding rate constant of CBZ (∼38,000m − 1/sec− 1) is ∼5 times faster than that of DPH (∼7,700m − 1/sec− 1).
Although use-dependent block of repetitive discharges resulting from inhibition of Na+ channels is viewed as the major antiepileptic mechanism for both CBZ and DPH, no clear-cut differences between these two drugs has been forwarded to explain the clinical experience that some patients respond much better to one drug than to the other and that some patients require both drugs (combined therapy) to reach a satisfactory control. We have shown that the effects of CBZ and DPH on central neuronal Na+ currents are quite different in both binding affinity and binding kinetics. These differences, when correlated with the established cellular mechanisms of epilepsy, may be helpful in contemplating the pathophysiology and pharmacotherapy for individual seizure patients.
The significance of different binding affinities.
In most focal epilepsy, the cellular events that characterize ictal discharges are prolonged (sustained) depolarization superimposed with high-frequency bursts of action potentials (16, 17; for reviews, see refs. 18, 19). Normally, the Na+ current in hippocampal neurons is huge, and blocking part of it may not affect cellular firings. However, during ictal discharges, prolonged depolarization may drive many Na+ channels into the inactivated state. Some further reduction of the available Na+ channels could therefore successfully inhibit the superimposing bursts of action potentials.
The binding affinity between CBZ and the inactivated neuronal Na+ channel is ∼3 times lower than that of DPH. With high therapeutic concentrations in the cerebrospinal fluid [e.g., ∼8 μm for DPH, ∼13 μm for CBZ (20-23)] and apparent dissociation constants at ∼7 μm (DPH) or ∼25 μm (CBZ), the available Na+ channels would be decreased by ∼53% (DPH) or ∼34% (CBZ) when the steady state of drug action is reached after prolonged depolarization (assuming one-to-one binding). With its stronger steady state inhibition, DPH potentially could be more effective than CBZ against seizures characterized by a relatively long depolarization shift, especially seizures that require such a long depolarization and the superimposing bursts of action potentials to develop and spread (i.e., to drive more neurons to join the hypersynchronous discharge). If the Na+channels in skeletal muscles also carry the same differential affinities to DPH and CBZ as those in central neurons, then the stronger steady state inhibition of Na+ channels by DPH may also explain why DPH is probably better than CBZ in the treatment of myotonia, a disorder also characterized by prolonged membrane potential perturbation associated with repetitive discharges. Because the symptomatic abnormal depolarization of the affected muscle cell is likely quite longer than a few seconds and because the dampening of the repetitive discharges a few hundred milliseconds earlier or later is not critical in this case, DPH may represent a better choice than CBZ for this disorder.
The significance of different binding kinetics.
From the kinetic point of view, the length of interictal or ictal depolarization shift is crucial in discussing the antiepileptic action of DPH and CBZ. With high therapeutic concentrations in the cerebrospinal fluid at ∼8 μm (20,21) and a binding rate constant at ∼8,000m − 1/sec− 1 at room temperature, DPH would have a macroscopic binding rate (the product of drug concentration and the binding rate constant) of ∼0.064 sec. With such a slow rate, DPH would apparently require a sustained depolarization for at least a few seconds to significantly approach its steady state blocking effect on Na+ channels. However, because a large proportion of Na+ channels may have been inactivated during ictal depolarization, DPH may not necessarily reach its steady state effect to abolish the bursts of firings superimposed on the sustained depolarization. Moreover, at body temperatures, the binding must be faster than it is at room temperature. Thus, in most clinical situations, DPH would probably not require seconds of long ictal depolarization to exert its antiepileptic effect, although depolarization for a few hundred milliseconds might still be needed. Such an attribute would ensure that most normal firings are preserved in the presence of DPH but may also make DPH relatively ineffective against seizures characterized by shorter ictal depolarization. This seems to be consistent with a common electroencephalographic concept that DPH blocks seizures but may have much less effect on the frequency of interictal bursting in the cortex. Because the interictal discharges are usually characterized by much shorter paroxysmal depolarization shift, DPH may not have enough time to accomplish the job it could do with more prolonged (sustained) ictal depolarization.
The binding rate constant of CBZ is ∼5 times faster than that of DPH. Along with the ∼1.5 times higher therapeutic concentrations of CBZ in cerebrospinal fluid [5–13 μm (22, 23)], the macroscopic binding rate of CBZ would be ∼7.5 times faster than DPH in clinical conditions. The remarkably faster binding rate of CBZ may make it more effective than DPH against the bursts of discharges superimposed on relatively short depolarization. Those seizures and neuralgias that have a better response to CBZ than to DPH may have underlying cellular correlates that fall into this category. In this regard, it would be interesting to examine whether CBZ is more effective than DPH in decreasing interictal discharges in some seizure patients.
Further arguments for the quantitative concepts.
It is not uncommon to have a patient in whom seizure control is dramatically improved by a small increment in anticonvulsant dose and an increase of the plasma drug concentration from the low to the high therapeutic range, which usually means an increase of anticonvulsant concentration in the cerebrospinal fluid to no more than 1.5 or 2 times the original level. The experiences of different clinical effects with a small change in drug concentration support the view that a ∼3-fold difference in affinity and a ∼5-fold difference in binding rate constant are probably important attributes in accounting for the different clinical effects of DPH and CBZ. The quantitative arguments also provide more insight into the mechanistic rationale underlying combined therapy with CBZ and DPH. With the exception that CBZ might cover shorter ictal depolarization and DPH might have a stronger steady state inhibitory effect on Na+ channels, the clinically relevant concentrations of DPH or CBZ in the cerebrospinal fluid are usually no more than the measured KI of each drug. This indicates that the binding sites in the inactivated Na+ channels are not saturated by CBZ and DPH in most clinical conditions. The combination of the two drugs thus should block significantly more Na+ channels and increase the possibility of abolishing seizure discharges.
Although it is ideal to classify epilepsy and to institute appropriate pharmacotherapy according to the ictal cellular events in each individual seizure patients, so far no practical clinical means could effectively yield such information. On the other hand, correlation of the molecular action of different anticonvulsants with their therapeutic effect in individual patients may represent an indirect but realistic approach to elucidating the underlying pathophysiological events in the patient. Characterization of the molecular action of anticonvulsants may therefore not only contribute to a more sophisticated use of medication but also be helpful in delineating the manifold ictal cellular attributes of human epilepsy.
- Received October 22, 1996.
- Accepted February 4, 1997.
Send reprint requests to: Chung-Chin Kuo, Department of Physiology, National Taiwan University College of Medicine, No. 1 Jen-Ai Rd., 1st Section, Taipei, 100, Taiwan, Republic of China. E-mail: cckuo{at}ntumcl.mc.ntu.edu.tw
This work was supported by Grant NSC-85–2331-B-002–195-M10 from the National Science Council, Taiwan, Republic of China.
- carbamazepine
- phenytoin
- ethylene glycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- The American Society for Pharmacology and Experimental Therapeutics


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Osborne's position is safe, insists Downing Street: No 10 dismisses talk of Hague moving in as Chancellor Downing Street guaranteed George Osborne will stay in his job until 2015Some Tories called for William Hague or Philip Hammond to take the positionTory high command is quietly encouraged by positive signs in the economySource said that the more you criticise Cameron's team the less likely he is to change it PUBLISHED: 00:13 GMT, 1 April 2013 | UPDATED: 02:13 GMT, 1 April 2013 Downing Street guaranteed George Osborne will stay in his job until 2015 last night as the Treasury hailed a new corporation tax cut as a way to boost the faltering economy.
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An unfair policy that fails on every test
An unfair policy that fails on every test By Daily Mail Comment PUBLISHED: 23:36 GMT, 3 January 2013 | UPDATED: 14:59 GMT, 4 January 2013 Unfair: The new plan makes a mockery of David Cameron's oft-made promise to stand up for the traditional family On Monday, the Government's wrong-headed, fiendishly-complicated plan to strip child benefit from 1.2million families will officially come into force. The Mail has long argued this policy – which will remove the benefit altogether from couples where one person earns more than 60,000, yet leave untouched a household in which two parents earn up to 50,000 each – is grotesquely unfair on mothers who wish to stay at home to raise children. It makes a mockery of David Cameron's oft-made promise to stand up for the traditional family, punishes aspiration and, as we reveal today, will disproportionately impact on voters in the Tory heartlands.

subset: commoncrawl


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But it also requires careful research before making a purchase. Because the cannabis plant readily absorbs pesticides, heavy metals and other chemicals that are in the soil and water, it's so important that cannabis plants are frequently tested while they are growing. And it's up to manufactures to test CBD products, too. When you are shopping for CBD oil, look for products that have been tested for contaminants and for CBD vs. THC levels.
A study performed at the Italian Piemonte University and published in 2008 implied that all cannabinoids help the immune system to fight bacteria. Especially potent are five cannabinoids (including CBD), with the study focusing on antibiotic-resistant strains of the Staphylococcus Aureus, a relevant example of the antibiotics abuse the last few decades have witnessed.
A study highlighting this was performed approximately one decade ago. The study found a link between IBS sufferers and clinical endocannabinoid deficiency, which relates back to the fact that the system directly impacts intestinal motility and function. When CBD was used to activate and regulate the endocannabinoid system, sufferers of IBS saw significant symptom improvement. (42)
If you prefer to take your supplements in capsule form, this is one of the best and most cost-effective on the market. The Zipvit CBD is derived from the hemp seed, rather than the hemp plant and that is reflected in the price. The potency remains and the reviews of the products are some of the best online. It's also a much longer lasting product on account of its pack size.
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Dice casino odds
Mar 08, · The following shows the probability of throwing each total in a chart format. As the chart shows the closer the total is to 7 the greater is the probability of it being thrown. Now that we understand the probability of throwing each total we can apply this information to . Knowing the mathematical odds of the dice achieving a certain outcome is the essence of the 2048GAME.MOBI you are going to play for money, then try and remember these odds. For a description of the kind of bets you can make playing Craps, see instructions from a real casino or dice-play's Craps 2048GAME.MOBI you want to understand more about how odds work, see dice odds. The entire process of becoming an expert in playing craps begins with a thorough understanding of all dice combinations as well as the odds. The first important rule to remember is that the combinations determine the odds as well as the payout. Most casinos use red-coloured dice although you can also come across green or blue ones.
Craps Game Odds
Blackjack Blackjack has the best odds of winning, with a house edge of just 1 percent in most casinos, Bean said. If one or both leave the table, it is also a "no roll", and the dice may either be replaced or examined by the boxman and returned to play. Students are trained in every aspect in a casino form running card tables to servicing slot machines. That means that if the shooter rolls a 7 on the come-out roll, any players with active come bets waiting for a come-bet point lose their initial wager but will have their odds bets returned to them. Bean's advice? The dice game Craps offers the best odds in an online casino or a brick and mortar casino, but only if you make the right bets. The following tables show the true odds for the specified outcome of the dice.
Interesting Fact about casino
- The casino is the most common place in which suicides are committed
- The center of the casino is Las Vegas. Every year 40 million gambling people from all over the world come here.
Before you go gambling: The best and worst casino game odds
This page explains both types of craps odds. We refer to payout odds as the number that a bet pays off, and true odds as the probability that a given outcome will appear. The difference between the true odds and the payout odds is the house edge, which is the number that explains how the casinos stay so probable.
Probability is that branch of mathematics that deals with the likelihood of something happening or not happening. A simple example of a probability is a coin flip. The probability of the result being heads is 0. The equation for calculating a probability is to divide the number of ways something can happen by the number of total ways it could happen.
When rolling dice, you can calculate the odds of rolling a 1 by dividing 1 by 6. There are 6 possible outcomes, but the one you want to know is the chance of rolling a 1. For example, if you want to calculate the probability of rolling a total of 2 on 2 dice, you would multiply the probabilities of rolling a 1 on the first die by the probability of rolling a 1 on the second die. That would be expressed in odds as 2 to 1.
The difference between the true odds and the payout odds is what creates an edge for the casino. And like any other business, casinos exist to make a profit. For example, if you make a bet on something that has a 3 to 1 chance of happening, and the casino pays out at 2 to 1 on that bet, the casino will make a profit in the long run.
judging from the ease and even pride with which public health officials now confess their wrongdoing, it's business as usual. But Cassie was already there, her hands running across the lap of Jeff's jeans, squeezing and poking him into an erection. Чтобы побыть один на один со своей второй половинкой, длинноволосая красавица пришла в гостиничный номер и там разделась перед представителем сильной половины человечества.
После прогулки у озера без белья, красноволосая развратница пошла к усадьбе где начала хвастаться небольшими буферами в баньке, после которой длинноногая чика пошла шалить в спальню Великолепная нудистка приехала на море и первый день провела на пляже в оранжевом купальнике, которые сдвинула с интимных мест чтобы тем были видны. - Пропусти.
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Many people will be visiting a casino this summer, whether on a trip to Vegas, on a cruise ship, or just at a local casino during a "staycation. So we went behind the scene at two casinos, and spoke with the game managers, to find out which games give you an edge. Jay Bean, a Caesar's floor manager, agreed to sit down with us and talk about the games with the best odds. He said many people don't realize that table games have much better odds than slots.
They are intimidated by thoughts of card sharks taking their money, with images of an intense Texas Hold 'Em tournament in their minds, and so they stick with the safe games: the slots.
Bean's advice? After you've spent some time on the slot machines, move on to the Blackjack table, and start by just observing. Blackjack has the best odds of winning, with a house edge of just 1 percent in most casinos, Bean said. If you're a novice, Bean said to sit down during a less busy time, such as the afternoon, and the dealer will walk you through the game. But the same is not true with poker: You should practice the game with your friends first, at home, Bean said, until you are comfortable with it.
Bean said novices are best off passing on the poker tables, where yes, the competition can be tough. So from the Blackjack table, he suggests moving on to the dice game Craps, the game with the second best odds, also nearly The Craps table can be a bit intimidating for the beginner with all the boxes on the table, Bean admitted.
But it's really not tough, and it has one of your best chances of winning. In the end, all you are really doing is betting on a dice roll.
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2 thoughts on "John McAfee Endorses Karatbars KBC Coin!! The ICO For KCB Is Coming To An End!!"
Didnt watch your video Jaime but disliked it because McAfee featured on it!
LoL..the problem though with John McAfee is that he does not believe nor care in the functionality, as well as the utility of any token/ crypto by any means. All he cares about is that he gets paid by the company involved with the coin. There has been articles about this with past coins. I am pretty sure if Bitconnect, and Regal coin reached out to him with the right price. He would have promoted them, or talk about them also…just FYI. Not to be negative, just stating fact.


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Recap video of the first Ski to the Sun Marathon and Relay!
We are thrilled to Partner with Methow Trails to bring you the Second Annual Ski to the Sun Marathon and Relay:
The Ski to the Sun has something for every level of skier!
The 42km freestyle race is part of the 2020 American Ski Marathon Series and the new Worldloppet Global Ski Marathon Calendar. Starting in Mazama, skier cruise down valley through the heart of the Methow Valley trail system before an exhilarating climb to breathtaking views and the finish at Sun Mountain Lodge. With a course that links three of four sections of the largest cross-country trail system in North America, there is something for everyone – you can enjoy fantastic scenery as an individual or grab up to 5 friends and make a relay!
Enjoy the fun, festive atmosphere: aid station/relay exchanges with music, food and bonfires as well as your typical gels, water and sports drink; a delicious post-race lunch at Sun Mountain featuring hot drinks, soup, fresh bread and dessert from the Rocking Horse Bakery; finish the day with dinner and awards at the Barn in Winthrop.
Get the most detailed and up to date race information here.


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I don't have a problem with Trump signing MAGA hats for troops. I wouldn't have had a problem with Obama signing his book for troops.
Where I might have a problem is with the provenance of the hats. Is the Baghdad PX selling them? That's a no-no. Did they come in "care" packages from loved ones? That's fine, if misguided. Did the Trump advance team provide them? That's bad and illegal.


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Photo and briefing credit: John Chiseba Mwamba (Zambia) Review: Abdel Rahman El Gamal (Founder of the website) Historic use of termites: The long winged reproductive termite is edible and highly sought after as a delicacy. Moreover, wild-caught termites have been used as a bait to attract fish and insectivorous birds. Natives of South East Africa …
Category: Gallery
Mar 24 2020
Possible use of termites in fish feed
Permanent link to this article: http://fishconsult.org/?p=15493
Mar 08 2020
Extensive farming of red tilapia in Colombia
Photo credit: Andres Delgado (Colombia) Review: Andres Delgado and Abdel Rahman El Gamal (Founder of the website) The inserted pictures show the culture of red tilapia in small ponds at Ricaurte which is a town and municipality in the Nariño Department (Colombia). In such small ponds, extensive farming system is typically applied as locally available …
Permanent link to this article: http://fishconsult.org/?p=15488
Mar 07 2020
Super intensive shrimp farm in Phang Nga (Thailand) – Video
Video credit: Vannamei 101 Description: Vannamei 101 and Abdel Rahman El Gamal (Founder of the video channel) As the video caption tells, the video is affiliated to a super intensive shrimp farm located in Phang Nga, Thailand. The stocking rate of post larvae in the farm is 300 PL/m2. The shrimp culture in the farm …
Permanent link to this article: http://fishconsult.org/?p=15483
Mar 05 2020
Behind the pictures: Night training and water quality in fish ponds
One of the inserted pictures goes back to 1999 during the first training course hosted by the WorldFish Center (Abbassa – Egypt) for 14 Egyptian fish farmers while the second picture goes back to 2008 during an international training course held at the center. The purpose of night training was not just to measure the …
Permanent link to this article: http://fishconsult.org/?p=15480
Mar 05 2020
Marine life in Kuredu Island (Maldives)
Photos' credit: Leonel Antonio Zelaya Cerezo (Guatemala) Review: Abdel Rahman El Gamal (Founder of the website) The inserted picture shows Fish population surveys in Kuredu island (Maldives). Kuredu which is located 150 kilometers from Male, the capital is considered the most popular resort island in Maldives. The reefs fringing the island are easily accessible to …
Permanent link to this article: http://fishconsult.org/?p=15475
Mar 03 2020
Small-scale aquaculture training course – Africa (Egypt – EICA, 2020)
The inserted photo was taken on March 01, during the first technical day of the "Small-scale aquaculture" training course. This 12-day course is organized by the Egyptian International Centre for Agriculture (EICA). The course hosts 25 participants from 21 African countries. My contribution to this course includes two lectures and then supervising group activities on …
Permanent link to this article: http://fishconsult.org/?p=15469
Feb 14 2020
Jebel Aulia fish ladder in Sudan
I filmed this video during my visit to Jebel Aulia dam in October 2018. The dam was built in 1937 by the British across the White Nile to avoid the Nile flood. The dam is located 45 km from Khartoum. The fish ladder shown in the video is located along the eastern side of the …
Permanent link to this article: http://fishconsult.org/?p=15459
Feb 13 2020
Poisoning freshwater puffers in a fish pond (Egypt) or a reservoir (Sudan)
The puffers which have several common names including blowfish, ballonfish and others belong to the "Tetraodontidae" family include more than 120 species that occur worldwide. Although most of blow fish species occur in tropical and subtropical ocean waters, some fish species of this group live in brackish and even freshwater such as the ones shown …
Permanent link to this article: http://fishconsult.org/?p=15457
Feb 09 2020
Création d'une écloserie commerciale Oreochromis niloticus pour soutenir la pisciculture extensive et semi-intensive à Samendeni, Burkina Faso
This project document has been developed by a group of trainees who participated during 2019 in the "Fish Culture Development – Africa training course" which is annually hosted by the Egyptian International Centre for Agriculture (EICA) in partnership with Japan International Cooperation Agency (JICA). The proposed location of this project is Burkina Faso. The names …
Permanent link to this article: http://fishconsult.org/?p=15451
Feb 05 2020
Turtle Excluder Devices (Development and use)
Photo credit: The National Oceanic and Atmospheric Administration (NOAA) Review: Abdel Rahman El Gamal (Founder of the website) The inserted picture shows a turtle escape from a fishing gear. The accidental catch (by catch) of sea turtle in marine environments is a major threat to sea turtle populations worldwide. Often, turtles caught in fishing gear …
Permanent link to this article: http://fishconsult.org/?p=15385


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Having introduced general aspects of disturbance ecology, we can now start to integrate the complexification and the disturbance-induced dynamics of ecosystems. The respective approach is based upon the concepts of the "Resilience Alliance" (see e.g., Holling, 1986, 2004; Gundersson and Holling, 2002; Elmquist et al., 2003; Walker and Meyers 2004; Walker et al., 2004), but they have been restricted to ecosystem dynamics and combined with the sequence of growth forms after Jorgensen et al. (2000) (see also Ulanowicz, 1986a,b, 1997; Fath et al., 2004). Under these prerequisites, we can distinguish the following principle steps of ecosystem development:
- Start of the succession (pioneer stage, boundary growth after Jorgensen et al., exploitation function after Holling, 1986): In this initial state, an input of low-entropy material into the system starts the sere. The developmental potential depends on the genetic information that is available in the seed bank or by lateral inputs. Due to a minor connectivity between the elements, self-regulation is low, leakyness is high, and the sum of potential developmental opportunities (developmental uncertainty) is high. The system provides a very high adaptability and flexibility.
- Fast growth (pioneer stage, structural growth after Jorgensen et al., exploitation function after Holling): Pioneer stages can also be characterized by a high and rapid increase of biomass, correlated with an increase of the numbers and sizes of the ecosystem components. To provide the growing number of participants, the energy throughflow increases as well as exergy degradation, which is necessary for the maintenance of the components. Connectivity is low, and therefore external inputs can modify the system easily; the adaptability is high.
- Fast development (middle succession, network growth after Jorgensen et al., conservation function after Holling): After a first structure has been established, the successful actors start funneling energy and matter into their own physiology. Due to the mutual adaptation of the winning community, the connectivity of the system increases by additional structural, energetic, and material interrelations and cycling mechanisms. The single species become more and more dependent on each other, uncertainty decreases, and the role of self-regulating processes grows, reinforcing the prevailing structure. Adaptability is reduced.
- Maturity (information growth after Jorgensen et al., conservation function after Holling): In this stage, a qualitative growth in system behavior takes place, changing from exploitative patterns to more conservative patterns with high efficiencies of energy and matter processing. Species that easily adapt to external variability (r-selected species) have been replaced by the variability controlling K-strategists; the niche structure is enhanced widely, and loss is reduced. The information content of the system increases continuously. A majority of the captured exergy is used for the maintenance of the system; thus, there is only a small energetic surplus, which can be used for adaptation processes. Sensitivities versus external perturbations have become high, while the system's buffer capacities are much smaller compared with the former stages of the development. These items result in a rise of the system's vulnerability and a decrease of resilience (see Table 7.4). Adaptability has reached minimum values.
- Breakdown (release function after Holling, creative destruction after Schumpeter, 1942): Due to the "brittleness" of the mature stages (Holling, 1986), their structure may break down very rapidly due to minor changes of the exterior conditions. Accumulated resources are released, internal control and organization mechanisms are broken, and positive feedbacks provoke the decay of the mature system. Uncertainty rises enormously, hierarchies are broken, and chaotic behavior can occur (Figure 7.3). There are only extremely weak interactions between the system components, nutrients are lost and cycling webs are disconnected. Adaptability and resilience have been exceeded.
- Reorganization: During this short period the structural and functional resources can be arranged to favor in new directions, new species can occur and become successful, and—in spite of the inherited memory (e.g., seed bank of the old system and neighboring influences)—unpredictable developmental traits are possible. There are weak controls, and innovation, novelty, and change can lead to an optimized adaptation on a higher level. - Reset: A new ecosystem succession starts.
The described sequence has been illustrated in Figure 7.6 as a function of the system's internal connectedness and the stored exergy. Starting with the exploitation function, there is a slow development. The trajectory demonstrates a steady increase in mutual interactions as well as an increase in the stored exergy. As has been described above, this energetic fraction can be distinguished into a material fraction (e.g., biomass, symbolizing the growth conception of Ulanowicz, 1986a,b) and the specific exergy that refers to a complexification of the system's structure (development after Ulanowicz). In spite of multiple variability (e.g., annual cycles), the long-term development shows a steady increase up to the mature state. Here the maximum connectivity can be found, which on the one hand is a product of the system's orientation, but which also is correlated with the risk of missing adaptability, which has been nominated as over-connectedness by some authors. After the fast releasing event, the short-term conditions determine the further trajectory of the system. It might turn into a similar trajectory or find a very different pathway.
This figure looks very similar to the well-known four-box model of the Resilience Alliance, which has been depicted in Figure 7.7. The difference between these approaches lies in the definition of the y-axis. While for interdisciplinary approaches and analyses of human-environmental system the special definition of "potential" in the adaptive cycle metaphor seems to be advantageous; from our thermodynamic viewpoint, the key variable
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Start Saving On Your Electricity Bills Using The Power of the Sun And Other Natural Resources!


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Black Widow gets a release date!
With all of the movies and series that were announced at last year's San Diego Comic Con, Marvel has been really quiet about what is going on or what is coming out next. However, today we got a trailer for the latest MCU movie which is simply entitled, Black Widow. The movie focuses on Natasha Romanov who plays the title character as she ventures back to Russia. She is going back home to stop running from her past and to put old rivalries to rest. While in Russia she notices that she is being hunted by a character known only as Taskmaster. Black Widow knows she will need some help and she will have backup with not only her sister joining the fight but also a character known as Red Guardian.
Marvel Studios Drops Black Widow Teaser
Black Widow gets a release date!
This looks like it's going to be an amazing movie!
If you love the character featured in The Avengers then you need to check out Black Widow as it comes to movie theaters in May 2020!
What do you think about the new trailer for Black Widow? Are you excited to see this film? Let us know by commenting below!


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Book your computer in today for both Hardware and Software service together, for a bundle deal of £50, That's a saving of £20
We recommend getting your computer/laptop serviced at least once a year, that way you prolong the life of it but keep it running smoothly.
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Malware: Malware is short for malicious software that can damage your computer or track you and how you use the internet. A virus is a type is Malware.
Registry: Your computer has alot of stuff to store and do. The registry is a big database of settings and information the computer needs.
Bloatware: When you buy a brand new device, Bloatware is software that is bundled with it.
Driver: The software needs to talk to the hardware somehow, A driver is a bridge between them. Just like a car cannot drive itself, it needs a driver (Untill recently, Thanks Elon).
When it comes to replacing parts on your device, in the UK we have a few options available to us.
Genuine Parts are made by the same people who made your device, so you if want a Samsung made screen on your Samsung phone, ask for genuine.
OEM Parts, OEM, stands for Original Equipment Manufacturer, this means it is the exact same quality as the one found inside your phone already. These are typically made within the same factory as the manufacturer, or a licenced vender of the manufacturer.
Aftermarket Parts: Aftermarket Parts are not made by the manufacturer but are the same specifications or higher than Genuine and OEM by reputable companies such as replacing your HP laptop battery with a Duracell battery. Both HP and Duracell are big reputable companies.
Compatible Parts: from us these are the same as Aftermarket Parts. Other companies will have their own definition of Compatible Parts
eBay Compatible Parts: These vary from company to company. This depends on where you purchase it from and if they have branded it. Most compatible parts on eBay are cheap quality, whilst most would do the do job, they are not built to last. we do not sell or use these parts.
Fake/Counterfeit Parts We DO NOT sell, use, or even touch fake/counterfeit parts AT ALL. PERIOD. These are almost always very cheap components, with a high qualty finish that has the genuine logos stamped on the frame. These WILL break, and could cause lawsuits.
We at Central Computers Driffield will only work with parts from our trusted suppliers within the UK dealing with, Genuine where possible, OEM, or Aftermarket only.


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ADM expands feed production with new $40m facility
The Illinois-based company announced the opening of the new feed production facility in Quincy, Illinois last week [April 3]. The site is one of six company locations in the Quincy area.
The group invested $40m in the new feed facility, said Brad Dalke, vice president North American animal nutrition, ADM.
The technology and manufacturing capabilities within the new factory means it can adapt to suit customer needs. "We've also added automated process and packaging controls to improve efficiency, quality and employee safety," he told us.
Facility details
Construction on the new manufacturing facility started in September 2017, said Dalke. The location was selected based on strategic advantages already present in the area.
It also is next to the site of an older ADM feed production plant, according to company information.
Warehouse space, access to transportation and a location convenient to an existing customer base also helped recommend the spot for the new facility, Dalke said.
"The new site sits on approximately 10 acres," he said. "We've added about 24,000 square feet and 20% capacity."
The site also will have a dedicated non-medicated feed production line, he added.
Additionally, the new feed facility includes technology allowing it to generate pressed tubs for several species and improved manufacturing capabilities, the company said.
Work on the new production facility was done in conjunction with animal nutrition projects in China, said Dalke. And the project's completion follows the opening of livestock feed manufacturing sites in Effingham, Illinois; Columbus, Nebraska and Glencoe, Minnesota.
And ADM has underlined its ambitions for the global animal nutrition space over the past few years with several acquisitions, expansions and investments.
"With the recent acquisition of Neovia, we've substantially expanded our geographic reach and portfolio," he said. "By purchasing Crosswind Industries, we've become a leader in the pet treat segment of companion-animal nutrition [and] our partnership with China-based Qingdao Vland Biotech Group and our cutting-edge research lab in Davis, California, will help us develop and commercialize animal feed enzymes."
"Purchasing Protexin, a leading [UK} provider of probiotic supplements, has opened up new opportunities in health and wellness for the aquaculture, equine, livestock and companion-animal markets," he added.


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Monday, Mar 30 Go to Bare Necessities Store Rating: rate it
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Fried Brown Rice with Egg
A healthy fried brown rice with egg and lots of veggies. This Chinese restaurant-style fried rice is an excellent fibre-rich meal.
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Creamy and super flavourful baked chicken pasta, made with sausages and veggies which are tossed in a luscious bechamel sauce.
Chicken Spaghetti | Easy Dinner Recipe
Rich and comforting chicken spaghetti, made with minced chicken which is cooked in a tomato-based curry. This pasta dish is an excellent midweek dinner.
Kosha Mangsho | Bengali Mutton Curry
Authentic Bengali Kosha Mangsho recipe made in a pressure cooker. Learn how to cook this scrumptious and succulent mutton curry in just four easy stages.
Easy Chickpea Tikka Masala | Chickpea Recipes
Looking for a meatless or vegetarian protein-rich dish? This recipe is perfect for you. Chickpea tikka masala is incredibly tasty and satisfying.
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Soru chakli is a thin pancake made with rice and urad dal (black gram). It is an easy Bengali pithe recipe which takes only 35 minutes.


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Video demo : https://www.youtube.com/watch?v=qpqdbxZuo1M&t=0s
Mod portal link : https://mods.factorio.com/mods/devilwar ... tinguisher
Git repository : https://github.com/jfmmm/Factorio-fire-extinguisher-mod
It work just like the flamethrower, but remove flame instead of placing them.
The fire entity don't have health so they are removed instantly, I'm still trying to figure out if I can fade them out over several ticks.
I'm considering nerfing the range to about 60-75% the one of the flamethrower and would love your opinion about that.
- Bob mod ingredient support (better recipe with co2 and shit, not a chemist so would love some help with figuring that out)
Better ground texture and some powder that flow in the wind once I figure out how to tint the flamethrower smoke white.
- Fire extinguisher capsule with larger coverage area, for when you rather use you 3 weapon slot for something with more DPS.
- Fire extinguisher weapon slot for tank and car.
- Fire extinguisher turret (not sure how that would work yet).


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Thanks for your interest in Clickfunnels Get Clickopitin Link!
I'm currently working on a detailed video to get you the latest information on this…
But in the meantime…
Checkout the best ClickFunnels offers, benefits, and features below.
In this day and age, the method your service runs online can make or damage you.
Exactly how do most services currently have an existence online?
The truth of the issue is, nevertheless, that internet sites have considerably evolved over the past years – as well as the methods of old are no longer practical for modern day company.
Back then, it would be sufficient to have a straightforward website with a web page, services, prices, about us, and also contact web pages.
A prospective client would most likely to your site, scroll about, go to the different pages as well as take in material as they please.
Nonetheless, if you are an organisation investing any cash on advertising and marketing, you want to manage just what clients are learning about on your website, existing offers at the correct time, as well as optimize the earnings you make from each person.
How does one attain this?
Utilizing sales funnels.
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ClickFunnels is the simplest means to earn high converting sales as well as advertising funnels.
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Below is my thorough ClickFunnels Testimonial, consisting of favorite functions, prices, pros/cons, as well as comparisons against rivals.
Clickfunnels Get Clickopitin Link: But First, What Exactly Is a Sales Funnel?
Sales funnels (also called advertising funnels) are multi-step projects that are made to move prospective leads via your sales procedure, and also transform them into purchasers.
Image a real-life funnel. At the top, you pour fluid in, which narrows down in the direction of one taken care of destination.
In sales, a comparable event occurs. On top, site visitors arrive at your website, however not all that get in make it from the other end as purchasers.
Lots of things need to happen from the moment a visitor enters your funnel, to the time they act as well as successfully finish a purchase.
By damaging down the consumer's trip right into smaller sized actions, you could be a lot more specific regarding how when you offer an offer to your target market.
The comprehensive steps in a funnel might look something like this:
- Unqualified lead arrives at touchdown web page
- Page communicates the initial deal (something totally free to accumulate an e-mail).
- Once e-mail is collected, major offer is pitched.
- Lead becomes a paying consumer.
- Even more e-mail communication supplying consumer worth.
- More relationship building
- Repeating sales.
ClickFunnels also has a graphic that discusses this in a straightforward method:.
What is ClickFunnels?
As discussed earlier, ClickFunnels is the very best sales funnel software around today.
The business makes the vibrant case of giving you every little thing you need to market, sell, as well as supply your items online – and also they most definitely supply.
A standard channel will make use of an opt-in page (to gather e-mail addresses), an e-mail auto -responder (to send emails to your customers), plus an added sales web page with some web content and an order type, potentially adhered to by added material, a membership website, and so on
. Previously, you would certainly have to make use of different systems and also devices to complete every one of these tasks such as:
- Create a website
- Discover Hosting
- Discover an autoresponder solution
- Find membership site software program
- Discover split-testing software program … and so on
Yet ClickFunnels takes care of every little thing with their system. You not just save a ton of loan by not having to acquire various products/services, however you likewise avoid the technological mess of having to set every little thing up, and also could focus on just what's truly essential – growing your organisation.
ClickFunnels supplies a Free 14-Day Test, so you get to discover the tool and really see if it's ideal for your service.
Favored Attributes
* Rapidly Develop Pages Using Templates and also Components *.
Before obtaining also much, it is necessary to understand that a channel is a collection of web pages created in a calculated order, with the goal of converting as numerous potential customers right into consumers. And also a web page is merely a collection of various elements developed to obtain a person to take a certain activity.
ClickFunnels supplies more compared to 50 various elements to help you build the excellent web page. The editor is incredibly easy to make use of and all you have to do is drag and also go down various aspects on the page, and also upgrade the text as well as appearance to fit your requirements – no coding abilities called for!
ClickFunnels likewise makes your life easier by offering you with a ton of cost-free layouts.
As a matter of fact, ClickFunnels provides over 37 kinds of pages for you to blend as well as match with. These are broken down into the adhering to 10 classifications:
- Presell Pages: Study Web Page, Short Article Page, Presell Page, Clickpop Page
- Optin Pages: Press Page, Reverse Press Web Page, Lead Magnet, Discount Coupon
- Thanks Pages: Thank You Web Page, Offer Wall, Bridge Page, Share Page
- Sales Pages: Video Sales Web Page, Sales Letter Page, Item Release Web Page
- OTO Pages: Upsell Page, Downsell Web Page
- Order Forms: 2 Action Order Page, Conventional Order Page, Video Sales Letter Order Web Page, Sales Letter Order Web Page, Product Release Order Web Page
- Webinar Pages: Webinar Enrollment Web Page, Webinar Confirmation Page, Webinar Program Room, Webinar Replay Space
- Subscription Pages: Gain Access To Page, Member's Location
- Associate Pages: Accessibility Web Page, Associate Location
- Various Other Pages: Application Web Page, Ask Page, Shop Front, Home Page, Hero Web Page, Hangout Page, Live Demonstration Page
The pre-built layouts are totally personalized, as well as are just what most customers utilize.
You have the ability to pick a theme, modify or replace the elements with your own, and also your new web page is ready to go.
You could likewise connect any type of channel you develop with your own email advertising solution (if you do not use the one consisted of in ClickFunnels), and also use the ClickFunnels integrated in billing system.
This is additionally a fun time to mention that ClickFunnels offers really useful and understandable training videos when you first join. I very recommend going through those due to the fact that they promptly allow you to make use of the device at its complete capability, as well as you'll have more enjoyable playing around. Clickfunnels Get Clickopitin Link
* Create One-Click Subscription Websites *.
One of the most effective attributes with ClickFunnels is the capability to easily produce subscription websites as well as deliver web content to your audience in one area.
Your subscription website will certainly come complete with enrollment pages, subscription access web pages, and also content web pages which you can easily secure or drip feed to your clients according to purchases they made in your funnel.
ClickFunnels membership sites allow you to send e-mails, easily handle your emails, and also build an area all while removing the stress and anxiety that's associated with other solutions such as Kajabi, or WordPress platforms.
It's really convenient to not need to get a separate software or plugin to develop membership websites.
* Email Combination & Actionetics *.
With every funnel comes email list building opportunities.
ClickFunnels sustains email assimilation with every one of the significant email automation systems such as:
- Active Campaign
- Aweber
- Constant Contact
- ConvertKit
- Drip
- Get Response
- Hubspot
- InfusionSoft
- Mad Mimi
- MailChimp
- Market Hero
- Ontraport
- Salesforce
- Sendlane
- And others
However, ClickFunnels also has their very own powerful automation device called Actionetics.
Although you can produce, schedule, and deliver emails just like other e-mail advertising and marketing system, Actionetics is so much more.
I like Actionetics due to the fact that it not just changes your e-mail advertising and marketing however messenger advertising and marketing as well as SMS marketing software programs as well. This takes automation to a whole new level as well as aids you connect the best message to your consumers, precisely when they require it. A video clip summary of Actionetics will be offered even more listed below.
* Payment as well as Repayment Integration *.
A fantastic function within ClickFunnels is the capability to accumulate every one of the payment details from your clients precisely your sales page. Marketing is made so much easier when customers don't need to leave your website.
ClickFunnels incorporates with significant payment portals such as PayPal, Stripe, as well as InfusionSoft, among others.
ClickFunnels Pricing.
While you could begin with the Free 14-Day Trial, there are three different pricing choices with ClickFunnels:
- $ 97/month.
- $ 297/month.
- $ 997 bulk discount rate plan (advised).
I'll go into detail for each of these plans listed below.
1. ClickFunnels Requirement Plan – $97/month.
The conventional strategy consists of all the attributes you would certainly need within ClickFunnels, but with restrictions on the variety of funnels (20) and pages (100) you can have in your account, in addition to the number of site visitors (20K) can watch your pages monthly.
You likewise do not receive innovative functionality such as ClickFunnels very own email marketing and also affiliate tracking tools.
2. ClickFunnels Etison Suite – $297/month.
This strategy includes all the bells and also whistles of the basic plan, with no constraints. It also features two added products produced by ClickFunnels called Actionetics (email advertising) as well as Backpack (affiliate monitoring platform).
In Actionetics – you can manage all of your get in touches with that sign up for your list, send out e-mail broadcasts, and create a host of other automations. Clickfunnels Get Clickopitin Link
The distinction in between the two plans truly is the limitations, as well as Actionetics/Backpack. If you are a basic individual as well as do not anticipate to use more than 20 funnels in your account – the Criterion Plan must be sufficient.
However, if you prepare to have an affiliate program or intend to maintain your e-mail advertising within ClickFunnels as well as not utilize a third party software program, the Etison Suite is for you.
You could constantly begin on the reduced plan and upgrade if required.
3. Funnel Hacks System – $997
For anybody that's serious about their company, the ClickFunnels Funnel Hacks System is the offer of the century.
The $997 Funnel Hacks System consists of durable training programs bundled with 6-month accessibility to the ClickFunnels Etison Suite.
This is an extraordinary deal considering that beyond this program, 6-months of Etison Suite alone would cost you $1782.
Not only are you saving $785 however you're obtaining a ton of trainings and guides to aid you get the most out of ClickFunnels!
ClickFunnels Advantages And Disadvantages
- Creating funnels is really basic, very easy, as well as fast
- All-in-one platform with whatever your organisation has to win
- Split screening and conversion monitoring consisted of
- Email combination with all the significant e-mail autoresponder systems
- Settlement processing abilities within ClickFunnels
- ClickFunnels is always adapting and also updating to the times
- There is constantly sustain offered (whether live or otherwise).
- Exceptionally active Facebook Group Community.
- Free 14-Day Trial – permits you to attempt it take the chance of cost-free.
- As amazing as ClickFunnels is, it certainly is not a low-cost option as well as needs a continual subscription to make use of
- Support isn't really constantly the fastest and might take from 1 minute to 24-HOUR depending upon the issue.
ClickFunnels versus Every person Else.
Many individuals ask how ClickFunnels compares with various other landing page building contractors such as Leadpages, Unbounce, and Infusionsoft.
Generally it's not actually a reasonable comparison due to the fact that each of these tools stands out is one area or the various other.
The chart above gives a complete evaluation – however I'll highlight some of the major contrasts listed below.
ClickFunnels vs Leadpages
Before ClickFunnels, Leadpages was the huge pet dog.
Leadpages is simply a lead capture software – nothing more. You could produce touchdown web pages, lead boxes, gather leads … that's virtually it. Furthermore, the Leadpages themes are additionally restricted on modification.
ClickFunnels is far more flexible – it's much easier to utilize and does so a lot more compared to create lead capture pages.
Put simply, Leadpages is actually simply a touchdown page building contractor, while ClickFunnels is focused around constructing very integrated funnels.
ClickFunnels vs Infusionsoft
Infusionsoft is not a landing web page or sales page contractor. It has some of that functionality constructed it, but that's not just what it's understood for.
At it's core, Infusionsoft is a CRM system – one that permits you to manage your whole customer data source. ClickFunnels has this capability with Actionetics, however it's not nearly as advanced as Infusionsoft.
Infusionsoft is additionally incredibly pricey and also forces every new client to pay $2000 for a compulsory kickstart training bundle just to discover how you can utilize the complicated system (which is notoriously tough to make use of).
ClickFunnels Affiliate Program
There are 2 primary paths people decrease as ClickFunnels customers.
Those that choose to make use of the device for their company – in hopes of eventually attain both Comma Club (over $1M in revenue).
As well as those that have an interest in earning easy revenue as a ClickFunnels Associate as well as winning the Desire Auto Contest (where they pay $500/$1000 to your desire auto if you reach 100/200 active month-to-month signups, specifically).
With a monstrous 40% month-to-month reoccuring compensation, ClickFunnels quickly has among the greatest associate programs of any kind of system out there.
That's right – you get paid a recurring 40% payment on every associate signup you make through the ClickFunnels Affiliate Program. Yet, exactly what does that truly equate to?
The standard plan is a $97/month investment and also the Etison Collection strategy is a $297/month financial investment. therefore you make $38.80 per fundamental strategy and $118.80 each Etison Collection strategy … each and every month!
Typically, every 100 signups will bring in $4000/month in affiliate compensations (essentially relying on how many Etison Plan customers are in there).
Click here to learn more concerning becoming a ClickFunnels Affiliate.
All-time Low Line
ClickFunnels is pass on the greatest platform if you are planning to quickly develop high converting sales funnels.
Since it was built from scratch to be the best sales funnel building contractor, it vanquishes every one of the competition because regard.
Externally, it might not be the most affordable item available – but if you utilize it to its full capability, your organisation will become much more lucrative as well as you will save money from not needing to use various other tools. Clickfunnels Get Clickopitin Link
If you've reviewed this much into my ClickFunnels Review, I suggest you see on your own with a Free 14-Day Test below.


text:
浪琴錶 / Wittnauer "Weems Hour Angle Sidereal Time",機芯號 5442726,錶殼號 5442726,參考號 16,Cal. 18.69N,47 mm,約 1936
Longines / Wittnauer "Weems Hour Angle Sidereal Time", Movement No. 5442726, Case No. 5442726, Ref. 16, Cal. 18.69N, 47 mm, circa 1936
An aviator's rare, oversized wristwatch with centre seconds, sidereal time regulation and Weems second setting system
Case: silver, hinged push back. Dial: enamel chapter ring, inner silvered rotating disc.
During the early years of aviation between 1920 and 1930 the majority of pilots wore watches by Longines - at the time Longines was far ahead of other companies when it came to technical innovation.
Exact timekeeping was crucial for the progress in aviation and in the late 1920 an era of revolutionary developments in the navigation sector was set in motion. A pioneer in this field was US Navy Captain Philip Van Horn Weems, who was a teacher of the famous Charles A. Lindbergh. He invented a second-setting mechanism which allowed the pilots to set their watches to the closest second - Weems created a mobile dial for synchronising the second with the radio time signal. Longines patented this brilliant system in 1935.
錶殼 非常好, 少有使用過
錶盤 非常好
机蕊 非常好, 走動正常
錶盤 非常好
机蕊 非常好, 走動正常


text: International Research Journal of Engineering and Technology (IRJET) e-ISSN: 2395-0056 Volume: 06 Issue: 03 | Mar 2019 p-ISSN: 2395-0072 www.irjet.net Arduino based Four-Wheeler Accident Detection and Prevention System Ashwin Hukare1, Dhanashree Nannaware2, Himanshu Shukla3, Rupali Kumare4, Prof. S.K. Meshram5 1234UG Student, Department of Electronics &Telecommunication Engineering, UG Government College of Engg. Chandrapur, Maharashtra, India 5Assistant professor ---------------------------------------------------------------------------***--------------------------------------------------------------------------- Abstract -Nowadays we can track vehicles using many current location of the vehicle using the GPS module and the co-ordinates are then sent via messages to emergency services and/or contact the user to stored. The major components used in this device are:1) Arduino UNO 2) GPS eb-3531 with external antenna 3) GSM module with SIM card 300 4) IR sensor 5)MQ 3 6)ADXL-335 7)ultrasonic sensor applications which helps to achieve personal vehicles, public vehicles, feet units and others. Furthermore there is a quick increment in the phenomenon of the road accident . This paper is about the system which will detect the accident and inform to the nearest medical services about it. This system will directly track the place where accident has occurs and the medical facility will go there. The main aim of this system to prevent accident as well as to detect the accident using GPS and GSM. The system compare between accelerometer, MCU, gsm&gps module which will support in sending message. Accelerometer help to detect axis value when vehicle is tilled in clockwise and anticlockwise direction as well as ir sensor is used to detect whether the wheels are rotating or not. 1. INTRODUCTION Fig -1: Block Diagram of Accident Detection System We have observed that over the past decade the usage of automobile has improved linearly due to this there is a increase in risk of human life. This happened because of insufficient emergency facilities. In this paper we also detect the alcohol if driver has drunk it. A 3 axis accelerometer sensor is also used to detect the accident. When the accident occurs, the axis coordinate will change and data will collect by the arduino. The accident will detect with the help of IR sensor and ADXL-335. The angle of rolling of car is indicated through message. This application helps in providing practical solution to the poor emergency facilities and can save the precious life. Advantages of this systems are: Disadvantages of this system are: 2. SYSTEM DESIGN In this project arduino is used for controlling entire process with a GPS receiver and GSM module. GSM module is used for sending the alert message with the coordinate and link to Google map. The GPS + GSM shield and the impact sensor will get power from the Arduino board itself. The circuit is first started the GPS + GSM module is turned on. The system waits till the GSM module gets a signal and is registered with the network. The system then goes on hold until the impact sensor gives a positive output. Once the accident is detected, arduino get the © 2019, IRJET | Impact Factor value: 7.211 The vehicle which has undergone to an accident can be identified by using tracking technology without any delay. The immediate medication will be provided to the accident victims in the remote area. Mobile number can be changed at any time. The system isn't police dependent. | In some places where there is no provision of GSM networks it is difficult for communication This sensor is partial pressure sensitive and therefore may change sensitivity with change in altitude and elevation. The system cannot prevent due to others fault however if any mishap happens the system sends a message to the family members. ISO 9001:2008 Certified Journal | Page 5299 International Research Journal of Engineering and Technology (IRJET) e-ISSN: 2395-0056 Volume: 06 Issue: 03 | Mar 2019 p-ISSN: 2395-0072 www.irjet.net 3. COMPONENTS 3.1Arduino UNO The arduino UNO board is a microcontroller based on the atmega328. It contains 14 digital input/output pins , six analog inputs, a 16 MHz crystal oscillator, a power jack, a USB connection and a reset button. It has everything needed to help the microcontroller; simply connect it to a computer by using USB cable or power it with an ac-to-dc adapter. Fig -2: ADXL-335 The Arduino UNO vary from all previous boards because it does not use the Parallel-to-serial driver chip. Instead of it aurdino UNO features the atmega8u2 programmed as a USB-to-serial converter. Revision 2 of the arduino UNO board has a resistor pulling the 8u2 hwb line to ground, making it simple to put into mode. The Arduino UNO smd r3 is a microcontroller board based on the atmega328. Extra features coming with the r3 version are: ‐ atmega16u2 instead 8u2 as USB‐to‐serial converter. ‐ 1.0 pinout: added SDA and SCL; pins for twi communication fixed near to the aref pin and two other new pins fixed near to the reset pin, the IO ref that allow the shields to adapt to the voltage obtained from the board and the second one is a not connected pin, that is reserved for future purposes. ‐ stronger reset circuit. In Italian "uno" means "one" and is named to mark the coming release of arduino 1.0. The UNO and version 1.0 will be the reference versions of arduino, the uno is the trending in a series of usb arduino boards, and the reference model for the arduino platform. The ADXL-335 is a small, thin, complete 3-axis ,low power accelerometer with signal conditioned voltage outputs. It can measure the static acceleration of gravity in the application of tilt-sensing , as well as in dynamic acceleration resulting from shock, vibration, or motion. We can selects the bandwidth of the accelerometer using the cx, cy, and cz capacitors at the xout, yout, and zout pins. Bandwidths can be selected to suit the application, with a range of 0.5 hz to 1600 hz for the x and y axes, and a range of 0.5 hz to 550 hz for the z axis. The adxl335 is available in a small, low profile, 4 mm × 4 mm × 1.45 mm plastic lead frame chip scale package (lfcsp_lq). 3.3 IR Sensor Infrared sensors has two typeswhich is passive or active. Passive infrared sensors are used for infrared detection. Passive infrared sensors do not use any infrared source and detects energy released by obstacles in the field of view. They are of two types: quantum and thermal. Thermal infrared sensors use infrared energy as the source of heat . Thermal infrared detector has types which are thermocouples, piezoelectric detectors and bolometers. Quantum type infrared detectors give higher detection performance and are faster than thermal type infrared detectors. Quantum type detectors has wavelength dependent photosensitivity . Quantum type detectors are further classified into two types which are intrinsic and extrinsic types. Intrinsic type quantum detectors have photoconductive cells and photovoltaic cells. Active infrared sensors consist of two elements which are infrared source and infrared detector. Infrared detectors include photodiodes or phototransistors. The energy released by the infrared source is reflected by an object and falls on the infrared detector. 3.2 ADXL-335 Acceleration is a process of changing of velocity with respect to time and it is a vector quantity. Similarly, velocity is a speed and direction. Accelaration can be explain by changing speed and direction .sometimes both are changed simultaneously. ADXL 335 accelerometer, is a device that is used for measuring acceleration of any object. It measures the acceleration in the form of analog inputs, in three dimension direction such as x,y and z. It is low noise and less power consume device.For acceleration measure purposes it is interfaced with any type of controller such as microcontroller or arduino etc. It is used in construction working machines such as driving piles drilling and demolition etc., human activities machines such walking, dancing and skipping, running etc © 2019, IRJET | Impact Factor value: 7.211 | ISO 9001:2008 Certified Journal | Page 5300 International Research Journal of Engineering and Technology (IRJET) e-ISSN: 2395-0056 Volume: 06 Issue: 03 | Mar 2019 p-ISSN: 2395-0072 www.irjet.net 3.4 GPS Module The modem needed only 3 wires (TX, RX,GND) power supply not required to interface with microcontroller or host pc. Using this modem, you will able to send and read SMS, connect to internet into the GPRS through simple at commands GPS is global positioning system and used to detect the latitude and longitude of any location on the earth. GPS module is used to find the location of accident . This device receives the data from the satellite for each and every time to find the location of accidents. GPS module send the data related to tracking position in real time, and it sends so many data. Format consists many sentences, in which we only need one sentence. Fig -4: GSM Module Features: • high quality product (not hobby grade) • band GSM/GPRS Fig -3: GPS Module • 850/ 900/ 1800/ 1900 MHz GPS satellites revolve around earth twice a day in a precise orbit. Each satellite transmits signal and orbital parameter allows GPS devices to decode and compute the precise location of the satellite. GPS receivers use this information. GPS receiver measures the distance each satellite by the amount of time takes to receive a transmitted signal. If the position is determined then gps system is use to find other information such as: • speed • bearing • track • distance to destination • SMA connector with GSM l type antenna. • audio interface connector • most status and controlling pins are available connector • input voltage is 5v-12v d. 3.6 Ultrasonic sensor 3.5 GSM Module GSM modem is develop by SIM com make sim900 and quad-band GPRS engine, works on frequencies 850 MHz, 900 MHz, 1800 MHz and 1900 mhz. It is very compact in size and easy to use in GSM modem. The modem is develop with RS232 level converter . Which is directly interface pc port .the baud rate configurable from 9600-115200 through at command. At start modem is auto baud mode. It is suitable for SMS and as well as for the data transfer application in m2m interface. © 2019, IRJET | Impact Factor value: 7.211 Fig -5: Ultrasonic Sensor | ISO 9001:2008 Certified Journal | Page 5301 International Research Journal of Engineering and Technology (IRJET) e-ISSN: 2395-0056 Volume: 06 Issue: 03 | Mar 2019 p-ISSN: 2395-0072 www.irjet.net REFERENCES The accident prevention system helps to avoid the accidents that will normally occurring on highways and city traffic. [1] C.prabha, r.sunitha, r.anitha. "automatic vehicle accident detection and messaging system using gsm and gps modem", vol. 3, issue 7, july 2014 These accidents are mainly happened due to various problem, unconsciousness, distance unknown between our vehicles. So now consider indian roads and we will have 2 ultrasonic sensors where one is placed in the front and another one behind the car. Due to this sensor, we can calculate the distance of other automobiles which are locating near us. Thus we can locate other cars and we can protect ourselves from accidents. [2] megalingam, r.k, nair, r.n. and pakya, s m(2010) wireless vehicular accident detection and reporting system, 2010 [3] jules white, christhompson, hamilton turner, briandougherty, and douglasc.schmidt, "wreckwatch: automatic traffic accident detection and notification with smartphones" in journal of mobile networks. 3.7 Alcohol Sensor MQ-3 The analog gas sensor - mq3 has the function to detecting alcohol, this sensor can be used to detect the alcohol. It has a high sensitivity to alcohol and low sensitivity to benzene and the sensitivity can be adjusted by the potentiometer. The material used for mq-3 gas sensor is sno2, which with lower conductivity in clean air. The sensor's conductivity is higher along with the gas concentration rising, use of simple electro circuit. The mq3 gas sensor is high sensitive to alcohol, and it has good resistance to disturb of gasoline, smoke and vapor. Character configuration: • good sensitivity to alcohol gas • simple drive circuit • long life and low cost • high sensitivity to alcohol 4. CONCLUSION The proposed system is developed to provide the information about the accident occur and the location of the accident. It helps to easily provide the assistant and useful for the victim of the accident. This system uses GPS module to locate the vehicle. GSM is used to give the information of accident. The results of the proposed systems are satisfactory. After this system can be implemented by using sound sensor, in order to make it more correct and beneficial to detect an accident. This is extended with alcoholic detection also. If the person has taken alcohol who is driving then the vehicle will be stopped immediately by giving alarm. This can also be developed by interconnecting camera to the controller module that takes the photograph of the accident place makes tracking easier. © 2019, IRJET | Impact Factor value: 7.211 | ISO 9001:2008 Certified Journal | Page 5302