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Block of a sarcoplasmic reticulum anion channel (SCl channel) by disulfonic stilbene derivatives [DIDS, dibenzamidostilbene-2,2′-disulfonic acid (DBDS), and 4,4′-dinitrostilbene-2,2′-disulfonic acid (DNDS)] was investigated in planar bilayers using SO as the conducting ion. All molecules caused reversible voltage-dependent channel block when applied to either side of the membrane. DIDS also produced nonreversible channel block from both sides within 1–3 min. Reversible inhibition was associated with a decrease in channel open probability and mean open duration but not with any change in channel conductance. The half inhibitory concentration for cis- and trans-inhibition had voltage dependencies with minima of 190 nM and 33 μM for DBDS and 3.4 and 55 μM for DNDS. Our data supports a permeant blocker mechanism, in which stilbenes block SCl channels by lodging in the permeation pathway, where they may dissociate to either side of the membrane and thus permeate the channel. The stilbenes acted as open channel blockers where the binding of a single molecule occludes the channel. DBDS and DNDS, from opposite sides of the membrane, competed for common sites on the channel. Dissociation rates exhibited biphasic voltage dependence, indicative of two dissociation processes associated with ion movement in opposite directions within the trans-membrane electric field. The kinetics of DNDS and DBDS inhibition predict that there are two stilbene sites in the channel that are separated by 14–24 Å and that the pore constriction is ∼10 Å in diameter.
- 4,4′-dinitrostilbene-2,2′-disulfonic acid
- dibenzamidostilbene-2,2′-disulfonic acid
- permeant blocker
disulfonic stilbene derivatives (stilbenes) are divalent anions at neutral pH (Fig. 1). They have been extensively used as pharmacological probes to study the transport kinetics and molecular structure of a wide range of membrane transporters [e.g., band-3 anion transporter (13) and CaATPase (10)] and ion channels [e.g., cation channels (25, 28) and anion channels (references given below)]. Disulfonic stilbenes are known to inhibit anion channels by reversible and nonreversible mechanisms (3). The nonreversible effects are presumably due to the covalent bonds that can form between isothiocyanate groups (e.g., DIDS has two isothiocyanate groups) and a variety of amino acid residues. DIDS can bind with NH2 groups on lysine residues, OH groups on serine residues, aromatic groups on tyrosine, and thiol groups on cysteine residues. 4,4′-Dibenzamidostilbene-2,2′-disulfonic acid (DBDS) and 4,4′-dinitrostilbene-2,2′-disulfonic acid (DNDS) both lack isothiocyanate groups and so cannot form covalent bonds with amino acids nor cause nonreversible inhibition.
Although stilbenes are widely used as pharmacological probes for anion channel function, few studies have addressed their mode of action. With the ClC family, a close association between the DIDS blocking site and the pore was first indicated by the finding that DIDS independently blocks each pore of the double-barrel Cl− channel in Torpedo electroplax (ClC0; Ref. 23). This line of work culminated with a recent report (26) that the specific amino acid residues that determine DIDS binding are located in the vestibule of the ClC channels. Mutational studies of the cystic fibrosis transport regulator anion channel show that the positive charges on the Lys95 and Arg347 play a major role in both channel conductance and block by a range of anionic inhibitors, including DNDS (8, 21, 22). Lys95 is positioned in the TM1 region of the amino acid sequence, which is thought to line the pore (8). Although evidence favors the hypothesis that anionic blocker molecules such as stilbenes lodge in the pore, there is no clear evidence that this is the case for cystic fibrosis transport regulator or for anion channels in general.
Stilbenes have been used to study anion fluxes across the sarcoplasmic reticulum (SR) of muscle. At micromolar concentrations they inhibited the transport of Cl−, Pi, oxalate, and SO across the SR membrane (4, 11, 12). With the use of the bilayer method, single channel recordings have identified an anion channel (SCl channel) that was strongly inhibited by the stilbene DIDS (20). It was highly regulated, being activated by μM cytoplasmic Ca2+ (17) and inhibited by cytoplasmic acidification (<7 pH), millimolar adenine nucleotides (1, 14), and inositol phosphates (16). It was activated and inhibited by oxidation and reduction, respectively (15). SCl channels have a bell-shaped voltage dependence with maximal activation between 0 and −80 mV (with respect to the lumen; Ref. 18).
Although the SCl channel was first identified as a Cl− channel (75 pS in 250/50 mM Cl−) (18), it has since been found to be a divalent anion channel, passing SO(60 pS in 250 mM SO) and the divalent form of Pi (maximum conductance = 22 pS) (20). The physiological ion for this channel is not clear. The SCl channel is unlikely to serve as a Cl− channel in muscle because its permeability to Cl− is three to six times lower than to divalent anions such as Pi and SO(20) and intracellular Cl− concentration (<10 mM) is relatively low. The SCl channel is the only SR channel known to pass SO and thus is likely to be the basis for the stilbene-sensitive fluxes reported in early studies (see above). In this study, the SO current through the SCl channel was used to examine the inhibition kinetics of DIDS, DBDS, and DNDS. This study aims to elucidate their mechanism of action and establish whether the molecules block the pore and permeate the channel. As yet, nothing is known about the structure of the SCl channel. A comparison of the block by stilbenes with different molecular sizes (DBDS and DNDS; see Fig. 1) has produced our first insights into the architecture of the SCl pore.
Preparations of SR microsomes.
SR vesicles were prepared from the back and leg muscles of New Zealand White rabbits. The rabbits (∼4 kg wt) were euthanized with a barbiturate (Lethobarb) overdose (7.5 ml iv) before the muscle was removed for biochemical processing. SR vesicles were prepared as described by Laver et al. (20).
Lipid bilayers, chemicals, and solutions.
Unless otherwise stated, lipid bilayers were produced using an 8:2 mixture of phosphatidylethanolamine and phosphatidylcholine dissolved in 20 μl n-decane to a final concentration of 50 mg/ml. Bilayers containing 30% phosphatidylserine also contained 50% phosphatidylethanolamine and 20% phosphatidylcholine. Lipids were obtained from Avanti Polar (Alabaster, AL). Bilayers were formed across a hole in a Delrin cup (aperture ∼100–200 μm diameter) separating the cis- and trans-solutions. SCl channels were mostly recorded using cis-solutions containing 250 mM MgSO4, 10 mM MgCl2, 10 TES (pH 7.4), and trans-solutions containing 50 mM MgSO4, 10 mM MgCl2, and 10 TES (pH 7.4). These solutions permitted measurement of SCl activity via their SO permeability. This obviated the effects of interfering signals from the BCl channels which are impermeable to SO and K+ channels, which are blocked by Mg2+. Ruthenium red (5 μM) was added to the cis-solution to inhibit ryanodine receptor activity.
Vesicles were added to the cis-solution where incorporation into the lipid bilayer was facilitated by the osmotic gradient (higher osmotic potential in the cis-bath) and the presence of 1–5 mM cis-Ca2+. Channels oriented in the bilayer such that their cytoplasmic side faced the cis-solution.
DNDS (Molecular Probes), DIDS, and DBDS (MP Biomedicals) were prepared as concentrated stocks in dimethyl sulfoxide (DMSO) in a range of 100 μM to 150 mM and added via aliquot additions to the cis- and trans-solutions. A large range of stock concentrations was prepared to keep the bath concentrations of DMSO to a minimum, preventing potential DMSO/SCl interactions. This precaution proved unnecessary because, unlike the ryanodine receptor (25), DMSO has no effect on the activity of the SCl (see results). In some experiments, DIDS was applied by perfusion tubes placed near the bilayer (25). This arrangement permitted both application and washout of DIDS.
Data acquisition and analysis.
Bilayer holding potentials were controlled using an Axopatch 200B amplifier (Axon Instruments). All electrical potentials are expressed as cytoplasmic side relative to luminal side at virtual ground. During the experiments, the bilayer current was recorded after low-pass filtering at 5 kHz, sampled at 50 kHz, and simultaneously stored on computer disk using data interfaces (Data Translation DT301 or DT3001) under the control of in-house software written in Visual Basic. Before analysis, the single channel recordings were filtered at 200 Hz and resampled at 1 kHz.
Analyses of channel conductance and open and closed durations were made using the Hidden Markov Model algorithm (5). The Hidden Markov Model finds the maximum likelihood estimate of the channel current transitions present in the record (i.e., an idealized representation of the recording) and provides for the determination of channel amplitudes, transition probabilities, and transition rates. It operates on the assumption that the channel current signal is the sum of a first-order, finite-state, Markov process, and white, uncorrelated, Gaussian noise of a known variance. Analysis was carried out on single-channel recordings, with steady baseline, varying in duration from 10 to 60 s.
Dwell-time frequency histograms of channel open and closed dwell times were compiled from idealized representations of the recordings containing between 102 and 103 events. The distributions are displayed either as probabilities or frequencies (the number of events of a particular duration per second of recording) and plotted using the "log-bin" method suggested by Sigworth and Sine (27). Sampling bins were equally spaced on a log scale with 7 bins per decade. Putative gating models were evaluated by fitting theoretical probability distribution functions to the dwell-time histograms using the Q-matrix method (6, 7). The algorithm of Blatz and Magleby (2) was used to calculate the effects of current steps that were too short to be detected. For current records, this detection limit (dead time) of channel events ranged from 0.5 to 1 ms, depending on their signal-to-noise ratio. Optimum model fits to the data were obtained using Newton's method and the quality of fit was determined from the root-mean-square of the differences between the theory and data.
DIDS: reversible and nonreversible inhibition.
DIDS inhibited SCl channels by both reversible and nonreversible mechanisms (Fig. 2). Figure 2A shows an example of cis application of 40 μM DIDS to an SCl channel (cis- and trans-baths correspond to cytoplasm and SR lumen, respectively). SO current through the channel was irreversibly inhibited within seconds, just as reported in a previous study (18) using Cl− as the permeant ion. In addition, it was found that DIDS added to the trans-bath permanently blocked the channel within 1–3 min (N = 3 not shown). Before permanent closure, DIDS produced a flicker block (Fig. 2A, dashed arrow), which could be reversed by removing DIDS from the solution (Fig. 2B). Reversible inhibition was characterized by a marked increase in the number of brief channel closures, which was more pronounced at negative membrane potentials. The unitary current was not sensitive to DIDS, being 2.9 ± 0.2 pA (−40 mV, N = 3) in the presence of 0–60 μM DIDS. In control experiments, DMSO was added to the cis- and trans-baths and at concentrations of up to 2% had no observable effect on SCl channel conductance and open and closed times (not shown).
Detailed analysis of the reversible effects of DIDS was hampered by the limited time window imposed on data collection by the onset of nonreversible channel inhibition. The reversible effects of stilbenes were more easily studied using DBDS and DNDS, which did not produce nonreversible inhibition of SCl channels. These compounds, when added to either the cis- or trans-solution, produced a similar flicker block as seen during reversible DIDS inhibition (Figs. 3 and 4).
DNDS and DBDS: effect on channel conductance.
The SO conductance of SCl channels was 54 ± 1 pS in the presence of 250/50 mM MgSO4 (cis/trans) as determined from a linear fit to current-voltage data in Fig. 5B. This compares with a conductance of 75 pS in 250 mM Cl− (18), in which a large proportion of channel openings were conductance substrates (∼40% substate probability). In the presence of SO, substate probabilities were >10-fold lower than in Cl−. Maximum likelihood amplitude histograms revealed a 20 pS substate (indicated by the arrow in Fig. 5A). This substate accounted for <1% of the channel activity and so the channel gating analysis could be simplified by grouping substates and channel closures. Histograms in Fig. 5A show that DBDS reduced the proportion of the 54 pS channel openings (∼2 pA) and 20 pS substates while increasing the proportion of the baseline. Figure 5B shows that DBDS applied from either the cis- or trans-sides did not alter channel conductance. In the presence of DBDS (5 μM cis or 50 μM trans) the conductance changed by <2% (each from N = 3 paired experiments). Similarly, cis- or trans-DNDS produced <2% change in channel conductance (each from N = 4 paired experiments, not shown).
DIDS: analysis of reversible flicker block.
The dose response of the DIDS reversible flicker block is shown in Fig. 6A. The half-inhibitory concentration (Ki) was 60 μM at −60 mV (N = 7). The kinetics of SCl inhibition was analyzed by compiling dwell-time histograms of open and closed events from single channel recordings. Under control conditions, open-time distributions were single exponentials with time constants of 100–200 ms, whereas closed-time histograms exhibited three exponential components with time-constants of 2.6 ± 0.2, 14 ± 2, and 327 ± 24 s (−40 mV; e.g., Figs. 6C, 8B, and 10B). Cis inhibition by DIDS was associated with a decrease in the open exponential time-constant (Fig. 6B) and a new exponential component in the closed-time frequency distribution (Fig. 6C, arrow). The time constant of DIDS-induced closures was 7 ± 2 ms (N = 4).
DBDS: analysis of flicker block.
The dose responses of DBDS-induced inhibition of open probability (Po) are shown in Fig. 7A, and Ki values are shown in Fig. 7B and Table 1. The effect of anionic lipids on Ki was measured because the negative surface charge on the bilayer reduces the effect of stilbenes on Ca2+ release channels (25). The inclusion of 30% phosophatidylserine in the bilayer-forming mixture had no significant affect on Ki (see Table 1, rows 1 and 2). The voltage dependence of inhibition is summarized by the plot in Fig. 7B. The Ki for cis- and trans-block had opposite voltage dependencies with each voltage dependence exhibiting a broad minimum. The minimum Kis for cis- and trans-block were 190 nM and 33 μM, respectively.
Inhibition by cis- and trans-DBDS was associated with a decrease in the open exponential time constant. The time constant was inversely proportional to concentration when the concentration exceeded Ki (Fig. 8, A and D). DBDS induced a new exponential component in the closed-time frequency distribution (Fig. 8, B and C). The size of this component increased with increasing concentration yet its time constant was concentration independent (Fig. 8D). Taken together, these data suggest that the binding of a single DBDS molecule to the channel is sufficient to cause block.
The voltage dependencies of DBDS blocking kinetics are summarized in Fig. 8, E and F. Because open times, τo, were inversely related to concentration, the DBDS binding kinetics were expressed by τo × [DBDS] ≈ binding rate−1. The binding rates have an exponential dependence on bilayer voltage. Binding from cis- and trans-sides have opposite voltage dependencies with respect to the effect on τo. Both cis- and trans-DBDS produce very similar values of τc (τc ≈ unbinding rate−1), which follow biphasic voltage dependencies with maxima at around −20 mV. This similarity is highlighted by the example shown in Fig. 8C (+40 mV), which shows means ± SE of closed histograms from several experiments. The voltage dependencies of DBDS binding and unbinding can be broadly understood in terms of the Woodhull (29) model for voltage-dependent ion block of channels, where the binding and unbinding rates have an exponential voltage dependence determined by the location of the blocker binding sites and energy barriers within the trans-membrane electric field. The strong voltage dependencies of DBDS binding suggest a binding site within the pore. Curiously, τc, and hence unbinding rates, could be described by the sum of two dissociation mechanisms with opposite voltage dependencies, indicating molecular movements in opposite directions within the trans-membrane electric field. This is consistent with an unbinding mechanism that can release DBDS to either the cis- and trans-sides of the membrane. The similar values of τc for cis- and trans-block indicate that the DBDS unbinding rate is independent of the side from which DBDS first enters the channel. This is consistent with a DBDS binding site within the pore that is accessible from both sides of the membrane. The possibility that DBDS permeates the channel is explored in Combined cis and trans inhibition.
DNDS: analysis of flicker block.
The dose responses of DNDS-induced inhibition are shown in Fig. 9A and Ki are given in Fig. 9B and Table 1. Like DBDS, the Ki for cis- and trans-block by DNDS had opposite voltage dependencies, which were biphasic. The most potent affinities for cis- and trans-block were 3.4 and 5.5 μM, respectively. Thus DNDS is a less potent blocker than DBDS.
The concentration- and voltage-dependent effect of DNDS on open-time distributions was qualitatively the same as DBDS (Fig. 10, A and E). However, closed-time distributions in the presence of cis-DNDS were quite different, showing two clear exponential components (Fig. 10B, arrows). The time constants in closed times were independent of concentration but the proportion of closed events in each exponential shifted markedly toward the longer component with increasing concentration (Fig. 10D). DNDS-induced closures significantly differed for cis- and trans-DNDS (Fig. 10F), although they shared very similar short time constants at negative bilayer voltages. The presence of two distinct time constants was unique to block from the cis-side at negative voltage. The time constants for DNDS-induced closures followed biphasic voltage dependencies, suggesting a permeation/blocking mechanism similar to that suggested for DBDS. However, it appears that the blocking mechanism for DNDS is more complex than that proposed for DBDS.
Combined cis and trans inhibition.
To further explore the possibility that DBDS and DNDS permeate through the anion pore experiments were carried out to detect interactions between blocking ions from opposite sides of the membrane. If blocker permeation occurs, then one would expect inhibitors on opposite sides of the membrane to exhibit competitive blocking kinetics. Ki was measured for cis-DBDS at −40 mV in the presence and absence of DNDS (5 mM) in the trans-bath. DNDS was chosen for the trans-bath because it was more soluble than DBDS (∼200 μM max) and could be used at concentrations well above its Ki. The addition of 5 mM DNDS in the trans-bath caused 85% reduction in Po. After this, addition of cis-DBDS caused further inhibition. The dose-response of DBDS inhibition, normalized to Po in the presence of 5 mM DNDS and no DBDS, is shown in Fig. 7A and the values for Ki are given in Table 1. DNDS in the trans-bath increased the Ki for cis-DBDS by ∼20-fold, which is a clear indication of competition between DBDS and DNDS on opposite sides of the membrane.
To gain a more detailed understanding of cis/trans drug interactions the combined effects of cis- and trans-block on closed dwell-time distributions were analyzed. The addition of cis- (20 μM) or trans- (2,000 μM) DNDS to channels, that were already inhibited by DNDS on the opposite side, increased the average duration of DNDS-induced channel closures (Fig. 11, A and C). In the case of the trans-addition (Fig. 11C), the lengthening of channel closures appeared to be due to a shift in the proportion of events associated with short and long exponential components. The lengthening of channel closures indicates that DNDS from cis- and trans-sides can simultaneously interact with the channel at what must be at least two separate sites.
The combined actions of cis- and trans-DBDS block were quite different from DNDS. DBDS induced channel closures with a time constant of ∼300 ms (Fig. 11, B and D, arrow). Although the addition of cis (2 μM) or trans (200 μM) DBDS increased the inhibition in channels already partly inhibited from the opposite side, this inhibition was not associated with a lengthening of time constant for DBDS-induced channel closures. Therefore, in the case of DBDS, there is no indication that two molecules can simultaneously bind from opposite sides of the channel.
Effect of permeant ion, SO42−, on stilbene inhibition.
In three experiments, inhibition by cis-DNDS was measured at −40 mV in the presence of symmetric 50 mM SO(cis and trans). Under these conditions, open and closed dwell-time histograms differed markedly from similar experiments carried out in fivefold higher (250 mM) cis-SO(Fig. 12). In 50 mM SO, 5 μM DNDS reduced mean open times to 6.5 ± 1 ms, which is threefold shorter than 22 ± 3 ms observed in 250 mM SO(N = 4). This is consistent with competition between DNDS and SO for common sites on the channel. Reduced SO concentration also increased closed durations. In the presence of 50 mM SO, DNDS induced mean closed time of 80 ± 10 ms, which is twofold longer than 39 ± 4 ms observed in 250 mM SO(N = 6).
Development of a model for stilbene block.
To quantitatively assess the blocker permeation model for SCl inhibition the data were compared with theoretical probability distribution functions that were derived from various kinetic schemes comprising combinations of channel open, closed, and blocked (drug-induced closure) states. These were fitted with the experimental open- and closed-time distributions using the method of least squares. As a starting point, the control dwell-time histograms for each experiment were characterized by voltage-dependent exponential distributions (a single exponential for open times and three exponentials for closed times) using a voltage-dependent kinetic scheme (Scheme I, shown below). The connectivity between states is arbitrary and there is no intention to draw conclusions about the gating mechanism of the native channel. The characteristics of DNDS inhibition suggested a mechanism in which DNDS inhibits by blocking the pore and where DNDS may be released to either side of the membrane. The two exponential components in the distribution of DNDS-induced channel closures indicate the presence of at least two blocked states. The synergistic action of cis- and trans-DNDS on the duration of blocked durations indicate the presence of at least two sites, which can be simultaneously occupied by DNDS. The simplest model that incorporated these features, and which fitted that data, is shown in Fig. 13 and Scheme II. In this scheme, stilbenes bind within the vestibules on each side of the channel and block the pore (the vestibules are labeled C and T, symbolizing cis- and trans-sites, respectively). From these sites the blocking molecules may pass through the pore and bind to the opposite vestibule. In Scheme II, X symbolizes the blocking molecule and the nomenclature for transition rates, k, is given for those rates that are associated with the outside arrows (the full set of transitions is listed in Table 2). Each rate constant is voltage dependent and is governed by two parameters; k0, the rate at 0 V, and δ, which is the degree of voltage dependence (the voltage-dependent equations are shown in Fig. 13). The model includes provision for the C and T sites to be both occupied (BCT). The values of δ were assumed to be independent of the presence of a second ion in the channel (see Table 2). Furthermore, to satisfy conditions for ionic equilibrium, addition constraints were placed on the parameters (see Table 2). Initially, Scheme II was fitted separately to voltage- and concentration-dependent dwell-time histograms from each experiment (e.g., data in Figs. 8, A and B, 10, A and B, 11, A–D, and 12, A and B). Within each experiment, this amounted to fitting 10–25 pairs of dwell-time histograms. The final parameter set was obtained from fitting mean data from many experiments, where the same parameters were used to fit cis- and trans- and combined cis/trans-inhibition (e.g., Figs. 8, D–F and 10, D–F).
The curves in Figs. 8 and 10–12 show fits of this model to dwell-time data from DBDS and DNDS. The parameter values used for DBDS and DNDS block are given in Table 2. Deviations between the data from individual experiments and the model predictions seen here (e.g., Fig. 11) reflect variations between individual experiments and the mean data set from which the parameters were derived. The model predicts two time constants in the DNDS-induced closed times, which are shown by the two arms of the theoretical curves in Fig. 10F. The dashed curves predict the two closed time constants shown in the cis-DNDS blocked events at negative voltages. However, block by cis-DNDS at positive voltages and trans-DNDS over the entire experimental voltage range revealed only one time constant. Under these conditions, the model still predicts two exponential components but only one time constant contained enough events to make a significant contribution to the mean closed time. The data in Fig. 10D shows that at more positive voltages the relative number of short time-constant closures due to cis-DNDS is relatively low. The model predicts that at +40 and +60 mV the mean blocking time of cis-DNDS will be similar to the longer time constant. The solid curves in Fig. 10F, which show the short and long time constants for the trans-DNDS blocked events have only been shown over the voltage range where they make a significant contribution to the overall block.
Disulfonic stilbene derivatives are permeant blockers.
This study presents a broad data set that supports a permeant blocker mechanism for inhibition of the SCl channel by stilbenes (i.e., stilbenes block channels by lodging within the anion permeation pathway and can also permeate through the channel to the opposite side of the membrane). The following data provide evidence for binding of stilbenes in the anion permeation pathway. 1) The stilbenes are open channel blockers. The concentration dependencies of open and blocked durations indicate that binding can only occur when the channel is open and that the binding of a single stilbene molecule occludes the channel (Fig. 8D). 2) Stilbene molecules bind in the transmembrane regions. This is indicated by the strongly voltage-dependent binding kinetics shown in Figs. 8, E and F, and 10, E and F. 3) Stilbenes and permeant anions compete for common sites. The model fit to the data in Fig. 12 indicates that the binding rate of DNDS increases threefold from 5.6 to 19 (Ms)−1 when [SO] is decreased from 250 mM to 50 mM. Furthermore, two lines of evidence indicate that stilbene molecules permeate through the channel. 4) The stilbenes can block the channel from both sides of the membrane and from opposite sides they compete for common sites within the channel (Fig. 7A). 5) Stilbene dissociation can occur in opposite directions within the trans-membrane electric field. Hence, upon dissociation, the blocking molecule can enter either the cis- or trans-baths. This is demonstrated by the biphasic voltage dependencies of DBDS and DNDS dissociation in Figs. 8F and 10F.
It is unknown whether DIDS can also permeate the pore. However, the fact that DIDS can permanently block the channel from each side of the membrane is consistent with DIDS permeating the pore and cross linking with amino acid residues in the permeation pathway of the channel.
Functional evidence linking stilbene inhibition with binding in the permeation pathway has been reported for DNDS inhibition of epithelial anion channels (3). It was reported that DNDS was an open channel blocker that competed with permeant ions. However, DNDS only blocked from the cis-side of the channel and its action showed no significant voltage dependence. Permeant blockade of an anion channel by stilbenes is a novel finding. A permeant blocker mechanism has been invoked previously to explain the biphasic voltage dependence of dissociation from BK channels of alkaline earth ions, such as Ca2+ and Ba2+ (19, 24). In those studies, interactions between permeant K+ and blocking ions were able to elucidate the detailed mechanism for K+ permeation long before crystal structures for K+ channels were available.
The stilbene permeation mechanism.
The simplest permeant blocker mechanism would involve a single binding site in the channel that was accessible from both sides of the membrane. Our data rules against this in favor of a multisite mechanism. First, the blocked durations for DNDS showed two exponential components, which depended on concentration and voltage (Fig. 10, B and F). Second, the presence of DNDS on both sides of the membrane produced blocked periods with longer duration than could be produced by DNDS on one side alone (Fig. 11, A and C).
To gain more information about the permeation mechanism an attempt was made to quantitatively fit two site models to the data. A model that did not fit the data was one in which DNDS could bind at one site within the pore and another site on the cis-surface, where binding modulated permeation via an allosteric effect. This model could not account for the combined action of DNDS on both sides of the membrane. The simplest two-site model that fitted our data was one in which DNDS could bind at two sites in the permeation pathway as shown in Fig. 13 and Scheme II. Examination of the model parameters in Table 2 reveals that DNDS kinetics are not significantly affected by the presence of another DNDS molecule, except for dissociation from the trans-site, which was slowed almost fourfold (i.e., kct-c = 5.4 s−1 and kt-o = 19 s−1 in Table 2). This reduced exit rate was responsible for the long exponential seen in the blocked time distributions. This stabilizing of the dual binding conformation is counter intuitive because one would expect proximity of two anions in the channel to mutually destabilize each other. This problem can be resolved by explicitly considering the effects of SO on stilbene permeation. The model fits to the data in Fig. 12 show that decreasing [SO] in the cis-bath from 250 mM to 50 mM causes a fivefold reduction in the rate of DNDS dissociation to the trans-bath. Thus it appears that the presence of SO in the pore destabilizes DNDS binding. In light of this finding, it can be seen that two adjacent DNDS molecules could be more stable than one DNDS molecule with SO in the pore. DNDS at the cis-site might displace SO and hence protect DNDS at the trans-site from the destabilizing effects of SO.
It is clear from the data that DNDS and DBDS behave quite differently in the channel. The lower blocking potency of DNDS appears to be attributable to its considerably faster exit rates from the cis-site. Furthermore, the data shows no indication that more than one DBDS molecule can reside in the channel at any time. The blocked time distributions show only one exponential component and the combined effects of cis- and trans-DBDS produce blocked durations that were indistinguishable from the those caused by cis or trans alone (Fig. 11, B and D). The marked differences in the cis- and trans-blocking potencies of the stibenes stem mainly from the lower stilbene binding constants on the trans-side of the channel (Table 2).
It is worth noting that the voltage dependencies of the model parameters are larger than expected from the movement of a divalent ion through the transmembrane electric field. The Woodhull model predicts that the total magnitudes of δs associated with translocation of DNDS across the membrane (δo-c + δc-o + δc-t + δt-c + δt-o + δo-t) should be 1, whereas in this study, it equals 2.47 for DBDS and 2.02 for DNDS. This underscores the fact that the model transition rates shown here do not depend solely on the energy profile for stilbenes within the pore. The model in Scheme II does not explicitly include the effects of SO permeation, which is shown to be an important modulator of the blocker kinetics. Voltage dependence of the model parameters will include contributions from the voltage dependence of SO occupancy of binding sites in the channel.
Scheme II was used to predict the rate of ion permeation through the SCl channel (Fig. 13). Although DNDS is a weaker channel blocker than DBDS, its maximal transport rate at each membrane potential is an order of magnitude higher than DBDS. Curiously, the concentration dependence of the DNDS transport rate shows a decrease at concentrations >10 μM, which is due to the lower permeability of DNDS when two molecules are in the pore.
Insights into channel architecture.
The presence of negative lipids has been shown to strongly attenuate the action of stilbenes on ryanodine receptor activity, indicating that the negative charges on the lipids are close enough to the binding site to repel anionic molecules (25). In contrast to this, negative lipids had no effect on DBDS inhibition of SCl channels (Fig. 7B). Hence the binding site is sufficiently far (>1 Debye length; ∼1 nm) from the lipid head groups so as not to be significantly affected by charge repulsion.
Because DBDS and DNDS pass through the pore, their molecular dimensions give clues to the size of the anion permeation pathway. The molecular cross section perpendicular to the long axis of the molecules fits into a rectangle ∼10 Å × 6 Å (Fig. 1). This places a lower limit on the pore diameter of ∼10 Å. Such a pore diameter is consistent with a channel that poorly discriminates between anion species but is selective among ions of different valency (9). The data suggest that the permeation pathway can only hold one DBDS molecule but can contain two DNDS molecules. If the binding sites are produced by interactions between the pore and the stilbene SO groups and if the stilbene molecules are constrained to lay end-on-end within the pore then a separation of <24 Å between cis- and trans-sites would exclude a second DBDS from being in the pore. With the use of similar logic, two DNDS molecules could fit in the pore if the cis- and trans-sites are separated by more than 14 Å. This indicates that the cis- and trans-sites have a separation of 14–24 Å. The presence of permeant anions within the pore affects the dissociation kinetics of stilbene block. This property endows stilbene molecules with the potential to be powerful probes for the conduction pathway and the mechanisms for permeation of small anions.
This work was supported by National Health and Medical Research Council project grant 211030 and by an infrastructure grant from the Hunter Medical Research Institute. D. R. Laver was supported by an Australian Research Council Professorial Fellowship.
We thank Melissa Dafo and Paul Johnson for assisting with the experiments and Dr. Renate Griffith for help in producing the molecular diagrams.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 the American Physiological Society


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Investment in Education and Redistributive Taxation without Precommitment
This paper compares private investment in risky education in a laissezfaire economy and with income redistribution. Obtaining higher education requires time and may require paying nondeductible resource costs. The paper shows that redistributive taxation may actually increase private investment in risky education also without precommitment.
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|Published in FinanzArchiv 2 59(2003): pp. 177-188
|Contact details of provider:
| Postal: Ludwigstr. 28, 80539 Munich, Germany
Phone: +49-(0)89-2180-3405
Fax: +49-(0)89-2180-3510
Web page: http://www.vwl.uni-muenchen.de
More information through EDIRC
References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- Sinn, Hans-Werner, 1995.
" A Theory of the Welfare State,"
Scandinavian Journal of Economics,
Wiley Blackwell, vol. 97(4), pages 495-526, December.
- Hans-Werner Sinn, 1994. "A Theory of the Welfare State," CESifo Working Paper Series 65, CESifo Group Munich.
- Sinn, Hans-Werner, 1995. "A Theory of the Welfare State," CEPR Discussion Papers 1278, C.E.P.R. Discussion Papers.
- Hans-Werner Sinn, 1994. "A Theory of the Welfare State," NBER Working Papers 4856, National Bureau of Economic Research, Inc.
- Hansson, Ingemar & Stuart, Charles, 1989. "Why Is Investment Subsidized?," International Economic Review, Department of Economics, University of Pennsylvania and Osaka University Institute of Social and Economic Research Association, vol. 30(3), pages 549-559, August.
- Anderberg Dan & Perroni Carlo, 2003. "Time-Consistent Policy and Politics: Does Voting Matter When Individuals Are Identical?," The B.E. Journal of Economic Analysis & Policy, De Gruyter, vol. 3(1), pages 1-19, March.
- Andersson, Frederik & Konrad, Kai A., 2001. "Globalization and human capital formation
[Globalisierung und Humankapitalinvestitionen]," Discussion Papers, Research Unit: Market Processes and Governance FS IV 01-01, Social Science Research Center Berlin (WZB).
- Andersson, Fredrik & Konrad, Kai A., 2001. "Globalization and Human Capital Formation," IZA Discussion Papers 245, Institute for the Study of Labor (IZA).
- Andersson, Fredrik & Konrad, Kai A., 2001. "Globalization and Human Capital Formation," CEPR Discussion Papers 2657, C.E.P.R. Discussion Papers.
- Boadway, Robin & Marceau, Nicolas & Marchand, Maurice, 1996. "Investment in Education and the Time Inconsistency of Redistributive Tax Policy," Economica, London School of Economics and Political Science, vol. 63(250), pages 171-189, May.
- Boadway, R. & Marceau, N. & Marchand, M., "undated". "Investment in education and the time inconsistency of redistributive tax policy," CORE Discussion Papers RP 1219, Université catholique de Louvain, Center for Operations Research and Econometrics (CORE).
- Robin Boadway & Nicolas Marceau & Maurice Marchand, 1992. "Investment in Education and the Time Inconsistency of Redistributive Tax Policy," Working Papers 860, Queen's University, Department of Economics.

subset: commoncrawl


text:
This is the error I had to go on.
System.InvalidOperationException: Timeout expired. The timeout period elapsed prior to obtaining a connection from the pool. This may have occurred because all pooled connections were in use and max pool size was reached.
It sounds pretty obvious that it is a database connection that was not being closed. But I have hundreds of points of connection in my webapp. How do I figure out which one I am forgetting to close?
First exec
on sql server and look at all those connections, now find a bunch connected to your database with the status "sleeping" and the command "AWAITING COMMAND". They also give you the SPID which comes in very handy.
Take the SPID and run it in dbcc inputbuffer()
dbcc inputbuffer(SPID)
This will tell you the command that was last run by that process id, then all you have to do is find that query or stored procedure in your apps code and make sure you close the connection.
This can be a symptom of a larger problem with your database connection class. You should not have to manually close a connection every time you connect.
SqlConnection uses the iDisposable interface so wrap your connection statement in a using statement. When a SqlConnection is disposed it is also closed so simplify and let .net take care of it for you.
using (SqlConnection connection = new SqlConnection(connectionString)) { .... }


text:
Summit Racing press release
Line Grabs Provisional Pole on Friday at Gatornationals
Jason Line and the Summit Racing team took a somewhat interesting road to the provisional pole at the Tire Kingdom NHRA Gatornationals in Gainesville, FL. During the first session on Friday afternoon, they were forced to wait out a brief shower which interrupted the action and changed conditions. Even so, Line was able to post the third-quickest time of the round at 6.563 seconds with a top speed of 211.13 mph. Without any such distractions on his afternoon run, Line was able to improve on his previous performance, stepping up to a 6.545 second time with a speed of 211.46 mph to sit atop the field with two sessions remaining on Saturday, where the four-time Gatornationals champion looks to pick up the pace even further.
"For some reason, the Summit Racing team always seems to run well here in Gainesville," said Line. "If we knew what it was, we'd apply it to some of the other tracks we go to. We've won the last three races here, and I'd certainly like to make it four in a row this weekend, and there would be no better place to start than from the No. 1 spot.
"The good news is that there is still room for improvement. For example, if I had done a little better job of driving in Q1, we could have been quickest for that session as well. It just shows what a great job our guys did of getting our car down the racetrack, especially considering how long it's been since we saw conditions like this. Tomorrow we'll come back and see what we can do to make even better runs and put us in a good position for race day."


text:
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If you are using IE 9 or later, make sure you turn off "Compatibility View".
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PRAY FOR SNOW || @blzablaine and the rest of the #disidual crew are waiting patiently for the snow to fall in the PNW. Keep your heads up #distinctindividuals, our storm will come ❄❄


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Yankee White (NCIS)
The topic of this article may not meet Wikipedia's notability guideline for television. (January 2012) (Learn how and when to remove this template message)
|"Yankee White"
|NCIS episode
|Episode no.
|Season 1
Episode 1
|Directed by
|Donald P. Bellisario
|Written by
|Donald P. Bellisario & Don McGill
|Original air date
|September 23, 2003
|Guest appearance(s)
"Yankee White" is the first episode in the first season of the American crime drama television series NCIS. It first aired on CBS in the United States on September 23, 2003. The episode is written by Donald P. Bellisario & Don McGill and directed by Donald P. Bellisario, and was seen by 13.04 million viewers.[1]
While on Air Force One, a Navy Commander tasked with carrying the "football" dies under mysterious circumstances, forcing an emergency landing in Wichita, Kansas but while his death is originally thought be to a tragic accident, NCIS eventually uncovers evidence suggesting the commander was murdered and that it might be connected to a possible assassination attempt on the President of the United States.
The episode introduces Caitlin "Kate" Todd (as a replacement for NCIS agent Vivian "Viv" Blackadder), and FBI Agent Tobias Fornell, who would later become a major recurring character of the show. The rest of the team were all introduced in a double episode of JAG season 8, "Ice Queen" and "Meltdown".
The episode title (Yankee White) is the administrative nickname for a background check conducted on Department of Defense personnel and prospective US citizens.
While on Air Force One, U.S. Navy Commander Ray Trapp dies of an apparent stroke after having lunch with the President despite the efforts of the President's doctor and medical team. The plane is forced to land at Wichita, Kansas and the President is flown to his original destination on a back-up plane. Trapp visited Air Force One only because Marine Major Timothy Kerry was sick with the flu. NCIS arrive to investigate the death, but meet some jurisdictional problems with both the FBI and Secret Service who each want to take the lead. With Secret Service agent Caitlin Todd grudgingly agreeing to help, NCIS Special Agents Leroy Jethro Gibbs and Tony DiNozzo, and NCIS Medical Examiner Donald "Ducky" Mallard examine the body. The local coroner, a friend of Ducky's, manages to stall the FBI long enough for NCIS to begin preliminary investigations. On Gibbs' orders, Tony shuts the door with the FBI agents still outside and has the pilot immediately fly the plane back to Washington after receiving authorization from Agent Todd.
Back at the NCIS headquarters, Ducky is autopsying the body of Commander Trapp, only to find he suffered a cerebral embolism, which is considered a natural cause of death. Gibbs wants the team to keep looking while he joins Agent Todd aboard Air Force One. Later, another senior officer revealed to be Marine Major Timothy Kerry, is found dead in his car in Georgetown with similar symptoms to those of Commander Trapp. NCIS Forensic Specialist Abby Sciuto is able to find DMSO and snake venom from an Australian Taipan on both Commander Trapp and Major Kerry's uniforms, which could explain why they died. DiNozzo investigates both of them, finding out that Trapp and Kerry used the same dry cleaner.
Aboard Air Force One, Agent Todd tells Gibbs about her relationship with Major Kerry, resulting in an interrogation concerning her motive for his death. Todd's reaction makes Gibbs believe that she is innocent. Todd explains the differences between the backup plane and the main plane. Gibbs focuses on the armory, which has locks instead of digital keypads. If terrorists are planning an attack, they must have copied the keys.
Aware about the threat, Gibbs checks the armory while Todd protects the President. The armory is open, and a journalist is trying to get to the President's quarters in an attempt to kill him. Gibbs confronts the journalist, who attacks, but is killed before any damage is done.
At the end of the episode, Agent Todd resigns from the Secret Service for breaking fraternization rules. She is then recruited by Gibbs as an NCIS agent.
The episode is written by Donald P. Bellisario & Don McGill and directed by Donald P. Bellisario. According to the DVD commentary, the episode was written as an homage to the 1997 film Air Force One. According to Bellisario, the NCIS pilot episode was easy to sell to CBS because of its low costs compared to the JAG pilot. Together with Billy Webb (Editor of Photography), Bellisario wanted to give NCIS a different look than other shows, starting with the first episode of the series. First find out "how would we normally shoot this, now let's figure another way to shoot it". Short clips in between scenes became a trademark. "We moved fast, we jump cut in the middle of scenes, and we jump cut dialogues". "What we ended up with was a completely different shooting style".[2]
In the first pilot episodes (back-door pilot), as a part of JAG, Robyn Lively is seen in the role as NCIS agent Vivian Blackadder. Bellisario stated that "she was a little soft for this kind of role", and is replaced by a new and different character in this episode.[3] Portrayed by Sasha Alexander, Secret Service agent Caitlin Todd is recruited by Gibbs at the end of the episode, filling Blackadder's place at Gibbs' team.
Together with Alexander's character, two recurring characters were introduced. FBI agent Tobias C. Fornell (portrayed by Joe Spano), who still is a part of the series, and medical assistant Gerald Jackson (Pancho Demmings). Jackson departed from the series later in season 1 before returning for one final time in the Season 3 opening episodes, "Kill Ari (Part I)" and "Kill Ari (Part II)".
Gibbs' rules[edit]
The first three of Gibbs' rules are revealed:
- No. 1 "Never let suspects stay together."
- No. 2 "Always wear gloves at a crime scene."
- No. 3 "Don't believe what you're told. Double-check."
According to executive producer Shane Brennan, the first three rules is a double set. "When [Gibbs] joined NCIS, Mike Franks told him he didn't need dozens of different rules to be an agent... just three 'golden rules'. This is why we have double ups [...]. Three of them are Gibbs' rules; three of them are Mike Franks' rules". Whether it is Gibbs or Frank's rules shown in the episode, Brennan does not tell.[4]
"Yankee White" was seen by 13.04 million live viewers following its broadcast on September 23, 2003, with an 8.6/14 share among all households.[5] A share means the percentage of television sets in use tuned to the program.
- ^ "No Title Found". Cbspressexpress.com.
- ^ NCIS: Defining the Look (NCIS: The First Season (DVD)). CBS Home Entertainment. 2006.
- ^ Coleridge, Daniel R. (August 6, 2003). "JAG Spinoff Secrets". TV Guide. Retrieved 16 January 2012.
- ^ Marsi, Steve (May 22, 2010). "NCIS Spoilers: What is Gibbs' Rule #51?". TV Fanatic. Retrieved 5 March 2012.
- ^ "Fast National ratings for Tuesday, Sept. 23, 2003". Zap2it. Archived from the original on 29 January 2007. Retrieved 16 January 2012.


text:
Browsing Tag addiction
Get Out Of Your Addiction With The Help Of InTheRooms.com
By Guest Post at December 24, 2011 | 12:01 pm | 0 Comment
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text:
Israel News
Middle East
American Politics
Edition française
Green Israel
Dog trauma 370.
(photo credit:Courtesy of Kineret Rozen-Edelman)
When I began posting messages to Facebook and Twitter on Monday morning asking
for comments from pet owners whose dogs and cats were experiencing trauma in the
South, I did not expect to be called unprintable names and even have at least
three people call for my death.On both sides of the Gaza border,
children and their families are suffering — sometimes even dying. Tragedy has
struck each of the populations, particularly those too young to even understand
the gravity of the situation and just want to be back in school, playing in
parks without a constant need to duck their small heads.
By GREER FAY CASHMAN
By YAAKOV LAPPIN
Sponsored Content
By HERB KEINON
By Gil Stern Stern HOFFMAN
By GREER FAY CASHMAN
Please insert a valid email address


text:
Cervical Disease and Neoplasms. Maria Horvat, MD, FACOG. Cervical Disease – Risk factors. HPV Smoking – 2 fold increase Young age at 1 st coitus Multiple sexual partners A partner with multiple sexual partners High parity Lower socioeconomic status Young age at 1 st pregnancy.
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Maria Horvat, MD, FACOG
Grade 1 = CIN 1; Grade 2 = CIN 2; Grade 3 = CIN 3
< 18 yrs old with CIN 1
Repeat Cytology at 12 mos
Repeat Cytology at 12 mos
Negative > ASC Colposcopy
Routine Screening
<18 yrs old with CIN 2,3
Either treatment or observation is acceptable, provided colposcopy is satisfactory.
When CIN 2 is specified, observation is preferred. When CIN 3 is specified, or colposcopy is unsatisfactory, treatment is recommended.
Observation OR Treatment
With colposcopy and cytology with excision or
at 6 mos intervals for 24 mos ablation of T-zone
2x negative cytology colposcopy worsens or
And normal colpo. High-grade cytology or
colpo. Persists for 1 yr.
Routine Screening Repeat Biopsy CIN 3, or CIN 2 that persists
Recommended for 24 mos since initial dx
>20 yrs old with ASC-H
Coloposcopic Examination
>20 yrs old with ASC-US
Repeat Cytology HPV DNA testing
@ 4-6 mos
Negative >ASC Positive Negative
(for high risk type)
@ 4-6 mos Colposcopy Repeat cytol.
@ 12 mos
Negative HPV type Positive
Repeat Pap Refer for
in 6 mos coloposcopy
< 18 yrs old >18 yrs old
Repeat Pap Colposcopy
(adolescents may perform colposcopy q 6 mos up to 24 mos)
Endometrial Sample, women >35 yrs


text:
I'm a bike fan with a new build flat in Peel. The flat is situated on a queit estate 10mins walk from the town centre, although the nearest pub, corner shop and chinese is 1mins walk away.
I have a clean and tidy spare room which can sleep 2 (2 x single).
It is available on a room only basis with free tea and coffee but you can bring your own breakfast as long as you wash your dishes!!!
There is ample parking (not under cover).
The room is available for the whole of the MGP and is £50 per night for 2 sharing or £35 for 1.
If you'd like to know more drop me a line at firstname.lastname@example.com


text:
Bowl Game Preview: Las Vegas Bowl
865% of Bets Placed on BYU -3 | Matchup | CFB Picks
Quarterback John Beck and Brigham Young should have enough motivation to overcome the malaise that accompanies nearly a one-month layoff between their regular-season finale and bowl appearance.
The 19th-ranked Cougars look to channel that emotion when they play in the Las Vegas Bowl for a second straight season to face Oregon on Dec. 21 at Sam Boyd Stadium.
Oddsmakers have made BYU -3 point spread favorites (College Football Odds) for Thursday's game, the over/under has been set at 62 total points (View CFB Sports Books).
After leading a last-second victory that enabled BYU (10-2) to end the regular season with a nine-game win streak and its first Mountain West title since 2001, Beck returns to the site where last season ended with a loss on a costly interception.
As the Cougars seek to end a four-game bowl losing streak and record their first postseason victory in 10 years, Beck will oppose the person who brought he and coach Bronco Mendenhall to BYU. Oregon offensive coordinator Gary Crowton, who coached BYU from 2001-04 before he was forced out, recruited and coached Beck and hired Mendenhall as his defensive coordinator in 2003.
``I have the deepest respect for coach Crowton,'' Mendenhall said. ``He is a dear friend and I am grateful for the opportunities he has provided me throughout my coaching career.''
Beck's development is reflected in his comeback attempts in this bowl game last year, as well as his most recent performance.
The 25-year-old senior completed a 75-yard drive in a 1:01 span with an 11-yard scoring pass to tight end Jonny Harline as time expired to give BYU a 33-31 win at Utah on Nov. 25.
Despite setting Las Vegas Bowl records for completions (35), attempts (53) and passing yards (353) last year, Beck could not lead the Cougars all the way back from a 21-point deficit in the fourth quarter as they lost 35-28 to California. BYU had a chance to tie the game with the ball near midfield, but Beck's arm was hit as he attempted a pass and the ball was intercepted with 1:25 to play.
The Mountain West offensive player of the year has reduced his interceptions from 13 to six this season. Beck completed more than 70 percent of his passes while finishing among the country's top 10 in passing yardage (3,510) and touchdown passes (30).
``He's a great quarterback and will be measured with the greats here,'' BYU coach Bronco Mendenhall said of Beck, who threw for at least 247 yards in each of his 12 starts.
He will oppose a Ducks defense that allowed an average of 34 points and nearly 350 total yards during a three-game losing streak to close the regular season. However, Oregon did finish with the best pass defense in the Pac-10, allowing 156.7 yards per game.
The Ducks (7-5) are looking to avoid a fourth straight loss overall and in bowl games. They haven't won one since beating Colorado 38-16 in the Fiesta Bowl five years ago. Their only appearance in the Las Vegas Bowl - in its 15th year of existence - was a 41-13 rout of Air Force in 1997.
Eliminating turnovers could be a key for Oregon, which tied for the ninth-most giveaways in Division I-A with 30. Eighteen of those turnovers came in the team's five losses.
``We talk about possession of the football as more than nine-tenths of the law,'' Oregon coach Mike Bellotti said. ``In this case, it's the whole deal.''
While both teams have high-scoring offenses - BYU is ranked sixth in Division I-A with a 36.7 scoring average and Oregon is 17th at 31.3 - the Ducks' quarterback situation is unsettled.
After Dennis Dixon struggled with six total interceptions and no more than 130 yards in his last three games, Brady Leaf made his first start in the regular-season finale at Oregon State.
Leaf completed 25 of 42 passes for 274 yards with a touchdown and an interception, but the Ducks allowed a go-ahead field goal with 1:12 left and their 44-yard attempt 40 seconds later was blocked as they lost 30-28. Dixon did not play.
Both quarterbacks played in Oregon's 17-14 defeat to Oklahoma in last year's Holiday Bowl when Leaf, the brother of former San Diego Chargers quarterback Ryan Leaf, threw an interception at the 10-yard line with 33 seconds left.
``We've just got to make sure we cut down on our turnovers,'' Oregon center Enoka Lucas said, ``make sure we keep the ball in our hands.''
Running back Jonathan Stewart has provided some stability for the Ducks offense. The sophomore had a career-high three touchdowns against Oregon State, giving him 10 for the season, and finished with 960 yards rushing.
``They run the ball extremely well, they pass the ball,'' BYU linebacker Cameron Jensen said. ``So we know we're going to have to be sound in our run and pass defense.''
The Ducks lead the all-time series 3-2 and won the last meeting, 32-16 in 1990.
by: Anthony White - theSpread.com - Email Us
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text:
Drill My Hole
Bashed and Furious (Paddy O'Brian & Issac Jones)
Pornstars: Issac Jones,Paddy O'Brian
About this Video:
Speed is the name of the game in this sexy adventure. UK hotties Paddy O'Brian and Isaac Jones star in the sex fueled parody that is sure to leave you breathless.
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text:
Thomas's Birth Story!
View Single Post
August 14th, 2006, 09:00 PM
Platinum Supermommy
Join Date: Jan 2005
Location: New Haven, CT
Posts: 53,701
tuesday, sept 6th 2005, i started having contractions @ 2:30am woke up, pooed, back to sleep same at 330am at 430 same thing but i stayed awake and posted in my DDC until around 9a when the contractions were about 3-7 minutes apart, tom then called the dr. (i was too busy pooping
) he told me to come on in, well i get to the drs office (9:30-45a), he checks im already 5-6cm!!!!!! they tell me to go to the hospital by the time every thing is set up and all, it was 10:30ish and the contractions were pretty painful but still not too bad, i kept thinking i could still be home, this is going to take forever LITTLE DID I KNOW! around 12:00 i was 8-9cm and everyone was trying to convince me to get the epidural i was really in pain, and screaming with each contraction at one point i did throw up, grossest part ever! by 12:45pm it was in LOL i couldnt do it anymore, at 1:15 i was at a 10, (i was thinking wth was the point of the epi then) then the lovely nurse i had let me rest before i began to push, at 1:50pm i started pushing, while pushing, all i kept thinking was DO NOT POO ON THE TABLE!
and i didnt i think i was more focused on that than pushing the baby out, since pushing literally felt the same as going poo at2:43pm, little thomas came with a few little cries, he was place on my stomach and looked directly at me, i was in shock! the nurse took him and within a few minutes my dr was getting the placenta and stitching me up (i had a small epesiotmy{sp???}) while he was doing that i was taking pictures of tom with the baby LOL! his apgars were 9 and 9, the pediatrition said he is absolutly perfect, he has had a few issues with latching on, but nursing is going great, but OUCH! my nipples hurt LOL, during his bath, he trying punching the nurse when she wet his head so i have been calling him slugger LOL he is so perfect and amazing, i still dont find it real! oh! and the nurses looked at the paper i was keeping the times of the contractions on, they say labore really started arounf 7:30am so that means i wasnt even in labor for 8 hours!!! i am so proud i stayed home so long, and everyone around me cannot believe this is my 1st child because i did so well! (had to brag LOL)
Thomas Harold, Jr.
September 6th, 2005
7lbs 6oz
Nicole: Tom's Wife [5.7.05]; Mommy of Thomas [9.6.05], Collin [1.17.08], & Bailey [10.2.09]
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text:
Storm Shadow Kids Costume
75% off
So, you're cute as a button yet crazy like a cat (you know, Cheshire Cat). You're looking for the perfect costume to compliment your quirky personality. You need something that says, "I am the cutest little thing in town, but you'd better watch yourself because I'm unpredictable!"
You've thought about other costumes, nun (not sexy enough), baker (not crazy enough), walking dead (too dead). This is the costume you've been dreaming of! This will be the finest moment in your costuming life! Don't deny yourself this chance! It is time to take the plunge and be the cutest, craziest Alice in Wonderland you can be. After all isn't that what Alice in Wonderland is all about?
Step through the looking glass.
When you do you'll come out with this awesome costume. It includes such delights as the one sleeve, blue dress (tell me that having an asymmetrical dress doesn't just scream, I'm totally psychedelic.) The dress is detailed with a layered skirt and black and white waist cincher. It comes accessorized with the collar choker and large checkered head bow.
The tights and heart staff are not included, but never fear you can find those items right here on our website.
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text:
Online searches in countries with high per capita gross domestic product (GDP) are more likely to search topics related to the future than the past, a new study found.
Researchers at University College London said their findings may point to a correlation between online behavior and a country's economic indicators, reported UPI.
"Our results are consistent with the intriguing possibility that there is a relationship between the economic success of a country and the information-seeking behaviour of its citizens online," the authors write, according to the New Scientist.
The British researchers compared online searches between 45 countries from 2010 testing how often the word "2009" was used versus "2011."
According to Ars Technica, the authors then divided the results by country, graphing the results by per capita GDP.
"We see two leading explanations for this relationship between search activity and GDP," said UCL visiting researcher Tobias Preis, according to WebProNews.
"Firstly, these findings may reflect international differences in attention to the future and the past, where a focus on the future supports economic success. Secondly, these findings may reflect international differences in the type of information sought online, perhaps due to economic influences on available Internet infrastructure"
The researchers eliminated countries with less than five million internet users as those countries might confound the data.
The study has been published in the journal Scientific Reports.
More from GlobalPost: Promises, pitfalls await investors in Burma's frontier economy


text:
PL30 3LB, Mr Jonathan Dray and Mrs Theresa Margaret Dray: environmental permit application advertisement
This publication was withdrawn on
The consultation period for this application has ended. You can view current licences on the Public Registers.
View the application submitted by Mr Jonathan Dray and Mrs Theresa Margaret Dray for Rosebud Farm Touring Park, St Teath, Bodmin, Cornwall, PL30 3LB.


text: Potential Impact of Human Papillomavirus Vaccines on Public STD Clinic Workloads and on Opportunities to Diagnose and Treat Other Sexually Transmitted DiseasesDempsey, Amanda F. MD, PhD, MPH*; Koutsky, Laura A. PhD†; Golden, Matthew MD, MPH‡Sexually Transmitted Diseases: July 2007 - Volume 34 - Issue 7 - pp 503-507 doi: 10.1097/01.olq.0000253337.62932.29 Article Abstract In Brief Author Information Article Outline Background: Eradicating genital warts through HPV immunization could decrease STD clinic utilization but may result in missed opportunities to diagnose other STDs. Objectives: To define the proportion of STD clinic visits attributable to HPV and to describe the prevalence of other STD diagnoses among visits for HPV-related presenting concerns. Study Design: Cross-sectional analysis of medical records (1994–2004) from a single STD clinic. Prevalences of STDs were calculated for male and female patients with and without HPV-related presenting concerns. Results: Of the 66,537 visits included in the study, 10.3% were HPV-related. Of the 3085 HPV-related "new problem" visits, only 281 non-HPV diagnoses were made, with nonspecific urethritis and CT being the most common diagnosis for males and females, respectively. Nearly 25% of the 14,574 follow-up visits were for HPV. Conclusions: Newly developed HPV vaccines may substantially decrease public STD clinic workloads with little associated lost opportunity to diagnose and treat other STDs. A retrospective study of medical records from an STD clinic in Washington State demonstrated that patients presenting specifically for HPV-related concerns had a low prevalence of other sexually transmitted infections. From the *Department of Pediatrics, University of Michigan, Ann Arbor, Michigan; and Departments of †Epidemiology and ‡Medicine, University of Washington, Seattle, Washington This work was supported by a 2005 developmental grant from the University of Washington STI TM Cooperative Research Center (STITMCRC), an NIH funded program (U19 AI 31448). Correspondence: Amanda Dempsey, Department of Pediatrics, 300 N. Ingalls St., Room 6E08, Ann Arbor, MI 48109-0456. E-mail: email@example.com. Received for publication June 1, 2006, and accepted October 30, 2006. Abstract Materials and Methods Study Population and Design Inclusion/Exclusion Criteria Diagnostic Criteria Statistical Analysis Follow-Up Visit Analysis Results Discussion References Cited By The burden of HPV-associated illnesses like genital warts and cervical neoplasia may be greatly reduced in the future by the use of effective HPV vaccines. Two candidate HPV vaccines have been developed, and one of these was recently licensed by the US Food and Drug Administration for use in adolescent and young women aged 9–26.1 Both candidate vaccines target the two HPV types most commonly associated with cervical cancer (HPV 16 and HPV 18), and both have been shown to be highly successful in preventing cervical intraepithelial neoplasia.2–4 One of the candidate vaccines also targets two additional HPV types, HPV 6 and HPV11, which cause >80% of cases of genital warts. Clinical trial data of this quadravalent HPV vaccine have shown high-level efficacy for preventing genital warts in young women,4 and trials of this vaccine in young men are currently underway. Widespread HPV vaccination is likely to result in substantial health benefits to the individuals who are vaccinated. However, the potential impact of these vaccines on health care system utilization has not been extensively examined. Furthermore, having genital warts may prompt many patients to seek complete STD evaluations, and eliminating this disease through HPV vaccination could result in lost opportunities to test and treat individuals for bacterial STDs, herpes, HIV, or other infections that might have been previously unrecognized. In this study, we assess the proportion of STD clinic visits attributable to HPV-related complaints and describe the prevalence of other STD diagnoses among visits motivated by concerns related to HPV infection. Back to Top | Article Outline Materials and Methods Study Population and Design Since 1994, Public Health-Seattle & King County has maintained an electronic database of medical records from patients seen at a community hospital-based STD clinic. This database contains information collected by clinicians using a standardized medical record form and includes information about presenting symptoms and complaints; sexual, social, and reproductive history; physical examination findings; laboratory test results; and diagnoses and treatment. We performed a cross-sectional analysis of records from all patients seen in this clinic between January 1, 1994, and December 31, 2004. The University of Washington institutional review board approved all study procedures. Back to Top | Article Outline Inclusion/Exclusion Criteria All visit types were initially considered for evaluation. However, as our primary interest was in new STD diagnoses and few such diagnoses are made during follow-up visits for established problems, only visits categorized as "new problem" were considered in the analysis of STD prevalence (eliminated from this analysis were "test results" visits, "follow-up" visits, and visits prompted by referral from an outside provider). New problem visits were divided into those with and without HPV-related concerns as the reason for visit, according to the inclusion/exclusion criteria outlined below. In our analysis, HPV-related visits (the "HPV group") were defined as those visits with either: 1) an indication of "anorectal symptoms" and/or "genital lesions" as a reason for visit and a visit diagnosis of genital warts, or 2) "contact to HPV" as the reason for visit, regardless of whether a genital warts diagnosis was obtained. As a comparison, STD diagnosis prevalence was calculated among visits with presenting complaints unrelated to HPV. This group (the "No HPV group") was composed of the remaining new-problem visits that were not included in the HPV group (Fig. 1). In all cases, the reason for visit was obtained and recorded by the providing clinician using an open-ended question and prespecified response categories. Clinicians could choose as many response categories as needed to reflect the patient's presenting complaints. Fig. 1 We also calculated STD diagnosis prevalence using two other sets of criteria to define the visit categories. In the first of these other analyses, we eliminated from the HPV group those visits where additional presenting concerns that appeared unrelated to HPV (e.g., vaginal discharge or contact to CT) were present. By using these more restrictive criteria to define the HPV group, we could focus on STD diagnosis prevalence among visits where HPV-related concerns appeared to be the sole motivating factor for seeking care, thus eliminating the potential confounding effect of other presenting concerns on STD diagnosis frequency. In the second of these analyses, we limited our calculation of diagnosis prevalence to only those visits where diagnostic testing for that particular STD was performed (e.g., calculating HIV diagnosis prevalence only among visits where HIV testing had been performed). This was done to assess the effect of potential differences in testing patterns between the two-visits groups (HPV and no HPV) on diagnosis frequencies for other STDs. Back to Top | Article Outline Diagnostic Criteria Diagnostic criteria for 12 different STDs were derived using a combination of lab and clinical data. Our interest was specifically in new STD diagnoses; thus we classified diseases as those that were chronic and therefore could be newly diagnosed only once in a person's lifetime (HIV, hepatitis B, and genital herpes) and those that could be repeatedly newly diagnosed after interval clearing of clinical infection (Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), trichomonas, genital warts, nonspecific pelvic inflammatory disease (PID), nonspecific mucopurulent cervicitis (MPC), nonspecific urethritis (NGU), syphilis and pubic lice). The chronic STDs were counted only once per person when calculating the prevalence of different STD diagnoses. Diagnostic criteria for genital warts, pubic lice, and trichomonas were based exclusively on the indication of a "presumptive diagnosis" for these diseases in the medical record since these illnesses are detectable by clinical examination findings and/or microscopic examination by providers of genital specimens obtained in the clinic at the time of the examination. Information on trichomonas infection was available only for females. Diagnostic criteria for MPC, PID, and NGU were specific for those cases unrelated to GC or CT and thus required a combination of a presumptive diagnosis of MPC, PID, or NGU in the medical record plus no laboratory evidence of CT or GC infection (described below). Diagnostic criteria for the remaining STDs were derived from a combination of lab and historical data as follows: GC and CT—one or more of the following: 1) positive urethral/cervical swab Gram stain (GC only) and/or, 2) positive culture (from urethra, cervix, throat, or rectum) and/or, 3) positive urine ligase chain reaction (Abbott Labs) or Aptima Combo 2; syphilis—no history of disease plus at least one of the following: 1) newly positive RPR plus a positive treponemal antibody test, 2) newly positive darkfield examination, 3) newly positive VDRL plus a positive treponemal antibody test; HIV—no history of disease and a positive rapid HIV test and/or positive HIV serology; genital herpes (HSV2)—no history of disease plus a positive HSV2 ELISA assay and/or positive Western blot for HSV2; hepatitis B—positive HBsAg. Back to Top | Article Outline Statistical Analysis Because only new problem visits were being considered, and because some STDs could be newly diagnosed more than once in the same individual, clinic visits (rather than unique individuals) were the unit of analysis. In some instances, diagnostic criteria for one of the chronic STDs (HIV, HSV2, or hepatitis B) were present in multiple visits for the same individual. In this case the diagnosis was counted only once when determining diagnosis prevalence. Demographic and clinical characteristics were determined for the various groups using descriptive characteristics. Prevalence of the different STDs was calculated by dividing the number of visits fulfilling the diagnostic criteria described above by the total number of visits in that group. Differences in disease prevalence among the groups were evaluated using Pearson's χ2 or Fisher exact test under the assumption that each visit was an independent observation. Because the HPV vaccine is currently licensed only for females, and because asymptomatic STD infections have greater clinical impact on women than men, all analyses were stratified by gender. Data were analyzed using Stata8.2 statistical software (StataCorp, LP, College Station, TX). Back to Top | Article Outline Follow-Up Visit Analysis A separate analysis of visit types designated as follow-up was performed to more fully describe the potential impact of widespread HPV vaccination. The follow-up visit data set did not include information about the "reason for visit" and also could not be linked back to specific preceding new problem visits. Because of this, we were unable to directly determine the proportion of follow-up visits attributable to HPV-related concerns. Instead, we calculated the proportion of follow-up visits that resulted in a diagnosis of genital warts. This was done by dividing the number of follow-up visits fulfilling the diagnostic criteria for this disease (described above) by the total number of follow-up visits. In addition, new STD diagnoses among follow-up visits were evaluated using the methods described above. However, analysis of other STD diagnoses among follow-up visits was limited to diseases that did not require information on history as part of the diagnostic criteria (GC, CT, trichomonas, PID, MPC, NGU, hepatitis B, genital warts, and pubic lice), since history data were not available for these visits. Back to Top | Article Outline Results During the study period, 46,963 (71%) of visits were classified as new problem visits, and 22% were for follow-up (Fig. 1), with male visits predominating for both visit types. Among males, 7.9% of 32,263 new problem visits were for HPV-related presenting concerns. In contrast, the proportion of new problem visits attributable to HPV-related concerns was lower among women, comprising only 3.6% of the 14,700 female new problem visits. To more fully describe the potential impact of widespread HPV vaccination on STD clinic resource utilization, we also determined the percentage of follow-up visits attributable to HPV. During the study period, there were 10,289 follow-up visits among men, of which 2595 (25.2%) were for genital warts. Among women, 744 of 4285 follow-up visits (17.3%) were for genital warts. Overall, 10.3% of clinic visits during the study period were for HPV-related concerns, after combining genders and visit types in the analysis. Compared with the group of new problem visits unrelated to HPV (the No HPV group), "symptoms" and contact to HPV were more common presenting complaints among the HPV-related new problem visits (Table 1). As expected, the distribution of presenting symptom types varied in accordance with differences in the criteria used to define the groups (Table 1). There were no substantial differences in the average age at visit, insurance status, or median number of visits per person between the No HPV group and the HPV-related group of visits for either gender (Table 2). However, compared with visits in the No HPV group, new problem visits for HPV-related concerns were less often by members of racial minority groups, less often by men who have sex with men, and with the exception of genital warts, less frequently associated with a history of prior STDs. Table 1 Table 2 For both genders, more than 75% of the HPV-related visits resulted in a diagnosis of genital warts (Table 3). A few genital warts diagnoses were also found in the No HPV group (2.9% and 1.1% for male and female visits, respectively; Table 3), likely representing patients with small lesions of which they had been previously unaware, or patients with a known prior history of genital warts who came to the clinic for other concerns. Though the percentage of visits resulting in a genital warts diagnosis within the No HPV group was low, this represented nearly 27% of the HPV diagnoses made in new problem visits overall during the study period. Table 3 New, non-HPV, STD diagnoses among the HPV-related group of visits were uncommon, with only 242 additional diagnoses found among 2550 male new problem visits, and only 39 additional new diagnoses found among 535 female new problem visits (Table 3). For males, a large proportion of these new diagnoses (42%) were for nonspecific (i.e., nongonococcal, nonchlamydial) NGU. When nonspecific NGU, MPC, and PID were eliminated from the analysis (because these diagnoses may not always be sexually transmitted), we found only 133 new, non-HPV diagnoses among male visits and only 24 new diagnoses among female visits, with GC, CT, and HSV being the most prevalent additional diagnoses for both genders. The prevalence of all non-HPV STD diagnoses was higher in the No HPV group than in the HPV-related group. When we reanalyzed the STD diagnosis prevalence using only those visits where diagnostic tests for a given STD had been performed, we saw a similar pattern of statistical significance between the HPV and No HPV groups, implying that the differences in STD diagnosis prevalence between these groups were not the result of differential screening practices. We also analyzed the prevalence of additional STD diagnoses among a more restricted subset of HPV-related visits where HPV-related complaints appeared to be the singular reason for seeking care (i.e., eliminating HPV visits where additional, potentially confounding, presenting complaints seemingly unrelated to HPV were present). In this analysis, we found an even lower prevalence of additional, non-HPV, STD diagnoses in both genders with only 112 additional STD diagnoses among 2013 male new problem visits and only 20 additional STD diagnoses among 377 female visits. Back to Top | Article Outline Discussion Widespread vaccination against HPV is likely to reduce the incidence of cervical neoplasia and to decrease the burden of other HPV-associated illnesses such as genital warts. Such reduction in HPV-associated morbidity has the potential to decrease the clinical burden on public STD clinics; however, this could result in unanticipated negative effects, including missed opportunities to diagnose other STDs in persons seeking care for genital warts or other HPV-related complaints. We determined the proportion of clinic visits attributable to HPV-related complaints and evaluated the prevalence of unrecognized STDs other than HPV in patients presenting to an STD clinic for HPV-related concerns. We found few additional STD diagnoses among patients with HPV-related concerns. Though risk factors associated with HPV infection have been identified,5–11 the finding that HPV is nearly ubiquitous among sexually active individuals12 supports the notion that infection often occurs outside the setting of "risky sexual behavior." Because of this, it is not surprising that we found a paucity of other STD diagnoses among the HPV-related visits since many of the individuals with HPV-related concerns may not engage in behaviors placing them at increased risk for other sexually transmitted infections. Our study suggests that widespread utilization of HPV vaccines that include protection against HPV 6 and HPV 11 could ultimately decrease the demand for STD clinic services by ∼10% without a substantial impact on the diagnosis and treatment of other, non-HPV STDs. This reduction in demand for services could provide STD clinics with the opportunity to shift personnel, financial assets, and other resources to other areas of need in the future as these vaccines become more widely utilized. However, the true population-level benefits of HPV vaccines remain to be determined and will likely be influenced by many factors. These include the expected future availability of two different HPV vaccine products with different spectrums of clinical protection (one with the ability to prevent genital warts, the other without), anticipated changes in age- and gender-related licensure restrictions for HPV vaccines, and federal, state, and private insurance coverage for HPV vaccination, among others. Furthermore, some have expressed concern that behavioral disinhibition resulting from widespread HPV vaccine availability, and a "false sense of protection" against other STDs, could actually lead to higher rates of non-HPV STD acquisition. Many of these issues could be formally explored in future studies once HPV vaccines become more widely utilized. As with any retrospective study, our analysis was limited by the type of data available. The accuracy of visit type specification and of the characteristics used to define STD diagnoses and the reason(s) for clinic visit could not be confirmed. To circumvent this, we used both less- and more-restrictive criteria to define HPV-related visits but found similar results in terms of other STD diagnosis frequency. An additional limitation of our analysis is that we studied a single STD clinic population, and our findings may not be generalizable to other, non-STD clinic populations, or to STD clinic populations in other geographic locations. Furthermore, the STD clinic evaluated in this study did not provide ongoing management of Pap smear abnormalities, and we were therefore not able to capture this subgroup of patients with "HPV-related concerns." It will be important to expand future studies on the prevalence of additional STDs in people with HPV-related concerns to the other populations and to include women seeking care specifically for follow-up of abnormal Pap smears. In summary, we found that while a substantial number of STD clinic patients seek evaluation or follow-up care for complaints related to genital warts, non-HPV STD diagnoses were uncommon among these patients. This suggests that if genital warts were eliminated by widespread use of HPV vaccines, public STD clinics would likely realize substantial gains in availability of clinic resources while sacrificing relatively little in terms of missed opportunities for diagnosing other, unrecognized STDs in this population. Back to Top | Article Outline References1. U.S. Food and Drug Administration. Product Approval Information-Licensing Action. Gardasil. 2006. Cited Here... 2. Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: A randomised controlled trial. Lancet 2004; 364:1757–1765. Cited Here... | PubMed | CrossRef 3. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of human papillomavirus type 16 vaccine. NEJM 2002; 347:1645–1651. Cited Here... 4. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6:271–278. Cited Here... 5. Bauer HM, Hildesheim A, Schiffman MH, et al. Determinants of genital human papillomavirus infection in low-risk women in Portland, Oregon. Sex Transm Dis 1993; 20:274–278. Cited Here... | View Full Text | PubMed | CrossRef 6. Wheeler CM, Parmenter CA, Hunt WC, et al. Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center. Sex Transm Dis 1993; 20:286–289. Cited Here... | View Full Text | PubMed | CrossRef 7. Hildesheim A, Gravitt P, Schiffman MH, et al. Determinants of genital human papillomavirus infection in low-income women in Washington, D.C. Sex Transm Dis 1993; 20:279–285. Cited Here... | View Full Text | PubMed | CrossRef 8. Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003; 157:218–226. Cited Here... | View Full Text | PubMed | CrossRef 9. Burk RD, Ho GY, Beardsley L, et al. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis 1996; 174:679–689. Cited Here... | View Full Text | PubMed | CrossRef 10. Peyton CL, Gravitt PE, Hunt WC, et al. Determinants of genital human papillomavirus detection in a US population. J Infect Dis 2001; 183:1554–1564. Cited Here... | View Full Text | PubMed | CrossRef 11. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338:423–428. Cited Here... | View Full Text | PubMed | CrossRef 12. STD Facts: Human Papillomavirus. 2004. Available at http://www.cdc.gov/std/HPV/STDFact-HPV.htm. Accessed May 10, 2006 Cited Here... Cited By: This article has been cited 1 time(s). International Journal of Gynecological CancerEfficacy of Human Papillomavirus Vaccines: A Systematic Quantitative ReviewMedeiros, LR; Rosa, DD; da Rosa, MI; Bozzetti, MC; Zanini, RRInternational Journal of Gynecological Cancer, 19(7): 1166-1176.10.1111/IGC.0b013e3181a3d100 PDF (861) | CrossRef Back to Top | Article Outline© Copyright 2007 American Sexually Transmitted Diseases Association Article Outline Abstract Materials and Methods Study Population and Design Inclusion/Exclusion Criteria Diagnostic Criteria Statistical Analysis Follow-Up Visit Analysis Results Discussion References Cited By Source Potential Impact of Human Papillomavirus Vaccines on Public STD Clinic Workloads and on Opportunities to Diagnose and Treat Other Sexually Transmitted Diseases Sexually Transmitted Diseases34(7):503-507, July 2007. 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TOKYO, May 24 (Reuters) - Worldwide output at Nissan Motor Co. Ltd. , Japan's second-largest auto maker, plunged by a fifth in April, the company said on Wednesday, a drop that reflects planned inventory cutbacks but also falls in sales. Global production fell 21 percent from a year earlier to 230,175 vehicles, with output in Japan dropping 30 percent and U.S. production declining 20 percent. British production slid 19 percent while output in Mexico was down 17 percent. The fall stands ...
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I need a macro to duplicate the slide, or create a new one, with only the title of the original.
Look, I had the slide 1, with the title and the image. I want to create, or duplicate the slide 1, but keep only the title. For many slides, "Frankenstein, AAA, I don't know...", in other words, duplicate various slides, with various titles.


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Place, Culture and Tourism
Understanding society in an era of mobility and globalization requires a thorough knowledge of the complex interplay between place, culture and tourism.
PhD Students about the programme
Exploring all dimensions of tourism
How can we make sense of New Zealand's 50% increase in tourism after the release of the Lord of the Rings trilogy? What motivates over 1.5 million people each year to visit Auschwitz in Poland? And why are the majority of Air France's destinations former colonies of France? This master will help you understand the international and dynamic field of cultural tourism and help you jumpstart a career in this ever-expanding field.
The tourism sector has grown into one of the most important industries in today's world economy. Cities, regions and nations are involved in a non-stop competition for the favours of the global tourist flows. The field has become more and more diverse, as a result of globalization and digitization. As an increasing amount of people is able and eager to travel across the globe, different cultures around the world become interconnected. This calls for new professionals in culture and tourism, who possess the knowledge and skills to anticipate and understand the global dynamics between societies, cultures, media and tourism.
In this master, you focus on questions such as:
- How can we disclose cultural heritage sites to international tourism in an environmentally and community friendly way?
- Which opportunities and challenges does the tourist industry pose for Indigenous communities?
- How do the history of tourism and our colonial heritage resonate in contemporary tourist practices?
- How have globalization and the emergence of digital technologies affected tourism and other types of mobility?
In this programme, you will build upon a wide range of disciplines and innovative perspectives on tourism. You will develop your expertise by adopting different ways of looking at problems, finding creative solutions, providing advice and even implementing policy or organizational changes in the tourism industry. While looking at today's challenges, you will always keep in mind, and keep track of, the wider historical or contemporary socio-cultural context.
Five reasons to choose for Place, Culture and Tourism at the EUR
- Contrary to other tourism masters, this programme is truly interdisciplinary. You will study the relation between place, culture and tourism from various angles, including sociology, cultural economics, media studies and cultural studies.
- Your broad theoretical knowledge of the field will make you an interesting candidate for many employers, as you can approach challenges in today's tourist industry from different perspectives.
- Your lecturers are renowned researchers, who are partaking in global research projects. In their classes, they will provide you with knowledge of the most current and cutting-edge studies in the field.
- Studying at Erasmus University Rotterdam means you will be part of a truly international environment. In this programme you will not only study intercultural communication, but experience it yourself.
- Rotterdam is an upcoming tourist destination by itself, with a rich and vibrant cultural scene. The ideal place to start building your professional network!
Our students
The Master's programme Place, Culture and Tourism in Rotterdam will be ideal for:
- students who want to become creative and critical professionals in the field of tourism;
- students who want to study tourism as part of the bigger picture and wish to understand the relations between tourism and international economies, societies, media and cultures.
- students who want to pursue an academic career in the field of cultural studies, media studies and/or tourism studies.