SU-E-T-313: Probe-Type Experimental Dosimetry in Terms of Absorbed Dose to Water in Photon-Brachytherapy a Proposal for a Radiation-Quality Index.

PURPOSE: In photon-brachytherapy (BT), all data for clinical dosimetry (e.g., the dose-rate constant) are not measured in water, but calculated, based on MC-simulation. To enable the measurement of absorbed dose to water, DW, in the vicinity of a source, the complex energy-dependence and other influence quantities must be considered. METHODS: The detectors response, R=M/D, is understood as product of a detector-material dependent 'absorbed dose response', Ren, and Rin, the 'intrinsic response'. Ren is described by the Burlin-theory and because of dissimilarities between the detector-material and water, will have energy dependent correction factors which convert Ren into the clinically relevant DW,Qo=MQo × ND,W,Qo. To characterize BT- source-types, we propose a new 'radiation-quality index' QBT=Dprim(2cm)/Dprim(1cm), the ratio of the primary-dose to water at r=2cm to that at the reference distance r=1cm, similar to external beam dosimetry. Although QBT cannot be measured directly, it can be derived from primary and scatter separated dose-data, published as consensus data e.g., in the Carlton AAPM-TG-43-database. RESULTS: Mean QBT-values are: for nine HDR and four PDR 192Ir-sources: 0.2258±0.5%; one 169Yb- source: 0.2142; and one 125I-source: 0.1544. CONCLUSIONS: The main benefit of this new QBT-concept is that a type of BT-dosimetry-detector needs to be calibrated only for one reference radiation-quality, e.g., for Q0=192Ir. To measure the dose for different source-types, DW can be determined using calculated radiation-quality conversion factors kQ,QoBT, to be included in the AAPM-database and to be provided by the manufacturer for each detector-type. Typical BT-dosimetry-detectors are plastic scintillation detectors, radiochromic film, thermoluminescence detectors, optically stimulated detectors, and small volume ionization chambers. Recently, different DW(1cm)-primary standards have been developed in several European NMIs, enabling to calibrate BT-radiation- sources and BT-dosimetry-detectors and allowing to verify MC-calculated dose-rate constant values. The proposed definition of QBT has to be discussed internationally to find broad consensus.

[Overview of measles, mumps, rubella and varicella vaccination in adolescents and adults]. / Masern-, Mumps-, Röteln- und Varizellenimpfung bei Jugendlichen und Erwachsenen - eine Ubersicht.

It is evident that the complete elimination of measles, mumps and varicella has not yet been accomplished, as various outbreaks have shown. In the recent past the number of infections of teenagers and adults with these so called 'children's diseases' have been increasing. The course of the infections in these cases are often severe. To improve the current situation it will be necessary to: strictly undertake (re-)vaccination of all persons who may not be protected; extensive immunization for occupational indications (including apprentices, trainees and students); broad postexposure vaccinations; outbreak response immunizations of persons having no proof of proper vaccination (twice) or immunity. Teenagers and adults, in addition to children should obtain protection by being immunized against measles, mumps, rubella and chickenpox (varicella).

Incomplete dissociation of glibenclamide from wild-type and mutant pancreatic K ATP channels limits their recovery from inhibition.

BACKGROUND AND PURPOSE: The antidiabetic sulphonylurea, glibenclamide, acts by inhibiting the pancreatic ATP-sensitive K(+) (K(ATP)) channel, a tetradimeric complex of K(IR)6.2 and sulphonylurea receptor 1 (K(IR)6.2/SUR1)(4). At room temperature, recovery of channel activity following washout of glibenclamide is very slow and cannot be measured. This study investigates the relation between the recovery of channel activity from glibenclamide inhibition and the dissociation rate of [(3)H]-glibenclamide from the channel at 37 degrees C. EXPERIMENTAL APPROACH: K(IR)6.2, K(IR)6.2DeltaN5 or K(IR)6.2DeltaN10 (the latter lacking amino-terminal residues 2-5 or 2-10 respectively) were coexpressed with SUR1 in HEK cells. Dissociation of [(3)H]-glibenclamide from the channel and recovery of channel activity from glibenclamide inhibition were determined at 37 degrees C. KEY RESULTS: The dissociation kinetics of [(3)H]-glibenclamide from the wild-type channel followed an exponential decay with a dissociation half-time, t(1/2)(D) = 14 min; however, only limited and slow recovery of channel activity was observed. t(1/2)(D) for K(IR)6.2DeltaN5/SUR1 channels was 5.3 min and recovery of channel activity exhibited a sluggish sigmoidal time course with a half-time, t(1/2)(R) = 12 min. t(1/2)(D) for the DeltaN10 channel was 2.3 min; recovery kinetics were again sigmoidal with t(1/2)(R) approximately 4 min. CONCLUSIONS AND IMPLICATIONS: The dissociation of glibenclamide from the truncated channels is the rate-limiting step of channel recovery. The sigmoidal recovery kinetics are in quantitative agreement with a model where glibenclamide must dissociate from all four (or at least three) sites before the channel reopens. It is argued that these conclusions hold also for the wild-type (pancreatic) K(ATP) channel.

KATP channel openers of the benzopyran type reach their binding site via the cytosol.

BACKGROUND AND PURPOSE: ATP-sensitive K+ (KATP) channels are composed of pore-forming subunits (Kir6.x) and of sulphonylurea receptors (SUR). Both sulphonylureas and K(ATP) channel openers act by binding to SUR. Sulphonylureas reach their binding site from the cytosol but it remains unknown whether this holds for openers too. EXPERIMENTAL APPROACH: A poorly membrane-permeant sulphonic acid derivative of the benzopyran-type opener, bimakalim, was synthesized, descyano-bimakalim-6-sulphonic acid (BMSA). Binding of BMSA and bimakalim was compared in membranes and intact cells expressing the Kir6.2/SUR2B channel and channel opening was compared in inside-out patches and whole cells. KEY RESULTS: In membranes, bimakalim and BMSA bound to Kir6.2/SUR2B with Ki values of 61 nM and 4.3 microM, showing that the negative charge decreased affinity 69-fold. In intact cells, however, binding of BMSA was much weaker than in membranes (75-fold) whereas that of bimakalim was unchanged. The Ki value of BMSA decreased with increasing incubation time. In inside-out patches, bimakalim (1 microM) and BMSA (100 microM) opened the Kir6.2/SUR2B channel closed by MgATP to a similar degree whereas in whole-cell experiments, only bimakalim was effective. CONCLUSIONS AND IMPLICATIONS: Despite its negative charge, BMSA is an effective channel opener. The fact that BMSA binds and acts more effectively when applied to the inner side of the cell membrane shows that benzopyran openers reach their binding site at SUR from the cytosol. This suggests that the binding pocket of SUR is only open on the cytoplasmic side.

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels.

AIMS/HYPOTHESIS: Sulfonylureas and glinides close beta cell ATP-sensitive K(+) (K(ATP)) channels to increase insulin release; the concomitant closure of cardiovascular K(ATP) channels, however, leads to complications in patients with cardiac ischaemia. The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K(ATP) channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K(ATP) channels may be overstated. We therefore re-examined repaglinide's potency at and affinity for the recombinant pancreatic, myocardial and vascular K(ATP) channels in comparison with glibenclamide. METHODS: K(ATP) channel subunits (i.e. inwardly rectifying K(+) channels [Kir6.x] and sulfonylurea receptors [SURx]) were expressed in intact human embryonic kidney cells and assayed in whole-cell patch-clamp and [(3)H]glibenclamide binding experiments at 37 degrees C. RESULTS: Repaglinide and glibenclamide, respectively, were >or=30 and >or=1,000 times more potent in closing the pancreatic than the cardiovascular channels and they did not lead to complete inhibition of the myocardial channel. Binding assays showed that the selectivity of glibenclamide was essentially based on high affinity for the pancreatic SUR, whereas binding of repaglinide to the SUR subtypes was rather non-selective. After coexpression with Kir6.x to form the assembled channels, however, the affinity of the pancreatic channel for repaglinide was increased 130-fold, an effect much larger than with the cardiovascular channels. This selective effect of coexpression depended on the piperidino substituent in repaglinide. CONCLUSIONS/INTERPRETATION: Repaglinide and glibenclamide show higher potency and efficacy in inhibiting the pancreatic than the cardiovascular K(ATP) channels, thus supporting their clinical use.

Interaction of the sulfonylthiourea HMR 1833 with sulfonylurea receptors and recombinant ATP-sensitive K(+) channels: comparison with glibenclamide.

The novel sulfonylthiourea 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR 1883), a blocker of ATP-sensitive K(+) channels (K(ATP) channels), has potential against ischemia-induced arrhythmias. Here, the interaction of HMR 1883 with sulfonylurea receptor (SUR) subtypes and recombinant K(ATP) channels is compared with that of the standard sulfonylurea, glibenclamide, in radioligand receptor binding and electrophysiological experiments. HMR 1883 and glibenclamide inhibited [(3)H]glibenclamide binding to SUR1 with K(i) values of 63 microM and 1.5 nM, and [(3)H]opener binding to SUR2A/2B with K(i) values of 14/44 microM and 0.5/2.8 microM, respectively (values at 1 mM MgATP). The interaction of HMR 1883 with the SUR2 subtypes was more sensitive to inhibition by MgATP and MgADP than that of glibenclamide. In inside-out patches and in the absence of nucleotides, HMR 1883 inhibited the recombinant K(ATP) channels from heart (Kir6.2/SUR2A) and nonvascular smooth muscle (Kir6.2/SUR2B) with IC(50) values of 0.38 and 1.2 microM, respectively; glibenclamide did not discriminate between these channels (IC(50) approximately 0.026 microM). In whole cells, the recombinant vascular K(ATP) channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC(50) values of 5.3 and 0.043 microM, respectively. The data show that the sulfonylthiourea exhibits a selectivity profile quite different from that of glibenclamide with a major loss of affinity toward SUR1 and slight preference for SUR2A. The stronger inhibition by nucleotides of HMR 1883 binding to SUR2 (as compared with glibenclamide) makes the sulfonylthiourea an interesting tool for further investigation.

[Suspected diphtheria. Immediately start therapy!]. / Diphtherieverdacht. Leiten Sie sofort die Therapie ein!

Only those strains of corynebacteria that carry the gene for diphtheria toxin may cause diphtheria. The only known reservoir of C. diphtheriae is man. The past decade has seen a return of diphtheria in the newly independent states of the former Soviet Union. Owing to a lack of immunization of the population, more than 150,000 people went down with the disease. In Germany, too, contact resulted in a number of cases and two deaths. The sole effective protection is immunization. Although more than 90% of children and adolescents are protected, only 40% to 60% of adults are.

Chromanol 293B, a blocker of the slow delayed rectifier K+ current (IKs), inhibits the CFTR Cl- current.

The cystic fibrosis transmembrane conductance regulator (CFTR) and the sulphonylurea receptor subunit (SUR) of the KATP channel are both members of the ATP-binding cassette (ABC) protein superfamily. Many compounds that open or block the KATP channel by binding to SUR also inhibit the CFTR Cl- current (ICFTR); an example in point is the chromanol-type KATP channel opener, cromakalim. The structurally related chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane), a blocker of the slow component of the delayed rectifier K+ current (IKs) in the heart, is also a weak inhibitor of KATP. This suggests that 293B may affect also ICFTR- We have addressed this question with human CFTR expressed in Xenopus oocytes. In two-electrode voltage-clamp experiments, 293B inhibited ICFTR with an IC50-value of 19 microM and Hill coefficient of 1.0; the inhibition was weakened by increasing concentrations of isobutyl-methylxanthine (IBMX). Patch-clamp recordings gave an IC50-value of 30 microM but showed a unusual variability in the sensitivity to 293B. The data show that 293B inhibits ICFTR and suggest that the mechanism of inhibition may depend on the phosphorylation state of the CFTR protein. The concentrations required for inhibition of ICFTR are three- to fivefold higher than those reported for inhibition of KvLQT1 + minK expressed in Xenopus oocytes. Since CFTR is expressed also in cardiac myocytes, the effects of 293B in these cells must be analysed with caution.

Characterization of a mutant sulfonylurea receptor SUR2B with high affinity for sulfonylureas and openers: differences in the coupling to Kir6.x subtypes.

ATP-dependent K(+) channels are composed of pore-forming subunits of the Kir6.x family and of sulfonylurea receptors (SURs). SUR1, expressed in pancreatic beta-cells, has a higher affinity for sulfonylureas, such as glibenclamide, than SUR2B, expressed in smooth muscle. This difference is mainly caused by serine 1237 in SUR1 corresponding to tyrosine 1206 in SUR2B. To increase the affinity of SUR2B for glibenclamide, the mutant SUR2B(Y1206S) was constructed. In whole-cell patch-clamp experiments, glibenclamide inhibited the channel formed by coexpression of mutant SUR2B with Kir6.1 or 6.2 in human embryonic kidney cells with IC(50) values of 2.7 and 13 nM, respectively (wild-type, 43 and 167 nM). In intact cells, [(3)H]glibenclamide bound to mutant SUR2B with a K(D) value of 4.7 nM (wild-type, 32 nM); coexpression with Kir6.1 or 6.2 increased affinity by 4- and 8-fold, respectively. Binding of the opener [(3)H]P1075 to SUR2B(Y1206S) was the same as to wild-type and was unaffected by coexpression. In cells, the ratio of glibenclamide:P1075 sites was approximately 1:1; in membranes, it varied with the MgATP concentration. Heterologous competition curves were generally biphasic; the shape of the curve depended on the Kir-subtype. The effects of coexpression were weakened or abolished when binding assays were conducted in membranes. It is concluded that the mutation Y1206S increases the affinity of SUR2B for and the channel sensitivity toward glibenclamide by 7- to 15-fold. The interaction of glibenclamide (but not opener) with mutant SUR2B is modified by coexpression with Kir6.x in a manner depending on the Kir subtype and on the integrity of the cell.

Synthesis and characterization of a novel tritiated KATP channel opener with a benzopyran structure.

The synthesis of a tritiated benzopyran-type opener of the ATP-dependent K+ channel (KATP channel), [3H]-PKF217 - 744 (3S,4R)-N-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-methyl-4-pyridinyl)-2H-1-benzopyran-4-yl]-3-[2,6-3H]pyridinecarboxamide with a specific activity of 50 Ci mmol(-1) is described. Binding of the ligand was studied in membranes from human embryonic kidney cells transfected with the sulphonylurea receptor isoforms, SUR2B and SUR2A, respectively. PKF217 - 744 was confirmed as being a KATP channel opener by its ability to open the Kir6.1/SUR2B channel, the recombinant form of the vascular KATP channel, and to inhibit binding of the pinacidil analogue, [3H]-P1075, to SUR2B (Ki=26 nM). The kinetics of [3H]-PKF217 - 744 binding to SUR2B was described by rate constants of association and dissociation of 6.9x10(6) M(-1) min(-1) and 0.09 min(-1), respectively. Binding of [3H]-PKF217 - 744 to SUR2B/2A was activated by MgATP (EC50 approximately 3 microM) and inhibited (SUR2B) or enhanced (SUR2A) by MGADP: Binding of [3H]-PKF217 - 744 to SUR2B was inhibited by representatives of the different structural classes of openers and sulphonylureas. Ki values were identical with those obtained using the opener [3H]-P1075 as the radioligand. Glibenclamide accelerated dissociation of the SUR2B-[3H]-PKF217 - 744 complex. The data show that the affinity of [3H]-PKF217 - 744 binding to SUR2B is approximately 6 times lower than that of [3H]-P1075. This is due to a surprisingly slow association rate of the benzopyran-type ligand, suggesting a complex mechanism of opener binding to SUR. The other pharmacological properties of the two opener radioligands are identical.

The influence of guiding equipment and stents on the beta dose distribution in the brachytherapy of in-stent restenosis.

BACKGROUND: Intracoronary devices such as stents or guide wires may disturb the dose distribution of beta sources in cardiovascular brachytherapy. As clinical observations indicate that underdosage increases the risk of restenosis, accurate measurements are mandatory to investigate these effects. METHODS AND RESULTS: Dose perturbation effects of different interventional equipment were systematically determined. Dose distributions of 90Sr-beta line sources were measured by means of a special set-up employing plastic scintillator dosimeters in a water phantom. Shielding effects were found to be 2-5% for single stents and 5-10% for graft stents, stent-in-stent geometries, and guiding catheters. Guide wires close to the source reduced the dose by 25-30%. CONCLUSIONS: Beta dose perturbation effects of typical stent types are almost negligible and can be corrected by an increased source dwell time if necessary. Guide wires produce effects which are clinically much more important and should therefore be retracted from the irradiation area.

Potent stimulation and inhibition of the CFTR Cl(-) current by phloxine B.

The effects of the fluoresceine derivative, phloxine B, on the Cl(-) current through the cystic fibrosis transmembrane conductance regulator (CFTR) were examined in Xenopus oocytes expressing human CFTR. In whole oocytes, the CFTR Cl(-) current (I(CFTR)) was activated by superfusion with isobutylmethylxanthine and forskolin. I(CFTR) was stable during activation and deactivated rapidly upon washout of the activation solution. Phloxine B slowed deactivation and, at high concentrations, inhibited I(CFTR) weakly. In excised inside-out macropatches, I(CFTR) was activated by the catalytic subunit of protein kinase A (cPKA) and MgATP. Phloxine B (0.01 - 3 microM), applied after activation, increased I(CFTR) within 30 s followed by a slow decrease which became dominant at high concentrations. Slowing of deactivation of the CFTR was observed at all concentrations. The effect of phloxine B after 30 s had a bell-shaped concentration-dependence with midpoints at 45 and 1600 nM for the stimulatory and the inhibitory limb, respectively; maximum stimulation was about 1.8 times. The slow inhibitory component, measured after 6 min, occurred with an IC(50) value of approximately 1 microM. In the absence of cPKA, phloxine B did not stimulate I(CFTR). In the presence of cPKA and MgATP, the effects of phloxine B were more prominent at low (0.02 mM) than at high ATP (2 mM). The data show that phloxine B modulates I(CFTR) by increasing channel activity and slowing channel deactivation; at high concentrations inhibition dominates. The effects may be mediated by direct interactions with CFTR from the inside of the cell.

In-phantom response of LiF TLD-100 for dosimetry of 192Ir HDR source.

An experiment was carried out to reevaluate the response of LiF TLD-100 rods (1 mmx1 mmx6 mm) at different depths in a water substituting phantom to provide an answer to a prevailing controversy about the over-response of LiF to the softened photon spectra of 192Ir HDR source at depths in phantom due to its photon energy dependence. Claims of some authors that LiF TLDs over-responds by 8.5% at 10 cm depth in phantom, necessitating depth-dependent correction factors even for an 192Ir source and of some others for no over-response were evaluated. The over-response of LiF TLD-100 rods, against a calibrated ion chamber having a photon energy-independent response within 2%, was found to be not exceeding 2.5% at a depth of 10 cm in the phantom as compared to a depth at 1 cm, for a precision of the order of +/- 1% (1sigma) in the TLD measurements. By using ISO equivalent photon beams, photon energy dependence of the dosimeters was evaluated and for LiF TLD-100 rods it was found to be in close agreement (within 3%) with the ratios of mass energy absorption coefficients of LiF and water in the range of effective photon energy from 26 keV to 1.25 MeV. Parameters that could contribute to the discrepancy in the reported values of experimental results have been discussed.

A high-precision, high-resolution and fast dosimetry system for beta sources applied in cardiovascular brachytherapy.

A fast dosimetry system based on plastic scintillator detectors has been developed which allows three-dimensional measurement of the radiation field in water of beta-sources appropriate for application in cardiovascular brachytherapy. This system fulfills the AAPM Task Group 60 recommendations for dosimetry of cardiovascular brachytherapy sources. To demonstrate the use of the system, measurements have been performed with an 90Y-wire source. The dose distribution was determined with a spatial resolution of better than 0.2 mm, with only a few minutes needed per scan. The scintillator dosemeter was absolutely calibrated in terms of absorbed dose to water with a precision of +/-7.5%. The relative precision achievable is +/-2.5%. The response of the system is linear within +/-2% for dose rates from 0.5 mGy s(-1) to 500 mGy s(-1).

Atypical effect of minoxidil sulphate on guinea pig airways.

The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.