bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined hERG channel inhibition and disruption of trafficking in drug‐induced long QT syndrome by fluoxetine: a case‐study in cardiac safety pharmacology
Authors: Hancox J C , Mitcheson J S 
Published: September 2006

Drug‐induced prolongation of the rate‐corrected QT interval (QTCI) on the electrocardiogram occurs as an unwanted effect of diverse clinical and investigational drugs and carries a risk of potentially fatal cardiac arrhythmias. hERG (human ether‐à‐go‐go‐related gene) is the gene encoding the α‐subunit of channels mediating the rapid delayed rectifier K+ current, which plays a vital role in repolarising the ventricles of the heart. Most QTCI prolonging drugs can inhibit the function of recombinant hERG K+ channels, consequently in vitro hERG assays are used widely as front‐line screens in cardiac safety‐testing of novel chemical entities. In this issue, Rajamani and colleagues report a case of QTCI prolongation with the antidepressant fluoxetine and correlate this with a dual effect of the drug and of its major metabolite norfluoxetine on hERG channels. Both compounds were found to produce an acute inhibition of the hERG channel by pharmacological blockade, but in addition they also were able to disrupt the normal trafficking of hERG protein to the cell membrane. Mutations to a key component of the drug binding site in the S6 region of the channel greatly attenuated channel block, but did not impair disruption of trafficking; this suggests that channel block and drug effects on trafficking were mediated by different mechanisms. These findings add to growing evidence for disruption of hERG channel trafficking as a mechanism for drug‐induced long QT syndrome and raise questions as to possible limitations of acute screening methods in the assessment of QTcI prolonging liability of drugs in development.British Journal of Pharmacology (2006) 149, 457–459. doi:10.1038/sj.bjp.0706890
Drug‐induced long QT syndrome: hERG K+channel block and disruption of protein trafficking by fluoxetine and norfluoxetine
Authors: Rajamani S , Eckhardt L L , Valdivia C R , Klemens C A , Gillman B M , Anderson C L , Holzem K M , Delisle B P , Anson B D , Makielski J C , January C T 
Published: September 2006

Background and purpose:Fluoxetine (Prozac®) is a widely prescribed drug in adults and children, and it has an active metabolite, norfluoxetine, with a prolonged elimination time. Although uncommon, Prozac causes QT interval prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms underlying this clinical finding by analysing the effects of fluoxetine and norfluoxetine on ion channelsin vitro.Experimental approach:We studied the effects of fluoxetine and norfluoxetine on the electrophysiology and cellular trafficking of hERG K+and SCN5A Na+channels heterologously expressed in HEK293 cells.Key results:Voltage clamp analyses employing square pulse or ventricular action potential waveform protocols showed that fluoxetine and norfluoxetine caused direct, concentration‐dependent, block of hERG current (IhERG). Biochemical studies showed that both compounds also caused concentration‐dependent reductions in the trafficking of hERG channel protein into the cell surface membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous current. Mutations in the hERG channel drug binding domain reduced fluoxetine block of IhERGbut did not alter fluoxetine's effect on hERG channel protein trafficking.Conclusions and implications:Our findings show that both fluoxetine and norfluoxetine at similar concentrations selectively reduce IhERGby two mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel protein trafficking. These two effects are not mediated by a single drug binding site. Our findings add complexity to understanding the mechanisms that cause drug‐induced long QT syndrome.British Journal of Pharmacology(2006)149, 481–489. doi:10.1038/sj.bjp.0706892
Needle vs surgical cricothyroidotomy: a short cut to effective ventilation
Authors: Scrase I. , Woollard M. 
Published: September 2006

SummaryCricothyroidotomy can be performed using three techniques. This literature review seeks to determine which is more appropriate for use in prehospital can't intubate/can't ventilate scenarios where laryngeal mask airways prove ineffective. The common approach of inserting a 14‐gauge cannula and using low‐pressure ventilation via intermittent occlusion of an opening in oxygen tubing (15 l.min−1 flow) results in ineffective ventilation within 60 s or less, depending on the degree of airway obstruction. In the absence of a high degree of upper airway obstruction, ventilation can be effective if the cannula is attached to a high pressure (45 psi) jet ventilator, but such devices are rare in UK prehospital practice. A self‐inflating bag used with a cuffed tube inserted through a horizontal scalpel incision provides sustained adequate ventilation, has a relatively low complication rate compared to needle cricothyroidotomy and is a skill that can be easily taught to paramedics, nurses and doctors.
The history of extracorporeal oxygenators*
Authors: Lim M. W. 
Published: September 2006

SummaryExtracorporeal oxygenators are artificial devices that substitute for anatomical lungs by delivering oxygen to, and extracting carbon dioxide from, blood. They were first conceptualised by the English scientist Robert Hooke (1635–1703) and developed into practical extracorporeal oxygenators by French and German experimental physiologists in the 19th century. Indeed, most of the extracorporeal oxygenators used until the late 1970s were derived from von Schroder's 1882 bubble oxygenator and Frey and Gruber's 1885 film oxygenator. As there is no intervening barrier between blood and oxygen, these are called ‘direct contact’ oxygenators; they contributed significantly to the development and practice of cardiac surgery till the 1980s. Membrane extracorporeal oxygenators introduce a gas–permeable interface between blood and oxygen. This greatly decreased the blood trauma of direct‐contact extracorporeal oxygenators, and enabled extracorporeal oxygenators to be used in longer‐term applications such as the intensive therapy of respiratory distress syndrome; this was demonstrably beneficial for neonates but less so for older patients. Much work since the 1960s focused on overcoming the gas exchange handicap of the membrane barrier, leading to the development of high‐performance microporous hollow‐fibre oxygenators that eventually replaced direct‐contact oxygenators in cardiac theatres.
An in vitro study of the compliance of paediatric tracheal tube cuffs and tracheal wall pressure
Authors: Bernet V. , Dullenkopf A. , Cannizzaro V. , Stutz K. , Weiss M. 
Published: September 2006

SummaryCuff volume‐pressure curves and cuff pressure‐tracheal wall pressure relationships were investigated in eight brands of currently available cuffed, paediatric tracheal tubes with internal diameters of 5.0 mm. Cuff volume‐pressure curves were measured with the cuff unrestricted and with the cuff placed within a tracheal model with wall pressure measurements. With the tracheal tube cuffs, unrestricted cuff compliance at 20 cmH2O cuff pressure varied between 0.06 and 0.3 ml.cmH2O−1. With the cuff restricted within the model trachea, all tracheal tube cuffs became considerably less compliant (0.01–0.09 ml.cmH2O−1). We found tracheal wall pressure was similar to the cuff pressure as long as the resulting cuff diameter was sufficiently large freely to drape the inner tracheal wall. We found that, regardless of whether a higher or lower compliant tube cuff was used, cuff hyperinflation uniformly resulted in potentially compromised tracheal mucosal blood flow; cuff pressure monitoring using cuff pressure limitation is therefore strongly recommended.
Acute peri‐operative beta blockade in intermediate‐risk patients
Authors: Biccard B. M. , Sear J. W. , Foëx P. 
Published: September 2006

SummaryPeri‐operative beta‐blockade has been shown to reduce the incidence of postoperative cardio‐ vascular complications including cardiac death in high‐risk non‐cardiac surgical patients. However, the recent analysis by Lindenauer et al. suggests that it is inappropriate to administer beta‐blockers blindly to all surgical patients. In an attempt to determine the appropriateness of peri‐operative beta‐blocker administration across patients with a spectrum of cardiovascular risks, we have examined studies of intermediate‐risk patient groups (that is those undergoing intermediate risk surgery or those with a Lee Revised Cardiac Risk Score of≤2). We analysed data from randomised prospective studies of the effects of acute peri‐operative beta‐blockade on the incidence of peri‐operative myocardial ischaemia. By examining the demographics and surgical interventions in these patients, we have compared these studies with other studies of peri‐operative silent myocardial ischaemia representing patients of similar risk. We thus estimated the expected long‐term postoperative cardiovascular complication rate associated with myocardial ischaemia in these patients in terms of number needed to treat for ischaemia prevention and for prevention of major cardiovascular complications. Prevention of peri‐operative myocardial ischaemia with acute beta‐blockade in non‐cardiac surgical patients with 1–2 RCRI clinical risk factors can be achieved with a number needed to treat of 10. It is not associated with a significant increase in drug associated side‐effects. However, acute beta‐blockade shows no real benefit in the prevention of major cardiovascular complications in intermediate risk non‐vascular surgical patients with a number‐needed‐to‐treat of 833. Vascular surgical patients undergoing intermediate‐risk surgery may benefit from the protective effects of acute peri‐operative beta‐blockade, however, with a number‐needed‐to‐treat of 68 it would require a randomised clinical trial of over 24 000 patients to prove their efficacy.
Determination of the optimal angle for needle insertion during caudal block in children using ultrasound imaging
Authors: Park J. H. , Koo B. N. , Kim J. Y. , Cho J. E. , Kim W. O. , Kil H. K. 
Published: September 2006

SummaryUsing ultrasound imaging, the optimal angle for needle insertion during caudal epidural injection in children was estimated. After general anaesthesia, ultrasonography was performed at the sacral hiatus in 130 children aged 2–84 months positioned in the lateral position. The median [range] values for the intercornual, caudal space depth and the distance from skin to the posterior sacral bony surface were 17.0 [9.6–24] mm, 3.5 [1–8] mm and 21.0 [10–39] mm, respectively. The optimal angle showed no significant correlation with age, weight, height or body surface area. The median [range] calculated optimal angle for the needle was 21.0 [10–38]°. We conclude that the needle should be inserted at about 20° to the skin to avoid puncture of the bone and potential intra‐osseous injection.
Use of continuous positive airway pressure during spinal anaesthesia in a patient with severe chronic obstructive pulmonary disease
Authors: Bapat P. P. , Anderson J. A. , Bapat S. , Sule A. 
Published: September 2006

SummaryWe report the case of a patient with severe chronic obstructive pulmonary disease who underwent local resection of a carcinoma of the rectum under spinal anaesthesia. Although the patient was keen to avoid general anaesthesia and to have the operation under a spinal anaesthetic, pre‐operative assessment showed that he could not lie flat. As the surgical procedure required the patient to be in the lithotomy position, ideally with a head‐down tilt, it was hoped that continuous positive airway pressure with a facemask during spinal anaesthesia might help him to tolerate the position comfortably. Continuous positive airway pressure at 7.5 cmH2O was successfully used to facilitate breathing during surgery under spinal anaesthesia. A combination of regional anaesthesia and continuous positive airway pressure via a facemask is easy to use and may be a useful option in the management of these challenging patients.
A human monoclonal antiprothrombin antibody is thrombogenic in vivo and upregulates expression of tissue factor and E‐selectin on endothelial cells
Authors: Vega‐Ostertag Mariano , Liu Xiaowei , Kwan‐Ki Hwang , Chen Pojen , Pierangeli Silvia 
Published: September 2006

SummaryProthrombin is now accepted as one of the target antigens recognised by antiphospholipid (aPL) antibodies. However, it is not clear whether anti‐prothrombin antibodies are pathogenic in vivo and if so, the possible mechanism(s) involved. Here, we examined the pathogenic effects of the IS6 monoclonal anti‐prothrombin antibody isolated from a patient with Antiphospholipid Syndrome (APS). IS6 antibody was purified from hybridoma supernatant. Its pathogenic potentials were studied in an in vivo model of induced thrombosis. The expression of tissue factor (TF) and E‐selectin on human umbilical vein endothelial cells (HUVEC) was determined by cyto‐enzyme‐linked immunosorbent assay. Transcription of TF mRNA was determined by quantitative real time‐polymerase chain reaction (RT‐PCR). In vivo, the thrombus size increased significantly when treated with IS6 compared with control‐treated mice (5388 ± 1035 μm2 vs. 2845 ± 1711 μm2). In vitro, IS6 induced significant expression of TF and E‐selectin on HUVEC, when compared with control preparation (3·1‐ and 5·1‐fold increase compared with the control‐treated cells). RT‐PCR analysis of TF mRNA transcription showed a 2·5‐fold increase of IS6‐treated cells over the value obtained with control‐treated cells. Taken together, these data show that IS6 monoclonal anti‐prothrombin antibody promotes thrombosis and this is associated with TF and E‐selectin expression.
Changes in compaction stress distributions in roots resulting from canal preparation
Authors: Versluis A. , Messer H. H. , Pintado M. R. 
Published: September 2006

AbstractAim  To examine if canal enlargement with instruments of controlled taper leads to more uniform stress distributions within a root, thereby reducing fracture susceptibility.Methodology  Finite element models of a mandibular incisor were constructed with round and oval canal profiles, based on measurements from extracted teeth. The shapes of rotary nickel–titanium instruments (ProTaper F1, F2, and F3 and ProFile size 30, 0.04 taper and size 30, 0.06 taper; Dentsply Maillefer) were superimposed on the canals. Equivalent stresses and circumferential stresses in the root were calculated for a compaction load.Results  The highest stresses were found at the canal wall. Round canals showed lower uniform distributions, whilst oval canals showed uneven distributions with high concentrations at the buccal and lingual canal extensions and greater stresses in the coronal and middle thirds than in the apical third. Preparation of round canals introduced only small circumferential stress increases in the apical half; preparation of oval canals produced substantial reductions where the canal was enlarged to a smooth round shape. Even where fins were not completely eliminated, the maximum stresses were still reduced by up to 15%. External distal and mesial surfaces of roots with oval canals showed moderate stress concentrations that were minimally affected by preparations, whilst stress concentrations emerged on roots with round canals when preparation sizes increased.Conclusions  The potential for reducing fracture susceptibility exists as a result of round canal profiles achieved and smooth canal taper. Even when fins were not contacted by the instrument, stresses within the root were lower and more evenly distributed than before preparation.
Cytotoxicity of Epiphany® and Resilon® with a root model
Authors: Susini G. , About I. , Tran‐Hung L. , Camps J. 
Published: September 2006

AbstractAim  To record the cytotoxicity of Resilon and Epiphany (Pentron clinical technologies, Wallingford, CT, USA) using a root model.Methodology  Thirty teeth with single roots were sectioned at the enamel–cementum junction, the root canals prepared and each root then sterilized before filling with the lateral condensation technique using one of three filling materials (n = 10 per group): Resilon and Epiphany, Sealite (Septodont, Pierre Rolland, Merignac, France) and gutta‐percha, Roekoseal Automix (Coltène/Whaledent, Langenau, Germany) and gutta‐percha. The roots were stored at 37 °C in an incubator to allow for setting of the root filling materials. The apices of the roots were dipped in 1 mL of MEM culture medium for 1, 2, 7 and 30 days renewing the medium every day. After 24 h contact between the medium and the filled roots, the medium was used to measure the cytotoxicity on mouse fibroblasts L 929 with the MTT assay that recorded the mitochondrial activity of the target cells. An additional test according to ISO 10993‐5 standards was undertaken to compare Resilon and Epiphany.Results  The root model showed no statistically significant differences between the sealers at 7 and 30 days (NS). Epiphany and Resilon were the most cytotoxic materials at 1 and 2 days (P < 0.001). Unlike Epiphany, Resilon was not cytotoxic when tested according to ISO 10993‐5 standards.Conclusions  The cytotoxicity of Resilon + Epiphany, due mainly to Epiphany, decreased after 2 days to reach a level comparable with commonly used root canal sealers.
The influence of various automated devices on the shaping ability of Mtwo rotary nickel‐titanium instruments
Authors: Bürklein S. , Schäfer E. 
Published: September 2006

AbstractAim  To compare the shaping ability of Mtwo rotary nickel‐titanium instruments in simulated curved canals and in curved canals of extracted teeth when set into permanent rotation with two different torque‐limited automated devices.Methodology  Root canal instrumentation was performed with two different torque‐limited automated devices (Mtwo direct handpiece and Endo IT motor) using Mtwo rotary nickel‐titanium instruments up to size 35. Simulated canals: 28° and 35° curved canals in resin blocks (n = 20 canals in each group) were prepared. Pre‐ and post‐instrumentation images were recorded and assessment of canal shape was completed with a computer image analysis program. Extracted teeth: a total of 40 curved root canals were divided into two groups, which were balanced with respect to the angle and the radius of canal curvature. Straightening of the canal curvatures was determined with a computer image analysis program. Incidence of canal aberrations, preparation time, changes of working length and instrument failures were recorded both in simulated and real canals and were analysed using the t‐test and a chi‐square test.Results  In simulated canals, instrumentation with Endo IT was significantly faster than with Mtwo direct (P < 0.05). No significant differences between the two devices were noted when all other parameters were assessed (P > 0.05). Only one instrument separated (Mtwo direct) during the enlargement of 28° curved simulated canals. All systems maintained working distance well.Conclusions  Both systems respected original root canal curvature well and were safe, indicating that the Mtwo direct handpiece is suitable for preparing curved root canals with the Mtwo instruments.
An evaluation of localized debonding between fibre post and root canal wall by finite element simulation
Authors: Yu W. J. , Kwon T. Y. , Kyung H. M. , Kim K. H. 
Published: September 2006

AbstractAim  To investigate the effect of localized bonding defects between fibre post and root canal wall on the stress distribution in the radicular dentine.Methodology  A tooth restored with a fibre post together with the alveolar bone were axisymmetrically modelled. A total of four models with localized debonding at the post to canal wall interface in different locations were analysed: Model A: perfect bonding layer over the entire interface; Model B: debonding at the cervical 1/3 of the interface; Model C: debonding at the mid 1/3; and Model D: debonding at the apical 1/3. A tooth restored without using a post was also included as the control (Model E). A load of 50 N was applied to the top of the full veneer cast crown at angles of 0, 15, 30, and 45° with the tooth's longitudinal axis. The stress distribution across the fibre post and root dentine was compared.Results  Higher stresses were generated in the radicular dentine as a function of the load angle. The differences in the stress distribution were negligible between the four models and virtually the same as that for model E (control).Conclusions  In this simulation, localized debonding at the fibre post to root canal wall interface, regardless of its location along the post, had little effect on the stress distribution in the root dentine.
ORIGINAL ARTICLE: Can Ellenberg's indicator values for Mediterranean plants be used outside their region of definition?
Authors: Godefroid Sandrine , Dana Elías D. 
Published: September 2006

AbstractAim  The aims of this study are: (1) to explore the relationships between the Ellenberg indicator values (light, temperature and moisture) recently developed for two Mediterranean regions (Italy and Greece); and (2) to evaluate the possibility of using these values in other Mediterranean areas.Location  Southern Greece and the Mediterranean part of Italy.Methods  A global matrix containing 966 items of information (161 species × 3 indicator variables × 2 values assigned in each study, one in Italy and one in Greece) was constructed. A test of the accuracy of the values in predicting actual environmental conditions was provided using a detrended correspondence analysis (DCA) on published vegetation relevés from the Mediterranean region. The gamma statistic was used to express relationships of ecological indicator values between the two regions, and pairs of indicator values calculated for each species were compared using Wilcoxon matched pairs tests.Results  The results showed that indices developed for Greece and Italy were not similarly correlated to sample scores along DCA axis 1. Species’ indicator values for Italy and for Greece were highly significantly correlated for light and moisture and significantly correlated for temperature, but the correlations were weak (0.20 ≤ gamma ≤ 0.31). Pairwise testing gave significantly different indicator values for the two regions. Discrepancies below or equal to 2 units on 9‐point scales (12 points for moisture) were found for 88%, 70% and 54% of the species respectively for light, temperature and moisture indices. A substantial number of species showed higher discrepancies, from 3 up to 6 units.Main conclusions  In the light of the present work, it seems clear that the indicator values developed for Italy and for Greece should not be used outside the region for which they were defined. This constitutes additional evidence that indicator values can be influenced by the identity of potential competitors. It also underlines the need to use standardized methods for calibrating indicator values against measured variables in such a way that indicator systems can serve as general reference systems.