bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells
Authors: Jehle J , Ficker E , Wan X , Deschenes I , Kisselbach J , Wiedmann F , Staudacher I , Schmidt C , Schweizer PA , Becker R , Katus HA , Thomas D 
Published: October 2012

Background and PurposeZolpidem, a short‐acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether‐a‐go‐go‐related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels.Experimental ApproachTwo‐electrode voltage clamp and whole‐cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human‐induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes.Key ResultsZolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage‐ and frequency‐independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady‐state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC‐derived cardiomyocytes.Conclusions and ImplicationsZolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose.
Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor
Authors: Schrage R , Seemann WK , Klöckner J , Dallanoce C , Racké K , Kostenis E , De Amici M , Holzgrabe U , Mohr K 
Published: October 2012

Background and PurposeArtificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’.Experimental ApproachSignalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label‐free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G‐protein activation, evaluation of cell surface agonist binding and computation of operational efficacies.Key ResultsIn CHO‐hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss‐of‐function mutant M2‐Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC‐5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points.Conclusion and ImplicationsSupraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo‐like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators.Linked ArticleThis article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142
The anti‐cancer agent SU4312 unexpectedly protects against MPP+‐induced neurotoxicity via selective and direct inhibition of neuronal NOS
Authors: Cui Wei , Zhang Zaijun , Li Wenming , Hu Shengquan , Mak Shinghung , Zhang Huan , Han Renwen , Yuan Shuai , Li Sai , Sa Fei , Xu Daping , Lin Zhixiu , Zuo Zhong , Rong Jianhui , Ma Edmond Dik‐Lung , Choi Tony Chunglit , Lee Simon MY , Han Yifan 
Published: October 2012

Background and PurposeSU4312, a potent and selective inhibitor of VEGF receptor‐2 (VEGFR‐2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1‐methyl‐4‐phenylpyridinium ion (MPP+)‐induced neurotoxicity and further explored the underlying mechanisms.Experimental ApproachMPP+‐treated neurons and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms.Key ResultsSU4312 unexpectedly prevented MPP+‐induced neuronal apoptosis in vitro and decreased MPTP‐induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well‐studied VEGFR‐2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti‐angiogenic action. Furthermore, SU4312 exhibited non‐competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS.Conclusions and ImplicationSU4312 exhibited neuroprotection against MPP+ at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO‐mediated neurotoxicity.
Altered pharmacology of native rodent spinal cord TRPV1 after phosphorylation
Authors: Mogg AJ , Mill CEJ , Folly EA , Beattie RE , Blanco MJ , Beck JP , Broad LM 
Published: October 2012

Background and PurposeEvidence suggests that phosphorylation of TRPV1 is an important component underlying its aberrant activation in pathological pain states. To date, the detailed pharmacology of diverse TRPV1 receptor agonists and antagonists has yet to be reported for native TRPV1 under phosphorylating conditions. Our goal was to optimize a relatively high‐throughput methodology to allow pharmacological characterization of the native TRPV1 receptor using a spinal cord neuropeptide release assay under naive and phosphorylating states.Experimental ApproachHerein, we describe characterization of rodent TRPV1 by measurement of CGRP release from acutely isolated lumbar (L1‐L6) spinal cord using a 96‐well technique that combines use of native, adult tissue with quantitation of CGRP release by elisa.Key ResultsWe have studied a diverse panel of TRPV1 agonists and antagonists under basal and phosphorylating conditions. We show that TRPV1‐mediated CGRP release is evoked, in a temperature‐dependent manner, by a PKC activator, phorbol 12,13‐dibutyrate (PDBu); and that treatment with PDBu increases the potency and efficacy of known TRPV1 chemical agonists, in an agonist‐specific manner. We also show that the pharmacological profile of diverse TRPV1 antagonists is dependent on whether the stimulus is PDBu or capsaicin. Of note, HPPB was identified as an antagonist of capsaicin‐evoked, but a potentiator of PDBu‐evoked, CGRP release.Conclusions and ImplicationsOur findings indicate that both TRPV1 agonist and antagonist profiles can be differentially altered by PKC activation. These findings may offer new insights for targeting TRPV1 in pain states.
Burden of proof: the evidence clinicians require before implementing an intervention
Authors: Allen Brian , Armstrong Natalie E. 
Published: October 2012

BackgroundGreater implementation of evidence‐based practice for children and adolescents is a current emphasis in the mental health field; however, there is a need to understand how best to disseminate these interventions and convince community clinicians to use them.MethodA sample of 255 clinicians reported on the likelihood that they would use an intervention given various types of evidence.ResultsCase studies and clinical trials with an active or placebo control group scored as the most preferred types of evidence; however, more positive attitudes toward evidence‐based practice predicted preferences for clinical trials, but were not related to case studies.ConclusionImplementation of evidence‐based practice may be improved by greater dissemination of case studies demonstrating the use of these interventions in ‘real world’ settings. In addition, fostering a greater appreciation of research‐derived interventions among clinicians appears necessary.
Phase II study of preoperative chemoradiation with S‐1 plus oxaliplatin in patients with locally advanced rectal cancer
Authors: Lee Eun Mi , Hong Yong Sang , Kim Kyu‐pyo , Lee Jae‐Lyun , Kim Sun Young , Park Young Suk , Choi Doo Ho , Kim Jong Hoon , Lim Seok‐Byung , Yu Chang Sik , Kim Jin Cheon , Lee Ju Hee , Kim Ah Young , Kim Tae Won 
Published: October 2012

A phase II study of preoperative chemoradiation (CRT) with S‐1 plus oxaliplatin in patients with locally advanced rectal cancer was conducted. The total radiotherapy dose was 50.4 Gy. Chemotherapy consisted of oxaliplatin 50 mg/m2 on days 1, 8, 22 and 29 and S‐1 80 mg/m2 per day on days 1–14 and 22–35. The tumor apparent diffusion coefficient (ADC) was measured using diffusion‐weighted magnetic resonance imaging (DW‐MRI) before and after CRT. Total mesorectal excision was performed within 6 ± 2 weeks. The primary end‐point was the pathological complete response (pCR) rate. A total of 38 patients were enrolled. The pCR rate was 22.9% (8/35; 95% CI, 10.9–42.1), and 10 (28.6%) patients showed near‐total tumor regression. There was no grade 4 adverse event, and grade 3 adverse events included leukopenia (5.4%), diarrhea (5.4%), anorexia (2.7%) and nausea (2.7%). The tumor ADC was calculated in 38 patients (including those who participated in the phase I study). The post‐CRT ADC (P = 0.037) and the percentage change in ADC (P = 0.026) were significantly correlated with pathological response. In conclusion, preoperative CRT with S‐1 plus oxaliplatin showed promising results in pathological responses and favorable toxicity profiles. (Cancer Sci 2013; 104: 111–115)
Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma
Authors: Galan S. R. , Kann P. H. 
Published: October 2012

SummaryAlthough most pheochromocytomas (PCCs) and paragangliomas (PGLs) are sporadic, molecular genetic medicine has revealed that a considerable number of patients with apparently sporadic PCC actually have a genetic predisposition to the development of these tumors. After decades of intensive research, several genes are now known to play an important role in the pathogenesis of PCC. At present, these areRETproto‐oncogene, von Hippel–Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunitsSDHB,SDHC, andSDHD, but alsoSDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2orhSDH5), and the newly describedTMEM127andMAXtumor suppressor genes. In addition to these ten PCC susceptibility genes, two other genes,KIF1BandPHD2, have also been associated with PCC. Studying the pathogenesis and the molecular correlation of these mutations has revealed the existence of two main transcription signatures: a pseudohypoxic cluster (VHLandSDHmutations) and a cluster rich in kinase receptor signaling and their downstream pathways (RET, NF1, TMEM127,andMAXmutations). However, the general mechanism in the pathogenesis of a syndrome does not entirely apply in the particular pathogenesis of PCC as a manifestation of that syndrome. A better understanding of the complexity and high genetic diversity of PCC and PGL may lead to more efficient diagnosis and management of the disease.
Elevated Levels of Interleukin 6 and C‐Reactive Protein Associated With Cognitive Impairment in Heart Failure
Authors: Athilingam Ponrathi , Moynihan Jan , Chen Leway , D’Aoust Rita , Groer Maureen , Kip Kevin 
Published: October 2012

©2012 Wiley Periodicals, Inc.There is abundant evidence on inflammatory mechanisms in heart failure (HF) that are used for prognostication of the disease; however, data are lacking regarding the association between elevated cytokines, C‐reactive protein (CRP), and cognition in HF. A cross‐sectional pilot study of 38 patients with HF, aged 62 years (standard deviation± 9 years), predominantly men (68%) and Caucasian (79%) were screened for cognitive function using the Montreal Cognitive Assessment (MoCA). The study aimed to examine cognitive scores on MoCA with cytokines, interleukin 6 [IL‐6] and tumor necrosis factor α [TNF‐α], and CRP as indicators of early cognitive changes in HF. The result showed no direct correlation between cardiac variables and the MoCA score. The MoCA score, however, was inversely associated with IL‐6 (r=−0.53, P=.001) and CRP (r=−0.34, P=.04), with no association to TNF‐α. Regression analysis on the MoCA score and log‐transformed IL‐6 accounted for an additional 11% variation and remained statistically significant (P=.008) after controlling for covariates of education, living arrangements, and loneliness. The large effect size (R2=0.87) found in this pilot study provides rationale for a larger exploratory study to examine associations between cognitive function, cytokines, and CRP levels and help design future intervention studies.
Peri‐implant tissue reactions to immediate nonocclusal loaded implants with different collar design: an experimental study in dogs
Authors: Negri Bruno , Calvo Guirado José L. , Maté Sánchez de Val José E. , Delgado Ruíz Rafael A. , Ramírez Fernández María P. , Barona Dorado Cristina 
Published: October 2012

AbstractPurposeThe aim of this study was to evaluate bone remodelling and soft tissue reactions around immediate nonocclusal loaded implants with different collar configuration in beagle dogs.Material and methodsThe mandibular bilateral second, third and fourth premolars of six beagle dogs were extracted. After 3 months of healing, four implants were placed in the mandibles of each dog. Randomly, two implants with a 1.5 mm polished surface collar (TSA, control group) and two implants with a 0.7 mm polished surface collar and 2.5 mm microthreaded area (TSAA, test group) were inserted. Both groups were treated with a minimal mucoperiosteal flap elevation approach. Impressions were taken and two single screw‐retained restorations were inserted in each hemi‐mandible 2 days after the implant placement. The animals were sacrificed at 1, 2 and 3 months (two specimens each), and biopsies were obtained. Samples were processed for ground sectioning. Histomorphometric analysis was carried out to compare buccal and lingual bone height loss and soft tissue behaviour between the two groups.ResultsCrestal bone resorption was significantly higher in the control group (P > 0.05). The establishment of the biological width showed similar outcomes for both groups. Only the distance from the top of the peri‐implant mucosa to the apical portion of the barrier epithelium at lingual aspect was significantly more pronounced in the control group (P > 0.05).ConclusionsThe alterations that occurred in the peri‐implant tissues were related to the adaptation that occurred after the loading conditions in both groups. The microthread design might have an effect in maintaining the marginal bone loss against loading.
Osteoblastic and cytokine gene expression of implant‐adherent cells in humans
Authors: Bryington Matthew , Mendonça Gustavo , Nares Salvador , Cooper Lyndon F. 
Published: October 2012

AbstractObjectivesImplant surface topography is a key determinant affecting osteoblastic differentiation and cell–cell signaling of implant‐adherent cells.Materials and methodsTo assess the early osteoinductive and cell–cell signaling events in adherent cells, commercially pure titanium implants (2.2 × 5 mm) with nanotopography (HF‐treatedTiO2grit‐blasted) were compared with micron‐scale topographyTiO2grit‐blasted (micron‐scale, control) implantsin vivo. Six implants (n = 3/surface) were placed in 10 systemically healthy subjects and removed by reverse threading at 1, 3, and 7 days. Gene expression profiles of adherent cells were interrogated using low‐densityRT‐PCRarrays.ResultsOsteoinduction was not observed at day 1 on either surface. At 3 days, elevated levels ofBMP6, osteopontin, and osterix (OSX) were observed inRNAof cells adherent to both micron‐scale and nanotopography surfaces. Both surfaces supported osteoinductive gene expression at 7 days; however, modest elevations of most mRNAs and significantly higherOSX mRNAlevels were measured for cells adhered to nanotopography implants. Further, chemokine and cytokine profiles includingCXCL10,CXCL14,IL‐9,IL‐22, andTOLLIPwere upregulated on nanotopographic surfaces as compared with microtopographic surfaces.ConclusionsImplants with superimposed nanoscale topography generate a greater induction of genes linked to osteogenesis and cell–cell signaling during the early phases of osseointegration.
Triage of patients with acute diverticulitis: are some inpatients candidates for outpatient treatment?
Authors: Abbas M. A. , Cannom R. R. , Chiu V. Y. , Burchette R. J. , Radner G. W. , Haigh P. I. , Etzioni D. A. 
Published: October 2012

AbstractAimCurrent recommendations regarding the triage of patients with acute diverticulitis for inpatient or outpatient treatment are vague. We hypothesized that a significant number of patients treated as an inpatient could be managed as an outpatient.MethodA retrospective cohort study was carried out of 639 patients admitted for a first episode of diverticulitis. The diagnosis of acute diverticulitis was confirmed by computed tomography (CT). The endpoints included length of stay, need for surgery, percutaneous drainage and mortality. Patients were considered to have had a minimal hospitalization, defined as survival to discharge without needing a procedure, hospitalization of ≤ 3 days and no readmission for diverticulitis within 30 days after discharge.ResultsOf 639 patients, 368 (57.6%) had a minimal hospitalization. Female gender and CT scan findings of free air/fluid were negatively associated with the likelihood of minimal hospitalization. The presence of an abscess < 3 cm and stranding on CT did not predict the need for a higher level of care. Despite the statistical significance of several patient‐level predictors, the model did not identify patients likely to need only minimal hospitalization.ConclusionMost patients admitted with acute diverticulitis are discharged after minimal hospitalization. Free air/liquid in a patient admitted for acute diverticulitis indicates a more severe clinical course.
Adaption of horses to a novel dynamic feeding system: Movement and behavioural responses
Authors: Hampson B. A. , de Laat M. A. , Monot J. , Bailliu D. , Pollitt C. C. 
Published: October 2012

SummaryReasons for performing studyMany domestic horses and ponies are sedentary and obese due to confinement to small paddocks and stables and a diet of infrequent, high‐energy rations. Severe health consequences can be associated with this altered lifestyle.ObjectivesThe aims of this study were to investigate the ability of horses to learn to use a dynamic feeder system and determine the movement and behavioural responses of horses to the novel system.MethodsA dynamic feed station was developed to encourage horses to exercise in order to access ad libitum hay. Five pairs of horses (n = 10) were studied using a randomised crossover design with each pair studied in a control paddock containing a standard hay feeder and an experimental paddock containing the novel hay feeder. Horse movement was monitored by a global positioning system (GPS) and horses observed and their ability to learn to use the system and the behavioural responses to its use assessed.ResultsWith initial human intervention all horses used the novel feeder within 1 h. Some aggressive behaviour was observed between horses not well matched in dominance behaviour. The median distance walked by the horses was less (P = 0.002) during a 4 h period (117 [57–185] m) in the control paddock than in the experimental paddock (630 [509–719] m).ConclusionsThe use of an automated feeding system promotes increased activity levels in horses housed in small paddocks, compared with a stationary feeder.Potential relevanceThe novel feeder system may have application in the husbandry of horses and ponies kept in small paddocks by encouraging a natural pattern of exercise without human intervention and an ad libitum diet of hay. This may improve the health and welfare of horses.
Characteristics of palatal instability inThoroughbred racehorses and their association with the development of dorsal displacement of the soft palate
Authors: Allen K. , Franklin S. 
Published: October 2012

SummaryReason for performing studyTwo forms of dynamic upper respiratory tract obstruction affecting racehorses that involve the soft palate have been described: palatal instability (PI) and dorsal displacement of the soft palate (DDSP). Observation ofDDSPis straightforward in that it is an all or nothing event, whereas observation ofPIis subjective and interpretation may vary between clinicians.ObjectivesThe aim of this study was to attempt to characterisePIand to investigate endoscopic features that precedeDDSP.MethodsA retrospective study on the endoscopic observations ofThoroughbred racehorses referred for high‐speed treadmill endoscopy was performed. Endoscopic observations were reviewed during the last 10 s of the exercise test or the last 10 s prior toDDSP. The degree of axial deviation of the aryepiglottic folds (ADAF), the conformation of the epiglottis, the conformation of the soft palate and the amount of obstruction of therima glottidisby the soft palate (i.e. soft palate stability) were assessed.ResultsA total of 72 horses were included in this study, of which 7 showed no evidence ofPI. Of the 65 horses withPI, 30 (46%) developedDDSP. There were significant associations between the stability of the soft palate, epiglottic conformation andADAF. Furthermore, development ofDDSPwas associated with increased severity ofPIandADAFand with changes in epiglottic conformation.ConclusionsThis study has characterised the endoscopic features associated withPIand identified certain characteristics that precedeDDSP.Potential relevanceThese observations may assist veterinary surgeons in recognisingPIand the prodromal signs ofDDSP.