bluuebunny/crossref_metadata_2025 huggingface dataset:
Melatonin inhibits tachykinin NK2receptor‐triggered 5‐HT release from guinea pig isolated colonic mucosa
Authors: Kojima Shu‐ichi , Tohei Atsushi , Ikeda Masashi
Published: November 2010

BACKGROUND AND PURPOSEMelatonin is involved in the regulation of colonic motility, and sensation, but little is known about the influence of melatonin on 5‐hydroxytryptamine (5‐HT) release from colonic mucosa. A tachykinin NK2receptor‐selective agonist, [β‐Ala8]‐neurokinin A4‐10[βAla‐NKA‐(4‐10)] can induce 5‐HT release from guinea pig colonic mucosa via NK2receptors on the mucosal layer. The present study was designed to determine the influence of melatonin on 5‐HT release from guinea pig colonic mucosa, evoked by the NK2receptor agonist, βAla‐NKA‐(4‐10).

EXPERIMENTAL APPROACHThe effect of melatonin was investigated on the outflow of 5‐HT and its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) from muscle layer‐free mucosal preparations of guinea pig colon, using high‐performance liquid chromatography with electrochemical detection.

KEY RESULTSMelatonin caused a sustained decline in the βAla‐NKA‐(4‐10)‐evoked 5‐HT outflow from the muscle layer‐free mucosal preparations, but failed to affect its metabolite 5‐HIAA outflow. The specific MT3receptor agonist, 5‐methoxycarbonylamino‐N‐acetyltryptamine mimicked the inhibitory effect of melatonin on βAla‐NKA‐(4‐10)‐evoked 5‐HT outflow. A MT3receptor antagonist prazosin shifted the concentration‐response curve of melatonin to the right in a concentration‐dependent manner and depressed the maximum effect, but neither a combined MT1/MT2receptor antagonist luzindole, nor a MT2receptor antagonist N‐pentanoyl‐2‐benzyltryptamine modified the concentration–response curve to melatonin.

CONCLUSIONS AND IMPLICATIONSMelatonin inhibits NK2receptor‐triggered 5‐HT release from guinea pig colonic mucosa by acting at a MT3melatonin receptor located directly on the mucosal layer, without affecting 5‐HT degradation processes. Possible contributions of MT1/MT2melatonin receptors to the inhibitory effect of melatonin appear to be negligible. Melatonin may act as a modulator of excess 5‐HT release from colonic mucosa.
The glucocorticoid‐induced TNF receptor family‐related protein (GITR) is critical to the development of acute pancreatitis in mice
Authors: Galuppo M , Nocentini G , Mazzon E , Ronchetti S , Esposito E , Riccardi L , Sportoletti P , Di Paola R , Bruscoli S , Riccardi C , Cuzzocrea S
Published: November 2010

BACKGROUND AND PURPOSE Pancreatitis represents a life‐threatening inflammatory condition where leucocytes, cytokines and vascular endothelium contribute to the development of the inflammatory disease. The glucocorticoid‐induced tumour necrosis factor (TNF) receptor family‐related protein (GITR) is a costimulatory molecule for T lymphocytes, modulates innate and adaptive immune system and has been found to participate in a variety of immune responses and inflammatory processes. Our purpose was to verify whether inhibition of GITR triggering results in a better outcome in experimental pancreatitis.

EXPERIMENTAL APPROACH In male GITR knock‐out (GITR−/−) and GITR+/+ mice on Sv129 background, acute pancreatitis was induced after i.p. administration of cerulein. Other experimental groups of GITR+/+ mice were also treated with different doses of Fc‐GITR fusion protein (up to 6.25 µg·mouse−1), given by implanted mini‐osmotic pump. Clinical score and pro‐inflammatory parameters were evaluated.

KEY RESULTS A less acute pancreatitis was found in GITR−/− mice than in GITR+/+ mice, with marked differences in oedema, neutrophil infiltration, pancreatic dysfunction and injury. Co‐treatment of GITR+/+ mice with cerulein and Fc‐GITR fusion protein (6.25 µg·mouse−1) decreased the inflammatory response and tissue injury, compared with treatment with cerulein alone. Inhibition of GITR triggering was found to modulate activation of nuclear factor κB as well as the production of TNF‐α, interleukin‐1β, inducible nitric oxide synthase, nitrotyrosine, poly‐ADP‐ribose, intercellular adhesion molecule‐1 and P‐selectin.

CONCLUSIONS AND IMPLICATIONS The GITR‐GITR ligand system is crucial to the development of acute pancreatitis in mice. Our results also suggest that the Fc‐GITR fusion protein could be useful in the treatment of acute pancreatitis.
Microarray analysis of nemorosone‐induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR)
Authors: Holtrup Frank , Bauer Andrea , Fellenberg Kurt , Hilger Ralf A , Wink Michael , Hoheisel Jörg D
Published: November 2010

BACKGROUND AND PURPOSE Pancreatic cancer is one of the leading cancer‐related causes of death due to high chemo‐resistance and fast metastasation. Nemorosone, a polycyclic polyprenylated acylphloroglucinol, has recently been identified as a promising anticancer agent. Here, we examine its growth‐inhibitory effects on pancreatic cancer cells. Based on transcription profiling, a molecular mode of action is proposed.

EXPERIMENTAL APPROACH Nemorosone cytotoxicity was assessed by the resazurin proliferation assay on pancreatic cancer cells and fibroblasts. Apoptosis was determined by Annexin V/propidium iodide staining as well as cytochrome c and caspase activation assays. Staining with the voltage‐dependent dye JC‐1 and fluorescence microscopy were used to detect effects on mitochondrial membrane potential. Total RNA was isolated from treated cell lines and subjected to microarray analysis, subsequent pathway identification and modelling. Gene expression data were validated by quantitative polymerase chain reaction and siRNA‐mediated gene knock‐down.

KEY RESULTS Nemorosone significantly inhibited cancer cell growth, induced cytochrome c release and subsequent caspase‐dependent apoptosis, rapidly abolished mitochondrial membrane potential and elevated cytosolic calcium levels, while fibroblasts were largely unaffected. Expression profiling revealed 336 genes to be affected by nemorosone. A total of 75 genes were altered in all three cell lines, many of which were within the unfolded protein response (UPR) network. DNA damage inducible transcript 3 was identified as a key regulator in UPR‐mediated cell death.

CONCLUSIONS AND IMPLICATIONS Nemorosone could be a lead compound for the development of novel anticancer drugs amplifying the already elevated UPR level in solid tumours, thus driving them into apoptosis. This study forms the basis for further investigations identifying nemorosone's direct molecular target(s).
Metformin inhibits HMGB1 release in LPS‐treated RAW 264.7 cells and increases survival rate of endotoxaemic mice
Authors: Tsoyi Konstantin , Jang Hwa Jin , Nizamutdinova Irina Tsoy , Kim Young Min , Lee Young Soo , Kim Hye Jung , Seo Han Geuk , Lee Jae Heun , Chang Ki Churl
Published: November 2010

BACKGROUND AND PURPOSERecently, metformin, a well‐known anti‐diabetic drug, has been shown to possess anti‐inflammatory activities. This study investigated the effect of metformin on the expression of pro‐inflammatory cytokines including high mobility group box 1 (HMGB1) in lipopolysaccharide (LPS)‐treated animals and cells.

EXPERIMENTAL APPROACHWe investigated whether metformin inhibits the release of HMGB1 in LPS‐treated RAW 264.7 cells and increases survival rate in endotoxaemic mice (lethal endotoxaemia was induced by an i.p. injection of LPS). This was achieved by a range of techniques including Western blotting, enzyme‐linked immunosorbent assay, specific pharmacological inhibitors, knock out of α1‐subunit of AMP‐activated protein kinase (AMPK) and recombinant HMGB1.

KEY RESULTSBoth pre‐ and post‐treatment with metformin significantly improved survival of animals during lethal endotoxaemia (survival rate was monitored up to 2 weeks), decreased serum levels of tumour necrosis factor‐alpha (TNF‐α), interleukin‐1β, HMGB1 expression and myeloperoxidase activity in lungs. However, metformin failed to improve survival in endotoxaemic animals that had additionally been treated with recombinant HMGB1. In anin vitrostudy, metformin dose‐dependently inhibited production of pro‐inflammatory cytokines and HMGB1 release. Metformin activated AMPK by its phosphorylation. Compound C (pharmacological inhibitor of AMPK) and siAMPKα1 reversed the anti‐inflammatory effect of metformin in LPS‐treated cells.

CONCLUSIONS AND IMPLICATIONSOur data indicate that metformin significantly attenuates the pro‐inflammatory response induced by LPS bothin vivoandin vitro. Metformin improved survival in a mouse model of lethal endotoxaemia by inhibiting HMGB1 release. AMPK activation was implicated as one of the mechanisms contributing to this inhibition of HMGB1 secretion.
Principles of early drug discovery
Authors: Hughes JP , Rees S , Kalindjian SB , Philpott KL
Published: November 2010

Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.
Improving planning, design, reporting and scientific quality of animal experiments by using the Gold Standard Publication Checklist, in addition to the ARRIVE guidelines
Authors: Hooijmans Carlijn R , de Vries Rob , Leenaars Marlies , Curfs Jo , Ritskes‐Hoitinga Merel
Published: November 2010

Several studies have demonstrated serious omissions in the way research that use animals is reported. In order to improve the quality of reporting of animal experiments, the Animals in research: reporting in vivo experiments (ARRIVE) Guidelines were published in the British Journal of Pharmacology in August 2010.

However, not only the quality of reporting of completed animal studies needs to be improved, but also the design and execution of new experiments. With both these goals in mind, we published the Gold Standard Publication Checklist (GSPC) in May 2010, a few months before the ARRIVE guidelines appeared. In this letter, we compare the GSPC checklist with the ARRIVE Guidelines. The GSPC describes certain items in more detail, which makes it both easier to use when designing and conducting an experiment and particularly suitable for making systematic reviews of animal studies more feasible. In order to improve not only the reporting but also the planning, design, execution and thereby, the scientific quality of animal experiments, we strongly recommend to all scientists involved in animal experimentation and to editors of journals publishing animal studies to take a closer look at the contents of both the ARRIVE guidelines and GSPC, and select the set of guidelines which is most appropriate for their particular situation.

LINKED ARTICLES To view the article by Kilkenny et al. visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00872.x. To view the editorial by McGrath et al. visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00873.x
Pregnane X receptor‐ and CYP3A4‐humanized mouse models and their applications
Authors: Cheng Jie , Ma Xiaochao , Gonzalez Frank J
Published: November 2010

Pregnane X receptor (PXR) is a pivotal nuclear receptor modulating xenobiotic metabolism primarily through its regulation of CYP3A4, the most important enzyme involved in drug metabolism in humans. Due to the marked species differences in ligand recognition by PXR, PXR‐humanized (hPXR) mice, and mice expressing human PXR and CYP3A4 (Tg3A4/hPXR) were established. hPXR and Tg3A4/hPXR mice are valuable models for investigating the role of PXR in xenobiotic metabolism and toxicity, in lipid, bile acid and steroid hormone homeostasis, and in the control of inflammation.
β2‐Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another ‘radical’ road to heart failure?
Authors: Di Lisa Fabio , Kaludercic Nina , Paolocci Nazareno
Published: November 2010

Persistent activation of the cardiac β‐adrenergic system may contribute to the pathogenesis of congestive heart failure. Both β1‐ and β2‐adrenoceptors are known to mediate these noxious effects, yet the β1‐adrenoceptor‐PKA axis has received greater attention with less information available on β2‐adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that β2‐adrenoceptor over‐expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up‐regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen‐activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N‐acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that β2‐adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4.

LINKED ARTICLE This article is a commentary on Xu et al., pp. 1012–1028 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476‐5381.2010.01043.x
How accurate is in vitro prediction of carcinogenicity?
Authors: Walmsley Richard Maurice , Billinton Nicholas
Published: November 2010

Positive genetic toxicity data suggest carcinogenic hazard, and this can stop a candidate pharmaceutical reaching the clinic. However, during the last decade, it has become clear that many non‐carcinogens produce misleading positive results in one or other of the regulatory genotoxicity assays. These doubtful conclusions cost a lot of time and money, as they trigger additional testing of apparently genotoxic candidates, both in vitro and in animals, to discover whether the suggested hazard is genuine. This in turn means that clinical trials can be put on hold. This review describes the current approaches to the ‘misleading positive’ problem as well as efforts to reduce the use of animals in genotoxicity assessment. The following issues are then addressed: the application of genotoxicity testing screens earlier in development; the search for new or improved in vitro genotoxicity tests; proposed changes to the International Committee on Harmonisation guidance on genotoxicity testing [S2(R1)]. Together, developments in all these areas offer good prospects of a more rapid and cost‐effective way to understand genetic toxicity concerns.
Epidermal growth factor enhances the malignant phenotype in canine mammary carcinoma cell lines
Authors: Kennedy K. C. , Qurollo B. A. , Rose B. J. , Thamm D. H.
Published: November 2010

Canine mammary gland tumours (CMTs) are the most common malignancies in female dogs. The receptor tyrosine kinase EGFR (erbb1), a receptor for epidermal growth factor (EGF) and related factors, mediates multiple oncogenic functions in human epithelial neoplasms. While previous studies have demonstrated EGFR expression in canine tumours, its function has not been studied in canine cancer. The purpose of this study was to determine the in vitro effects of EGF and vandetanib (ZD6474), a small molecule inhibitor of VEGFR‐2, EGFR and RET tyrosine kinases, on proliferation, invasion, survival and chemosensitivity in CMT cells. In low serum, EGF enhanced proliferation and chemotaxis, attenuated apoptosis, and stimulated vascular endothelial growth factor (VEGF) production. Vandetanib dose‐dependently inhibited EGFR phosphorylation as well as PI3K/Akt activation, and inhibited all EGF‐induced phenotypic effects. In conclusion, EGF stimulates multiple features promoting the malignant phenotype in CMT. Thus, CMT may be an important translational model for the investigation of novel EGFR‐directed therapies.
A Strain‐Based Flow‐Induced Hemolysis Prediction Model Calibrated by In Vitro Erythrocyte Deformation Measurements
Authors: Chen Yangsheng , Sharp M. Keith
Published: November 2010

Hemolysis is caused by fluid stresses in flows within hypodermic needles, blood pumps, artificial hearts, and other cardiovascular devices. Developers of cardiovascular devices may expend considerable time and effort in testing of prototypes, because there is currently insufficient understanding of how flow‐induced cell damage occurs to accurately predict hemolysis. The objective of this project was to measure cell deformation in response to a range of flow conditions, and to develop a constitutive model correlating cell damage to fluid stresses. An experimental system was constructed to create Poiseuille flow under a microscope with velocities up to 4 m/s, Reynolds number to 200, and fluid stresses to 5000 dyn/cm2. Pulsed laser illumination and a digital camera captured images of cells deformed by the flow. Equilibrium equations were developed to relate fluid stresses to cell membrane tension, and a viscoelastic membrane model was used to predict cell strain. Measurements of aspect ratio as a function of shear stress and duration of shear were used to calibrate the cell deformation model. Hemolysis prediction was incorporated with a threshold strain value for cell rupture. The new model provides an improved match to experimentally observed hemolytic stress thresholds, particularly at long exposure times, and may reduce the empiricism of hemolysis prediction.
Continuous Hemodiafiltration in Children After Cardiac Surgery
Authors: Watanabe Kenichi , Suzuki Yasuyuki , Goto Takeshi , Yamauchi Sanae , Daitoku Kazuyuki , Fukui Kozo , Fukuda Ikou
Published: November 2010

Acute renal failure (ARF) after congenital cardiac surgery remains a serious complication and leading cause of morbidity and mortality. Continuous hemodiafiltration (CHDF) is presently accepted for pediatric applications. We retrospectively evaluated the effects of CHDF against ARF after congenital cardiac surgery at our hospital. We analyzed data from seven patients aged 23 days to 9 years and weighing 1.7–22.4 kg requiring dialysis therapy using CHDF after congenital cardiac surgery between April 2002 and January 2009. One patient who died could not be weaned from extracorporeal membrane oxygenation support and another died of multiple organ failure. Renal function recovered to normal in the other five (71%) patients. Treatment by CHDF lasted from 14 to 680 h and net ultrafiltration was 3.5 ± 1.4 mL/kg/h. Serum creatinine and urea concentrations were, respectively, 2.3 ± 1.6 and 43.7 ± 17.0 mg/dL before, and 0.5 ± 0.2 and 13.5 ± 8.1 mg/dL, after CHDF (P < 0.05). Thrombocytopenia developed in all patients, and platelet concentrates (0.76 ± 0.7 mL/kg/h) were infused during CHDF. Hypotension developed after changing the CHDF set in one patient. We suggest that CHDF is an effective alternative strategy for treating renal dysfunction after congenital cardiac surgery.
Albumin Dialysis Without Anticoagulation in High‐Risk Patients: An Observational Study
Authors: Tan Han K. , Yang Wen S. , Choong Hui L. , Wong Kok S.
Published: November 2010

Severe liver failure causes coagulopathy and high bleeding risk. Albumin dialysis with Molecular Adsorbent Recirculating System (MARS) (Gambro, Lund, Sweden) is useful for treatment. However, anticoagulation during its use is of uncertain value. We omitted heparin‐saline priming and intradialytic heparin and examined its effects. Albumin dialysis was performed in critically ill patients with intermittent circuit saline flushes (2664 ± 2420 mL per treatment). A total of 12 patients (M : F = 10:2; age 49 ± 9 years) were thus treated: 6 for fulminant hepatic failure and 6 for acute‐on‐chronic liver failure. The overall hospitalization duration was 31 ± 30 days. A total of 44 treatment sessions were performed (average 8 ± 7 sessions per patient). Prescribed versus achieved MARS duration were 13 ± 3 versus 11 ± 4 h, P < 0.05. Twenty‐three percent (10/44) of MARS sessions clotted, 11% (5/44) of treatments were electively terminated, and 2% (1/44) developed vascular catheter occlusion. Spontaneous bleeding occurred in 9% (4/44). Pre‐ versus post‐MARS systemic and blood circuit transmembrane pressures (mm Hg), and albumin dialysate afferent and efferent pressures were all stable. Coagulation indices were (pre‐ vs. post‐MARS): (i) prothrombin time (seconds): 36 ± 30 versus 42 ± 33, P = 0.143; (ii) activated partial thromboplastin time (seconds): 78 ± 43 versus 88 ± 45, P = 0.117; and (iii) platelet count (×103/µL): 87 ± 40 versus 76 ± 48, P = 0.004. Systemic blood solute concentrations pre‐ versus post‐MARS were: (i) serum urea (mg/dL): 22.4 ± 19.6 versus 14.0 ± 8.4, P < 0.05; (ii) serum creatinine (mg/dL): 2.8 ± 2.3 versus 1.9 ± 1.5, P < 0.05; (iii) total bilirubin (mg/dL): 29.5 ± 8.8 versus 20.5 ± 5.1, P < 0.05; and (iv) plasma ammonia (µg/dL): 186 ± 85 versus 129 ± 66, P < 0.05. Anticoagulant‐free albumin dialysis remained effective despite frequent circuit clotting. This led to significant exacerbation of thrombocytopenia although bleeding risk remained low.
Air‐Handling Capabilities of Blood Cardioplegia Delivery Systems in a Simulated Pediatric Model
Authors: Palanzo David , Guan Yulong , Wan Caihong , Baer Larry , Kunselman Allen , Qiu Feng , Ündar Akif
Published: November 2010

Blood cardioplegia delivery systems are employed in most pediatric open heart cases to arrest the heart and keep it preserved during aortic cross‐clamping. They are also used as part of a modified ultrafiltration system at the end of cardiopulmonary bypass. We evaluated and compared the air‐handling capabilities of different types of blood cardioplegia delivery devices. A simple circuit incorporating a cardiotomy reservoir, a roller pump, a cardioplegia test system, and two emboli detection and classification sensors were used to investigate the air‐handling capabilities of the following cardioplegia delivery systems: GISH Vision, Maquet Plegiox, Medtronic Trillium MYOtherm XP, Sorin Group BCD Vanguard, Sorin Group CSC14, and Terumo Sarns Conducer and Bubble Trap. The 0.25‐in. circuit was primed with 400 mL of Lactated Ringer's. Outdated packed red blood cells were added to obtain a hematocrit of 24–28%. System pressure was maintained at 50 mm Hg. Air (0.1, 0.3, 0.5 mL) was injected at a speed of 0.1 mL/s into the circuit just after the pump head. Gaseous microemboli (GME) were measured prior to the cardioplegia system and after the device to evaluate the air‐handling characteristics. The tests were run at 100, 200, and 400 mL/min blood flow for both 4 and 37°C. There were no significant differences among the groups when comparing precardioplegia delivery system GME, thus demonstrating that all devices received the same amount of injected air. When comparing the groups for postcardioplegia delivery system GME, significant differences were noted especially at the 400 mL/min blood flow rate. These results suggest that for the devices compared in this study, the Maquet Plegiox and the Medtronic Trillium MYOtherm XP eliminated GME the best.
The Discrete Weibull Distribution: An Alternative for Correlated Counts with Confirmation for Microbial Counts in Water
Authors: Englehardt James D. , Li Ruochen
Published: November 2010

Distributions of pathogen counts in treated water over time are highly skewed, power‐law‐like, and discrete. Over long periods of record, a long tail is observed, which can strongly determine the long‐term mean pathogen count and associated health effects. Such distributions have been modeled with the Poisson lognormal (PLN) computed (not closed‐form) distribution, and a new discrete growth distribution (DGD), also computed, recently proposed and demonstrated for microbial counts in water (Risk Analysis 29, 841–856). In this article, an error in the original theoretical development of the DGD is pointed out, and the approach is shown to support the closed‐form discrete Weibull (DW). Furthermore, an information‐theoretic derivation of the DGD is presented, explaining the fit shown for it to the original nine empirical and three simulated (n = 1,000) long‐term waterborne microbial count data sets. Both developments result from a theory of multiplicative growth of outcome size from correlated, entropy‐forced cause magnitudes. The predicted DW and DGD are first borne out in simulations of continuous and discrete correlated growth processes, respectively. Then the DW and DGD are each demonstrated to fit 10 of the original 12 data sets, passing the chi‐square goodness‐of‐fit test (α= 0.05, overall p = 0.1184). The PLN was not demonstrated, fitting only 4 of 12 data sets (p = 1.6 × 10−8), explained by cause magnitude correlation. Results bear out predictions of monotonically decreasing distributions, and suggest use of the DW for inhomogeneous counts correlated in time or space. A formula for computing the DW mean is presented.
Renin‐Angiotensin System Blocker Use May Be Associated with Suppression of Atrial Fibrillation Recurrence after Pulmonary Vein Isolation
Authors: ISHIKAWA KIYOTAKE , YAMADA TAKUMI , YOSHIDA YUKIHIKO , TAKIGAWA MASATERU , AOYAMA YUTAKA , INOUE NATSUO , TATEMATSU YASUSHI , NANASATO MAMORU , KATO KAZUO , TSUBOI NAOYA , HIRAYAMA HARUO
Published: November 2010

Introduction:

An additional approach may be essential to reduce recurrences of atrial fibrillation (AF) after pulmonary vein isolation (PVI). We examined the efficacy of renin‐angiotensin system blockers (RAS‐B) in suppressing AF recurrences after PVI.

Methods and Results:

We retrospectively studied 264 consecutive patients (195 male, median age: 63 years) who underwent successful PVI of paroxysmal (n = 94) or persistent AF (n = 170). RAS‐B treatment was performed in 145 patients (angiotensin‐converting enzyme inhibitors; n = 13, angiotensin receptor blockers; n = 129, both; n = 3). Echocardiography was performed before and 3 months after the ablation to examine the occurrence of left atrial structural reverse remodeling (LA‐RR). After a median follow‐up of 195 (interquartile range: 95–316) days, AF recurred in 51 (19.3%) patients. A Cox regression analysis revealed that AF recurrence was significantly lower in the patients with RAS‐B than in those without (hazard ratio [HR] = 0.41 [95% confidence interval (CI): 0.23–0.71], P = 0.002). After a multivariate adjustment for potential confounders, the use of RAS‐B (HR = 0.39 [95% CI: 0.19–0.77], P = 0.007) and type of AF (HR = 0.30 [95% CI: 0.13–0.66], P = 0.003) were the independent predictors for AF recurrence during the entire follow‐up. Although effect of RAS‐B was not significant during the early follow‐up (<3 month), it was the only independent predictor during the late follow‐up (>3 months) (HR = 0.21 [95% CI: 0.08–0.53], P = 0.001). There were no significant differences in LA‐RR occurrence regarding RAS‐B medication. The use of RAS‐B was an independent predictor of late AF recurrences irrespective of an early LA‐RR occurrence.

Conclusions:

Treatment with RAS‐B significantly reduced the AF recurrence after PVI. This benefit became more prominent 3 months after the PVI. (PACE 2011; 34:296–303)
Idiopathic Premature Ventricular Contractions Arising from the Intraventricular Septum Adjacent to the His Bundle
Authors: YAMADA TAKUMI , TABEREAUX PAUL B. , McELDERRY H. T. , DOPPALAPUDI HARISH , KAY G. N.
Published: November 2010

A 57‐year‐old woman with idiopathic premature ventricular contractions (PVCs) exhibiting a left bundle branch block and left inferior axis QRS morphology underwent electrophysiological testing. Mapping revealed that the earliest ventricular activation times during the PVCs recorded on either side of the interventricular septum were the same and no excellent pace maps were reproduced at these sites. Successful radiofrequency catheter ablation was achieved in the right ventricular septum adjacent to the recording site of the His bundle electrogram. These findings suggested that the origin of this PVC was located in the intraventricular septum rather than the endocardial surface. (PACE 2012; 35:e108–e111)
Successful Ablation for Atrioventricular Nodal Reentrant Tachycardia in a Patient with Left Atrial Isomerism
Authors: CHEN ZHONG , SUNNI NADIA , A’ATTY OSAMA , WARD DAVID E. , SUTHERLAND GEORGE R. , GALLAGHER MARK M.
Published: November 2010

Left atrial isomerism (LAI) is characterized by the presence of two morphologically identical atria. It is commonly associated with conduction defects. We report a case of LAI presenting with highly symptomatic atrioventricular nodal reentrant tachycardia, which was cured by ablation. (PACE 2012; 35:e291–e292)
Evaluation of Patients with “Faint” in an American Teaching Hospital: A Dire Need for a Standardized Approach
Authors: BRIGNOLE MICHELE , MALASANA GANGADHAR , SHERWOOD RANDALL P. , DACCARETT MARCOS , JETTER TAWNI L. , HAMDAN MOHAMED H.
Published: November 2010

Background:

Fainting is a major healthcare problem with significant morbidity, mortality, and healthcare cost. We sought to assess the appropriateness of current clinical practice when compared to a guideline‐based algorithm.

Methods:

The records of 100 consecutive patients who presented with faint and were referred to the University of Utah for further evaluation by specialists were reviewed. We analyzed the clinical characteristics, tests performed, diagnosis made, and number of admissions. In addition, we applied a guideline‐based algorithm to assess the appropriateness of these evaluations.

Results:

The mean age was 49 ± 21 years with 57% being female. One‐third presented with their first event. Structural heart disease was present in 22% of the cases. Twelve (36%) of 32 admissions were inappropriate. There was an underutilization of orthostatic testing, carotid sinus massage, and implantable loop recorder and overutilization of imaging studies and neurologic consultation. Specifically, active standing and tilt‐table testing were performed in only 24% and 7% of the cases, respectively, none of the patients had carotid sinus massage despite 26% of them being ≥65 years old, and only 3% of the patients received an implantable loop recorder. With the current practice, a final diagnosis was made in 45 cases with 17 (38%) of the 45 final diagnoses not being sufficiently supported by the completeness of the evaluation.

Conclusion:

With the current practice at a major university hospital, the cause of faint was unexplained in a high number of cases. Our findings highlight the need for a standardized approach to patients presenting with faint. (PACE 2011; 34:284–290)
Noncavotricuspid Isthmus‐Dependent Right Atrial Tachycardia after Paroxysmal Atrial Fibrillation Ablation
Authors: JU WEIZHU , YANG BING , CHEN HONGWU , ZHANG FENGXIANG , ZHAI LISHANG , CAO KEJIANG , CHEN MINGLONG
Published: November 2010

Background:
 Atrial tachycardia (AT) is commonly encountered after atrial fibrillation (AF) ablation. But no study exclusively on noncavotricuspid isthmus‐dependent right AT (NCTI‐RAT) post‐AF ablation has been reported. The present study aims to describe its prevalence, electrophysiological mechanisms, and ablation strategy and to further discuss its relationship with AF.

Methods:
 From July 2006 to November 2009, 350 consecutive patients underwent catheter ablation for paroxysmal AF. A total of seven patients (2.0%) developed NCTI‐RAT after left atrium ablation for AF. In these highly selected patients (two male, mean age 54 ± 11 years, mean left atrium diameter of 34 ± 7 cm), all had circumferential pulmonary vein isolation in their initial procedures and three of them had additional complex fractionated electrograms ablation in the left atrium and the coronary sinus.

Results:
 Totally, nine NCTI‐RATs were mapped and successfully ablated in the right atrium with a mean cycle length of 273 ± 64 ms in seven patients. Five ATs in three patients were electrophysiologically proved to be macroreentry and the remaining four were focal activation. All the ATs were successfully abolished by catheter ablation. After a mean follow‐up of 29 ± 15 months post‐AT ablation, all patients were free of AT and AF off antiarrhythmic drugs.

Conclusions:
 NCTI‐RAT is relatively less common post‐AF ablation. Totally, 2.0% of paroxysmal AF patients were revealed to have NCTI‐RAT. (PACE 2011; 34:391–397)
Henry Cuthbert Bazett (1885–1950)—The Man behind the QT Interval Correction Formula
Authors: ROGUIN ARIEL
Published: November 2010

The “Bazett formula” is used for correcting the observed QT interval and is named after Henry Cuthbert Bazett who was born in England in 1885. He studied medicine and worked in Oxford and served in the British Medical Corps during World War I. In 1920, Bazett published his seminal paper on the different intervals length of the electrocardiogram recordings in a small group of healthy individuals, and proposed a formula for correcting the QT length for heart rate. Later, he moved to the University of Pennsylvania, in Philadelphia, and from 1931 until his death in 1950, he served as head of the Department of Physiology and a leader of the American Society of Physiology. Bazett's scientific work was largely concerned with temperature control, circulation, and blood volume, and he contributed greatly to the study of circulation in humans by using invasive catheterization. (PACE 2011; 34:384–388)
Safety and Feasibility of Cephalic Venous Access for Cardiac Resynchronization Device Implantation
Authors: USSEN BASSEY , DHILLON PARAMDEEP S. , ANDERSON LISA , BEETON IAN , HICKMAN MIKE , GALLAGHER MARK M.
Published: November 2010

Background:

Cardiac resynchronization therapy (CRT) devices are usually implanted using subclavian vein access, which is associated with the risk of pneumothorax. We examined whether cephalic venous access is an effective alternative to subclavian access by the Seldinger technique for CRT delivery.

Methods:

We retrospectively analyzed all CRT procedures performed over a 1‐year period at our center with respect to the access methods, primary success rate, safety, and efficiency.

Results:

We retrospectively analyzed 103 consecutive primary implantation procedures. The procedure was accomplished using cephalic access alone for 54 of 61 (89%) CRT implants attempted by this route. The overall success rate was 100% (61/61) with additional use of subclavian access. CRT implantation via subclavian vein access was successful in 37 of 42 (88%) (P < 0.05 vs cephalic group). The procedure duration was shorter for the cephalic group (118 ± 39 vs 147 ± 36 minutes, P < 0.0005) as were the screening times and radiation exposure (15 ± 9 vs 27 ± 18 minutes and 4.7 ± 5.8 vs 9.3 ± 9.1 Gcm2, both P < 0.01). In the cephalic group, procedure duration and radiation exposure diminished significantly with increasing experience of the technique. Complications occurred in two of 61 (3.3%) cases in the cephalic group and three of 42 (7.1%) in the subclavian group (P = NS).

Conclusion:

CRT devices can be implanted using cephalic access alone in a large majority of cases. This approach is safe and efficient. (PACE 2011; 34:365–369)
Interatrial Septum Pacing Decreases Atrial Dyssynchrony on Strain Rate Imaging Compared with Right Atrial Appendage Pacing
Authors: YASUOKA YOSHINORI , ABE HARUHIKO , UMEKAWA SEIKO , KATSUKI KEIKO , TANAKA NORIO , ARAKI RYO , IMANAKA TAKAHIRO , MATSUTERA RYO , MORISAWA DAISUKE , KITADA HIROKAZU , HATTORI SUSUMU , NODA YOSHIKI , ADACHI HIDENORI , SASAKI TATSUYA , MIYATAKE KUNIO
Published: November 2010

Background:

Interatrial septum pacing (IAS‐P) decreases atrial conduction delay compared with right atrial appendage pacing (RAA‐P). We evaluate the atrial contraction with strain rate of tissue Doppler imaging (TDI) during sinus activation or with IAS‐P or RAA‐P.

Methods:

Fifty‐two patients with permanent pacemaker for sinus node disease were enrolled in the study. Twenty‐three subjects were with IAS‐P and 29 with RAA‐P. The time from end‐diastole to peak end‐diastolic strain rate was measured and corrected with RR interval on electrocardiogram. It was defined as the time from end‐diastole to peak end‐diastolic strain rate (TSRc), and the balance between maximum and minimum TSRc at three sites (ΔTSRc) was compared during sinus activation and with pacing rhythm in each group.

Results:

There were no significant differences observed in general characteristics and standard echocardiographic parameters except the duration of pacing P wave between the two groups. The duration was significantly shorter in the IAS‐P group compared with the RAA‐P group (95 ± 34 vs 138 ± 41; P = 0.001). TSRc was significantly different between sinus activation and pacing rhythm (36.3 ± 35.7 vs 61.6 ± 36.3; P = 0.003) in the RAA‐P group, whereas no significant differences were observed in the IAS‐P group (25.4 ± 12.1 vs 27.7 ± 14.7; NS). During the follow‐up (mean 2.4 ± 0.7 years), the incidence of paroxysmal atrial fibrillation (AF) conversion to permanent AF was not significantly different between the two groups.

Conclusions:

IAS‐P decreased the contraction delay on atrial TDI compared to RAA‐P; however, it did not contribute to the reduction of AF incidence in the present study. (PACE 2011; 34:370–376)
High‐Sensitivity C‐Reactive Protein as a Predictor of Atrial Fibrillation Recurrence after Primary Circumferential Pulmonary Vein Isolation
Authors: LIU JUN , FANG PI‐HUA , DIBS SAMER , HOU YU , LI XIAO‐FENG , ZHANG SHU
Published: November 2010

Background: Atrial fibrillation (AF) recurrence after circumferential pulmonary vein isolation (CPVI) is difficult to predict. Inflammation is associated with the development of AF. Inflammatory markers, such as high sensitivity C‐reactive protein (hsCRP), are related to AF development via atrial remodeling. However, it is unknown whether plasma hsCRP concentration before CPVI can be used as a predictor for AF recurrence.

Methods: A total of 121 patients without structural heart disease who underwent primary CPVI by a single operator were included in the study (paroxysmal/persistent AF: 77/44). Left atrial diameter was measured by transesophageal echocardiography. Plasma hsCRP concentration was determined by enzyme‐linked immunosorbent assay. Based on the follow‐up outcomes, patients were divided into two groups, a recurrence group and a nonrecurrence group. AF recurrence was defined as AF or atrial flutter or atrial tachycardia episodes lasting for ≥30 s during regular follow‐up (>12 months).

Results: A total of 36 (29.8%) patients (paroxysmal/persistent AF: 19 [24.7%]/17 [38.6%]) had AF recurrence in a mean 23 (range, 12–44) month follow‐up period. The plasma hsCRP concentration in the recurrence group was significantly higher than that in the nonrecurrence group for all patients (median [quartile range] 2.22 [1.97] mg/L vs 0.89 [1.30] mg/L, P < 0.001), for patients with paroxysmal AF (2.12 [2.78] mg/L vs 0.84 [1.15] mg/L, P = 0.028), and for those with persistent AF (2.29 [1.08] mg/L vs 0.89 [1.53] mg/L, P = 0.005). Multiple logistic regression analyses showed that the higher level of the plasma hsCRP (P < 0.001) was a significant prognostic predictor of AF recurrence, both for patients with paroxysmal AF (P = 0.012) and those with persistent AF (P = 0.003).

Conclusion: Plasma hsCRP concentration before CPVI was associated with AF recurrence after primary CPVI procedure for both paroxysmal and persistent AF patients. Plasma hsCRP concentration could play a role in prediction of AF recurrence after primary CPVI. (PACE 2011; 34:398–406)
An Algorithm to Predict the Site of Origin of Focal Atrial Tachycardia
Authors: QIAN ZHI‐YONG , HOU XIAO‐FENG , XU DONG‐JIE , YANG BING , CHEN MING‐LONG , CHEN CHUN , ZHANG FENG‐XIANG , SHAN QI‐JUN , CAO KE‐JIANG , ZOU JIAN‐GANG
Published: November 2010

Background: Only a few algorithms for predicting the site of origin of focal atrial tachycardia (AT) have been reported. We aimed to develop a new and more effective algorithm.

Methods: Surface 12‐lead electrocardiograms were collected during tachycardia and sinus rhythm in 61 patients who received successful radiofrequency ablation. P‐wave polarities, durations, and amplitudes were analyzed. Predictive values of the most significant parameters were determined. An algorithm was then developed and prospectively evaluated in 30 new consecutive AT patients.

Results: Thirty‐six percent (22/61) of the foci were located at the ostium of coronary sinus (CS). Other common foci included pulmonary veins (PVs, n = 15), right atrial appendage (RAA, n = 7), parahisian area (n = 7), and crista terminalis (CT, n = 3). Positive P waves in inferior leads (II, III, and aVF) and a negative P wave in lead aVR indicated high atrial origins (high CT, superior PVs, and RAA, defined as Area A), with a sensitivity of 95% and a specificity of 90%. Negative P waves in inferior leads and a positive P wave in lead aVR suggested right low septal origins (CS ostium and inferior tricuspid annulus, defined as Area B), with good sensitivity and specificity (88% and 89%, respectively). This new P‐wave diagnostic algorithm correctly identified the site of origin in 90% of AT cases.

Conclusion: Combination of data from multiple leads and regrouping of sites of origin provides a better predictive value. (PACE 2011; 34:414–421)
Idiopathic Mitral Annular PVCs with Multiple Breakouts and Preferential Conduction Unmasked by Radiofrequency Catheter Ablation
Authors: YAMADA TAKUMI , DOPPALAPUDI HARISH , MCELDERRY H. THOMAS , KAY G. NEAL
Published: November 2010

A 39‐year‐old man with idiopathic monomorphic premature ventricular contractions (PVCs), exhibiting a right bundle branch block and inferior axis QRS morphology, underwent electrophysiological testing. After a radiofrequency (RF) application to the anterior mitral annulus (MA) eliminated the spontaneous PVC morphology, a second PVC morphology occurred. Pacing from the first ablation site exhibited an excellent match to the second PVCs with a long stimulus to QRS interval. An RF application delivered near the first lesion eliminated all PVCs. The MA PVCs in this case exhibited a single origin with multiple breakouts and preferential conduction that were unmasked by RF ablation. (PACE 2012; 35:e112–e115)
Seeing Dead People Not Known to Have Died: “Peak in Darien” Experiences
Authors: Greyson Bruce
Published: November 2010

The ubiquitous belief that, after death, our consciousness might persist in some discarnate form is fueled in part by phenomena like near‐death experiences (NDEs) and deathbed visions, mystical experiences reported on the threshold of death. Some NDEs, called “Peak in Darien” experiences, include visions of deceased people who are not known at the time to be dead. Cases of this kind provide some of the most persuasive evidence for the survival of consciousness after bodily death.
Understanding the Conundrum of Rebirth Experience of the Beaver, Gitxsan, and Witsuwit'en
Authors: Mills Antonia
Published: November 2010

The First Nations people of British Columbia experience reincarnation as a revitalization of their culture. This article documents the perseverance of reincarnation experiences among the Beaver, Witsuwit'en, and Gitxsan peoples of British Columbia, as well as my own growth in understanding such experiences. It recounts examples of rebirth cases. It explains what rebirth experiences mean to the First Nations people. It describes how these experiences are embedded in their perception of this world and embodied in their beliefs of spiritual realms, which include the interconnected and parallel worlds of fish and land animals, on this world and in spiritual dimensions. While the rebirth worldview contrasts with that of the Western scientific world, this is a worldview I have come to endorse.
Anthropology, Shamanism, and Alternate Ways of Knowing–Being in the World: One Anthropologist's Journey of Discovery and Transformation
Authors: Glass‐Coffin Bonnie
Published: November 2010

From over 20 years of working with shamans and their apprentices in northern Peru and the United States, this article describes my own journey from scientist and skeptic to humanist and adept. It tells of the fundamental shift in consciousness I experienced as a result of a specific instance in which the veil between the seen and unseen worlds temporarily lifted, allowing me to engage with Spirit in new ways. It presents, as a result of this shift, the struggles I have faced in redefining my own relationship to my work as an anthropologist. Finally, it suggests some of the advantages to our discipline that can come from thinking outside the paradigmatic box that has, for much too long, kept us disengaged from the world in which we live.
The Shortage of On‐call Surgical Specialist Coverage: A National Survey of Emergency Department Directors
Authors: Rao Mitesh B. , Lerro Catherine , Gross Cary P.
Published: November 2010

Objectives:  Problems with on‐call specialist physician coverage have been identified as a significant issue for our nation’s health care system. Despite this, little is known about the full extent of these coverage deficiencies in emergency departments (EDs), their effect on emergency care provision, or the subsequent effect on patient flow should specialist‐requiring patients need to be transferred to centers of higher‐level care. The objective was to report the experiences of a national sample of ED directors regarding the degree of difficulty in providing specialist coverage and the effect of on‐call coverage problems on emergency patient care.

Methods:  The authors conducted a cross‐sectional self‐administered survey of a national sample of ED directors. How frequently ED directors reported on‐call coverage problems, whether they recently lost on‐call coverage, whether their current on‐call coverage was reliable, and the potential effect on emergency care provision were all assessed.

Results:  The overall response rate was 62% (442 of 715). Seventy‐four percent of respondents reported on‐call coverage problems with specialist physicians. Sixty percent reported having lost 24/7 coverage for at least one specialty in the past 4 years. Twenty‐six percent reported unreliability in their current on‐call coverage. Twenty‐three percent noted that their trauma center designation level had been affected by on‐call coverage, and 22% noted an increase in patients leaving before being seen by a medically needed specialist.

Conclusions:  Difficulties in obtaining specialty on‐call coverage are a pervasive issue for EDs at the national level. Emergency care provision appears to have been affected, and this issue is further impacted by a perceived unreliability in current on‐call coverage provision as well as the attrition of coverage for individual specialties.

ACADEMIC EMERGENCY MEDICINE 2010; 17:1374–1382 © 2010 by the Society for Academic Emergency Medicine
A Seven‐Year Follow‐Up Study on Parents' Expectations of Their Children's Further Education
Authors: Räty Hannu , Kasanen Kati
Published: November 2010

This study examined the role of parents' perceptions of their children's competencies and their educational optimism in forming expectations of their children's further education. A group of parents (N = 352) were asked to estimate the probability of their children's entering gymnasium or vocational school and to assess the child's competencies in the course of primary school years. Parents had crystallized anticipations of their children's further education as early as preschool, and the differences bound to parents' education and child's gender were well established in their expectations. By the end of the 7thschool year, the relationships between the expectations and the competence assessments strengthened and became more uniform among parents, although there were also group‐specific profiles.