Stable secondary arrhythmias late after intraoperative radiofrequency ablation of atrial fibrillation: incidence, mechanism, and treatment.

INTRODUCTION Intraoperative radiofrequency (RF) ablation is an effective treatment of atrial fibrillation (AF). However, secondary arrhythmias late after ablation may complicate the patient's course. We report on the incidence, mechanisms, and treatment of gap-related atrial flutter and other secondary arrhythmias during long-term follow-up. METHODS AND RESULTS In 129 patients who underwent intraoperative RF ablation with placement of left atrial linear lesions using minimally invasive surgical techniques, secondary arrhythmias were analyzed during long-term follow-up (20 +/- 6 months). Transient atrial arrhythmias during the first 3 postoperative months were excluded. In 8 (6.2%) of 129 patients, sustained stable secondary arrhythmias were documented. Left atrial, gap-related atrial flutter was observed in 4 patients (3.1%). The flutter was treated by percutaneous RF ablation in 3 patients (2.3%) and with drugs in 1 patient (0.8%). In 2 patients (1.6%), right atrial isthmus-dependent atrial flutter occurred and was treated successfully by percutaneous RF ablation. In 2 patients (1.6%), ectopic right atrial tachycardias occurred and were treated with percutaneous RF ablation. CONCLUSION Late after intraoperative RF ablation of atrial fibrillation, three types of stable secondary arrhythmias were observed in 6% of patients: left atrial gap-related atrial flutter, right atrial isthmus-dependent atrial flutter, and ectopic atrial tachycardia. Gaps after intraoperative RF ablation due to noncontinuous or nontransmural linear lesions may lead to stable left atrial macroreentrant tachycardias, requiring new interventional therapy.

Dual dispatch early defibrillation in out-of-hospital cardiac arrest in a mixed urban–rural population

Aims The effects of a system based on minimally trained first responders (FR) dispatched simultaneously with the emergency medical services (EMS) of the local hospital in a mixed urban and rural area in Northwestern Switzerland were examined. Methods and results In this prospective study 500 voluntary fire fighters received a 4-h training in basic-life-support using automated-external-defibrillation (AED). FR and EMS were simultaneously dispatched in a two-tier rescue system. During the years 2001–2008, response times, resuscitation interventions and outcomes were monitored. 1334 emergencies were included. The FR reached the patients (mean age 60.4 ± 19 years; 65% male) within 6 ± 3 min after emergency calls compared to 12 ± 5 min by the EMS (p < 0.0001). Seventy-six percent of the 297 OHCAs occurred at home. Only 3 emergencies with resuscitation attempts occurred at the main railway station equipped with an on-site AED. FR were on the scene before arrival of the EMS in 1166 (87.4%) cases. Of these, the FR used AED in 611 patients for monitoring or defibrillation. CPR was initiated by the FR in 164 (68.9% of 238 resuscitated patients). 124 patients were defibrillated, of whom 93 (75.0%) were defibrillated first by the FR. Eighteen patients (of whom 13 were defibrillated by the FR) were discharged from hospital in good neurological condition. Conclusions Minimally trained fire fighters integrated in an EMS as FR contributed substantially to an increase of the survival rate of OHCAs in a mixed urban and rural area.

Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response

BACKGROUND Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. OBJECTIVE Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. METHODS Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naïve HLA-B*58:01(+) and HLA-B*58:01(-) individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and (51) Cr release assay. RESULTS Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status. CONCLUSIONS AND CLINICAL RELEVANCE This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele.

Use of a hand-assisted laparoscopic surgical technique for closure of an extensive mesojejunal rent in a horse

CASE DESCRIPTION A 7-year-old 573-kg (1,261 -lb) Swiss Warmblood gelding was evaluated because of signs of acute abdominal pain. CLINICAL FINDINGS Physical examination revealed a markedly distended abdomen with subjectively reduced borborygmi in all abdominal quadrants. A large, gas-distended viscus was present at the pelvic brim preventing complete palpation of the abdomen per rectum. Ultrasonographic evaluation could not be safely performed in the initial evaluation because of severe signs of abdominal pain. TREATMENT AND OUTCOME Ventral midline celiotomy was performed, and right dorsal displacement of the ascending colon was corrected. Progressive signs of abdominal pain after surgery prompted repeat ventral midline celiotomy, and small intestinal incarceration in a large, radial mesojejunal rent was detected. The incarceration was reduced, but the defect was not fully accessible for repair via the celiotomy. Repair of the mesenteric defect was not attempted, and conservative management was planned after surgery; however, signs of colic returned. A standard laparoscopic approach was attempted from both flanks in the standing patient, but the small intestine could not be adequately mobilized for full evaluation of the rent. Hand-assisted laparoscopic surgery (HALS) allowed identification and reduction of jejunal incarceration and repair of the mesenteric rent. Although minor ventral midline incisional complications were encountered, the horse recovered fully. CLINICAL RELEVANCE HALS techniques should be considered for repair of mesenteric rents in horses. In the horse of this report, HALS facilitated identification, evaluation, and repair of a large radial mesenteric rent that was not accessible from a ventral median celiotomy.

The influence of bedrock orientation on the landscape evolution, surface morphology and denudation (10Be) at the Niesen, Switzerland

Landscape evolution and surface morphology in mountainous settings are a function of the relative importance between sediment transport processes acting on hillslopes and in channels, modulated by climate variables. The Niesen nappe in the Swiss Penninic Prealps presents a unique setting in which opposite facing flanks host basins underlain by identical lithologies, but contrasting litho-tectonic architectures where lithologies either dip parallel to the topographic slope or in the opposite direction (i.e. dip slope and non-dip slope). The north-western facing Diemtigen flank represents such a dip slope situation and is characterized by a gentle topography, low hillslope gradients, poorly dissected channels, and it hosts large landslides. In contrast, the south-eastern facing Frutigen side can be described as non-dip slope flank with deeply incised bedrock channels, high mean hillslope gradients and high relief topography. Results from morphometric analysis reveal that noticeable differences in morphometric parameters can be related to the contrasts in the relative importance of the internal hillslope-channel system between both valley flanks. While the contrasting dip-orientations of the underlying flysch bedrock has promoted hillslope and channelized processes to contrasting extents and particularly the occurrence of large landslides on the dip slope flank, the flank averaged beryllium-10 (10Be)-derived denudation rates are very similar and range between 0.20 and 0.26 mm yr−1. In addition, our denudation rates offer no direct relationship to basin's slope, area, steepness or concavity index, but reveal a positive correlation to mean basin elevation that we interpret as having been controlled by climatically driven factors such as frost-induced processes and orographic precipitation. Our findings illustrate that while the landscape properties in this part of the northern Alpine border can mainly be related to the tectonic architecture of the underlying bedrock, the denudation rates have a strong orographic control through elevation dependent mean annual temperature and precipitation.

Consistency of thromboelastometry analysis under scrutiny: Results of a systematic evaluation within and between analysers.

While the use of thromboelastometry analysis (ROTEM®) in evaluation of haemostasis is rapidly increasing, important validity parameters of testing remain inadequately examined. We aimed to study systematically the consistency of thromboelastometry parameters within individual tests regarding measurements between different analysers, between different channels of the same analyser, between morning and afternoon measurements (circadian variation), and if measured four weeks apart. Citrated whole blood samples from 40 healthy volunteers were analysed with two analysers in parallel. EXTEM, INTEM, FIBTEM, HEPTEM and APTEM tests were conducted. A Bland-Altman comparison was performed and homogeneity of variances was tested using the pitman test. P-value ranges were used to classify the level of homogeneity (p<0.15 - low homogeneity, p = 0.15 to 0.5 - intermediate homogeneity, p>0.5 high homogeneity). Less than half of all comparisons made showed high homogeneity of variances (p>0.5) and in about a fifth of comparisons data distributions were heterogeneous (p<0.15). There was no clear pattern for homogeneity. On average, comparisons of MCF, ML and LI30 measurements tended to be better, but none of the tests assessed outperformed another. In conclusion, systematic investigation reveals large differences in the results of some thromboelastometry parameters and lack of consistency. Clinicians and scientists should take these inconsistencies into account and focus on parameters with a higher homogeneity such as MCF.

The Role of IL-6 in Adenosine-Mediated Pulmonary Fibrosis

Adenosine is a purinergic signaling molecule that regulates various aspects of inflammation and has been implicated in the pathogenesis of chronic lung diseases. Previous studies have demonstrated that adenosine up-regulates IL-6 production through the engagement of the A2B adenosine receptor in various cell types, including alveolar macrophages. IL-6 is elevated in mouse models and humans with chronic lung disease, suggesting a potential role in disease progression. Furthermore, chronic elevation of adenosine in the lungs of adenosine deaminase deficient (Ada-/-) mice leads to the development of pulmonary inflammation, alveolar destruction, and fibrosis, in conjunction with IL-6 elevation. Thus, it was hypothesized that IL-6 contributes to pulmonary inflammation and fibrosis in this model. To test this hypothesis, Ada/IL-6 double knockout mice (Ada/IL-6-/-) were generated to assess the consequences of genetically removing IL-6 on adenosine-dependent pulmonary injury. Ada/IL-6-/- mice exhibited a significant reduction in inflammation, alveolar destruction, and pulmonary fibrosis. Next, Ada-/- mice were treated systematically with IL-6 neutralizing antibodies to test the efficacy of blocking IL-6 on chronic lung disease. These treatments were associated with decreased pulmonary inflammation, alveolar destruction, and fibrosis. To determine the role of IL-6 in a second model of pulmonary fibrosis, wild type mice and IL-6-/- mice were subjected to intraperitoneal injections of bleomycin twice a week for four weeks. Results demonstrated that IL-6-/- mice developed reduced pulmonary fibrosis. To examine a therapeutic approach in this model, wild type mice exposed to bleomycin were treated with IL-6 neutralizing antibodies. Similar results were observed as with Ada-/- mice, namely diminished pulmonary inflammation and fibrosis. In both models, elevations in IL-6 were associated with increased phosphorylated STAT-3 in the nuclei of numerous cell types in the airways, including type II alveolar epithelial cells (AEC). Genetic removal and neutralization of IL-6 in both models was associated with decreased STAT-3 activation in type II AEC. The mechanism of activation in these cells that lack the membrane bound IL-6Ra suggests IL-6 trans-signaling may play a role in regulating fibrosis. Characterization of this mechanism demonstrated that the soluble IL-6Ra (sIL-6Ra) is upregulated in both models during chronic conditions. In vitro studies in MLE-12 alveolar epithelial cells confirmed that IL-6, in combination with the sIL-6Ra, activates STAT-3 and TWIST in association with enhancement of epithelial-to-mesenchymal transition, which can contribute to fibrosis. Similarly, patients with idiopathic pulmonary fibrosis demonstrated a similar pattern of increased IL-6 expression, STAT-3 activation, and sIL-6Ra increases. These findings demonstrate that adenosine-dependent elevations in IL-6 contribute to the development and progression of pulmonary inflammation and fibrosis. The implications from these studies are that adenosine and/or IL-6 neutralizing agents represent novel therapeutic targets for the treatment of pulmonary disorders where fibrosis is a detrimental component.

THE EXPRESSION PROFILE OF A GWAS DETECTED GENE (NINJ2) IN THE BRAIN OF A MOUSE MODEL OF ISCHEMIC STROKE

Stroke is the third leading cause of death and a major debilitating disease in the United States. Multiple factors, including genetic factors, contribute to the development of the disease. Genome-wide association studies (GWAS) have contributed to the identification of genetic loci influencing risk for complex diseases, such as stroke. In 2010, a GWAS of incident stroke was performed in four large prospective cohorts from the USA and Europe and identified an association of two Single Nucleotide Polymorphisms (SNPs) on chromosome 12p13 with a greater risk of ischemic stroke in individuals of European and African-American ancestry. These SNPs are located 11 Kb upstream of the nerve injury-induced gene 2, Ninjurin2 (NINJ2), suggesting that this gene may be involved in stroke pathogenesis. NINJ2 is a cell adhesion molecule induced in the distal glial cells from a sciatic-nerve injury at 7-days after injury. In an effort to ascribe a possible role of NINJ2 in stroke, we have assessed changes in the level of gene and protein expression of NINJ2 following a time-course from a transiently induced middle cerebral artery ischemic stroke in mice brains. We report an increase in the gene expression of NINJ2 in the ischemic and peri-infarct (ipsilateral) cortical tissues at 7 and 14-days after stroke. We also report an increase in the protein expression of NINJ2 in the cortex of both the ipsilateral and contralateral cortical tissues at the same time-points. We conclude that the expression of NINJ2 is regulated by an ischemic stroke in the cortex and is consistent with NINJ2 being involved in the recovery time-points of stroke.

Ice Core Paleovolcanic Records from the St. Elias Mountains, Yukon, Canada

We previously reported a record of regionally significant volcanic eruptions in the North Pacific using an ice core from Eclipse Icefield (St. Elias Mountains, Yukon, Canada). The acquisition of two new ice cores from Eclipse Icefield, along with the previously available Eclipse Icefield and Mount Logan Northwest Col ice cores, allows us to extend our record of North Pacific volcanism to 550 years before present using a suite of four ice cores spanning an elevation range of 3 - 5 km. Comparison of volcanic sulfate flux records demonstrates that the results are highly reproducible, especially for the largest eruptions such as Katmai ( A. D. 1912). Correlation of volcanic sulfate signals with historically documented eruptions indicates that at least one-third of the eruptions recorded in St. Elias ice cores are from Alaskan and Kamchatkan volcanoes. Although there are several moderately large ( volcanic explosivity index (VEI) >= 4) eruptions recorded in only one core from Eclipse Icefield, the use of multiple cores provides signals in at least one core from all known VEI >= 4 eruptions in Alaska and Kamchatka since A. D. 1829. Tephrochronological evidence from the Eclipse ice cores documents eruptions in Alaska (Westdahl, Redoubt, Trident, and Katmai), Kamchatka (Avachinsky, Kliuchevoskoi, and Ksudach), and Iceland (Hekla). Several unidentified tephra-bearing horizons, with available geochemical evidence suggesting Alaskan and Kamchatkan sources, were also found. We present a reconstruction of annual volcanic sulfate loading for the North Pacific troposphere based on our ice core data, and we provide a detailed assessment of the atmospheric and climatic effects of the Katmai eruption.

Determination of αs from the QCD static energy: An update

We present an update of our determination of the strong coupling αs from the quantum chromodynamics static energy. This updated analysis includes new lattice data, at smaller lattice spacings and reaching shorter distances, the use of better suited perturbative expressions to compare with data in a wider distance range, and a comprehensive and detailed estimate of the error sources that contribute to the uncertainty of the final result. Our updated value for αs at the Z-mass scale, MZ, is αs(MZ)=0.1166+0.0012−0.0008, which supersedes our previous result.