2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.     

Double ischemic ileal stenosis secondary to mesenteric injury after blunt abdominal trauma

The authors describe a rare case in which blunt abdominal trauma resulted in mesenteric injury with delayed double ischemic ileal stenosis. Abdominal computed tomography demonstrated stenotic ileal loop with mural thickening. At surgery, a double stenotic bowel loop was found adjacent to a healed defect in the mesentery. Histological examination of the two resected segments showed fibrotic and ischemic lesions within the mesentery. Ischemic intestinal stenosis from mesenteric injury should be considered in the differential diagnosis in patients suffering from intestinal occlusion with a history of blunt abdominal trauma.     

Impact of anthropogenic atmospheric nitrogen and sulfur deposition on ocean acidification and the inorganic carbon system

Fossil fuel combustion and agriculture result in atmospheric deposition of 0.8 Tmol/yr reactive sulfur and 2.7 Tmol/yr nitrogen to the coastal and open ocean near major source regions in North America, Europe, and South and East Asia. Atmospheric inputs of dissociation products of strong acids (HNO(3) and H2SO(4)) and bases (NH(3)) alter surface seawater alkalinity, pH, and inorganic carbon storage. We quantify the biogeochemical impacts by using atmosphere and ocean models. The direct acid/base flux to the ocean is predominately acidic (reducing total alkalinity) in the temperate Northern Hemisphere and alkaline in the tropics because of ammonia inputs. However, because most of the excess ammonia is nitrified to nitrate (NO(3)(-)) in the upper ocean, the effective net atmospheric input is acidic almost everywhere. The decrease in surface alkalinity drives a net air-sea efflux of CO(2), reducing surface dissolved inorganic carbon (DIC); the alkalinity and DIC changes mostly offset each other, and the decline in surface pH is small. Additional impacts arise from nitrogen fertilization, leading to elevated primary production and biological DIC drawdown that reverses in some places the sign of the surface pH and air-sea CO(2) flux perturbations. On a global scale, the alterations in surface water chemistry from anthropogenic nitrogen and sulfur deposition are a few percent of the acidification and DIC increases due to the oceanic uptake of anthropogenic CO(2). However, the impacts are more substantial in coastal waters, where the ecosystem responses to ocean acidification could have the most severe implications for mankind.     

CardioDiabetes: Core Competencies for Cardiovascular Clinicians in a Rapidly Evolving Era of Type 2 Diabetes Management

A sea change in the management of diabetes is occurring with the publication of clinical trials showing unequivocal cardiovascular (CV) protection through the use of certain antihyperglycemic agents. This change is similar to the change that occurred when lipid lowering with statins was first shown to have CV benefits, an event necessitating changes in training and the proactive treatment of lipids by CV specialists. As was the case then, many CV specialists currently feel poorly equipped to address diabetes with this new information even though diabetes is common in CV practice. The purpose of this overview is to provide an updated, comprehensive, and evidence-based CV protection plan for patients with type 2 diabetes, intended specifically for cardiologists and vascular medicine specialists. We attempt to elucidate a set of “CardioDiabetes” core competencies by merging the CV-relevant elements of the Diabetes Canada 2018 guidelines within a framework of comprehensive vascular protection as supported by other CV guidelines. We review the rationale for measuring hemoglobin A1C, understanding its use for establishing a diagnosis and for monitoring treatment. We also provide a brief review of the medications most important for a CV specialist to know. We provide useful memory aids and a succinct set of reminders and tips (“ABCDEFR’S”) that can serve as a comprehensive checklist in the clinic and help to motivate trainees and clinicians to consult the original guideline source documents to enrich their knowledge and improve treatment in this rapidly changing arena.     

Outcomes, utilization, and costs among thalassemia and sickle cell disease patients receiving deferoxamine therapy in the United States

Deferoxamine mesylate (DFO) reduces morbidity and mortality associated with transfusional iron overload. Data on the utilization and costs of care among U.S. patients receiving DFO in typical clinical practice are limited however. This was a retrospective study using a large U.S. health insurance claims database spanning 1/97-12/04 and representing 40 million members in >70 health plans. Study subjects (n = 145 total, 106 sickle cell disease [SCD], 39 thalassemia) included members with a diagnosis of thalassemia or SCD, one or more transfusions (whole blood or red blood cells), and one or more claims for DFO. Mean transfusion episodes were 12 per year. Estimated mean DFO use was 307 g/year. Central venous access devices were required by 20% of patients. Cardiac disease was observed in 16% of patients. Mean total medical costs were $59,233 per year including $10,899 for DFO and $8,722 for administration of chelation therapy. In multivariate analyses, potential complications of iron overload were associated with significantly higher medical care costs. In typical clinical practice, use of DFO in patients with thalassemia and SCD receiving transfusions is low. Administration costs represent a large proportion of the cost of chelation therapy. Potential complications of iron overload are associated with increased costs.     

Airborne measurements of organic bromine compounds in the Pacific tropical tropopause layer

Very short-lived brominated substances (VSLBr) are an important source of stratospheric bromine, an effective ozone destruction catalyst. However, the accurate estimation of the organic and inorganic partitioning of bromine and the input to the stratosphere remains uncertain. Here, we report near-tropopause measurements of organic brominated substances found over the tropical Pacific during the NASA Airborne Tropical Tropopause Experiment campaigns. We combine aircraft observations and a chemistry−climate model to quantify the total bromine loading injected to the stratosphere. Surprisingly, despite differences in vertical transport between the Eastern and Western Pacific, VSLBr (organic + inorganic) contribute approximately similar amounts of bromine [∼6 (4−9) parts per thousand] to the stratospheric input at the tropical tropopause. These levels of bromine cause substantial ozone depletion in the lower stratosphere, and any increases in future abundances (e.g., as a result of aquaculture) will lead to larger depletions.Until the end of the last century, it was believed that only long-lived species, like bromomethane (CH₃Br) and halons, contributed to the global burden of stratospheric bromine. However, disagreement between the observed amount of reactive stratospheric bromine and the sources of long-lived trace gases suggested the existence of an additional contributor: Very short-lived brominated substances (VSL_org) [VSL_org = bromoform (3CHBr₃) + dibromomethane (2CH₂Br₂) + minor_VSLBr, where minor_VSLBr = bromochloromethane (CH₂BrCl) + dibromochloromethane (2CHBr₂Cl) + bromodichloromethane (CHBrCl₂)] that originate mainly from ocean biogenic sources (1, 2).Several studies have described the processes involved in the transformation of biogenic bromocarbons to inorganic bromine, and their transport through the tropical tropopause layer (TTL) (1–5). These studies have led to significant progress in modeling the VSL_org contribution to the formation of stratospheric inorganic bromine (Br_y) (3, 4, 6–11). However, the scarcity of observations to constrain the emissions, the impact of deep convection, and the effect of dehydration processes limit the prediction of short-lived source gases that reach the stratosphere (3). On the other hand, atmospheric observations of VSL_org have been provided by ground measurements and cruise, balloon, and airborne campaigns (12–14), but the different instruments used between campaigns, and the low spatial and temporal coverage of each study, contribute to the uncertainties in the estimations of total bromine and its partitioning (15). In an attempt to reduce these limitations, we present unique measurements of organic bromine substances carried out with the same instrument, the Global Hawk Whole Air Sampler (GWAS), deployed during the NASA Airborne Tropical Tropopause Experiment (ATTREX), which covered the tropical Pacific region during 2013 and 2014 (see SI Text for details of the campaign).Because coastal areas of tropical waters (like the Maritime Continent) are an important source for VSL_org (16–18) and highly convective zones can transport air masses from the troposphere into the stratosphere through the TTL (19), we focus this study on observations taken over the Western Pacific (120°E−165°E) and the Eastern Pacific (187°E−268°E) (Fig. S1). We compared these regions in terms of VSL_org mixing ratios at the tropopause level (∼17 km; Fig. S2), which defines the chemical composition of air that enters the stratosphere.Open in a separate windowFig. S1.GWAS sample locations during ATTREX campaign. Dotted lines define the Western (120°E–165°E) and Eastern Pacific (187°E–268°E) limits for this study.Open in a separate windowFig. S2.Sample density of measurements of organic bromine species (A) during ATTREX-2014 (Western Pacific) and (B) during ATTREX-2013 (Eastern Pacific).Whole air samples were collected during two deployments of the ATTREX campaigns, on board the unmanned aerial vehicle Global Hawk. Measurements of VSL_org were carried out in the field using a combination of gas chromatography with mass selective, flame ionization, and electron capture detectors (Materials and Methods). Fig. 1 A and B displays the observations of CHBr₃, CH₂Br₂, and minor_VSLBr, as well as the total organic bromine mixing ratio, in the upper troposphere/lower stratosphere (UTLS) of the Western and Eastern Pacific. GWAS observations indicate that the total amount of VSL_org that enters the stratosphere over the Western and Eastern Pacific is approximately similar, 3.27 ± 0.47 parts per thousand (ppt) and 2.96 ± 0.42 ppt, respectively. These observations are compared with the state-of-the-art Community Atmosphere Model (CAM-Chem) simulations (4, 20) (see Materials and Methods). The results show good agreement with the measurements, and simulate the injection of VSL_org to the stratosphere of 3.84 ± 0.64 ppt and 3.18 ± 1.49 ppt organic Br for the Western and Eastern Pacific, respectively (Fig. 1 A and B).Open in a separate windowFig. 1.GWAS measurements and CAM-Chem simulations ±1 SD. Filled symbols are the 1 km average bins from GWAS measurements. Lines are the CAM-Chem simulation. Values from the arrows represent the mean mixing ratio (ppt) of VSL_org and Br_y at the tropopause level (∼17 km) derived from CAM-Chem simulations. (A and B) Organic brominated species multiplied by their atomicity for (A) Western Pacific and (B) Eastern Pacific. (C and D) CAM-Chem estimations of inorganic bromine (Br_y) from measured brominated VSLS with shaded ±1 SD for (C) Western Pacific and (D) Eastern Pacific.Although negligible differences of the organic fraction of VSLBr were observed between the Western and Eastern Pacific, we quantified the inorganic fraction coming from the degradation of VSL_org. Estimations of inorganic bromine (Br_y = Br + BrO + HOBr + BrONO₂ + HBr + BrCl + 2Br₂ + BrNO₂ + IBr), with a focus at ∼17 km, were calculated with the CAM-Chem model using assimilated meteorological fields for each Global Hawk flight. According to these simulations, the amount of Br_y over the Eastern Pacific is 3.02 ± 1.90 ppt, whereas, in the Western Pacific, the mixing ratio of Br_y is 1.97 ± 0.21 ppt (Fig. 1 C and D). Br_y/VSL_org ratios show that at ∼17 km, the abundance of Br_y over the Western Pacific is almost half the amount of VSL_org, in contrast to the Eastern Pacific, where the abundance of Br_y is similar to the value of VSL_org (

Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway

Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-kappaB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.     

Saccharomyces boulardii interferes with enterohemorrhagic Escherichia coli-induced signaling pathways in T84 cells

Enterohemorrhagic Escherichia coli (EHEC) infections are associated with the modification of tight-junction permeability and synthesis of proinflammatory cytokine interleukin-8 (IL-8). In a previous study, it was demonstrated that EHEC-induced IL-8 secretion is due to the involvement of the mitogen-activated protein kinase (MAPK), AP-1, and NF-kappaB pathways. In this study, we investigated the effect of the yeast Saccharomyces boulardii on EHEC infection in T84 cells. For this purpose, cells were (i) incubated with bacteria and yeast at the same time or (ii) incubated overnight with yeast cells that were maintained during infection or eliminated by several washes before infection. Coincubation is sufficient to maintain the transmonolayer electrical resistance (TER) of EHEC-infected cells, whereas the preincubation of cells with the yeast without elimination of the yeast during infection is necessary to significantly decrease IL-8 secretion. We thus analyzed the mechanisms of S. boulardii action. We showed that S. boulardii has no effect on EHEC growth or on EHEC adhesion. Kinetics studies revealed that EHEC-induced myosin light chain (MLC) phosphorylation precedes the decrease of TER. ML-7, an MLC kinase inhibitor, abolishes the EHEC-induced MLC phosphorylation and decrease of TER. Studies show that S. boulardii also abolishes EHEC-induced MLC phosphorylation. We demonstrated that the preincubation of cells with S. boulardii without washes before EHEC infection inhibits NF-kappaB DNA binding activity, phosphorylation and degradation of IkappaB-alpha, and activation of the three members of a MAPK group (extracellular signal-regulated protein kinases 1 and 2, p38, and c-jun N-terminal kinase). These findings demonstrate that S. boulardii exerts a preventive effect on EHEC infection by (i) interfering with one of the transduction pathways implicated in the control of tight-junction structure and (ii) decreasing IL-8 proinflammatory secretion via inhibition of the NF-kappaB and MAPK signaling pathways in infected T84 cells.     

稳定层流剪应力对内皮细胞骨架调节蛋白VASP表达的影响

为探讨生理强度的稳定层流剪应力对内皮细胞骨架actin相关蛋白VASP特征影响规律，我们采用胰蛋白酶消化法分离人脐静脉内皮细胞(HUVECs)，模拟体内流动环境，建立平行板流动腔模型。利用细胞图像分析系统和ALEXA488—若丹明一次毒蕈环肽双标记法，观察内皮细胞在稳态层流下形态、actin排列变化与VASP分布变化之间的规律。采用Western blot定量动态检测细胞内VASP表达及磷酸化的水平。结果表明，内皮细胞在10dyn／cm^2剪切作用后，随时间细胞逐渐延长，长轴趋于剪应力作用方向排列，细胞与静息态的细胞相比，细胞内骨架沿剪应力方向重组，与此同时VASP表达增强，沿着actin纤维呈点状分布，尤其集中在细胞膜下actin末端区域；Western blot检测显示在剪切后，细胞内VASP出现快速磷酸化，VASP总体表达量增加，2h达高峰后逐渐恢复，8h后再次逐渐升高。以上结果提示血流动力学特性中剪应力引起了细胞胞质内骨架蛋白分子重组，血管内皮细胞形态改变，在此过程中，VASP发挥骨架调节蛋白的作用。