Rotational angiography in monitoring of covered CP stent implantation in patient with critical aortic coarctation and patent ductus arteriosus

In presented case rotational angiography with three dimensional reconstruction (3DRA) was used for diagnostic and control angiograms during covered CP stent implantation in patient with critical aortic coarctation and patent ductus arteriosus. Administering less contrast then for standard two perpendicular projections, good quality images were obtained in at least seven projections.     

Monomeric site-specific nucleases for genome editing

Targeted manipulation of complex genomes often requires the introduction of a double-strand break at defined locations by site-specific DNA endonucleases. Here, we describe a monomeric nuclease domain derived from GIY-YIG homing endonucleases for genome-editing applications. Fusion of the GIY-YIG nuclease domain to three-member zinc-finger DNA binding domains generated chimeric GIY-zinc finger endonucleases (GIY-ZFEs). Significantly, the I-TevI-derived fusions (Tev-ZFEs) function in vitro as monomers to introduce a double-strand break, and discriminate in vitro and in bacterial and yeast assays against substrates lacking a preferred 5'-CNNNG-3' cleavage motif. The Tev-ZFEs function to induce recombination in a yeast-based assay with activity on par with a homodimeric Zif268 zinc-finger nuclease. We also fused the I-TevI nuclease domain to a catalytically inactive LADGLIDADG homing endonuclease (LHE) scaffold. The monomeric Tev-LHEs are active in vivo and similarly discriminate against substrates lacking the 5'-CNNNG-3' motif. The monomeric Tev-ZFEs and Tev-LHEs are distinct from the FokI-derived zinc-finger nuclease and TAL effector nuclease platforms as the GIY-YIG domain alleviates the requirement to design two nuclease fusions to target a given sequence, highlighting the diversity of nuclease domains with distinctive biochemical properties suitable for genome-editing applications.     

Right ventricular dysfunction and exercise capacity after inferior (posterior) wall acute myocardial infarction

Tissue Doppler echocardiography is a novel technique that can be used to diagnose right ventricular (RV) systolic dysfunction. Until recently, there have been no data on the influence of tissue Doppler-derived RV systolic dysfunction on exercise capacity after inferior (posterior) myocardial infarction (MI). We studied 90 consecutive patients (76% men, mean age 61 ± 10 years) with first inferior ST-segment elevation MI and left ventricular ejection fraction ≥45%. RV systolic dysfunction was defined as RV systolic myocardial velocity <11.5 cm/s at the basal segment of the RV free wall assessed by pulse tissue Doppler. Patients were categorized as with or without RV systolic dysfunction (RV systolic myocardial velocity 9.34 ± 1.36 and 13.74 ± 1.58 cm/s, respectively). A cardiopulmonary exercise test was performed before or soon after discharge (day 14 ± 10). Patients with RV systolic dysfunction had lower oxygen consumption assessed as percent predicted oxygen uptake in liters per minute and milliliters per kilogram per minute at their anaerobic threshold (61 ± 11% vs 69 ± 17%, p = 0.007; 53 ± 12% vs 61 ± 19%, p = 0.012, respectively) and at peak exercise (71 ± 12% vs 83 ± 16%, p = 0.0001; 62 ± 14% vs 74 ± 21%, p = 0.002, respectively). Multivariate regression analysis revealed that the following independent factors negatively influenced exercise capacity: RV systolic dysfunction, female gender, age, lower body mass index, current smoking, and maximal troponin I concentration. In conclusion, we found decreased exercise capacity in patients with systolic RV dysfunction assessed by pulse tissue Doppler in patients with inferior (posterior) wall acute MI despite preserved left ventricular function.     

Salt and Hypertension: Is Salt Dietary Reduction Worth the Effort?

In numerous epidemiologic, clinical, and experimental studies, dietary sodium intake has been linked to blood pressure, and a reduction in dietary salt intake has been documented to lower blood pressure. In young subjects, salt intake has a programming effect in that blood pressure remains elevated even after a high salt intake has been reduced. Elderly subjects, African Americans, and obese patients are more sensitive to the blood pressure-lowering effects of a decreased salt intake. Depending on the baseline blood pressure and degree of salt intake reduction, systolic blood pressure can be lowered by 4 to 8 mm Hg. A greater decrease in blood pressure is achieved when a reduced salt intake is combined with other lifestyle interventions, such as adherence to Dietary Approaches to Stop Hypertension. A high salt intake has been shown to increase not only blood pressure but also the risk of stroke, left ventricular hypertrophy, and proteinuria. Adverse effects associated with salt intake reduction, unless excessive, seem to be minimal. However, data linking a decreased salt intake to a decrease in morbidity and mortality in hypertensive patients are not unanimous. Dietary salt intake reduction can delay or prevent the incidence of antihypertensive therapy, can facilitate blood pressure reduction in hypertensive patients receiving medical therapy, and may represent a simple cost-saving mediator to reduce cardiovascular morbidity and mortality.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.     

Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study

Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means ± SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 ± 1.4 and 11.5 ± 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] ± SEM, -2.33 ± 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 ± 0.69 mg Fe/g dw, P < .001) for the 5 and 10 mg/kg/d deferasirox groups, respectively (baseline values [means ± SD], 13.11 ± 7.29 and 14.56 ± 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n = 11; 6.6%), rash (n = 8; 4.8%), and diarrhea (n = 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo.