A Novel Protein Isoform of the Multicopy Human NAIP Gene Derives from Intragenic Alu SINE Promoters

The human neuronal apoptosis inhibitory protein (NAIP) gene is no longer principally considered a member of the Inhibitor of Apoptosis Protein (IAP) family, as its domain structure and functions in innate immunity also warrant inclusion in the Nod-Like Receptor (NLR) superfamily. NAIP is located in a region of copy number variation, with one full length and four partly deleted copies in the reference human genome. We demonstrate that several of the NAIP paralogues are expressed, and that novel transcripts arise from both internal and upstream transcription start sites. Remarkably, two internal start sites initiate within Alu short interspersed element (SINE) retrotransposons, and a third novel transcription start site exists within the final intron of the GUSBP1 gene, upstream of only two NAIP copies. One Alu functions alone as a promoter in transient assays, while the other likely combines with upstream L1 sequences to form a composite promoter. The novel transcripts encode shortened open reading frames and we show that corresponding proteins are translated in a number of cell lines and primary tissues, in some cases above the level of full length NAIP. Interestingly, some NAIP isoforms lack their caspase-sequestering motifs, suggesting that they have novel functions. Moreover, given that human and mouse NAIP have previously been shown to employ endogenous retroviral long terminal repeats as promoters, exaptation of Alu repeats as additional promoters provides a fascinating illustration of regulatory innovations adopted by a single gene

Trypanosoma evansi control and horse mortality in the Brazilian Pantanal

The impact of three treatment strategies for Trypanosoma evansi control on horse mortality in the Brazilian Pantanal based on four size categories of cattle ranches is explored. The region's 49,000 horses are indispensable to traditional extensive cattle ranching and T. evansi kills horses. About 13% of these horses would be lost, annually, due to T. evansi if no control were undertaken. One preventive and two curative treatment strategies are financially justifiable in the Pantanal. The best available technology for the treatment of T. evansi from a horse mortality perspective is the preventive strategy, which spares 6,462 horses, annually. The year-round cure spares 5,783 horses, and the seasonal cure saves 5,204 horses on a regional basis relative to no control strategy. Regardless of the strategy adopted, 39% of the costs or benefits fall to the largest ranches, while 18% fall to the smallest ranches

Worldwide clinical experience with a new dual-chamber implantable cardioverter defibrillator system

Introduction: Management of atrial tachyarrhythmias represents a significant challenge in patients with implantable cardioverter defibrillators (ICDs). Drug therapy of these arrhythmias is limited by moderate efficacy, ventricular proarrhythmia, and drug-device interactions. This study tested the safety and efficacy of a new dual-chamber ICD to detect and treat atrial as well as ventricular tachyarrhythmias, Methods and Results: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 293 of 303 patients at 49 centers in Europe, Canada, and North America. Specific data were collected at implant and during a mean follow-up period of 7.9 +/- 4.7 months. There were no clinically evident failures to detect and treat ventricular arrhythmias. In patients with at least one of the dual-chamber detection criteria activated, 1,056 of 1,192 episodes of ventricular tachycardia or fibrillation detected were judged to be appropriate (89 % positive predictive accuracy). Therapy efficacy was 100 % in the ventricular fibrillation zone and 98 % in the ventricular tachycardia zone. Positive predictive accuracy for detection of atrial episodes was 95 % (1,052/1,107), For episodes classified as atrial tachycardia by the device, the efficacy of atrial antitachycardia pacing and high-frequency (50-Hz) burst pacing was 55% and 17%, respectively. High-frequency burst pacing terminated 16.8% of episodes classified as atrial fibrillation, and atrial defibrillation had an estimated efficacy of 76 %. The actuarial estimates of 6-month complication-free survival and total survival were 88 % and 94 %, respectively. Conclusion: This novel dual-chamber ICD is capable of safely and effectively discriminating atrial from ventricular tachyarrhythmias and of treating atrial tachyarrhythmias without compromising detection and treatment of ventricular tachyarrhythmias

Characteristics of Patients With Asymptomatic Atrial Fibrillation and Ischemic Stroke-Insights From the GLORIA-AF Registry (Phase 2).

BackgroundAsymptomatic nonvalvular atrial fibrillation is often suspected in patients with cryptogenic stroke which constitute 20%-30% of ischemic strokes. Detection of atrial fibrillation (AF) and treatment with anticoagulation can reduce the risk of stroke. We sought to investigate the prevalence of asymptomatic atrial fibrillation (aAF) in patients with a history of stroke or an acute stroke on admission.MethodsFrom November 2011 until December 2014, 15,308 patients with a first episode of AF were enrolled in phase 2 of the international, prospective, multicenter global registry on long-term oral anticoagulation treatment in patients with AF (GLORIA-AF) Registry. For the present analysis, we focused on patients with aAF regarding the prevalence of stroke.ResultsOne third of patients (n = 4892, 32%) had aAF. Of these, 611 (12.5%) had a history of stroke or an acute stroke on admission. In contrast, 519 of 10,416 (5.0%) patients with symptomatic AF (sAF) had a history of stroke or an acute stroke on admission. Higher age, male gender, permanent AF, stroke, and the combination of stroke, TIA or systemic embolism were associated with a higher prevalence of aAF on admission. In a multivariable analysis, patients with aAF had a 2.3-fold (95% confidence interval (CI), 2.02-2.54) risk for stroke compared to patients with sAF. Other independent risk factors for stroke were a history of prior bleeding (odds ratio 1.62, 95% CI, 1.34-1.92), chronic kidney disease (1.38, 1.21-1.56), and diabetes mellitus (1.24, 1.10-1.41).ConclusionaAF is reported in about one third of patients with newly diagnosed AF and is associated with a 2.3-fold risk for stroke compared to sAF. Therefore, screening for aAF in high-risk patients might be appropriate to prevent further embolic cerebrovascular events

The subgroup decomposable intermediate indices of inequality

Inequality invariance, Subgroup decomposable indices, Characterization, D31, D63,