Prions are self-perpetuating, alternative protein conformations associated with neurological diseases and normal cellular functions. Saccharomyces cerevisiae contains many endogenous prions – providing a powerful system to study prionization. Previously, we demonstrated that Swi1, a component of the SWI/SNF chromatin-remodeling complex, can form the prion [SWI+]. A small region, Swi11-38, with a unique amino-acid composition of low complexity, acts as a prion domain and supports [SWI+] propagation. Here, we further examine Swi11-38 through site-directed mutagenesis. We found that mutations of the two phenylalanine residues or threonine tract inhibit Swi11-38 aggregation. In addition, mutating both phenylalanines can abolish de novo prion formation by Swi11-38 whereas mutating only one phenylalanine does not. Replacement of half or the entire eight-threonine tract with alanines has the same effect, possibly disrupting a core region of Swi11-38 aggregates. We also show that Swi11-38 and its prion-fold-maintaining mutants form high-molecular-weight, SDS-resistant aggregates whereas the double phenylalanine mutants eliminate these protein species. These results indicate the necessity of the large hydrophobic residues and threonine tract in Swi11-38 in prionogenesis – possibly acting as important aggregatable regions. Our findings thus highlight the importance of specific amino-acid residues in the Swi1 prion domain in prion formation and maintenance.
Atrioventricular node (AVN) ablation is a strategy to manage patients with drugrefractory atrial fibrillation (AF) and heart failure in whom cardiac resynchronization therapy (CRT) device implantation has been prescribed. This study describes a practical method to perform these two procedures using the same surgical site. Twenty-seven patients were indicated for AVN ablation and concurrent CRT device implantation while presenting with AF and rapid ventricular response (RVR) refractory to medical therapy. After placement of the right and left ventricular leads, a third puncture was made in the axillary vein to obtain access to perform the ablation. After hand-injecting contrast media through a RAMP™ (Abbott Laboratories, Chicago, IL, USA) sheath positioned in the right atrial cavity, the anatomical area corresponding to the AVN was identified using fluoroscopy cine runs obtained in the right anterior oblique and left anterior oblique projections. The adequate site for ablation was confirmed by the bipolar recording of a His-bundle deflection at the tip of the ablation catheter. Radiofrequency energy was delivered to achieve complete heart block. Subsequently, device implant was completed. The method was successfully applied in 27 consecutive cases, achieving permanent complete heart block in all patients. The mean radiofrequency time to achieve heart block was 110 seconds ± 43 seconds. The average procedural time including AVN ablation and device implant was 87 minutes ± 21 minutes. The images obtained with the hand-injected contrast media provided adequate information to readily identify the anatomical area corresponding to the AVN with 100% accuracy. This study suggests that ablation of the AVN can be safely and effectively accomplished via a superior approach in patients undergoing a CRT device implant.
Background: The prevalence of major coronal and sagittal spinal curves (scoliosis and kyphosis) in Turner syndrome (TS) is not well established due to limited reporting. The relationship between growth hormone (GH) therapy and its effect on TS spinal curve incidence is also not well established. Methods: A retrospective chart review of 306 TS patients from 2007 to 2021 evaluated major coronal and sagittal spinal curves, progression of the curve, and treatment with GH. Statistical significance (defined as P <0.05) between curvature rates and curve progression was compared between GH-treated patients and non–GH-treated patients using a χ2 or Fisher exact test when appropriate. Results: Thirty-seven of 306 (12%) TS patients had a radiographically relevant spinal deformity. Twenty-seven of 37 (73%) had mild; 4 of 37 (11%) had moderate, and 6 of 37 (16%) had severe curves. Of those with severe, 4 underwent spinal fusion, 1 was treated with bracing, and 1 was braced before a cardiovascular-related death. Regarding GH use among TS patients, 190 of 306 (62%) used GH versus 116 of 306 (38%) who did not. Of those with a spinal curve, 24 of 37 (65%) used GH compared with 13 of 37 (35%) who did not. On univariate analysis, GH therapy was not a risk factor for the diagnosis of a major spinal curve, a more severe degree of the curve at the time of diagnosis, or spinal curve progression (P >0.05 for all). Conclusions: This is the largest single institution retrospective review of a TS cohort known to the authors assessing spinal curve prevalence and relation to GH treatment and demonstrates a TS spinal curve rate of 12% (37/306). Four of six (11%) TS patients with a severe curve underwent corrective spine fusion. There was no relationship between the use of GH and the presence of a spinal curve or curve progression. Further study is warranted to determine risk factors for curve progression. Level of Evidence: Level III. Clinical Relevance: This retrospective case series serves to review and address the prevalence of spinal deformity in TS patients and whether GH impacts worsening deformity.
OBJECTIVE The aim of this study was to summarize the prognosis of recurrent infratentorial ependymomas based on treatment and molecular characterization. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors searched the PubMed, Scopus, Embase, and Ovid databases for studies on recurrent infratentorial ependymomas in patients younger than 25 years of age. Exclusion criteria included case series of fewer than 5 patients and studies that did not provide time-dependent survival data. RESULTS The authors’ database search yielded 482 unique articles, of which 18 were included in the final analysis. There were 479 recurrent infratentorial pediatric ependymomas reported; 53.4% were WHO grade II and 46.6% were WHO grade III tumors. The overall mortality for recurrent infratentorial pediatric ependymomas was 49.1% (226/460). The pooled mean survival was 30.2 months after recurrence (95% CI 22.4–38.0 months). Gross-total resection (GTR) was achieved in 243 (59.0%) patients at initial presentation. The mean survival postrecurrence for those who received initial GTR was 42.3 months (95% CI 35.7–47.6 months) versus 26.0 months (95% CI 9.6–44.6 months) for those who received subtotal resection (STR) (p = 0.032). There was no difference in the mean survival between patients who received GTR (49.3 months, 95% CI 32.3–66.3 months) versus those who received STR (41.4 months, 95% CI 11.6–71.2 months) for their recurrent tumor (p = 0.610). In the studies that included molecular classification data, there were 169 (83.3%) posterior fossa group A (PFA) tumors and 34 (16.7%) posterior fossa group B (PFB) tumors, with 28 tumors harboring a 1q gain. PFA tumors demonstrated worse mean postprogression patient survival (24.7 months, 95% CI 15.3–34.0 months) compared with PFB tumors (48.0 months, 95% CI 32.8–63.2 months) (p = 0.0073). The average postrecurrence survival for patients with 1q+ tumors was 14.7 months. CONCLUSIONS The overall mortality rate for recurrent infratentorial ependymomas was found to be 49.1%, with a pooled mean survival of 30.2 months in the included sample population. More than 80% of recurrent infratentorial ependymomas were of the PFA molecular subtype, and both PFA tumors and those with 1q gain demonstrated worse prognosis after recurrence.
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