Induction of atrial fibrillation after the routine use of adenosine

We report a case of atrial fibrillation induction after the use of adenosine for the termination of supraventricular tachycardia in the emergency department. Atrial fibrillation is not an uncommon side effect of adenosine administration. Hemodynamic collapse may occur if an antegrade-conducting accessory pathway allows for a rapid ventricular response. Therefore, we would recommend that the use of adenosine be limited to situations in which there is appropriate electrocardiographic monitoring and emergency resuscitative capabilities.     

Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.Expression of several bacterial and eukaryotic genes is controlled by nascent peptide-dependent programmed translation arrest. In the general scenario, ribosome stalling at an upstream regulatory ORF (uORF) triggers isomerization of the mRNA structure, leading to activation of expression of downstream cistron(s). Translation arrest ensues when a distinctive amino acid sequence (the “stalling domain”) of the growing chain assembled in the ribosomal peptidyl transferase center (PTC) is placed in the nascent peptide exit tunnel (NPET). Ribosome stalling may require additional signals, thereby making this gene control mechanism sensitive to the physiological state of the cell or to the chemical composition of the environment. Often the external signal is a small molecule whose binding to the ribosome renders translation responsive to specific nascent peptides (reviewed in refs. 1, 2). In most of the examined cases of cofactor- and nascent peptide-dependent translation arrest, the binding site of the cofactor in the ribosome is unknown, which hampers understanding of the interplay among the cofactor, the nascent peptide, and the ribosome. The exception is the inducible antibiotic resistance, in which ribosome stalling and gene activation rely on binding of an antibiotic to a well-defined site in the ribosome.Expression of macrolide resistance genes is triggered by drug-induced ribosome stalling at a defined codon of the uORF (3–5). Macrolides, from the prototype erythromycin (ERY) to the newest macrolide derivatives—ketolides, e.g., solithromycin (SOL)—bind in the NPET at a short distance from the PTC (6–9) (Fig. 1A). When a nascent peptide grows to 4–7 aa, it reaches the site of antibiotic binding and has to negotiate the drug-obstructed NPET aperture. Subsequent events depend on the properties of the nascent chain (3, 10, 11). Although for many proteins the encounter of the peptide with the antibiotic results in peptidyl–tRNA dropoff, the N-termini of certain nascent peptides can bypass the antibiotic. Translation of some of such proteins can be arrested at specific sites within the gene, resulting in formation of a stable stalled complex (11). Such translation arrest defines the role of macrolides as cofactors of programmed ribosome stalling (3, 10–12).Open in a separate windowFig. 1.Antibiotic and nascent peptide in the ribosomal exit tunnel. (A) The relative locations of the macrolide binding site in the NPET and the PTC active site were rendered by aligning crystallographic structures of Thermus thermophilus 70S ribosome complexed with aminoacylated donor and acceptor tRNA substrates [Protein Data Bank (PDB) ID codes 2WDK, 2WDL (25)] and the vacant ribosome complexed with ERY [PDB ID codes 3OHC, 3OHJ (9)]. The PTC active site, defined as the middistance between the attacking amino group of the acceptor substrate and the carbonyl carbon atom of the donor, is marked by an asterisk. (B) The modeled position of the 9-aa–long ErmCL nascent peptide in the ribosomal tunnel obstructed by ERY (19). In the stalled complex, ErmCL is juxtaposed with the antibiotic in the tunnel.The regulatory leader peptides of macrolide resistance genes have been classified by the structure of their known or presumed stalling domains (4, 5). Translation of ErmAL1 and ErmCL peptides is arrested after the ribosome has polymerized the 8-aa (ErmAL1) or 9-aa (ErmCL) long nascent chains that carry the C-terminal stalling domains Ile-Ala-Val-Val (IAVV) and Ile-Phe-Val-Ile (IFVI), respectively (12–14). The drug-bound ribosome stalls because it cannot catalyze transfer of the peptide from the P-site peptidyl–tRNA to the A-site aminoacyl–tRNA (12, 14). Importantly, although the N-terminal sequences of these peptides are not critical, the N-terminal segments are required for translation arrest (12). The conservation of the distance of the stalling domain from the N-terminus among peptides of these classes (4) corroborates the importance of the nascent chain length for the arrest. The 8–9-aa long ErmAL1 or ErmCL stalling peptides reach far into the NPET and must be juxtaposed with the antibiotic molecule in the NPET; such apposition has been suggested to play a key role in the mechanism of arrest (12) (Fig. 1B). This view agrees with the strict structural requirements of the macrolide cofactor in which removal or modification of the C3 cladinose abolishes stalling, possibly by disrupting drug–peptide interactions (15).The resistance leader peptides of the third major class have been studied to a much lesser extent (16–18). These peptides were grouped together based on the presence of the Arg-Leu-Arg (RLR) motif in their sequence (4) (Table S1), although the role of this motif in programmed arrest has not been verified. Intriguingly, in striking contrast to the IAVV and IFVI classes, the placement of the RLR motif within these peptides is highly variable (4).By analyzing translation arrest controlled by the RLR peptides, we discovered that the N-terminus is dispensable and macrolide antibiotic can block peptide bond formation and halt translation when the nascent chain is only 3-aa long and barely reaches the antibiotic in the NPET. Structural probing and molecular dynamics (MD) modeling showed the existence of an allosteric link between the NPET and the PTC, illuminating how binding of an antibiotic in the NPET predisposes the ribosome for stalling when translating specific amino acid sequences.     

Prospective assessment after pediatric cardiac ablation: recurrence at 1 year after initially successful ablation of supraventricular tachycardia

OBJECTIVES: A multicenter prospective study was performed to assess the results and risks associated with radiofrequency ablation in children. This report focuses on recurrences following initially successful ablation. METHODS: Patients recruited for the study were aged 0 to 16 years and had supraventricular tachycardia due to accessory pathways or atrioventricular nodal reentrant tachycardia (AVNRT), excluding patients with more than trivial congenital heart disease. A total of 481 patients were recruited into the prospective cohort and were followed at 2, 6, and 12 months following ablation. RESULTS: There were 517 successfully ablated substrates out of 540 attempted (95.7%). Loss to follow-up for individual substrates was 3.3%, 10.6%, and 21.2% at 2, 6, and 12 months, respectively. Recurrence was observed in 7.0%, 9.2%, and 10.7% of these substrates at 2, 6, and 12 months, respectively (adjusted for loss to follow-up as an independent source of data censoring). Recurrence rate varied by substrate location (24.6% for right septal, 15.8% for right free wall, 9.3% for left free wall, and 4.8% for left septal), as well as for AVNRT versus all others (4.8% vs 12.9%) at 12 months. The recurrence rate was higher for substrates ablated using power control but was not a function of whether isoproterenol was used for postablation testing. CONCLUSIONS: Recurrence after initially successful ablation occurs commonly in children. It is least common after AVNRT ablation and most common following ablation of right-sided pathways. These results serve as a benchmark for the time course of recurrence following initially successful ablation of supraventricular tachycardia in children.     

Factor analysis of repetitive behaviors in Autism as measured by the Y-BOCS

The authors carried out a factor analysis of the Yale-Brown Obsessive-Compulsive Scale checklist at the category level in order to reduce the number of variables in this domain and ultimately identify possible endophenotypes; 181 children with autism were enrolled. The authors estimated a tetrachoric correlation matrix among the dichotomous symptom categories and then used exploratory and confirmatory factor analyses to identify a clinically meaningful factor structure for this correlation matrix. Their analysis supported a four-factor solution: obsessions, higher-order repetitive behaviors, lower-order repetitive behaviors, and hoarding. These findings are another step in the effort to identify genetically and biologically distinct groups within this population.