An αIIb mutation in patients with Glanzmann thrombasthenia located in the N‐terminus of blade 1 of the β‐propeller (Asn2Asp) disrupts a calcium binding site in blade 6

Summary. Background: Studies of Glanzmann thrombasthenia (GT)‐causing mutations has generated invaluable information on the formation and function of integrin αIIbβ₃. Objective: To characterize the mutation in four siblings of an Israeli Arab family affected by GT, and to analyze the relationships between the mutant protein structure and its function using artificial mutations. Methods and Results: Sequencing disclosed a new A97G transversion in the αIIb gene predicting Asn2Asp substitution at blade 1 of the β‐propeller. Alignment with other integrin α subunits revealed that Asn2 is highly conserved. No surface expression of αIIbβ₃ was found in patients’ platelets and baby hamster kidney (BHK) cells transfected with mutated αIIb and WT β₃. Although the αIIbβ₃ was formed, the mutation impaired its intracellular trafficking. Molecular dynamics simulations and modeling of the αIIbβ₃ crystal indicated that the Asn2Asp mutation disrupts a hydrogen bond between Asn2 and Leu366 of a calcium binding domain in blade 6, thereby impairing calcium binding that is essential for intracellular trafficking of αIIbβ₃. Substitution of Asn2 to uncharged Ala or Gln partially decreased αIIbβ₃ surface expression, while substitution by negatively or positively charged residues completely abolished surface expression. Unlike αIIbβ₃, αVβ₃ harboring the Asn2Asp mutation was surface expressed by transfected BHK cells, which is consistent with the known lower sensitivity of αVβ₃ to calcium chelation compared with αIIbβ₃. Conclusion: The new GT causing mutation highlights the importance of calcium binding domains in the β‐propeller for intracellular trafficking of αIIbβ₃. The mechanism by which the mutation exerts its deleterious effect was elucidated by molecular dynamics.     

The Relationship Between Electrogram Cycle Length and Dominant Frequency in Patients with Persistent Atrial Fibrillation

Introduction: Sites of complex fractionated atrial electrograms (CFAE) with a short mean cycle length (MCL) and sites with a high dominant frequency (DF) have been advocated as targets for ablation in patients with persistent atrial fibrillation (AF). However, there are little data on the relationship between theses 2 markers. This study assessed the relationship between the DF and electrogram MCL after pulmonary vein (PV) isolation in patients with persistent AF. Methods and Results: A total of 44 patients with persistent AF were studied. Four‐second bipolar electrograms were obtained with a multielectrode mapping catheter at regions throughout the left atrium after isolation of the pulmonary veins, with analysis of the MCL and DF at each site. The DF was defined as the largest frequency peak within a 2.5‐ to 16‐Hz spectral profile generated with fast Fourier transformation of the electrogram. A total of 9,262 electrograms from the 44 patients were analyzed. The average MCL and DF post‐PV isolation were 135 ± 24 ms and 6.1 ± 0.6 Hz, respectively. There was a statistically significant but weak correlation between the MCL and DF (r = 0.21, P < 0.001). Additionally, analysis of this relationship within each patient did not demonstrate a strong correlation (range of r values per patient =?0.18 to 0.47). Conclusions: There is a poor correlation between the electrogram MCL and DF in patients with persistent AF. Ablation strategies targeting DF and those targeting CFAE are therefore unlikely to direct ablation toward similar left atrial sites. Comparative studies are necessary to determine the effectiveness of each strategy in guiding catheter ablation of persistent AF.     

Initial Experience With a Multielectrode Catheter Equipped With the Single‐Axis Sensor Technology for High‐Density Electroanatomical Mapping in a Swine Model

Utility of Single‐Axis Sensor Technology in High‐Density Electroanatomical Mapping. Introduction: Magnetic‐based electroanatomical mapping systems are widely used during catheter ablation. Currently, the size of the sensor incorporated in the catheter to allow its localization is large, prohibiting the placement of more than one sensor on any single catheter. As a result, multielectrode catheters cannot be tracked by the magnetic‐based mapping systems. Single‐axis sensors (SAS) are new generation sensors that are significantly smaller in size. The small size of these new sensors allows the placement of more than one sensor on each catheter, allowing the tracking of multielectrode catheters. The objective of this study is to test the feasibility of creating high‐density magnetic electroanatomical maps using a new generation multielectrode catheter equipped with the SAS technology. Methods and Results: Anatomical reconstruction of cardiac chambers and the aorta, together with activation mapping of the right atrium during both sinus rhythm and pacing‐induced premature atrial contractions (PACs), were performed in 5 swine using both a conventional mapping catheter and the novel multielectrode catheter equipped with SAS. The multielectrode mapping provided a detailed definition of cardiac anatomy while requiring shorter acquisition times. In addition, mapping of PACs origin was significantly faster using the multielectrode catheter. Conclusion: The novel multielectrode catheter equipped with the SAS technology can be used in combination with magnetic electroanatomical mapping systems to generate high‐density anatomical reconstructions and activation maps. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1403‐1407, December 2010)     

Oligomeganephronia with Covered Anus in Twins

Binovular male twins are described, one of whom was brought to attention at birth because of a covered anus and the other at age 6 weeks because of vomiting, dehydration and failure to thrive. He was found to have a partially covered anus.
Investigation revealed the presence of bilateral renal hypoplasia with oligomeganephronia in twin II, whilst twin I had normal renal function and normal renal histology.
The only previous report of this condition occurring in twins was in monozygotic twins where again only one was affected.
The relationship to covered anus is obscure and may be fortuitous.
The condition is believed to be an acquired developmental defect.