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Background— A 2% to 5% background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. Methods and Results— Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A -encoded Na v 1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3–S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs. Conclusions— We have used a large case/control study to identify regions of Na v 1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant’s pathogenic status.

Preclinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss: (1) the various techniques used to create the aneurysm, (2) complications of aneurysm creation, (3) natural history of the arterial aneurysm, (4) histopathologic and hemodynamic features of the aneurysm, (5) devices tested using this model, and (6) weaknesses of the model. We demonstrate how preclinical studies using this model are applied in the treatment of intracranial aneurysms in humans. The model has similar hemodynamic, morphological, and histologic characteristics to human aneurysms, and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths, however, the model does have many weaknesses, including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore, the extracranial location of the model affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms, but further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms.

Calcilytics reduce airway hyperresponsiveness and inflammation and may represent effective asthma therapeutics.

Transoral laser microsurgery (TLM) is an alternative surgical technique for piecemeal endoscopic resection of mucosal-based aerodigestive tract tumors. Though uncommon, potentially catastrophic postoperative bleeding may occur with this technique secondary to vascular injury along invasive tumor inner margins. We describe our preliminary results using a preoperative dual-acquisition extracranial computed tomographic angiography (CTA)-enhanced neck computed tomographic (CT) imaging and postprocessing protocol developed to improve visualization of mucosal-based head and neck tumors and adjacent arterial branches with the objective of facilitating TLM surgery and reducing secondary bleeding complications. Twenty patients with known head and neck cancers anticipated for TLM resection were selected for a dual-acquisition CTA-CT scanning and postprocessing protocol. The mucosal-based pharyngeal tumors and peritumoral vessel enhancement were compared on matched CTA and enhanced neck CT axial images. Operative reports and clinical notes were retrospectively reviewed to identify patients in whom the TLM surgical approach was altered or changed to conventional open surgery as a result of presurgical CTA-CT findings. Enhancement of peritumoral vasculature was almost uniformly superior (19 of 20 patients) on extracranial CTA compared with enhanced neck CT images. In six candidates for TLM surgery (30%), CTA findings resulted in a change in surgical approach to improve intraoperative peritumoral vascular control. In this small pilot series, primary tumor-peritumoral vessel relationships delineated by the addition of extracranial CTA to preoperative enhanced neck CT frequently impacted the surgical approach and facilitated TLM planning.

FiberNet® is a second generation non-conventional embolization protection device (EPD) that purports to offer several advantages: ability to capture debris as small as 40 μm, more flexibility with placement and positioning in curved segments requiring a small landing zone, ability to conform to asymmetric vessels, and improved deliverability. The design features a low profile with large surface area to capture debris. Legitimate concerns include inducement of obstruction or low flow with debris capture and requirements in the IFU to aspirate during re-capture and device removal. Our goal was to compare the results of carotid artery stenting (CAS) using FiberNet® against a multi-center experience of CAS using other filter devices to identify any differences in technical success or event rates. FiberNet® (n=25) results were compared to all CAS cases performed at the Mayo Clinic in Rochester, MN, St Mary's/Duluth Clinic in MN, and North Central Heart Institute in Sioux Falls, SD (n=250) from March 2001 to December 2008. Chi-square or means were used to compare variables, as appropriate. Bivariate logistic regression was used to identify possible correlates of adverse outcome. Statistical significance was set at < 0.05. FiberNet® patients were more likely to be older (78.1+5.4 vs 73.6+9.4, p=0.019), female (48% vs 29%, p=0.047), and have peripheral vascular disease (84.0% vs 37.2%, p=0.025), and less likely to have diabetes (8.0% vs 29.8%, p=0.012) than patients in the comparison group. FiberNet® patients had more lesion calcification (40.0% vs 18.9%, p=0.014) and increased number of type 2 and 3 arches (44.2% vs 73.9%, p=0.006). Procedural success rate was 100% in both groups. None of the FiberNet® patients showed evidence of stagnant flow. The thirty-day outcome for TIA, CVA, or death was 4% in FiberNet® versus 4.8% in the comparison group (p NS). None of the independent variables – age gender, serum creatinine, arch complexity, lesion length, lesion calcium, lesion thrombus, PVD, diabetes, contralateral carotid occlusion, or ipsilateral carotid endarterectomy – predicted adverse events. Although FiberNet® patients had more lesion calcium and more challenging arch anatomy, procedural success and adverse events were comparable between groups. The advantages of FiberNet® can be applied to CAS with good technical results and may be a promising EPD for certain high-risk situations.

Unruptured intracranial aneurysms (UIAs) are a major public health issue. These lesions have become increasingly recognized in recent years with the advent of advanced cerebral imaging techniques. Epidemiological evidence from multiple sources suggests that most intracranial aneurysms do not rupture. Therefore, it is desirable to identify which UIAs are at greatest risk of rupture when considering which to repair. It is important to compare size-, site-, and group-specific natural history rates with size-, site-, and age-specific morbidity and mortality associated with UIA repair because increased natural history risk often is associated with increased risk of aneurysm repair. Patient age is crucial in decision making because of its major effect on operative morbidity and mortality; however, it does not substantially affect natural history. The effect of age is most notable in patients about 50 years of age and older for open surgery and about 70 years of age and older for endovascular procedures. In general, rupture risk is lowest for patients in asymptomatic group 1 (no history of subarachnoid hemorrhage) with UIAs less than 7 mm in diameter in the anterior circulation. Surgical morbidity and mortality are most favorable for asymptomatic patients younger than 50 years who have UIAs less than 24 mm in diameter in the anterior circulation and no history of ischemic cerebrovascular disease. Endovascular morbidity and mortality may be less age dependent, and this could favor endovascular procedures, particularly in patients aged 50 to 70 years. An important issue is determining immediate vs long-term risk regarding treatment effectiveness and durability. This issue emphasizes the importance of long-term follow-up in patients after surgical and endovascular procedures.

This study compared a high resolution contrast-enhanced MR angiography (MRA) sequence to conventional contrast-enhanced MRA sequence for imaging of rabbit carotid artery. Fifteen rabbits underwent an evaluation using both high resolution contrast-enhanced MRA sequence and conventional contrast-enhanced MRA sequence. Siemens 1.5 Tesla Magnetom Vision system was utilized. The parameters of high resolution sequence were: TR/TE= 6.2/2.0 msec, flip angle 25°, matrix 130×512, pixel size 0.96×0.49 mm, partition thickness 1.58 mm, acquisition time 24 sec. The parameters of conventional sequence were: TR/TE=3.8/1.4 msec, flip angle 35°, matrix 110×256, pixel size 1.48×1.02 mm, partition thickness 2mm, acquisition time 10 sec. Maximum intensity projection (MIP) images were created. Both original single slices and MIP images were used for image quality evaluation. Contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), distinctness of artery edge, and venous contamination were analyzed for both techniques. Higher average CNR and SNR were obtained with high resolution contrast-enhanced MRA, compared to average CNR and SNR with conventional contrast-enhanced MRA. The differences were statistically significant (P<0.01). The artery edge with high resolution method was more distinct than conventional method. Jugular venous contamination was found in five of 15 cases with high resolution contrast-enhanced MRA and in four of 15 cases with conventional contrast-enhanced MRA. High resolution contrast-enhanced MRA has significant potential for high quality noninvasive vascular imaging. The image quality with high resolution contrast-enhanced MRA sequence is better than conventional contrast-enhanced MRA sequence.

We sought to obtain high resolution 3D contrast-enhanced MR angiograms of the carotid arteries, vertebral arteries and aortic arch with venous signal suppression utilizing novel timing techniques. A secondary purpose was to compare contrast-enhanced MR angiograms with 2D time-of-flight MR angiograms of the carotid arteries.