Citations

ABSTRACT Recombinant human adenovirus is a useful gene delivery vector for clinical gene therapy. Minor capsid protein IX of adenovirus has been of recent interest since multiple studies have shown that modifications can be made to its C terminus to alter viral tropism or add molecular tags and/or reporter proteins. We examined the structure of an engineered adenovirus displaying the enhanced green fluorescent protein (EGFP) fused to the C terminus of protein IX. Cryoelectron microscopy and reconstruction localized the C-terminal EGFP fusion between the H2 hexon and the H4 hexon, positioned between adjacent facets, directly above the density previously assigned as protein IIIa. The original assignment of IIIa was based largely on indirect evidence, and the data presented herein support the reassignment of the IIIa density as protein IX.

Multiple endocrine neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.

Background and Purpose— Development of stroke networks is critical to bringing guideline-driven stroke care to rural, underserved areas. Methods— A Web-based telestroke tool, REACH, was developed to provide a foundation for a rural stroke network that delivered acute stroke consults 24 hours per day 7 days per week to 8 rural community hospitals in Georgia. Results— There were 194 acute stroke consults delivered. Thirty patients were treated with tissue plasminogen activator (tPA). The mean National Institutes of Health Stroke Score (NIHSS) was 15.4, and the median NIHSS was 12.5. The mean onset to treatment time (OTT) was 122 minutes. The OTT dropped from 143 minutes in the first 10 patients treated to 111 minutes in last 20 patients. Of the 30 patients treated with tPA, 23% (7) were treated in ≤90 minutes and 60% (18) were treated within 2 hours. There were no symptomatic intracerebral hemorrhages. Conclusions— The REACH telestroke system permits the rapid and safe use of tPA in rural community hospitals. Over time, the system became more efficient and OTT decreased.

Background— Although segmental or circumferential ablation is effective in eliminating pulmonary vein (PV)–mediated atrial fibrillation (AF), this procedure may be complicated by the occurrence of PV stenosis. Methods and Results— To establish the clinical presentation, diagnostic manifestations, and interventional management of PV stenosis, 23 patients with stenosis of 34 veins complicating ablation of AF were evaluated. Each patient became symptomatic 103±100 days after undergoing ablation. In 8 veins, the ablation producing the PV stenosis was a repeated procedure for continued AF. Nineteen patients presented with dyspnea on exertion, 7 with dyspnea at rest, 9 with cough, and 6 with chest pain. On multirow spiral computed tomography examination, the narrowest lumen of the affected PVs measured 3±2 mm compared with 13±3 mm at baseline ( P ≤0.001). The relative perfusion of affected lung segments on isotope scans was reduced to 4±3% of total perfusion compared with 22±10% in unaffected segments. At percutaneous intervention, these veins showed 80±13% stenosis, with a mean gradient of 12±5 mm Hg. This was significantly reduced to a residual stenosis of 9±8% ( P ≤0.001) and a residual gradient of 3±4 mm Hg ( P ≤0.001). Twenty veins were treated with balloon dilatation alone, whereas 14 veins were stented with standard 10-mm-diameter bare-metal stents. Although the symptomatic response was nearly immediate and impressive, 14 patients developed in-stent or in-segment restenosis, requiring repeated interventions in 13. Conclusions— Percutaneous intervention produces rapid and dramatic symptom relief in patients with highly symptomatic PV stenosis after radiofrequency ablation for AF. Nevertheless, alternative treatment methods will be required to decrease recurrent in-stent or in-segment restenosis.

Background— Revascularization strategies often hinge on the presence and degree of left anterior descending coronary artery (LAD) stenosis. A decision for bypass surgery is often based on the durability of surgical LAD revascularization compared with percutaneous approaches. By decreasing restenosis, drug-eluting stents may have reduced the “reintervention gap” between surgery and percutaneous intervention, making the percutaneous route preferable. Methods and Results— Of the 1101 patients in the SIRIUS trial, 459 with an LAD stenosis were randomized to percutaneous intervention with either sirolimus-eluting or bare-metal stents. Baseline demographic, clinical, and angiographic data were obtained. Patients had 1-year clinical and 8-month angiographic follow-up. Baseline characteristics were similar in both groups. The majority of lesions were tubular type B lesions (69.7%) with a mean diameter of 2.73 mm and a mean length of 14.0 mm. The binary in-stent restenosis rate was 2% for the sirolimus stent group and 41.6% for the bare-metal arm (relative risk, 0.05; 95% CI, 0.02 to 0.1; P <0.001). One-year major adverse events (defined as cardiac death, Q-wave and non–Q-wave myocardial infarction, or target vessel revascularization) was decreased 59% in the sirolimus-stent group (9.8% versus 24.9%; relative risk, 0.39; 95% CI, 0.26 to 0.61; P <0.001). Subgroup analysis of 135 patients with proximal LAD lesions showed similar benefits. In-stent restenosis was 0 in the proximal LAD sirolimus-eluting group (n=67), compared with 38% in the bare-metal arm (n=68), and major adverse events demonstrated a similar trend, with a 50% decrease compared with control patients (10.4% versus 20.6%, P =NS). Conclusions— Sirolimus-eluting stents significantly decrease revascularization rates in LAD lesions. At 1 year, sirolimus-eluting stent revascularization rates are comparable to historic single vessel bypass surgery revascularization rates.