Choice of autogenous conduit for lower extremity vein graft revisions

AbstractBackground: Surgical revision to repair stenosis is necessary in about 20% of lower extremity vein grafts (LEVGs). Alternate conduit, especially arm vein, is often necessary to achieve a policy of all-autogenous revisions. Although basilic vein harvest necessitates deep exposure in proximity to major nerves, it typically uses a large vein unaffected by prior intravenous lines and as such appears ideally suited for revisions in which a segmental interposition conduit is needed for revision within the graft or for extension to a more proximal inflow or distal outflow site. In this report, we describe our experience with the use of the basilic vein for LEVG revisions compared with other sources of autogenous conduit. Methods: All patients who underwent LEVG were placed in a duplex scan surveillance program. LEVGs that developed a focal area of increased velocity or uniformly low velocities throughout the graft with appropriate lesions confirmed with angiography were candidates for revision. All patients who underwent graft revision with basilic vein segments from January 1, 1990, to September 1, 2001, were identified, and their courses were reviewed for subsequent adverse events (further revision or occlusion) and complications of harvest. These revisions were compared with revisions in which cephalic and saphenous vein were used. Results: One hundred thirty basilic veins were used to revise 122 LEVGs. The mean follow-up period after revision was 28 ± 27 months. Ninety-three grafts (71%) remained patent with no further revision, and 37 grafts (29%) either needed additional revisions (22 grafts) or were occluded (15 grafts). Only four of these adverse events (11%) were directly attributed to the basilic vein segment. Ten of 43 grafts revised with cephalic vein (23%) were either revised or occluded, of which three were related to the cephalic vein segment (P = not significant, compared with basilic vein). Twenty-four of 81 grafts revised with saphenous vein (30%) were either revised or occluded, of which 11 were attributed to the saphenous vein segment (P < .01, compared with basilic vein). Two patients (1.5%) had complications from basilic vein harvest (one hematoma, one arterial injury). No neurologic injuries resulted from basilic vein harvest. Conclusion: The basilic vein is a reliable and durable conduit when used to segmentally revise LEVGs. Stenoses rarely occur within interposed basilic vein segments, and excellent freedom from subsequent revision or occlusion is possible. We conclude the basilic vein can be safely harvested with minimal complications and is ideally suited for use as a short segment interposition graft for LEVG revision. (J Vasc Surg 2002;36:238-44.

Comparison of axillofemoral and aortofemoral bypass for aortoiliac occlusive disease

AbstractPurpose: A comparison of aortofemoral bypass grafting (AOFBG) and axillofemoral bypass grafting (AXFBG) for occlusive disease performed by the same surgeons during a defined interval forms the basis for this report.Methods: Data regarding all patients who underwent AOFBG or AXFBG for lower-extremity ischemia caused by aortoiliac occlusive disease were prospectively entered into a computerized vascular registry. The decision to perform AOFBG rather than AXFBG was based on assessment of surgical risk and the surgeon's preference. This report describes results for surgical morbidity, mortality, patency, limb salvage, and patient survival for procedures performed from January 1988 through December 1993.Results: We performed 108 AXFBGs and 139 AOFBGs. AXFBG patients were older (mean age, 68 years compared with 58 years for AOFBG, p < 0.001), more often had heart disease (84% compared with 38%, p < 0.001), and more often underwent surgery for limb-salvage indications (80% compared with 42%, p < 0.001). No significant differences were found in operative mortality (AXFBG, 3.4%; AOFBG, <1.0%, p = NS), but major postoperative complications occurred more frequently after AOFBG (AXFBG, 9.2%; AOFBG, 19.4%; p < 0.05). Follow-up ranged from 1 to 83 months (mean, 27 months). Five-year life-table primary patency, limb salvage, and survival rates were 74%, 89%, and 45% for AXFBG and 80%, 79%, and 72% for AOFBG, respectively. Although the patient survival rate was statistically lower with AXFBG, primary patency and limb salvage rates did not differ when compared with AOFBG.Conclusion: When reserved for high-risk patients with limited life expectancy, the patency and limb salvage results of AXFBG are equivalent to those of AOFBG. (J VASC SURG 1996;23:263-71.

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per genome. The mean of APOBEC mutations in viral genomes was one (range 0–5). Viral APOBEC mutations, compared to non-APOBEC mutations, were more likely to be low-variant allele fraction mutations, suggesting that APOBEC mutagenesis actively occurrs in viral genomes during infection. HPV16 APOBEC-induced mutation patterns in OPSCC were similar to those previously observed in cervical samples. Paired host and viral analyses revealed that APOBEC-enriched tumor samples had higher viral APOBEC mutation rates (p = 0.028), and APOBEC-associated RNA editing (p = 0.008), supporting the concept that APOBEC mutagenesis in host and viral genomes is directly linked and occurrs during infection. Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial

Design and Rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short-term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double blind, placebo controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co., Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation

Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.</p> <p>Methods</p> <p>We examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies.</p> <p>Results</p> <p>We observed evidence of association for four SNPs in low to high linkage disequilibrium (r²ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, P_trend= 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10^-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage.</p> <p>Conclusions</p> <p>Our study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.</p