Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens

Background: Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy. Methods: A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddl plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA ≤ 400 copies/mL after ≥ 16 weeks of treatment with lamivudine /zidovudine or lamivudine/stavudine, plus 1 or 2 Pls. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24). Results: Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (<400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; <50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed. Conclusion: ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events

St Jude Medical Epic porcine bioprosthesis: Results of the regulatory evaluation

BackgroundThe St Jude Medical Epic heart valve (St Jude Medical, Inc, St Paul, Minn) is a tricomposite glutaraldehyde-preserved porcine bioprosthesis. The St Jude Medical Biocor porcine bioprosthesis is the precursor valve to the St Jude Medical Epic valve. The Epic valve is identical to the Biocor valve except that it is treated with Linx AC ethanol-based calcium mitigation therapy.MethodsThe St Jude Medical Epic valve was implanted in 761 patients (mean age 73.9 ± 9.2 years) between 2003 and 2006 in the US Food and Drug Administration regulatory study in 22 investigational centers. The position distribution was 557 aortic valve replacements, 175 mitral valve replacements, and 29 double valve replacements. Concomitant coronary artery bypass grafting was performed in 50.8% of patients undergoing aortic valve replacement and 36.6% of those undergoing mitral valve replacement.ResultsThe early mortality was 3.6% in aortic and 2.3% in mitral valve replacement. The follow-up was 1675.5 patient-years with a mean of 2.2 ± 1.2 years/patient. Late mortality was 5.2%/patient-year in aortic and 6.6%/patient-year in mitral valve replacement. The late major thromboembolism rate was 0.98%/patient-year for aortic and 2.6%/patient-year for mitral valve replacement. There were 19 reoperations, including 2 for structural valve deterioration, 1 for thrombosis, 9 for nonstructural dysfunction, and 7 for prosthetic valve endocarditis. The actuarial freedom from reoperation owing to structural valve deterioration for aortic valve replacement at 4 years for age 60 years or less was 93.3% ± 6.4%; for ages 61 to 70 years, 98.1% ± 1.9%; and for older than 70 years, 100% (P = .0006 > 70 vs ≤ 60 years). There were no events of structural deterioration with mitral valve replacement. The actuarial freedom from major thromboembolism for all patients at 4 years was 93.6% ± 1.0%. The 2 cases of structural valve deterioration occurred in aortic valves that became perforated without calcification causing aortic regurgitation.ConclusionsThe performance of the St Jude Medical Epic porcine bioprosthesis is satisfactory at 4 years for both aortic and mitral valve replacement. This study establishes the early clinical performance including durability of this porcine bioprosthesis

Ignition target fabrication and fielding for the national ignition facility

Continued advances in the design of ignition targets have stimulating new development paths for target fabrication, with potentially important simplifications for fielding cryogenic ignition targets for the National Ignition Facility. Including graded dopants in ablators as well as optimizing capsule and fuel layer dimensions increase implosion stability. This has led to developments of micron-scale fill tubes to fill and field the targets. Rapid progress has been made in development of the graded dopant layers in capsules as well as their characterization, in fabrication methods for micro-fill-tubes, and in fuel fill control with these fill tubes. Phase-contrast x-ray radiography has allowed characterization of fuel layers in beryllium targets. This target development program includes participation from General Atomics, Lawrence Livermore National Laboratory, and Los Alamos National Laboratory

Molecular Dissection of Cytokinesis by RNA Interference in Drosophila Cultured Cells

We have used double-stranded RNA-mediated interference (RNAi) to study Drosophila cytokinesis. We show that double-stranded RNAs for anillin, acGAP, pavarotti, rho1, pebble, spaghetti squash, syntaxin1A, and twinstar all disrupt cytokinesis in S2 tissue culture cells, causing gene-specific phenotypes. Our phenotypic analyses identify genes required for different aspects of cytokinesis, such as central spindle formation, actin accumulation at the cell equator, contractile ring assembly or disassembly, and membrane behavior. Moreover, the cytological phenotypes elicited by RNAi reveal simultaneous disruption of multiple aspects of cytokinesis. These phenotypes suggest interactions between central spindle microtubules, the actin-based contractile ring, and the plasma membrane, and lead us to propose that the central spindle and the contractile ring are interdependent structures. Finally, our results indicate that RNAi in S2 cells is a highly efficient method to detect cytokinetic genes, and predict that genome-wide studies using this method will permit identification of the majority of genes involved in Drosophila mitotic cytokinesis