The eradication of HIV-1 will likely require novel clinical approaches to purge the reservoir of latently infected cells from a patient. We hypothesize that this therapy should target a wide range of latent integration sites, act effectively against viral variants that have acquired mutations in their promoter regions, and function across multiple HIV-1 subtypes. By using primary CD4؉ and Jurkat cell-based in vitro HIV-1 latency models, we observe that single-agent latency reactivation therapy is ineffective against most HIV-1 subtypes. However, we demonstrate that the combination of two clinically promising drugs-namely, prostratin and suberoylanilide hydroxamic acid (SAHA)-overcomes the limitations of single-agent approaches and can act synergistically for many HIV-1 subtypes, including A, B, C, D, and F. Finally, by identifying the proviral integration position of latent Jurkat cell clones, we demonstrate that this drug combination does not significantly enhance the expression of endogenous genes nearest to the proviral integration site, indicating that its effects may be selective.HIV-1 postintegration latency poses the greatest barrier to complete eradication of the virus from a patient (25). Latent infections have low or no transcriptional activity and fail to generate viral progeny, rendering them untreatable with current antiretroviral treatments that target only actively replicating virus (78). Moreover, latent infections, which persist in resting memory CD4 ϩ T cells with a half-life of up to 44 months (79), provide a permanent reservoir for reactivation and reseeding of the replicating virus (83). Therapeutic reactivation of latent infections, combined with antiretroviral treatments, may accelerate the depletion of latent reservoirs (reviewed in reference 29). However, such latency reactivation strategies have yielded variable results in recent clinical trials (49,80,82), underscoring the difficulties associated with purging latent infections. Therefore, the complexities of latency warrant the further development of in vitro analytical and screening assays that can model the conditions of latency and test potential therapies (9).After viral entry and integration of the viral genome into the host chromosome, the HIV 5Ј long terminal repeat (5Ј LTR) promoter recruits RNA polymerase II (RNAPII) and other host factors to regulate viral gene expression. Initially, low basal transcription generates primarily abortive transcriptsdue to the stalling of RNAPII-and a small fraction of fully elongated viral transcript that is initially spliced to generate mRNA encoding a positive regulator, the transcriptional activator (Tat) (47). Tat protein interacts with cellular positive transcriptional elongation factor B (P-TEFb) (99), and the resulting Tat-P-TEFb complex binds to the trans-activation response (TAR) element at the 5Ј end of nascent viral transcripts (3). Here, P-TEFb phosphorylates the C-terminal domain (CTD) of stalled RNAPII to enhance the efficiency of elongation (98). This Tat-mediated transactivation...
Implant coatings can be customized with single or double antibiotic coatings to effectively fight different bacteria and also mixed infections in the treatment of a combat-acquired osteomyelitis. However, optimal drug load and degradation behaviour of individual antibiotics have to be considered.
Introduction: Achieving adequate acetabular correction in multiple planes is essential to the success of periacetabular osteotomy (PAO). Three-dimensional (3D) modeling and printing has the potential to improve preoperative planning by accurately guiding intraoperative correction. The authors therefore asked the following questions: (1) For a patient undergoing a PAO, does use of 3D modeling with intraoperative 3D-printed models create a reproducible surgical plan to obtain predetermined parameters of correction including lateral center edge angle (LCEA), anterior center edge angle (ACEA), Tonnis angle, and femoral head extrusion index (FHEI)? and (2) Can 3D computer modeling accurately predict when a normalized FHEI can be achieved without the need for a concomitant femoral-sided osteotomy? Methods: A retrospective review was conducted on 42 consecutive patients that underwent a PAO. 3D modeling software was utilized to simulate a PAO in order to achieve normal LCEA, ACEA, Tonnis angle, and FHEI. If adequate FHEI was not achieved, a femoral osteotomy was simulated. 3D models were printed as intraoperative guides. Preoperative, simulated and postoperative radiographic ACEA, LCEA, Tonnis angle, and FHEI were measured and compared statistically. Results: A total of 40 patients had a traditional PAO, and 2 had an anteverting-PAO. The simulated LCEA, ACEA, Tonnis angle, and FHEI were within a median difference of 3 degrees, 1 degrees, 1 degrees, and 0% of postoperative values, respectively, and showed no statistical difference. Of those that had a traditional PAO, all 34 patients were correctly predicted to need a traditional acetabular-sided correction alone and the other 6 were correctly predicted to need a concomitant femoral osteotomy for a correct prediction in 100% of patients. Conclusion: This study demonstrates that for PAO surgery, 3D modeling and printing allow the surgeon to accurately create a reproducible surgical plan to obtain predetermined postoperative hip coverage parameters. This new technology has the potential to improve preoperative/intraoperative decision making for hip dysplasia and other complex disorders of the hip.
The ACEA can be reliably measured on sagittal CT and significantly differs from dysplastic hips. ACEA measurements above 66° or below 34° may represent anterior over and under coverage.
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