Single- and Double-Loaded All-Suture Anchor Repairs of Anteroinferior Labral Tears Are Biomechanically Similar in a Cadaveric Shoulder Model.

Purpose: To compare the biomechanical strength of single- versus double-loaded all-suture constructs in an anteroinferior glenoid labral repair. Methods: Anteroinferior labral lesions were created on 6 matched pairs of cadaveric shoulder specimens. Each shoulder in a matched pair was randomized to either receive capsulolabral repair with 3 single-loaded all-suture anchors or 3 double-loaded all-suture anchors. Immediately following capsulolabral repair, the specimens underwent mechanical testing, which included cyclic testing (5 N to 50 N for 500 cycles) and load-to-failure testing (rate of 15 mm/min). The gap formation between the repaired labrum and glenoid (measured at 1, 25, 100, and 500 cycles), the load at 2-mm gap formation, the maximum load at failure and the method of failure were recorded. Data were analyzed with paired Student t tests and Bonferroni correction factor. Results: The single and double all-suture constructs did not differ significantly in gap formation at any number of cycles, load to 2-mm gap formation (P = .75), or maximum load to failure (P = .46) between the 2 groups. Conclusions: In this study, single-loaded and double-loaded all-suture anchor constructs demonstrated comparable biomechanical performance and did not significantly differ in gap formation, load to 2-mm gap formation, or maximum load to failure when used in the capsulolabral repair of anteroinferior glenoid labral tears in human cadaveric specimens. Clinical Relevance: Although studies have evaluated the biomechanical properties of various arthroscopic labral stabilization techniques, the biomechanical properties of all-suture anchors with regard to labral stabilization are not well understood.

Metal-on-metal total hip arthroplasty adverse local tissue reaction with intermittent unilateral vascular claudication.

Osteolysis and adverse local soft-tissue reactions are well-documented complications of metal-on-metal prosthetic implants. This case report describes a 68-year-old man who presented to the clinic 10 years after staged bilateral metal-on-metal total hip arthroplasty revisions with the primary complaint of groin pain, intermittent right leg pain, swelling, and muscle cramping while ambulating that resolved with rest. A complete workup was negative for deep venous thrombosis and infection. His symptoms were found to be secondary to an iliopsoas bursal mass externally compressing the femoral vasculature resulting in vascular claudication. He was treated with revision arthroplasty and drainage of the fluid within the iliopsoas bursal effusion with symptomatic resolution.

Historical Patterns and Variation in Treatment of Injuries in NFL (National Football League) Players and NCAA (National Collegiate Athletic Association) Division I Football Players.

We conducted a study to identify and contrast patterns in the treatment of common injuries that occur in National Football League (NFL) players and National Collegiate Athletic Association (NCAA) Division I football players. Orthopedic team physicians for all 32 NFL and 119 NCAA Division I football teams were asked to complete a survey regarding demographics and preferred treatment of a variety of injuries encountered in football players. Responses were received from 31 (97%) of the 32 NFL and 111 (93%) of the 119 NCAA team physicians. Although patellar tendon autograft was the preferred graft choice for both groups of team physicians, the percentage of NCAA physicians who allowed return to football 6 months or less after anterior cruciate ligament reconstruction was significantly (P = .03) higher than that of NFL physicians. Prophylactic knee bracing, which may prevent medial collateral ligament injuries, was used at a significantly (P < .0001) higher rate by NCAA teams (89%) than by NFL teams (28%). Ketorolac injections were given by a significantly (P < .01) higher percentage of NFL teams (93%) than of NCAA teams (62%). Understanding the current trends in the management of these injuries is beneficial in designing studies that may help improve the treatment and prevention of injuries in football players.

Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase.

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

A biomechanical comparison of anterior cruciate ligament suspensory fixation devices in a porcine cadaver model.

BACKGROUND: Suspensory fixation use during anterior cruciate ligament reconstruction has increased due to ease of use and high pullout strength. We hypothesize that there are no significant differences in biomechanical performance among four types of suspensory fixation devices: Stryker VersiTomic G-Lok, Smith & Nephew Endobutton, Biomet ToggleLoc, and Arthrex RetroButton. METHODS: Forty fresh frozen porcine femurs and flexor digitorum profundus tendons were obtained. Each tendon graft was sized to 8.5mm or 9.0mm. Ten of each device were used to fix the grafts in the femur at the 2 o'clock (left) or 10 o'clock (right) position. The graft-femur complex was secured to a servohydraulic test machine in line with the femoral tunnel. The graft was cyclically loaded from 50 to 250 N for 1000 cycles at 1 Hz then loaded to failure at 20mm/min. Actuator load and displacement were recorded. Data were analyzed with multiple one-way ANOVA and Tukey HSD post-hoc tests. Bonferroni correction was applied resulting in P ≤ 0.005 considered statistically significant for ANOVA, P ≤ 0.05 for Tukey. FINDINGS: There were no significant differences in cyclic displacement among any of the groups (P=0.43). The only significant difference in failure properties is the Endobutton exhibited at least 50% greater displacement at failure than the other three devices. INTERPRETATION: Suspensory femoral soft tissue fixation devices are biomechanically similar with respect to failure load but differ in failure displacement. However, there was no significant difference in displacement after cyclic loading. All four fixation devices should withstand the forces associated with daily activities without failure.

flowCore: a Bioconductor package for high throughput flow cytometry.

BACKGROUND: Recent advances in automation technologies have enabled the use of flow cytometry for high throughput screening, generating large complex data sets often in clinical trials or drug discovery settings. However, data management and data analysis methods have not advanced sufficiently far from the initial small-scale studies to support modeling in the presence of multiple covariates. RESULTS: We developed a set of flexible open source computational tools in the R package flowCore to facilitate the analysis of these complex data. A key component of which is having suitable data structures that support the application of similar operations to a collection of samples or a clinical cohort. In addition, our software constitutes a shared and extensible research platform that enables collaboration between bioinformaticians, computer scientists, statisticians, biologists and clinicians. This platform will foster the development of novel analytic methods for flow cytometry. CONCLUSION: The software has been applied in the analysis of various data sets and its data structures have proven to be highly efficient in capturing and organizing the analytic work flow. Finally, a number of additional Bioconductor packages successfully build on the infrastructure provided by flowCore, open new avenues for flow data analysis.

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.

Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.

Anterior and posterior cartilage graft dimensions in successful laryngotracheal reconstruction.

OBJECTIVE: To describe the dimensions of cartilage grafts used for successful laryngotracheal reconstruction, with the goal of establishing appropriate sizes for "off-the-shelf" tissue-engineered cartilage grafts. DESIGN: A retrospective review of prospectively maintained operative illustrations of a single surgeon's experience. SETTING: Two tertiary children's hospitals. PATIENTS: A consecutive sample of 54 patients (tracheotomized or intubated) with a diagnosis of subglottic stenosis. INTERVENTIONS: Each patient underwent anterior (n = 30), posterior (n = 3), or anterior and posterior (n = 22) laryngotracheal reconstruction. Rib cartilage was used in 51 patients and thyroid cartilage was used in 3 patients. MAIN OUTCOME MEASURE: Successful or failed extubation. RESULTS: Of the 54 patients, 48 (89%) were successfully decannulated. The mean +/- SEM length of the anterior graft was 20.7 +/- 10.3 mm, and the mean width of the anterior graft was 7.7 +/- 2.5 mm. The mean length of the posterior graft was 13.9 +/- 2.9 mm, and the mean width of the posterior graft was 4.2 +/- 0.9 mm. CONCLUSIONS: With the prospect of tissue-engineered cartilage implants becoming available for laryngotracheal reconstruction, the most appropriate templates for designing these implants should be based on the geometric dimensions of grafts carved from native tissues in cases that have been successfully decannulated. Based on our analysis, the use of 2-mm increments for the posterior grafts suggests a set of molds that are 2, 4, and 6 mm wide and 22 mm long. Using 2 x 2-mm increments for the anterior grafts indicates that 36 mold sizes will be sufficient for 90% of predicted cases.

Bioconductor: open software development for computational biology and bioinformatics.

The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells.

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.

Production and characterization of monoclonal antibodies against the vasoconstrictive peptide human urotensin-II.

We report the production and characterization of four monoclonal antibodies (MAbs) against human urotensin-II (hU-II). The antibodies were raised against human hU-II, which contains the C-terminus cyclic ring (CFWKYC) that is conserved across species. Multiple selection assays were applied to ensure antibody potency and reactivity against the ring structure. The MAbs reacted via ELISA with hU-II bound to plastic, immunoprecipitated [(125)I-Y(9)] hU-II, bound to biotinylated hU-II in BIAcore analysis and, by Western analysis, recognized the full-length human preprourotensin-II expressed in transfected HEK293 cells. All four MAbs cross-reacted with porcine A, porcine B, rat, mouse, and goby U-II in ELISA. By competitive RIA, hU-II(5-11) (identical to the C-terminus of goby U-II) reacted equivalently to hU-II and goby U-II. The IC(50)s were 0.8 nM for one MAb and 1.6 nM for the others. All four MAbs reacted 15-fold less potently with hU-II(5-10) and 50-fold less potently with hU-II(5-10) amide. Thus, the ring structure and terminal Val/Ile comprise the binding site for this group of MAbs. This panel of antibodies could be useful tools to help delineate the biology and pharmacology of U-II. They may also be of diagnostic value in monitoring hU-II in body fluids.