The Safety of Hip Arthroscopy within 3 Months of an Intra-Articular Injection.

BACKGROUND: Ultrasound-guided intra-articular hip injections have become a mainstay in the diagnosis and treatment of various hip disorders. Concern arises with regard to the chronological proximity of an injection to subsequent arthroscopy. Thus, the purpose of this study was to report the risk of postoperative infections among patients who have undergone an intra-articular corticosteroid injection within 3 months of hip arthroscopy. METHODS: In-office, ultrasound-guided, intra-articular hip injections were first performed at this center in 2011. Corticosteroid is used for therapeutic purposes in the presence of painful hip conditions to reduce joint symptoms, either to allow for more effective supervised physical therapy or simply as a last line of nonoperative management. A retrospective review of patient records was performed, identifying all patients who had undergone arthroscopy and had received an intra-articular injection of corticosteroid at this institution within 3 months of the surgical procedure. RESULTS: Five hundred patients underwent an ultrasound-guided intra-articular injection of corticosteroid within 3 months of a hip arthroscopy. The mean age was 37.6 years (range, 14 to 74 years), with 112 male patients and 388 female patients. The mean time between the injection and the arthroscopy was 59 days (range, 15 to 92 days). There were no postoperative infections. CONCLUSIONS: When both the injection and the procedure are performed in a tertiary referral center, an ultrasound-guided intra-articular injection of corticosteroid within 3 months prior to arthroscopy, at a mean time of 59 days, resulted in no postoperative infections among 500 cases and can represent an acceptably low rate of complication. To our knowledge, this is the largest reported series on this subject. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Infectious diseases in wild mice (Mus musculus) collected on and around the University of Pennsylvania (Philadelphia) Campus.

Laboratory mice serve as important models in biomedical research. Monitoring these animals for infections and infestations and excluding causative agents requires extensive resources. Despite advancements in detection and exclusion over the last several years, these activities remain challenging for many institutions. The infections and infestations present in laboratory mouse colonies are well documented, but their mode of introduction is not always known. One possibility is that wild rodents living near vivaria somehow transmit infections to and between the colonies. This study was undertaken to determine what infectious agents the wild mice on the University of Pennsylvania (Philadelphia) campus were carrying. Wild mice were trapped and evaluated for parasites, viruses, and selected bacteria by using histopathology, serology, and PCR-based assays. Results were compared with known infectious agents historically circulating in the vivaria housing mice on campus and were generally different. Although the ectoparasitic burdens found on the 2 populations were similar, the wild mice had a much lower incidence of endoparasites (most notably pinworms). The seroprevalence of some viral infections was also different, with a low prevalence of mouse hepatitis virus among wild mice. Wild mice had a high prevalence of murine cytomegalovirus, an agent now thought to be confined to wild mouse populations. Helicobacter DNA was amplified from more than 90% of the wild mice (59% positive for H. hepaticus). Given the results of this study, we conclude that wild mice likely are not a source of infection for many of the agents that are detected in laboratory mouse colonies at the University of Pennsylvania.

TRAIL inactivates the mitotic checkpoint and potentiates death induced by microtubule-targeting agents in human cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted interest as an anticancer treatment, when used in conjunction with standard chemotherapy. We investigated the mechanistic basis for combining low-dose TRAIL with microtubule-targeting agents that invoke the mitotic checkpoint. Treatment of T98G and HCT116 cells with nocodazole alone resulted in a robust mitotic block with initially little cell death; low levels of cell death were also seen with TRAIL alone at 10 ng/mL final concentration. In contrast, the addition of low-dose TRAIL to nocodazole was associated with maximally increased caspase-3, caspase-8, and caspase-9 activation, which efficiently abrogated the mitotic delay and markedly increased cell death. In contrast, the abrogation of mitotic checkpoint and increased cell death were blocked by inhibitors of caspase-8 and caspase-9 or pan-caspase inhibitor. The addition of TRAIL to either nocodazole or paclitaxel (Taxol) reduced levels of the mitotic checkpoint proteins BubR1 and Bub1. BubR1 mutated for the caspase cleavage sites, but not wild-type BubR1, was resistant to cleavage induced by TRAIL added to nocodazole, and partially blocked the checkpoint abrogation. These results suggest that adding a relatively low concentration of TRAIL to antimicrotubule agents markedly increases complete caspase activation. This in turn accentuates degradation of spindle checkpoint proteins such as BubR1 and Bub1, contributes to abrogation of the mitotic checkpoint, and induces cancer cell death. These results suggest that TRAIL may increase the anticancer efficacy of microtubule-targeting drugs.

Zebrafish as a "biosensor"? Effects of ionizing radiation and amifostine on embryonic viability and development.

The zebrafish (Danio rerio) has emerged as a popular vertebrate model system for cancer and treatment-related research. Benefits include ease of care, rapid development, optical clarity of embryos, which allows visualization of major organ systems, and opportunities for genetic manipulation. However, specific parameters of radiation sensitivity have not been systematically documented. We investigated the effects of radiation and a radiomodifier on zebrafish viability and embryonic development. Embryos were exposed to gamma-radiation (5, 10, or 20 Gy) at sequential times postfertilization and serially assessed for viability and morphologic abnormalities. As expected, lethality and morphologic perturbations were more pronounced earlier in embryogenesis and with higher radiation doses and were partially reversed by amifostine. The effects of radiation and concurrent treatment with amifostine on the developmental organization of the eye and brain were striking. Radiation resulted in hypocellularity and disorganization of the cellular layers of the retina, effects partially reversed by amifostine, as well as lens opacification. Radiation strikingly reduced the volume of brain, but the volume loss was substantially blocked by amifostine. Increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling signal was noted in both the irradiated eye and brain, but reduced by amifostine. Finally, irradiating embryos resulted in caspase activation detectable in 96-well microplates, which was proportional to the number of embryos and radiation dose; the degree of activation was markedly reduced by amifostine. These results together suggest the power and versatility of the zebrafish in assessing the effects of radiation and radiomodifiers on organ and tissue development.

Caspase-mediated specific cleavage of BubR1 is a determinant of mitotic progression.

The fidelity of chromosomal duplication is monitored by cell cycle checkpoints operational during mitosis. One such cell cycle delay is invoked by microtubule-targeting agents such as nocodazole or paclitaxel (Taxol) and is mediated by mitotic checkpoint proteins that include BubR1. Relatively little is known about the regulation of expression and stability of BubR1 (or other checkpoint proteins) and how these factors dictate the durability of the cell cycle delay. We report here that treatment of HeLa cells with spindle-disrupting agents resulted in caspase activation and precipitated the cleavage of BubR1. This mechanism ultimately leads to reduced levels of full-length protein, which are accompanied by abrogation of the mitotic block; the checkpoint abrogation is substantially accelerated by inhibition of de novo protein synthesis. In contrast, inhibition of caspase activity blocked BubR1 degradation and prolonged mitosis. To confirm a direct link between caspase activity and BubR1 protein expression, we identified by site-directed mutagenesis the specific caspase cleavage sites cleaved after exposure to paclitaxel. Surprisingly, BubR1 has two sites of cleavage: primarily at Asp607/Asp610 and secondarily at Asp576/Asp579. BubR1 mutated at both locations (BubR1Delta579Delta610) was resistant to paclitaxel-induced degradation. Expression of BubR1Delta579Delta610 augmented the mitotic delay induced by spindle disruption in transfected cells as well as in clones engineered to inducibly express the mutant protein upon exposure to doxycycline and ultimately led to increased aneuploidy. Underscoring the importance of these caspase cleavage sites, both tetrapeptide motifs are identified in the amino acid sequences of human, mouse, chicken, and Xenopus BubR1. These results are potentially the first to link the control of the stability of a key mitotic checkpoint protein to caspase activation, a regulatory pathway that may be involved in killing defective cells and that has been evolutionarily conserved.