Determination of the Inter- and Intra-rater Reliability of Fusion Assessment in First Tarsometatarsal Joint Arthrodesis Using CT Scan: An Observational Study.

Background: First tarsometatarsal joint arthrodesis is a common procedure performed by podiatrists and orthopedic surgeons. There remains debate on how useful CT scans are in assessing fusion status in the post-operative patient. The purpose of our study was to determine the reliability among both orthopedic surgeons and radiologists in reviewing both postoperative radiographs and CT in order to determine if fusion had occurred in patients undergoing 1st tarsometatarsal arthrodesis. A secondary purpose of this study was to determine if CT offered improved inter- and intra-rater reliability when compared to plain radiographs. Methods: Patients who underwent 1st tarsometatarsal arthrodesis were retrospectively reviewed and those who underwent CT post-operatively for persistent pain were identified. Orthopedic surgeons and radiologists then analyzed the radiographs and CT of these patients for union with a threshold for union being set at 50% of the joint being fused. Imaging was then re-evaluated by the same provider 6 months later. Results: 24 patients were identified meeting inclusion criteria. Inter-rater reliability and intra-rater reliability for assessment of 1st tarsometatarsal arthrodesis were better with CT compared to radiographs; however, this association was not deemed reliable. Both imaging modalities were not able to assess union status confidently and reliably across reviewers, although CT scan had better intra-rater reliability. Conclusions: While CT is frequently used to assess fusion in patients who have underwent 1st tarsometatarsal arthrodesis, it was not found to be better than radiographs. Practitioners should reconsider the use CT as the gold standard when assessing fusion in this population.

Lucent Patellar Lesions: A Pictorial Review.

A radiographically lucent patellar lesion may represent a variety of etiologies, ranging from more commonly seen degenerative, metabolic, infectious, developmental, posttraumatic, postoperative causes to rarer benign and malignant neoplasms. Clinical symptoms, surgical history, laboratory values, and radiographic features may help narrow the differential. In addition, radiographic features such as circumscribed borders and sharply delineated margins favor benign lesions while ill-defined margins suggest malignant etiologies. This case series illustrates the imaging findings and explores relevant clinical findings in a variety of interesting lucent patellar lesions.

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.

Discovery of Novel, Orally Bioavailable ß-Amino Acid Azaindole Inhibitors of Influenza PB2.

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

Intra-articular osteoid osteoma at the femoral trochlea treated with osteochondral autograft transplantation.

We present the case of an intra-articular osteoid osteoma at the femoral trochlea. Intra-articular osteoid osteoma can present a diagnostic challenge both clinically and with imaging because it presents differently from the classic cortical osteoid osteoma. Given the lesion's proximity to overlying cartilage, the patient underwent resection of the lesion with osteochondral autograft transplantation at the surgical defect. A comprehensive literature review and discussion of intra-articular osteoma will be provided.

Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 µM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 µM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors.

Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.

Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.

VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.

Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.

Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Traumatic ulnar artery aneurysm secondary to basketball dunk: a case report and review.

Ulnar artery aneurysms are uncommon lesions. They are often caused by traumatic injury to the hand. Ulnar artery aneurysms have been reported in association with multiple sports-related activities, but never secondary to a basketball injury. The following is a case presentation of an ulnar artery aneurysm likely formed secondary to repetitive basketball slam dunking with accompanying review of diagnosis and surgical treatment of ulnar artery aneurysms.

Core biopsy with curved needle technique.

OBJECTIVE: The purpose of this study was to define the technique and study the feasibility of curved needle biopsy performed with a coaxial core biopsy system. CONCLUSION: Curved core needle biopsy is a simple and feasible technique with a high technical success rate even with suboptimal coaxial needle placement. With the technique, different parts of a focal lesion can be biopsied without manipulation of the coaxial needle. This feature may help in avoiding injury to vital structures.

Alternative splicing in the NF-kappaB signaling pathway.

Activation of transcription factor NF-kappaB can affect the expression of several hundred genes, many of which are involved in inflammation and immunity. The proper NF-kappaB transcriptional response is primarily regulated by post-translational modification of NF-kappaB signaling constituents. Herein, we review the accumulating evidence suggesting that alternative splicing of NF-kappaB signaling components is another means of controlling NF-kappaB signaling. Several alternative splicing events in both the tumor necrosis factor and Toll/interleukin-1 NF-kappaB signaling pathways can inhibit the NF-kappaB response, whereas others enhance NF-kappaB signaling. Alternative splicing of mRNAs encoding some NF-kappaB signaling components can be induced by prolonged exposure to an NF-kappaB-activating signal, such as lipopolysaccharide, suggesting a mechanism for negative feedback to dampen excessive NF-kappaB signaling. Moreover, some NF-kappaB alternative splicing events appear to be specific for certain diseases, and could serve as therapeutic targets or biomarkers.

T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis.

Two distinct clinical phenotypes of experimental autoimmune encephalomyelitis are observed in BALB interferon-gamma knockout mice immunized with encephalitogenic peptides of myelin basic protein. Conventional disease, characterized by ascending weakness and paralysis, occurs with greater frequency after immunizing with a peptide comprising residues 59 to 76. Axial-rotatory disease, characterized by uncontrolled axial rotation, occurs with greater frequency in mice immunized with a peptide corresponding to exon 2 of the full length 21.5-kd protein. The two clinical phenotypes are histologically distinguishable. Conventional disease is characterized by inflammation and demyelination primarily in spinal cord, whereas axial-rotatory disease involves inflammation and demyelination of lateral medullary areas of brain. Both types have infiltrates in which neutrophils are a predominating component. By isolating T cells and transferring disease to naive recipients, we show here that the type of disease is determined entirely by the inducing T cell. Furthermore, studies using CXCR2 knockout recipients, unable to recruit neutrophils to inflammatory sites, show that although neutrophils are critical for some of these T cells to effect disease, there are also interferon-gamma-deficient T cells that induce disease in the absence of both interferon-gamma and neutrophils. These results highlight the multiplicity of T-cell-initiated effector pathways available for inflammation and demyelination.