Citations

The biological interface between an orthopedic implant and the surrounding host tissue may have a dramatic effect upon clinical outcome. Desired effects include bony ingrowth (osseointegration), stimulation of osteogenesis (osteoinduction), increased vascularization, and improved mechanical stability. Implant loosening, fibrous encapsulation, corrosion, infection, and inflammation, as well as physical mismatch may have deleterious clinical effects. This is particularly true of implants used in the reconstruction of load-bearing synovial joints such as the knee, hip, and the shoulder. The surfaces of orthopedic implants have evolved from solid-smooth to roughened-coarse and most recently, to porous in an effort to create a three-dimensional architecture for bone apposition and osseointegration. Total joint surgeries are increasingly performed in younger individuals with a longer life expectancy, and therefore, the postimplantation lifespan of devices must increase commensurately. This review discusses advancements in biomaterials science and cell-based therapies that may further improve orthopedic success rates. We focus on material and biological properties of orthopedic implants fabricated from porous metal and highlight some relevant developments in stem-cell research. We posit that the ideal primary and revision orthopedic load-bearing metal implants are highly porous and may be chemically modified to induce stem cell growth and osteogenic differentiation, while minimizing inflammation and infection. We conclude that integration of new biological, chemical, and mechanical methods is likely to yield more effective strategies to control and modify the implant–bone interface and thereby improve long-term clinical outcomes.

Background Proximal pole scaphoid fractures are less common than waist fractures, and successful management can be difficult. We hypothesize that time to union is increased by delays in surgical fixation, greater initial displacement, and higher energy mechanisms of injury. Methods A retrospective review was conducted of all patients undergoing open reduction internal fixation (ORIF) of acute proximal pole scaphoid fractures at our institution over a 19-year period. A review of clinical as well as radiographic data was undertaken. The mechanism of injury, patient demographics, timing of surgery, initial displacement, fixation method, smoking status, and lunate morphology were recorded. Functional outcome measures were recorded when available. Univariate analysis using Kaplan-Meier survival curves was performed. Results A total of 10 out of 23 patients (43 %) showed evidence of union at 14 weeks post-injury. Rates of early union were higher in non-displaced fractures (70 %) when compared to displaced fractures (23 %). Similarly, fractures sustained via low energy mechanisms had a higher rate of early union compared to high energy mechanisms (69 versus 10 %). A delay in ORIF did not appear to influence rate of union. Conclusions Initial displacement and mechanism of injury have the most significant effects on early rates of union. Delay in ORIF of up to 28 days did not affect the rate of initial union, but the authors recommend early fixation of these fractures to prevent further displacement. Patients with widely displaced fractures or those with high energy mechanisms should be counseled regarding prolonged healing time. Level of Evidence: IV—therapeutic

Abstract This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. Mol Cancer Ther; 13(12); 2919–29. ©2014 AACR.

Venous thrombosis is a common medical problem. Imaging differentiation of neoplasms and venous clots may prove challenging. We report three cases of “mistaken identities” of venous thrombi and neoplasms on the basis of clinical findings and different imaging modalities: ultrasound, computed tomography, and magnetic resonance imaging. Imaging studies are not always reliable and consideration of clinical features, including pretest probability, is necessary for correct diagnosis. A combination of imaging modalities and biopsies is needed for correct diagnosis in some cases.

SummaryBackgroundEstimation of the prevalence of oesophageal narrowing and its clinical relevance in patients with oesophageal eosinophilia is probably underestimated by endoscopy.AimsTo determine the sensitivity and specificity of oesophagogastroduodenoscopy (EGD) for oesophageal narrowing when compared to a structured oesophagram.MethodsWe conducted a retrospective chart review at Mayo Clinic, Rochester of adult patients with eosinophilic oesophageal infiltration of >15 eosinophils/hpf with symptomatic dysphagia, who underwent a structured barium oesophagram. The sensitivity and specificity of EGD were evaluated against the gold standard of oesophagram. Demographic and multiple clinical factors were evaluated as potential predictors of oesophageal narrowing.ResultsOf the 58 patients identified, 34 (58.6%) had a narrowed oesophageal diameter (<21 mm). EGD had poor sensitivity (14.7%, 95% CI 5.0–31.1%) for detection of a narrowed oesophagus and only modest specificity (79.2%, 95% CI 57.8–92.9%). Even at a cut‐off diameter of EDmax ≤ 15 mm, EGD had a sensitivity of only 25.0% (95% CI 5.5–57.2%) for narrowed oesophagus. A history of >5 food impaction episodes, endoscopic rings, and female sex were the best predictors of oesophageal narrowing. 86% (6/7) patients with persistent dysphagia despite remission of histological eosinophilia responded to oesophageal dilation all of whom had radiological oesophageal narrowing and 71% of whom had no perceived oesophageal narrowing at EGD.ConclusionsSymptomatic oesophageal narrowing identified by barium oesophagography is common and under‐recognised at endoscopy in patients with oesophageal eosinophilia.

ABSTRACTMolecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N‐terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non‐native intramolecular interactions. The hydrodynamic radius (Rh) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PPII) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution‐induced changes in Rh were not associated with folding. The experiments showed that changes in local PPII structure cause changes in Rh that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. Proteins 2014; 82:3373–3384. © 2014 Wiley Periodicals, Inc.