Pre-surgical radiologic identification of peri-prosthetic osteolytic lesions around TKRs: a pre-clinical investigation of diagnostic accuracy

Background: Emerging longitudinal data appear to demonstrate an alarming trend towards an increasing prevalence of osteolysis-induced mechanical failure, following total knee replacement (TKR). Even with high-quality multi-plane X-rays, accurate pre-surgical evaluation of osteolytic lesions is often difficult. This is likely to have an impact on surgical management and provides reasonable indication for the development of a model allowing more reliable lesion assessment. The aim of this study, using a simulated cadaver model, was to explore the accuracy of rapid spiral computed tomography (CT) examination in the non-invasive evaluation of peri-prosthetic osteolytic lesions, secondary to TKR, and to compare this to conventional X-ray standards. Methods: A series of nine volume-occupying defects, simulating osteolytic lesions, were introduced into three human cadaveric knees, adjacent to the TKR implant components. With implants in situ, each knee was imaged using a two-stage conventional plain X-ray series and rapid-acquisition spiral CT. A beam-hardening artefact removal algorithm was employed to improve CT image quality. After random image sorting, 12 radiologists were independently shown the series of plain X-ray images and asked to note the presence, anatomic location and 'size' of osteolytic lesions observed. The same process was repeated separately for review of the CT images. The corresponding X-ray and CT responses were directly compared to elicit any difference in the ability to demonstrate the presence and size of osteolytic lesions. Results: Access to CT images significantly improved the accuracy of recognition of peri-prosthetic osteolytic lesions when compared to AP and lateral projections alone (P = 0.008) and with the addition of bi-planar oblique X-rays (P = 0.03). No advantage was obtained in accuracy of identification of such lesions through the introduction of the oblique images when compared with the AP and lateral projections alone (P = 0.13) Conclusion: The findings of this study suggest that peri-prosthetic osteolytic lesions can be reliably described non-invasively using a simple, rapid-acquisition CT-based imaging approach. The low sensitivity of conventional X-ray, even with provision of supplementary bi-planar 45° oblique views, suggests a limited role for use in situ for TKR implant screening where peri-prosthetic osteolytic lesions are clinically suspected. In contrast, the accuracy of CT evaluation, linked to its procedural ease and widespread availability, may provide a more accurate way of evaluating osteolysis around TKRs, at routine orthopaedic follow up. These findings have direct clinical relevance, as accurate early recognition and classification of such lesions influences the timing and aggressiveness of surgical and non-operative management strategies, and also the nature and appropriateness of planned implant revision or joint-salvaging osteotomy procedures.Timothy P. Kurmis, Andrew P. Kurmis, David G. Campbell and John P. Slavotine

Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice

Objective and designCystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.Materials and methodsCFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-κB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.ResultsPharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.ConclusionsLack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury

Fractionated 131I anti-CEA radioimmunotherapy: effects on xenograft tumour growth and haematological toxicity in mice

Dose fractionation has been proposed as a method to improve the therapeutic ratio of radioimmunotherapy (RIT). This study compared a single administration of 7.4 MBq 131I-anti-CEA antibody given on day 1 with the same total activity given as fractionated treatment: 3.7 MBq (days 1 and 3), 2.4 MBq (days 1, 3, and 5) or 1.8 MBq (days 1, 3, 5, and 8). Studies in nude mice, bearing the human colorectal xenograft LS174T, showed that increasing the fractionation significantly reduced the efficacy of therapy. Fractionation was associated with a decrease in systemic toxicity as assessed by weight, but did not lead to any significant decrease in acute haematological toxicity. Similarly, no significant decrease in marrow toxicity, as assessed by colony-forming unit assays for granulocytes and macrophages (CFUgm), was seen. However, there was a significant depression of CFUgm counts when all treated animals were compared with untreated controls, suggesting that treatment did suppress marrow function. In conclusion, in this tumour model system, fractionated RIT causes less systemic toxicity, but is also less effective at treating tumours

Going Solo: Discovery of the First Parthenogenetic Gordiid (Nematomorpha: Gordiida)

Despite the severe fitness costs associated with sexual reproduction, its persistence and pervasiveness among multicellular organisms testifies to its intrinsic, short-term advantages. However, the reproductive assurance hypothesis predicts selection favoring asexual reproduction in sparse populations and when mate finding is difficult. Difficulties in finding mates is especially common in parasites, whose life cycles involve multiple hosts, or being released from the host into the external environment where the parasite can find itself trapped without a sexual partner. To solve this problem and guarantee reproduction, parasites in numerous phyla have evolved reproductive strategies, as predicted by the reproductive assurance hypothesis, such as hermaphroditism or parthenogenesis. However, this type of strategy has not been reported from species in the phylum Nematomorpha, whose populations have often been described as sparse. A new Nematomorpha species, Paragordius obamai n. sp., was discovered from Kenya, Africa, and appears to have solved the problem of being trapped without a mate by eliminating the need for males. Paragordius obamai n. sp. represents the first and only known species within this phylum to reproduce asexually. To determine the mechanism of this mating strategy, we ruled out the involvement of reproduction manipulating endosymbionts by use of next generation sequencing data, thus suggesting that parthenogenesis is determined genetically and may have evolved as a means to assure reproduction. Since this new parthenogenetic species and a closely related gonochoristic North American congener, P. varius, are easy to propagate in the laboratory, these gordiids can be used as model systems to test hypotheses on the genetic advantages and disadvantages of asexual reproduction and the genetic determinants of reproductive strategies in parasites

Landslide susceptibility mapping at VAZ watershed (Iran) using an artificial neural network model: a comparison between multilayer perceptron (MLP) and radial basic function (RBF) algorithms

Landslide susceptibility and hazard assessments are the most important steps in landslide risk mapping. The main objective of this study was to investigate and compare the results of two artificial neural network (ANN) algorithms, i.e., multilayer perceptron (MLP) and radial basic function (RBF) for spatial prediction of landslide susceptibility in Vaz Watershed, Iran. At first, landslide locations were identified by aerial photographs and field surveys, and a total of 136 landside locations were constructed from various sources. Then the landslide inventory map was randomly split into a training dataset 70 % (95 landslide locations) for training the ANN model and the remaining 30 % (41 landslides locations) was used for validation purpose. Nine landslide conditioning factors such as slope, slope aspect, altitude, land use, lithology, distance from rivers, distance from roads, distance from faults, and rainfall were constructed in geographical information system. In this study, both MLP and RBF algorithms were used in artificial neural network model. The results showed that MLP with Broyden–Fletcher–Goldfarb–Shanno learning algorithm is more efficient than RBF in landslide susceptibility mapping for the study area. Finally the landslide susceptibility maps were validated using the validation data (i.e., 30 % landslide location data that was not used during the model construction) using area under the curve (AUC) method. The success rate curve showed that the area under the curve for RBF and MLP was 0.9085 (90.85 %) and 0.9193 (91.93 %) accuracy, respectively. Similarly, the validation result showed that the area under the curve for MLP and RBF models were 0.881 (88.1 %) and 0.8724 (87.24 %), respectively. The results of this study showed that landslide susceptibility mapping in the Vaz Watershed of Iran using the ANN approach is viable and can be used for land use planning

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics

GM-CSF Increases Mucosal and Systemic Immunogenicity of an H1N1 Influenza DNA Vaccine Administered into the Epidermis of Non-Human Primates

Background: The recent H5N1 avian and H1N1 swine-origin influenza virus outbreaks reaffirm that the threat of a worldwide influenza pandemic is both real and ever-present. Vaccination is still considered the best strategy for protection against influenza virus infection but a significant challenge is to identify new vaccine approaches that offer accelerated production, broader protection against drifted and shifted strains, and the capacity to elicit anti-viral immune responses in the respiratory tract at the site of viral entry. As a safe alternative to live attenuated vaccines, the mucosal and systemic immunogenicity of an H1N1 influenza (A/New Caledonia/20/99) HA DNA vaccine administered by particle-mediated epidermal delivery (PMED or gene gun) was analyzed in rhesus macaques. Methodology/Principal Findings: Macaques were immunized at weeks 0, 8, and 16 using a disposable single-shot particlemediated delivery device designed for clinical use that delivers plasmid DNA directly into cells of the epidermis. Significant levels of hemagglutination inhibiting (HI) antibodies and cytokine-secreting HA-specific T cells were observed in the periphery of macaques following 1-3 doses of the PMED HA DNA vaccine. In addition, HA DNA vaccination induced detectable levels of HA-specific mucosal antibodies and T cells in the lung and gut-associated lymphoid tissues of vaccinated macaques. Importantly, co-delivery of a DNA encoding the rhesus macaque GM-CSF gene was found to significantly enhance both the systemic and mucosal immunogenicity of the HA DNA vaccine. Conclusions/Significance: These results provide strong support for the development of a particle-mediated epidermal DNA vaccine for protection against respiratory pathogens such as influenza and demonstrate, for the first time, the ability of skindelivered GM-CSF to serve as an effective mucosal adjuvant for vaccine induction of immune responses in the gut and respiratory tract. © 2010 Loudon et al