Diagnostic accuracy of ultrasonography, MRI and MR arthrography in the characterisation of rotator cuff disorders: A systematic review and meta-analysis

Background Different diagnostic imaging modalities, such as ultrasonography (US), MRI, MR arthrography (MRA) are commonly used for the characterisation of rotator cuff (RC) disorders. Since the most recent systematic reviews on medical imaging, multiple diagnostic studies have been published, most using more advanced technological characteristics. The first objective was to perform a meta-analysis on the diagnostic accuracy of medical imaging for characterisation of RC disorders. Since US is used at the point of care in environments such as sports medicine, a secondary analysis assessed accuracy by radiologists and nonradiologists. Methods A systematic search in three databases was conducted. Two raters performed data extraction and evaluation of risk of bias independently, and agreement was achieved by consensus. Hierarchical summary receiver-operating characteristic package was used to calculate pooled estimates of included diagnostic studies. Results Diagnostic accuracy of US, MRI and MRA in the characterisation of full-thickness RC tears was high with overall estimates of sensitivity and specificity over 0.90. As for partial RC tears and tendinopathy, overall estimates of specificity were also high (\u3e0.90), while sensitivity was lower (0.67â 0.83). Diagnostic accuracy of US was similar whether a trained radiologist, sonographer or orthopaedist performed it. Conclusions Our results show the diagnostic accuracy of US, MRI and MRA in the characterisation of fullthickness RC tears. Since full thickness tear constitutes a key consideration for surgical repair, this is an important characteristic when selecting an imaging modality for RC disorder. When considering accuracy, cost, and safety, US is the best option

Epstein Barr Virus-positive large T-cell lymphoma presenting as acute appendicitis 17 years after cadaveric renal transplant: a case report

<p>Abstract</p> <p>Introduction</p> <p>The majority of post-transplant lymphoproliferative disorders in renal transplant patients are of the B-cell phenotype, while the T-cell phenotype is rare. We report a case of Epstein Barr Virus-positive, T-cell lymphoma in a renal transplant patient, presenting unusually as acute appendicitis.</p> <p>Case presentation</p> <p>A 45-year-old Hispanic male renal transplant patient presented with right-side abdominal pain 17 years after transplant. The laboratory studies were unremarkable. Laparoscopic exploration showed an inflamed appendix so a laparoscopic appendectomy was performed. Pathology of the appendix showed large cells positive for CD3, CD56 and Epstein Barr Virus-encoded RNA staining, and negative for CD20 and CD30. The tissue tested positive for T-cell receptor gene rearrangement by polymerase chain reaction analysis. Treatment management involved reduction of immunosuppression and initiation of chemotherapy with cisplatin, etoposide, gemcitabine, and solumedrol followed by cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone). He recovered and the allo-grafted kidney is fully functional.</p> <p>Conclusion</p> <p>We report a rare case of post-renal transplant large T-cell lymphoma, with an unusual presentation of acute appendicitis and Epstein Barr Virus-positivity, which responded well to chemotherapy.</p

On two superintegrable nonlinear oscillators in N dimensions

We consider the classical superintegrable Hamiltonian system given by $H=T+U={p^2}/{2(1+\lambda q^2)}+{{\omega}^2 q^2}/{2(1+\lambda q^2)}$, where U is known to be the "intrinsic" oscillator potential on the Darboux spaces of nonconstant curvature determined by the kinetic energy term T and parametrized by {\lambda}. We show that H is Stackel equivalent to the free Euclidean motion, a fact that directly provides a curved Fradkin tensor of constants of motion for H. Furthermore, we analyze in terms of {\lambda} the three different underlying manifolds whose geodesic motion is provided by T. As a consequence, we find that H comprises three different nonlinear physical models that, by constructing their radial effective potentials, are shown to be two different nonlinear oscillators and an infinite barrier potential. The quantization of these two oscillators and its connection with spherical confinement models is briefly discussed.Comment: 11 pages; based on the contribution to the Manolo Gadella Fest-60 years-in-pucelandia, "Recent advances in time-asymmetric quantum mechanics, quantization and related topics" hold in Valladolid (Spain), 14-16th july 201

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Aerosolized BC-819 Inhibits Primary but Not Secondary Lung Cancer Growth

Despite numerous efforts, drug based treatments for patients suffering from lung cancer remains poor. As a promising alternative, we investigated the therapeutic potential of BC-819 for the treatment of lung cancer in mouse tumor models. BC-819 is a novel plasmid DNA which encodes for the A-fragment of Diphtheria toxin and has previously been shown to successfully inhibit tumor growth in human clinical study of bladder carcinoma. In a first set of experiments, we examined in vitro efficacy of BC-819 in human lung cancer cell-lines NCI-H460, NCI-H358 and A549, which revealed >90% reduction of cell growth. In vivo efficacy was examined in an orthotopic mouse xenograft lung cancer model and in a lung metastasis model using luminescent A549-C8-luc adenocarcinoma cells. These cells resulted in peri- and intra-bronchiolar tumors upon intrabronchial application and parenchymal tumors upon intravenous injection, respectively. Mice suffering from these lung tumors were treated with BC-819, complexed to branched polyethylenimine (PEI) and aerosolized to the mice once per week for a period of 10 weeks. Using this regimen, growth of intrabronchially induced lung tumors was significantly inhibited (p = 0.01), whereas no effect could be observed in mice suffering from lung metastasis. In summary, we suggest that aerosolized PEI/BC-819 is capable of reducing growth only in tumors arising from the luminal part of the airways and are therefore directly accessible for inhaled BC-819

Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function

<p>Abstract</p> <p>Background</p> <p>Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFα and IL-1β, rather than as regulatory cytokine.</p> <p>Objective</p> <p>To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease.</p> <p>Methods</p> <p>Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects.</p> <p>Results</p> <p>The levels of the proinflammatory biomarkers TNFα and IL-1β were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (r_S= 0.53, p < 0.05).</p> <p>Conclusions</p> <p>In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.</p

Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.</p> <p>Methods</p> <p>The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For <it>in vivo </it>studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired <it>t </it>test using GraphPad prism software.</p> <p>Results</p> <p>Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. <it>In vivo </it>testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine.</p> <p>Conclusion</p> <p>These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.</p

Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis