Homocysteine Levels, Haemostatic Risk Factors and Patency Rates after Endovascular Treatment of the Above-Knee Femoro-Popliteal Artery

AbstractObjectives. To investigate the relationship between plasma homocysteine and other haemostatic variables and restenoses or reocclusions after endovascular treatment of symptomatic atherosclerosis of the above-knee femoro-popliteal artery.Design. Prospective observational study.Setting. University hospital.Patients and methods. The study included 103 patients (116 limbs), treated with subintimal angioplasty in 58 cases (50%) and with intraluminal PTA in 58 (50%): 39 (34%) patients were treated for critical limb ischaemia. Blood samples for analyses of fasting plasma values of homocysteine, fibrinogen, D-dimer, activated protein C resistance were drawn upon admission. Median follow-up for all procedures was 11 months (range 0–42 months). Outcome events (arterial patency) were defined as ≥50% restenosis or reocclusion in the treated arterial segment. Patency rates were estimated with the product limit method and Kaplan–Meier curves. Variables found to be related significantly to patency were included in multivariate analysis performed with the Cox proportional hazard model.Results. The 1-year cumulative primary patency rate for all procedures was 48%. One-year limb salvage rate in cases of critical ischaemia was 74%. Multivariate analysis demonstrated significant independent associations between patency rates and plasma D-dimer, diabetes mellitus, the nature of the lesion treated (stenosis vs. occlusion) and antithrombotic therapy with aspirin after the procedure. Plasma levels of homocysteine, fibrinogen or activated protein C resistance were not associated with patency rates. Homocysteine levels were higher in patients with critical limb ischaemia than those with intermittent claudication.Conclusions. Early restenosis or reocclusion after endovascular intervention of lesions in the above-knee femoro-popliteal artery was more frequent following treatment of occlusion (versus stenosis), for patients with diabetes, patients with elevated D-dimer and those without antithrombotic therapy after the procedure. Plasma homocysteine did not appear to influence the outcome of endovascular intervention

Controlling protein interactions in blood for effective liver immunosuppressive therapy by silica nanocapsules

Immunosuppression with glucocorticoids is a common treatment for autoimmune liver diseases and after liver transplant, which is however associated with severe side-effects. Targeted delivery of glucocorticoids to inflammatory cells, e.g. liver macrophages and Kupffer cells, is a promising approach for minimizing side effects. Herein, we prepare core–shell silica nanocapsules (SiO2 NCs) via a sol–gel process confined in nanodroplets for targeted delivery of dexamethasone (DXM) for liver immunosuppressive therapy. DXM with concentrations up to 100 mg mL−1 in olive oil are encapsulated while encapsulation efficiency remains over 95% after 15 days. Internalization of NCs by non-parenchymal murine liver cells significantly reduces the release of inflammatory cytokines, indicating an effective suppression of inflammatory response of liver macrophages. Fluorescent and magnetic labeling of the NCs allows for monitoring their intracellular trafficking and biodegradation. Controlled interaction with blood proteins and good colloidal stability in blood plasma are achieved via PEGylation of the NCs. Specific proteins responsible for stealth effect, such as apolipoprotein A-I, apolipoprotein A-IV, and clusterin, are present in large amounts on the PEGylated NCs. In vivo biodistribution investigations prove an efficient accumulation of NCs in the liver, underlining the suitability of the SiO2 NCs as a dexamethasone carrier for treating inflammatory liver diseases.Fil: Jiang, Shuai. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Prozeller, Domenik. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Pereira, Jorge. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Simon, Johanna. Max-Planck-Institut für Polymerforschung; Alemania. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Han, Shen. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Wirsching, Sebastian. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Fichter, Michael. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Mottola, Milagro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Lieberwirth, Ingo. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Morsbach, Svenja. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Mailänder, Volker. Max-Planck-Institut für Polymerforschung; Alemania. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Gehring, Stephan. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Crespy, Daniel. Max-Planck-Institut für Polymerforschung; Alemania. Vidyasirimedhi Institute of Science and Technology; TailandiaFil: Landfester, Katharina. Max-Planck-Institut für Polymerforschung; Alemani

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction

A Damage Mechanics Approach to Fatigue Assessment in Offshore Structures

This article is intended to describe the development of a fatigue damage model capable of assessing fatigue damage in offshore structures. This is achieved by for mulating a set of damage coupled constitutive and evolution equations which make the for mulation of a unified approach possible under both low and high cycle fatigue damage and consistent with the structural dynamic response of the changing/deteriorating material be haviors. The structural analysis for the whole designed period, say about 30 years, can be carried out with the aid of the proposed analytical procedure, in which the fundamental characteristics of sea wave statistics responsible for the structural dynamic response can be sufficiently considered. An offshore structure subject to complex ocean environment is described by a general stochastic system which embeds a group of stochastic subsystems, each characterizing a duty cycle. An effective analytical method is established by introduc ing the concept of duty strain range with a clear mathematical definition and its analytical solution which covers all possible spectral parameters. The history-dependent damage is also included in the damage model so that the overload effects can be analyzed. It should be pointed out that the whole procedure can be fully computerized such that the practical or engineering significance of varying design variables can be readily highlighted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67255/2/10.1177_105678959300200405.pd

A T-cell antigen atlas for meningioma: novel options for immunotherapy

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma