Clinical relevance of heparin-PF4 complex antibody in DVT after total joint replacement

<p>Abstract</p> <p>Background</p> <p>Antibodies to the heparin-platelet factor-4 (HPF-4) complex (HIT antibodies) have been observed in patients with heparin-induced thrombocytopenia (HIT). These antibodies are thought to be involved in thrombosis through activation of platelet/endothelial cells. This prospective study was conducted to determine the incidence of post-operative HIT antibodies to assess the associated risk of deep vein thrombosis (DVT) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).</p> <p>Methods</p> <p>We studied 104 patients who underwent unilateral primary TKA (n = 44) and primary THA (n = 60) with short-duration prophylaxis (1–2 days of a fixed dose of unfractionated heparin). HIT antibodies were assayed using a sandwich-type ELISA before the operation and after heparin treatment (post-operative day 7).</p> <p>Results</p> <p>In the clinical outcome, the incidence of symptomatic DVT was 15.4% (16/104, TKA; 10, THA 6) and pulmonary embolism (PE) was not observed. The total seroconversion rate of HIT antibodies at post-operative day 7 was 34.6% (36/104). Among 36 seroconverted patients, 11 (30.6%) developed symptomatic DVT and 5 out of 68 of the non-seroconverted patients (7.4%) developed symptomatic DVT. The incidence for DVT was significantly higher in the seroconverted patients compared with that of the non-seroconverted patients (odds ratio 5.5, 95%CI: 1.7–17.6 <it>p </it>= 0.0028). Furthermore, in the patients with symptomatic DVT, the titer of HIT antibodies at post-operative day 7 was significantly higher compared with those without symptomatic DVT.</p> <p>Conclusion</p> <p>Our data therefore suggest that seroconversion for HIT antibodies generated by heparin is associated with a risk of DVT in patients undergoing total joint replacement.</p

Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations

Formation of Amyloid-Like Fibrils by Y-Box Binding Protein 1 (YB-1) Is Mediated by Its Cold Shock Domain and Modulated by Disordered Terminal Domains

YB-1, a multifunctional DNA- and RNA-binding nucleocytoplasmic protein, is involved in the majority of DNA- and mRNA-dependent events in the cell. It consists of three structurally different domains: its central cold shock domain has the structure of a β-barrel, while the flanking domains are predicted to be intrinsically disordered. Recently, we showed that YB-1 is capable of forming elongated fibrils under high ionic strength conditions. Here we report that it is the cold shock domain that is responsible for formation of YB-1 fibrils, while the terminal domains differentially modulate this process depending on salt conditions. We demonstrate that YB-1 fibrils have amyloid-like features, including affinity for specific dyes and a typical X-ray diffraction pattern, and that in contrast to most of amyloids, they disassemble under nearly physiological conditions

Impact of comorbidity on the short- and medium-term risk of revision in total hip and knee arthroplasty

Background: The impact of comorbidity on the risk of revision in patients undergoing Total Knee arthroplasty (TKA) and Total Hip Arthroplasty (THA) is not currently well known. The aim of this study was to analyze the impact of comorbidity on the risk of revision in TKA and THA. Methods: Patients recorded in the Catalan Arthroplasty Register (RACat) between 01/01/2005 and 31/12/2016 undergoing TKA (n = 49,701) and THA (n = 17,923) caused by osteoarthritis were included. As main explanatory factors, comorbidity burden was assessed by the Elixhauser index, categorized, and specific comorbidities from the index were taken into account. Descriptive analyses for comorbidity burden and specific conditions were done. Additionally, incidence at 1 and 5 years' follow-up was calculated, and adjusted Competing Risks models were fitted. Results: A higher incidence of revision was observed when the number of comorbidities was high, both at 1 and 5 years for THA, but only at 1 year for TKA. Of the specific conditions, only obesity was related to the incidence of revision at 1 year in both joints, and at 5 years in TKA. The risk of revision was related to deficiency anemia and liver diseases in TKA, while in THA, it was related to peripheral vascular disorders, metastatic cancer and psychoses. Conclusions: Different conditions, depending on the joint, might be related to higher revision rates. This information could be relevant for clinical decision-making, patient-specific information and improving the results of both TKA and THA.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The present study was funded by CIBER Epidemiology and Public Health (CIBERESP) as part of the aid for short internships granted to Jorge Arias-de la Torre in 2017 and 2018.published version, accepted versio

Explaining state development: Indonesia from its pre-independence origins to contemporary democracy.

Explaining State Development: Indonesia from Pre-Independence Origins to Contemporary Democracy. This thesis uses the Indonesian case to present a new paradigm for explaining the state development of new or relatively new (post-World War II) states. The first chapter describes this paradigm of organic and mechanical types of state development, argues that the development of the Indonesian state from the 1950s to 1990s is a good example of the mechanical type of development and shows how this can be confirmed by assessing and comparing the capabilities of the four different versions of a modern state developed by Indonesia since independence. The next chapter examines Indonesia’s pre-independence debates about the form of state to be adopted, which led to Indonesia accepting a Western model of the state that has since undergone a development process involving four different versions of a ‘modern’ state. These four versions of the state are defined according to their type of regime and policymaking institutions: I) parliamentary democracy, II) Sukarno’s civilian presidential monarchy, III) Suharto’s military presidential monarchy and IV) presidential democracy. Chapters Three to Six assess and compare these four versions’ capability in three key areas: 1) achieving legal legitimacy, 2) control of the military and 3) dealing with political disorder – a crucial area of state capability that requires two chapters. Then Chapter Seven examines and explains the pre-democratic origins of the present version of the Indonesian state, the presidential democracy of Version IV. The Conclusion collates the findings of Chapters Three to Six on capabilities and summarises the arguments of Chapters Two and Seven regarding the 1940s acceptance of the Western model of the state and the late 1990s opportunity for democratisation. Finally, there is a concluding assessment of the potential of the organic/mechanical typology as a new paradigm for studying state development in other countries, regions and eras