Hematopoietic stem cell transplantation for severe rheumatoid arthritis

The substantial morbidity and mortality associated with rheumatoid arthritis (RA), while not widely appreciated, provide adequate justification for consideration of high-dose immunoablative therapy followed by hematopoietic stem cell transplantation. While some patients with RA follow a benign course, selected subsets of patients have been identified with 5-year survival rates of 40-70%. A number of factors that can be easily determined serve as useful prognostic indicators for poor outcome. These include the presence of many involved joints (total joint count), the degree of functional disability as measured by the health assessment questionnaire and the presence of rheumatoid factor. This article summarises the present status of hematopoietic stem cell transplantation for rheumatoid arthritis and proposes future directions for research.     

Quantification of experimental myocardial infarction using nuclear magnetic resonance imaging and paramagnetic ion contrast enhancement in excised canine hearts

Determination of myocardial infarct size is important for clinical management of patients with ischemic heart disease and for research on limiting infarct size. Nuclear magnetic resonance (NMR) imaging permits tomographic depiction of the distribution of mobile tissue protons. NMR images have demonstrated high spatial resolution and contrast. To evaluate the potential of this technique in measuring myocardial infarct size, NMR imaging was performed in six canine hearts excised 24 hours after circumflex coronary artery ligation. Before sacrifice, the dogs received i.v. manganous chloride (0.05 mmol/kg). After NMR imaging, the heart were sectioned and the myocardial slices were stained with triphenyl tetrazolium chloride. The pathologically determined infarct size was compared with the infarct size measured by NMR imaging. The correlation was good (regression line slope 1.06; r = 0.94). We conclude that NMR imaging with paramagnetic contrast agents can be used to determine infarct size in excised hearts.     

Early Prosthetic Valve Dysfunction Due to Bioprosthetic Valve Thrombosis: The Role of Echocardiography

Objectives

The purpose of this study was to review the institutional practice of surveillance transthoracic echocardiography (TTE) for diagnosing early prosthetic valve dysfunction (PVD).

Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) binding to neutrophil elastase (NE) and proteinase 3 (PR3) are detectable in most patients with cocaine-induced midline destructive lesions (CIMDL), but the pathogenic role and antigen specificity of these antibodies are unknown. This study was undertaken to assess the effects of NE ANCA on the enzymatic activity of NE, to determine whether these antibodies interfere with the physiologic effect of secretory leukoprotease inhibitor (SLPI), and to investigate the antigen specificity of both NE and PR3 ANCA in patients with CIMDL. We also compared the binding of PR3 ANCA in patients with CIMDL with that in patients with Wegener's granulomatosis (WG). METHODS: PR3 ANCA and NE ANCA were detected by capture enzyme-linked immunosorbent assays (ELISAs) and by indirect immunofluorescence. IgG was purified from the patients' sera, and the influence of NE ANCA on the enzymatic activity of NE and on the inhibitory activity of SLPI was investigated by determining the hydrolysis of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide by NE. RESULTS: IgG from NE ANCA-positive sera of patients with CIMDL inhibited the enzymatic activity of NE and did not interfere with the activity of SLPI. In contrast to the findings in WG sera, measurement of PR3 ANCA in CIMDL sera showed only fair to moderate concordance between the 2 different capture ELISAs. Cross-inhibition experiments demonstrated that NE ANCA and PR3 ANCA represent distinct autoantibodies in patients with CIMDL. CONCLUSION: The functional effects of NE ANCA on the enzymatic activity of NE or on the activity of SLPI cannot be implicated in the pathogenesis of CIMDL. The autoimmune reaction that targets neutrophil serine proteases in patients with CIMDL is frequently directed against more than one antigen. The ANCA response, including the reactivity of PR3 ANCA, in patients with CIMDL differs from what has been described in patients with WG.     

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8⁺ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8⁺ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.     

The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis

Journal of Neurology - Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional...