Objective The ability to make an early, accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important with the availability of new, expensive, and targeted therapies. However, plain radiography, the traditional method of detecting the characteristic bone erosions and an important adjunct in establishing a diagnosis of RA, is known to be insensitive. This study compared sonography, a modern imaging technique, with conventional radiography for the detection of erosions in the metacarpophalangeal (MCP) joints of patients with RA. Methods One hundred RA patients (including 40 with early disease) underwent posteroanterior radiography and sonography of the MCP joints of the dominant hand. Twenty asymptomatic control subjects also underwent sonography. Erosion sites were recorded and subsequently compared using each modality. Magnetic resonance imaging (MRI) was performed on the second MCP joint in 25 patients with early RA to confirm the pathologic specificity of sonographic erosions. Intraobserver reliability of sonography readings was assessed using video recordings of 55 MCP joint scans of RA patients, and interobserver reliability was assessed by comparing 160 MCP joint scans performed sequentially by 2 independent observers. Results Sonography detected 127 definite erosions in 56 of 100 RA patients, compared with radiographic detection of 32 erosions (26 [81%] of which coincided with sonographic erosions) in 17 of 100 patients (P < 0.0001). In early disease, sonography detected 6.5‐fold more erosions than did radiography, in 7.5‐fold the number of patients. In late disease, these differences were 3.4‐fold and 2.7‐fold, respectively. On MRI, all sonographic erosions not visible on radiography (n = 12) corresponded by site to MRI abnormalities. The Cohen‐kappa values for intra‐ and interobserver reliability of sonography were 0.75 and 0.76, respectively. Conclusion Sonography is a reliable technique that detects more erosions than radiography, especially in early RA. Sonographic erosions not seen on radiography corresponded to MRI bone abnormalities. This technology has potential in the management of patients with early RA/inflammatory arthritis and is likely to have major implications for the future practice of rheumatology.
To investigate the development of a reduced DLCO in patients with HIV-related disease, we studied 474 HIV-seropositive patients and performed serial lung function measurements over 18 months. The mean values of DLCO at presentation were lower in patients with more advanced HIV disease compared with asymptomatic HIV-seropositive patients (DLCO 88% of predicted). When compared with the DLCO in asymptomatic HIV-seropositive patients, the DLCO had reduced values in patients with persistent generalized lymphadenopathy (PGL) (82% of predicted, p less than 0.05), acquired deficiency syndrome-related complex (ARC) (73% predicted, p less than 0.001), nonpulmonary Kaposi's sarcoma (KS) (72% of predicted, p less than 0.001), nonpulmonary complications of AIDS excluding KS (73% of predicted, p less than 0.001), pulmonary KS (63% of predicted, p less than 0.001), pulmonary mycobacterial infection (68% of predicted, p less than 0.05), pyogenic infection (70%, p less than 0.05), acute Pneumocystis carinii pneumonia (PCP; 49%, p less than 0.001), and following recovery from PCP (71%, p less than 0.001). Serial lung function measurements over 18 months revealed no change in DLCO within any patient group, and in particular there was no tendency for a gradual decline. Clinical deterioration due to the development of PCP was associated with a reduction in DLCO. Conversely, in patients recovering from PCP, there was a partial improvement in DLCO over 3 months. Zidovudine (AZT) use did not affect DLCO within any diagnostic group or the recovery in DLCO following PCP. However, cigarette smoking was associated with further reductions in DLCO in all patient groups and with an impaired recovery of DLCO following acute PCP.(ABSTRACT TRUNCATED AT 250 WORDS)
Background -Pulmonary disease is a major contributor to morbidity and mortality in patients with HIV infection and AIDS. The aim of this study was to describe bronchoscopic findings and the spectrum of pulmonary pathogens in HIV seropositive patients undergoing investigation ofrespiratory disease over a 10 year period in a major UK referral centre. Methods -Recruitment was procedure based with data being captured when bronchoscopy was clinically indicated. Data were evaluated from 580 HIV seropositive patients (559 men, age 13-65 years) over a 10 year period from June 1983 to March 1993. Results -A total of947 bronchoscopies was performed. The most frequent pulmonary pathogen isolated from bronchoalveolar lavage (BAL) fluid in 44% of all bronchoscopies was Pneumocystis carinii. Of
ObjectivesThe mammalian target of Rapamycin (mTOR) is a metabolic master regulator of both innate and adaptive immunity; however, its exact role in stromal cell biology is unknown. In this study we explored the role of the mTOR pathway on Rheumatoid Arthritis synovial fibroblast (RASF) metabolism and activation and determined if crosstalk with the Hippo-YAP pathway mediates their effects.MethodsPrimary RA synovial fibroblasts (RASF) were cultured with TNFα alone or in combination with the mTOR inhibitor Rapamycin or YAP inhibitor Verteporfin. Chemokine production, matrix metalloproteinase (MMP) production, and adhesion marker expression were quantified by real-time PCR, ELISA, and/or Flow Cytometry. Invasion assays were performed using Transwell invasion chambers, while wound repair assays were used to assess RASF migration. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyzer. Key metabolic genes (GLUT-1, HK2, G6PD) were measured using real-time PCR. Reanalysis of RNA-Seq analysis was performed on RA (n = 151) and healthy control (HC) (n = 28) synovial tissue biopsies to detect differential gene and pathway expression. The expression of YAP was measured by Western Blot.ResultsTranscriptomic analysis of healthy donor and RA synovial tissue revealed dysregulated expression of several key components of the mTOR pathway in RA. Moreover, the expression of phospho-ribosomal protein S6 (pS6), the major downstream target of mTOR is specifically increased in RA synovial fibroblasts compared to healthy tissue. In the presence of TNFα, RASF display heightened phosphorylation of S6 and are responsive to mTOR inhibition via Rapamycin. Rapamycin effectively alters RASF cellular bioenergetics by inhibiting glycolysis and the expression of rate limiting glycolytic enzymes. Furthermore, we demonstrate a key role for mTOR signaling in uniquely mediating RASF migratory and invasive mechanisms, which are significantly abrogated in the presence of Rapamycin. Finally, we report a significant upregulation in several genes involved in the Hippo-YAP pathway in RA synovial tissue, which are predicted to converge with the mTOR pathway. We demonstrate crosstalk between the mTOR and YAP pathways in mediating RASF invasive mechanism whereby Rapamycin significantly abrogates YAP expression and YAP inhibition significantly inhibits RASF invasiveness.ConclusionmTOR drives pathogenic mechanisms in RASF an effect which is in part mediated via crosstalk with the Hippo-YAP pathway.
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