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Objective: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus., Methods: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay., Results: KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis., Conclusion: Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells., (© 2022 American College of Rheumatology.)

Background: Biliary dilatation in the asymptomatic patient is a frequent incidental finding in the work-up for which there are no current guidelines., Objectives: The purpose of this study was to determine the yield of magnetic resonance cholangiopancreatography (MRCP) in asymptomatic patients with an incidental finding of biliary duct dilatation., Methods: The study included 68 consecutive patients for evaluation of biliary duct dilatation found incidentally on computed tomography (CT) or ultrasound (US). MRCP scans were reviewed, and data were retrospectively collected on demographics and laboratory work-up. Patients were divided by the presence of a significant or non-significant MRCP findings explaining the biliary duct dilatation and compared for normal or abnormal liver function., Results: Liver function was normal in 47 patients and abnormal in 21 patients. MRCP identified the cause of the bile duct dilatation in 41 patients (60.3%). Rates of insignificant causes were 51% in the normal-liver-function group and 7% in the abnormal-function group. Corresponding rates of significant causes were 27.7% and 61.9% ( p  = 0.007)., Conclusions: MRCP is a valuable tool in the work-up of biliary duct dilatation. Although significantly more significant causes of bile dilatation are identified in patients with abnormal liver function, almost one-third of patients with normal liver function need further work-up. This has important implications for establishing criteria for the use of MRCP in asymptomatic patients with biliary dilatation.

The risk of death from cardiovascular diseases (CVDs), which are exacerbated by oxidative stress, is higher in diabetic women. This phenomenon has been attributed to the loss of estradiol-vascular protection. Such knowledge led us to examine the potential of glabridin, a phytoestrogen, to substitute estradiol up-regulation of antioxidant enzymes under high glucose conditions. Chronic glucose stress was found to down-regulate catalase (CAT) and paraoxonase 2 (PON2) mRNA expression by 20% and 17%, respectively, and to decrease PON2 activity by 83% in macrophages. Inflammatory conditions had an additive effect on PON2 expression in a time-dependent manner. Treatment with glabridin, under high glucose stress, increased PON2 activity by 60% and up-regulated its mRNA expression by 3.5 fold. Furthermore, glabridin up-regulated the expression of manganese superoxide dismutase (Mn-SOD) and CAT in monocytes. In conclusion, glabridin has the potential of strengthening the antioxidant defense mechanism and may serve as an antiatherogenic agent in diabetes., (Copyright © 2010 John Wiley & Sons, Ltd.)