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Psoralen plus UVA (PUVA) is an effective therapy for mycosis fungoides (MF), the skin-limited variant of cutaneous T cell lymphoma (CTCL). In low-burden patients, PUVA reduced or eradicated malignant T cells and induced clonal expansion of CD8+ T cells associated with malignant T cell depletion. High-burden patients appeared to clinically improve but large numbers of malignant T cells persisted in skin. Clinical improvement was linked to turnover of benign T cell clones but not to malignant T cell reduction. Benign T cells were associated with the Th2-recruiting chemokine CCL18 before therapy and with the Th1-recruiting chemokines CXCL9, CXCL10, and CXCL11 after therapy, suggesting a switch from Th2 to Th1. Inflammation was correlated with OX40L and CD40L gene expression; immunostaining localized these receptors to CCL18-expressing c-Kit+ dendritic cells that clustered together with CD40+OX40+ benign and CD40+CD40L+ malignant T cells, creating a proinflammatory synapse in skin. Our data suggest that visible inflammation in CTCL results from the recruitment and activation of benign T cells by c-Kit+OX40L+CD40L+ dendritic cells and that this activation may provide tumorigenic signals. Targeting c-Kit, OX40, and CD40 signaling may be novel therapeutic avenues for the treatment of MF.
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Fixed fluidized bed reactor is widely used to evaluate the crackability of heavy oils and the activity of catalysts. To understand the hydrodynamics, reaction kinetics and thermodynamics in conventional and modified fixed fluidized bed reactors, the computational fluid dynamics method, energy-minimization multi-scale-based two-fluid model coupled with a six-lump kinetic model was used to investigate the gas-solid flow and cracking reactions. The gas mixing and particle volume fraction distributions, as well as product yields in the conventional and modified fixed fluidized bed reactors were analyzed. The residence time distribution model was utilized to obtain the parameters indicating the back-mixing degree, such as mean residence time and dimensionless variance of the gas. The results showed that the simulated product distribution is in reasonable agreement with the experimental data; the modified fixed fluidized bed reactor is closer to the ideal plug flow reactor, which can efficiently enhance the gas-solid mixing, reduce the gas back-mixing degree, and hence improve the reaction performance.
RESUMO
IMPORTANCE: Cryoglobulins are cold-precipitating immunoglobulins that occur secondary to lymphoproliferative disorders, chronic viral infections, and autoimmune disorders. The treatment of cryoglobulinemia should target the underlying disorder; however, such an approach may be difficult, and therapeutic options remain limited for type I cryoglobulinemia. OBSERVATIONS: We report a case of recalcitrant type I cryoglobulinemia treated successfully with long-term plasmapheresis in conjunction with thalidomide and dexamethasone. A woman in her 50s with cryoglobulinemia and bilateral lower extremity ulcers of 1 year's duration developed acute angle-closure glaucoma following the appearance of new macules on her upper extremities. An initial short course of 5 plasmapheresis treatments improved the patient's cutaneous lesions as well as the glaucoma. Three weekly doses of rituximab were not associated with any evidence of clinical improvement, so thalidomide and dexamethasone were administered as replacement therapy. Because of the increasing pain and persistence of the woman's ulcers, intensive plasmapheresis was resumed and continued 3 to 4 times per week for approximately 4 months, after which a slow tapering regimen was initiated. This therapy was associated with progressive, rapid healing of the ulcers, stabilization of the skin lesions, and control of the patient's intraocular pressure. CONCLUSIONS AND RELEVANCE: The long-term use of plasmapheresis may be a well-tolerated treatment option for therapeutically challenging cases of cryoglobulinemia.
