Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1ß Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet's disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1ß were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Learning Clinical Hypnosis Wide Awake: Can We Teach Hypnosis Hypnotically?

Conversational hypnosis has been promoted as both more congruent with mechanisms of psychobiological change and more feasibly integrated into clinical care than the more dominant, ritualistic, hierarchical, induction-based Standards of Training in Clinical Hypnosis. Further, it has been argued that, in teaching the legacy standard, clinical hypnosis training lacks pedagogical integrity. This article builds on these premises by piloting a mixed-methods approach to studying the pedagogy and participant evaluations of two professional education events that focused on conversational hypnosis. Results indicate that this is an effective methodology for studying the impact of teaching hypnosis hypnotically and fostering wider integration of hypnosis into health and care.

Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy.

BACKGROUND: The value of microbiological culture to diagnose late periprosthetic infection is limited, especially because standard methods may fail to detect biofilm-forming sessile or other fastidious bacteria. There is no agreement on the appropriate cultivation period, although this period is a crucial factor. This study was designed to assess the duration of culture that is necessary for reliable detection. PATIENTS AND METHODS: Ten periprosthetic tissue specimens each were obtained during revision from 284 patients with suspected late hip or knee arthroplasty infection. Five samples were examined by microbiological culture over a 14-day period, and 5 were subjected to histologic analysis. To define infection, a pre-established algorithm was used; this included detection of indistinguishable organisms in >/=2 tissue samples or growth in 1 tissue sample and a positive result of histologic analysis (>5 neutrophils in at least 10 high-power fields). The time to detection of organisms was monitored. RESULTS: Infection was diagnosed in 110 patients. After 7 days (the longest incubation period most frequently reported), the detection rate via culture was merely 73.6%. Organisms indicating infection were found for up to 13 days. "Early"-detected species (mostly staphylococci) emerged predominantly during the first week, whereas "late"-detected agents (mostly Propionibacterium species) were detected mainly during the second week. In both populations, an unequivocal correlation between the number of culture-positive tissue samples and positive results of histologic analysis was noted, which corroborated the evidence that true infections were detected over the entire cultivation period. CONCLUSIONS: Prolonged microbiological culture for 2 weeks is promising because it yields signs of periprosthetic infection in a significant proportion of patients that would otherwise remain unidentified.

Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma.

BACKGROUND: Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells. METHODS: Migration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model. RESULTS: Lenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals. CONCLUSION: Lenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.

Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs.

CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4+ and CD8+ peripheral blood T cells, production of IL-2 and IFN-gamma from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.