Paradoxical effect of lenalidomide on cytokine/growth factor profiles in multiple myeloma.

BACKGROUND: Lenalidomide is an active immunomodulatory and antiproliferative agent in multiple myeloma. However, the molecular mechanisms driving these activities are not yet fully elucidated. Therefore, we investigated the modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment. METHODS: Lenalidomide effect on myeloma cell proliferation was investigated in a myeloma cell line collection (n=23) by (3)H-thymidine incorporation. Modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment was analysed by real-time quantitative PCR. RESULTS: Lenalidomide inhibits the proliferation of two-thirds of myeloma cell lines independently of their genetic background. We demonstrated that LEN increased TNF-α and IL-8 inflammatory cytokines and insulin-like growth factor-1 (IGF-1) growth factor in both sensitive and resistant myeloma cells to LEN. CONCLUSION: Lenalidomide favours a uniform TNF-α and IL-8 inflammatory and IGF-1 secretory profile of myeloma cells, an observation that raises important questions for therapeutic approaches incorporating the agent.

[Pilot data from the Spirale project -- follow-up of occupational respiratory exposures]. / Les dispositifs pilotes existants du suivi post-professionnel : Spirale.

INTRODUCTION: The medical follow-up of individuals who have had occupational exposures to potential respiratory hazards is little known and under-utilised. The Spirale program aims to deliver this intervention effectively to all potential beneficiaries. METHODS: Spirale was introduced in two stages; i) identification of occupational exposures to asbestos or wood dust through a postal questionnaire; ii) for those initially identified, confirmation of exposure through attendance at a health centre for examination and further medical follow-up as necessary. RESULTS: In 2007, Spirale contacted 50,662 men born between 1942 and 1943, living in 13 departments in France. The initial response rate was 24%, rising to 50% after reminders. Seventy-two percent of people were identified as possibly having been exposed; 50% to asbestos, 3% to wood dust and 19% reporting a mixed exposure. Among the 8641 people located, 3843 (44.5%) benefited from an evaluation of their exposure. In total, 73.4% of people had their exposure to asbestos confirmed and in 1751 (64.2%) this was at a level to justify follow-up. CONCLUSION: TheSpirale program largely achieved its objective of location and initiation of medical monitoring of people who have been exposed through their work to respiratory carcinogens. It should now be implemented throughout the country.

Enteric glia inhibit intestinal epithelial cell proliferation partly through a TGF-beta1-dependent pathway.

Although recent studies have shown that enteric neurons control intestinal barrier function, the role of enteric glial cells (EGCs) in this control remains unknown. Therefore, our goal was to characterize the role of EGCs in the control of intestinal epithelial cell proliferation using an in vivo transgenic and an in vitro coculture model. Assessment of intestinal epithelial cell proliferation after ablation of EGCs in transgenic mice demonstrated a significant increase in crypt cell hyperplasia. Furthermore, mucosal glial network (assessed by immunohistochemical detection of S-100beta) is altered in colon adenocarcinoma compared with control tissue. In an in vitro coculture model of subconfluent Caco-2 cells seeded onto Transwell filters with EGCs, Caco-2 cell density and [3H]thymidine incorporation were significantly lower than in control (Caco-2 cultured alone). Flow cytometry analysis showed that EGCs had no effect on Caco-2 cell viability. EGCs induced a significant increase in Caco-2 cell surface area without any sign of cellular hypertrophy. These effects by EGCs were also seen in various transformed or nontransformed intestinal epithelial cell lines. Furthermore, TGF-beta1 mRNA was expressed, and TGF-beta1 was secreted by EGCs. Exogenously added TGF-beta1 reproduced partly the EGC-mediated effects on cell density and surface area. In addition, EGC effects on Caco-2 cell density were significantly reduced by a neutralizing TGF-beta antibody. In conclusion, EGCs have profound antiproliferative effects on intestinal epithelial cells. Functional alterations in EGCs may therefore modify intestinal barrier functions and be involved in pathologies such as cancer or inflammatory bowel diseases.

Diabetes as a result of atypical anti-psychotic drugs--a report of three cases.

AIMS: Atypical anti-psychotic drugs (APDs) are widely used in psychotic disorders refractory to conventional neuroleptic agents. RESULTS: Three cases of new-onset diabetes are reported in Caucasian men who were on clozapine (one) or olanzapine (two) for 3-6 months. They had a distinct presentation: weight loss, ketosis (one ketoacidosis), severe hyperglycaemia requiring insulin therapy, and relative insulin deficiency as reflected by glucagon stimulatory tests. In all cases, insulin was stopped within 1 month after the APD was discontinued. CONCLUSIONS: Novel APDs not only induce diabetes as a result of weight gain in predisposed patients, but can also lead to a reversible state of insulin deficiency, and sometimes ketoacidosis.