Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia

Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-alpha, PDGF-beta, but not c-Kit, and 1 microM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis.     

The cleansing result of oral sodium phosphate is inversely correlated with time between the last administration and colonoscopy

Background There is some evidence that the timing of sodium phosphate (NaP) ingestion affects the cleansing result. The objective of this study was to evaluate the correlation of cleansing result with the timing of ingestion of NaP. Methods 214 consecutive outpatients scheduled to undergo colonoscopy were enrolled in the study. All patients filled out a detailed questionnaire concerning the execution of bowel cleansing. Concomitant with colonoscopy, patient characteristics were recorded and after the procedure the cleansing result was scored. The correlation between cleansing score and time from the last dose of NaP to colonoscopy was evaluated. For further analysis, patients were divided into three groups regarding the time lag from NaP taking to colonoscopy (group 1, 6 h or less; group 2, 6–12 h; group 3, 12 h or more). Results 204 patients had complete colonoscopy and enough data to be analyzed for the study. The Pearson correlation coefficient for the time between the last dose of NaP and colonoscopy was -0.450 (p=0.0001) showing an inverse correlation. The mean cleansing score (±SEM) of group 1 was 4.00±0.12, for group 2 it was 3.56±0.12, and for group 3 it was 2.64±0.14. There were statistically significant differences between all groups. Conclusion The cleansing result of NaP is inversely correlated with the time between last dose of NaP and colonoscopy. Colonoscopy should be preferably performed within 12 hours of taking the second dose of NaP.     

Exogenous GTP increases cyclic GMP and inhibits thrombin-induced aggregation of washed human platelets: comparison with ATP, adenosine and guanosine.

The effects of exogenous guanosine 5'-triphosphate (GTP), guanosine, adenosine 5'-triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin-stimulated washed human platelets. GTP (10 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 microM-1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin-induced aggregation of washed human platelets was adenosine > GTP > ATP > guanosine. In conclusion, exogenous GTP inhibits thrombin-induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local antithrombotic effect also in vivo.     

Prolonged impairment in activities of daily living due to postdural puncture headache after diagnostic lumbar puncture

To assess the incidence of postdural puncture headache and its effects on patients' activities of daily living, we interviewed 325 adult patients subjected to a diagnostic lumbar puncture during a 1-year period. Two hundred and eighteen (67%) of the subjects replied to the questionnaire; 41 (19%) of these were diagnosed as having suffered a postdural puncture headache. Impairment of the activities of daily living persisting for 1 week or more was experienced by 16 (7%) of the subjects.     

Physicians’ self-assessment of cancer pain treatment skills—more training required

Purpose

Adequate pain control is essential in cancer treatment. We surveyed Finnish physicians’ perception on their skills and training needs on palliative pain management.

Methods

A structured questionnaire with multiple choices and open ended questions was used for collecting data in 2006–2008. Of 720 physicians participating, 59 were working in oncology and 661 physicians in internal medicine, geriatrics, and primary health care.

Results

The principles of the WHO guidelines of cancer pain management were not well known. Forty-six percent of oncologists and 32% of other physicians (P?Conclusions To have more confidence in treating cancer, pain physicians would benefit in training and education in palliative care. It should be systematically included both in general and specialist training and continuous medical education.     

Measles virus induces apoptosis in uninfected bystander T cells and leads to granzyme B and caspase activation in peripheral blood mononuclear cell cultures

Background Measles causes lymphopenia and depresses cell‐mediated immunity, but the mechanisms of immunosuppression and cell loss are poorly known. Methods We have used an in vitro model of measles virus (MV)‐infected peripheral blood mononuclear cells (PBMCs) and phytohaemagglutinin‐stimulated PBMCs in order to assess MV–leucocyte interactions. Cell population undergoing apoptosis was measured by flow cytometry and Annexin‐V‐fluos staining. The expression of Fas, FasL, TNRF1, and Bcl‐2 was analyzed by flow cytometry and Western blotting, and activation of caspase cascade was measured using a colourimetric caspase substrate set. The effects of caspase inhibitors were detected by flow cytometry. Results Measles virus was able to infect monocytes, but interestingly induced apoptosis in uninfected T cells, indicating that induction of apoptosis in T cells is mediated by MV‐infected adherent cells. Only 1% of T cells contained MV antigen day 3 p.i. Interestingly the percentage of early apoptotic T cells at the same time was 35%, showing that apoptosis was not the result of MV infection in T cells. Measles virus‐induced Fas but not FasL or TNFR1 expression on PMBC, as well as activation of granzyme B and caspase cascade. Simultaneously, overexpression of Bcl‐2 protein was detected. Caspase inhibitor decreased the amount of apoptotic T cells. Conclusion Measles virus‐infected monocytes induce apoptosis in uninfected T cells, suggesting that infected monocytes probably interact via cell–surface molecules with uninfected T cells and induce apoptosis by indirect mechanisms. Apoptosis of the lymphocytes may contribute to the pathogenesis of MV‐induced immunosuppression and cell loss.