Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immune-mediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to 'steroid-sparing'. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.     

Indolyl aryl sulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: role of two halogen atoms at the indole ring in developing new analogues with improved antiviral activity

Indolyl aryl sulfones bearing the 4,5-difluoro (10) or 5-chloro-4-fluoro (16) substitution pattern at the indole ring were potent inhibitors of HIV-1 WT and the NNRTI-resistant strains Y181C and K103N-Y181C. These compounds were highly effective against the 112 and the AB1 strains in lymphocytes and inhibited at nanomolar concentration the multiplication of the IIIBBa-L strain in macrophages. Compound 16 was exceptionally potent against RT WT and RTs carrying the K103N, Y181I, and L100I mutations.     

Effects of radial shock waves therapy on osteoblasts activities

Radial shock waves therapy (RSWT) differs from extracorporeal shock waves therapy (ESWT) in that it produces a non-focused wave that is dissipated radially at the skin. Few studies have yet explored the effects of RSWT on bone tissue. Osteoblasts in culture flasks were studied by polymerase chain reaction after treatment with RSW (500 impulses, 0.05?mJ/mm²). An inhibited osteoblastogenesis was observed, with a statistically significant reduction in type 1 collagen, osterix, bone sialoprotein and receptor activator NF kappa ligand expression at 24 and 48?h, of osteocalcin at 24, 48 and 72?h, and osteopontin at 48 and 72?h. These findings show that RSWT is not indicated for treatment of delayed fracture union, pseudoarthrosis, and complex regional pain syndrome. The observed reduction in the receptor activator of nuclear factor-kB ligand/osteoprotegerin ratio suggests that it has an inhibiting effect on osteoclastogenesis, which could make it a useful tool for applications in proliferative diseases.     

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α₂nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra_Ast^+/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra_Ast^+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1–parasympathetic–bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.     

AN EXPERIMENTAL STUDY OF GYE'S CANCER THEORY

It is obviously impossible to draw definite conclusions as to the significance of the differences between our work and Gye''s, and still less, of the differences between Gye''s work and that of Murphy and of Flu. We can only say that in a fairly large series of experiments, extending over a period of 12 months, we have had absolutely no indication of the necessity of two factors in the production of the Rous sarcoma. In other words, we have been unable to duplicate either the results of Gye or the modified confirmations of his work by Murphy and Flu. We have shown that uncontrollable local and individual variations may produce results in occasional chicks which simulate satisfactory experiments, but when viewed as a whole, mean nothing. Because of the conflicting nature of results obtained by those who have undertaken to repeat the work, and on account of the difficulty of controlling all factors involved, we do not feel that it may be stated definitely that Gye''s theory of the cause of cancer is wrong. On the other hand the theory apparently needs more evidence in its support if it is to receive further serious consideration. It is suggested, in order to untangle the subjéct as rapidly as possible, that future publications should include sufficient consecutive protocols to make the trend of the experiments obvious to the reader.     

Concentration of heparin-locking solution and risk of central venous hemodialysis catheter malfunction

Heparin is used as an interdialytic locking solution for hemodialysis (HD) central venous catheters (CVCs). The purpose of this study was to compare effectiveness of two heparin concentrations (10,000 and 1,000 U/mL) in preventing catheter malfunction. We compared two time periods: a 6-month period with heparin 10,000 U/mL and a 3-month period with heparin 1,000 U/mL. Adults on HD using a CVC (tunneled or untunneled) in Calgary, Alberta, were included. The primary outcome was catheter malfunction. A total of 139 and 134 patients in the heparin 10,000 and 1,000 U/mL periods, respectively, were included. The crude rate of catheter malfunction, per 1,000 HD sessions, was similar for heparin 10,000 (7.6; 95% CI, 5.3 to 10.8) and 1,000 (6.7; 95% CI, 4.3 to 10.3) U/mL periods, respectively (p = 0.76). After adjusting for CVC characteristics and use of recombinant tissue plasminogen activator (rt-PA), there was no association between heparin concentration and CVC malfunction (hazard ratio, 0.77; 95% CI, 0.37 to 1.61). In conclusion, the use of a lower concentration of heparin was not associated with an increased risk of catheter malfunction but may be associated with greater rt-PA use. The association between heparin concentration and rt-PA use requires further study.     

Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells

Cannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti-inflammatory and immunosuppressive effects, the underlying mechanisms of which remain unclear. In the current study, we questioned whether CBD modulates activation of mast cells, key players in inflammation. By using the rat basophilic leukemia mast cell line (RBL-2H3), we demonstrate that CBD (3-10 muM) augments beta-hexosaminidase release, a marker of cell activation, from antigen-stimulated and unstimulated cells via a mechanism, which is not mediated by G(i)/G(o) protein-coupled receptors but rather is associated with a robust rise in intracellular calcium ([Ca(2+)](i)) levels sensitive to clotrimazole and nitrendipine (10-30 muM). This action, although mimicked by Delta(9)-tetrahydrocannabinol (THC), is opposite to that inhibitory, exerted by the synthetic cannabinoids WIN 55,212-2 and CP 55,940. Moreover, the vanilloid capsaicin, a full agonist of transient receptor potential channel VR1, did not affect [Ca(2+)](i)levels in the RBL-2H3 cells, thus excluding the involvement of this receptor in the CBD-mediated effects. Together, these results support existence of yet-to-be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca(2+) influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.     

Creating clinically relevant knowledge from systematic reviews: the challenges of knowledge translation

RATIONALE AND OBJECTIVE: A research translation strategy for chronic pain was developed that has significant potential to advance the usefulness of systematic reviews (SRs) in clinical practice. METHOD: The strategy used interactive case-based workshops that summarize current evidence on treatments for chronic non-cancer pain. Health technology assessment researchers and clinicians collaborated to translate SR evidence into education aids, but this proved far from straightforward. RESULTS: Sourcing and selecting the SR evidence required maintaining a credible balance between the diametrical concepts of comprehensiveness and efficiency, and relevance and validity. On examination of the collated evidence base, further challenges were encountered in dealing with the lack of consistency among the SRs in the quality of execution, the scales used to rate the quality of the evidence, and the conclusions on common topic areas. Strategies for overcoming these difficulties are discussed. CONCLUSIONS: The key elements for creating clinically relevant knowledge from SRs are: a flexible, consistent and transparent methodology; credible research; involvement of renowned content experts to translate the evidence into clinically meaningful guidance; and an open, trusting relationship among all contributors.     

Tumor cell proliferation in early gastric cancer: biological and clinical behavior

BACKGROUND/AIMS: Recently, early gastric cancers without lymph node metastasis have successfully been removed through a simple endoscopic resection. Tumor cell proliferation may be related to the malignant potential of early gastric cancer. The purpose of this study is to prospectively investigate the relationship between the incorporation rate of bromodeoxyuridine (BrdU) into the DNA of dividing cells, and the main biological and clinical early gastric cancer characteristics. METHODOLOGY: Multiple tumor specimens were taken from 27 early gastric cancers and analyzed through anti-BrdU monoclonal antibody. Tumor BrdU labeling index (LI=% positive cells over 2,000 tumor cells) was determined. Early gastric cancers were evaluated in tumor size, mucosal and submucosal involvement, histologic type and grading, lymphatic and venous invasion, and nodal metastasis. RESULTS: BrdU LI was significantly higher in patients with submucosal neoplastic invasion, Pen A Kodama type, tumor vessel invasion and lymph node involvement. Early gastric cancer patients with over 22% BrdU LI showed a significantly higher incidence of submucosal invasion, lymphatic-venous involvement and a reduced survival when compared to patients with medium (12-22%) or low BrdU LI (<12%). CONCLUSIONS: Our results suggest that BrdU LI may be considered a useful indicator of early gastric cancer aggressiveness.