Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage

Elevated concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) in the synovial fluids and serum of patients with arthritis have been implicated in the joint tissue destruction associated with these conditions, however studies conducted to date on the role and effects of IL-6 in the process of cartilage proteoglycan (aggrecan) catabolism are disparate. In the present study, bovine articular cartilage explants were maintained in a model organ culture system in the presence or absence of IL-1α or TNF-α, and under co-stimulation with or without IL-6 and/or sIL-6R. After measuring proteoglycan loss from the explants, the proteolytic activity and expression profiles of aggrecanase(s) was assessed for each culture condition. Stimulation of cartilage explants with IL-6 and/or sIL-6R potentiated aggrecan catabolism and release above that seen in the presence of IL-1α or TNF-α alone. This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2

Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage

OBJECTIVE: To determine the effect of cyclosporin A (CSA) on aggrecanase- and matrix metalloproteinase (MMP)-mediated catabolism of proteoglycan (aggrecan) in articular cartilage explants stimulated with interleukin-1 (IL-1) in a culture system that mimics early pathologic processes associated with arthritic disease. METHODS: Proteoglycan (glycosaminoglycan) and lactate quantification, Western immunoblot analyses of aggrecan degradation products, reverse transcription-polymerase chain reaction analyses of aggrecanase-1, aggrecanase-2 (ADAM-TS4, ADAM-TS5, respectively), MMP-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, and TIMP-3 messenger RNA (mRNA) expression in articular cartilage explant cultures, and electrophoretic mobility shift assay analysis of nuclear factor of activated T cells (NF-AT) transcription factor activation were used. RESULTS: CSA inhibited, in a dose-dependent and noncytotoxic manner, aggrecanase-mediated proteoglycan catabolism and loss from IL-1-stimulated cartilage explants. There was no evidence of MMP-mediated aggrecan catabolism in this in vitro model. Treatment of articular cartilage explant cultures with 10 ng/ml of IL-1alpha up-regulated the expression of mRNA for ADAM-TS4, ADAM-TS5, MMP-1, MMP-3, and MMP-13. The expression of ADAM-TS4, ADAM-TS5, and MMP-13 was abrogated by the inclusion of 10 microM CSA in the culture medium. NF-AT activation was observed in chondrocytes but could not be inhibited by preincubation with 10 microM CSA. CONCLUSION: CSA can inhibit IL-1-induced aggrecanase-mediated proteoglycan catabolism in articular cartilage explants maintained in culture for 4 days, thus demonstrating molecular mechanisms whereby CSA may be an effective therapy for degenerative joint disease

Binding and localization of recombinant lubricin to articular cartilage surfaces

Lubricin is a secreted, cytoprotective glycoprotein that contributes to the essential boundary lubrication mechanisms necessary for maintaining low friction levels at articular cartilage surfaces. Diminishment of lubricin function is thereby implicated as an adverse contributing factor in degenerative joint diseases such as osteoarthritis. Lubricin occurs as a soluble component of synovial fluid, and is synthesized and localized in the superficial layer of articular cartilage (and thus has also been described as “superficial zone protein”, or SZP); however, defined interactions responsible for lubricin retention at this site are not well characterized. In the current studies, we identified molecular determinants that enable lubricin to effectively bind to articular cartilage surfaces. Efficient and specific binding to the superficial zone was observed for synovial lubricin, as well as for recombinant full-length lubricin and a protein construct comprising the lubricin C-terminal (hemopexin-like) domain (LUB-C, encoded by exons 7–12). A construct representing the N-terminal region of lubricin (LUB-N, encoded by exons 2–5) exhibited no appreciable cartilage-binding ability, but displayed the capacity to dimerize, and thus potentially influence lubricin aggregation. Disulfide bond disruption significantly attenuated recombinant lubricin and LUB-C binding to cartilage surfaces, demonstrating a requirement for protein secondary structure in facilitating the appropriate localization of lubricin at relevant tissue interfaces. These findings help identify additional key attributes contributing to lubricin functionality, which would be expected to be instrumental in maintaining joint homeostasis