Whereas many interacting proteins have been identified for AMPA and NMDA glutamate receptors, fewer are known to directly bind and regulate function of kainate receptors. Using a yeast two-hybrid screen for interacting partners of the C-terminal domain of GluR6a, we identified a novel neuronal protein of the BTB/kelch family, KRIP6. KRIP6 binds to the GluR6a C-terminal domain at a site distinct from the PDZ-binding motif and it co-immunoprecipitates with recombinant and endogenous GluR6. Co-expression of KRIP6 alters GluR6 mediated currents in a heterologous expression system reducing peak current amplitude and steady-state desensitization, without affecting surface levels of GluR6. Endogenous KRIP6 is widely expressed in brain and overexpression of KRIP6 reduces endogenous kainate receptor-mediated responses evoked in hippocampal neurons. Taken together, these results suggest that KRIP6 can directly regulate native kainate receptors and provide the first evidence for a BTB/kelch protein in direct functional regulation of a mammalian glutamate receptor.

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These findings confirm that medical CT cannot be used as the exclusive gold standard for SSCD and that, particularly for small dehiscences on CT, clinical symptoms must be clearly indicative of a dehiscence before surgical treatment is undertaken. Preoperative counseling for small dehiscences may need to include the possibility that no dehiscence may be found despite radiologic evidence for it.

Neuronal proteins of the BTB/kelch and PDZ domain families interact with different regions of the cytoplasmic C-terminal domain of the GluR6 kainate receptor subunit. The BTB/kelch protein KRIP6 binds within a 58 amino acid segment of GluR6 proximal to the plasma membrane. In contrast, PDZ domain proteins, such as PICK1 and PSD95, interact with the last 4 residues of the GluR6 C-terminus. KRIP6 reduces peak currents mediated by recombinant GluR6 receptors and by native kainate receptors in neurons, whereas PICK1 stabilizes kainate receptors at synapses. Thus, protein-protein interactions at the C-terminal domain of GluR6 are important for regulating kainate receptor physiology. Here, we show by co-clustering and co-immunoprecipitation that KRIP6 interacts with PICK1 in heterologous cells. In addition, we demonstrate a novel modulation of GluR6 receptors by PICK1 resulting in increased peak current and relative desensitization of GluR6-mediated currents, phenotypes opposite to those produced by KRIP6. Importantly, these effects cancel out when KRIP6 and PICK1 are co-expressed together with GluR6. KRIP6 and PICK1 strongly co-cluster and coimmunoprecipitate regardless of the presence of GluR6. Immunofluorescence analysis reveals that GluR6 can either join the KRIP6-PICK1 clusters or remain separate; however, co-expression of KRIP6 reduces the fraction of PICK1 that co-immunoprecipitates with GluR6. Taken together, these results indicate that, in addition to a previously demonstrated direct interaction with the GluR6 Cterminal domain, KRIP6 regulates kainate receptors by inhibiting PICK1 modulation via competition or a mutual blocking effect.

Conjunctive consolidation, one method of multivariable analysis by arranging data into clusters, is intuitive and transparent. An unexpected consequence in writing this article was the discovery of just how useful it is in critically analyzing articles and in designing new projects. It has stimulated a fresh understanding as to the value of multivariable thinking in all clinical research. This article is organized into the sequential steps for performing conjunctive consolidation for critically analyzing an article of interest and for completing the process, pending all required data are available. Investigators, particularly those who perform clinical research, should consider conjunctive consolidation as a valuable method of multivariable analysis with which to report data.

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With recent changes in the landscape of health care, clinical practice guidelines (CPGs) have proliferated. Attitudes about guidelines differ considerably, forming 2 competing viewpoints with considerable tension between them. Some feel CPGs are unneeded or are efforts to create automated "cookie cutter" medical practice; at best, they are perceived as suggestions that may be altered by experience. Others feel they are mandates that must be followed to the letter. This article attempts to explain how and why we have arrived at this point and to explain the origins of the differing viewpoints. We begin by describing the 2 viewpoints and proceed to define the origin of medicine as a profession and to chronicle the evolution of health insurance, medical education, and scientific methods for evaluating evidence.