Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels.

It has been established that Ca(V)3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of Ca(V)3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in Ca(V)3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of Ca(V)3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.

Speed, accuracy, and confidence in Google, Ovid, PubMed, and UpToDate: results of a randomised trial.

BACKGROUND: The explosion of biomedical information has led to an 'information paradox'-the volume of biomedical information available has made it increasingly difficult to find relevant information when needed. It is thus increasingly critical for physicians to acquire a working knowledge of biomedical informatics. AIM: To evaluate four search tools commonly used to answer clinical questions, in terms of accuracy, speed, and user confidence. METHODS: From December 2008 to June 2009, medical students, resident physicians, and attending physicians at the authors' institution were asked to answer a set of four anaesthesia and/or critical care based clinical questions, within 5 min, using Google, Ovid, PubMed, or UpToDate (only one search tool per question). At the end of each search, participants rated their results on a four point confidence scale. One to 3 weeks after answering the initial four questions, users were randomised to one of the four search tools, and asked to answer eight questions, four of which were repeated. The primary outcome was defined as a correct answer with the highest level of confidence. RESULTS: Google was the most popular search tool. Users of Google and UpToDate were more likely than users of PubMed to answer questions correctly. Subjects had the most confidence in UpToDate. Searches with Google and UpToDate were faster than searches with PubMed or Ovid. CONCLUSION: Non-Medline based search tools are not inferior to Medline based search tools for purposes of answering evidence based anaesthesia and critical care questions.