The receptor for glial cell line-derived neurotrophic factor (GDNF) consists of GFR␣-1 and Ret. Neurturin is a GDNF-related neurotrophin whose receptor is presently unknown. Here we report that neurturin can bind to either GFR␣-1 or GFR␣-2, a novel receptor related to GFR␣-1. Both GFR␣-1 and GFR␣-2 mediate neurturininduced Ret phosphorylation. GDNF can also bind to either GFR␣-1 or GFR␣-2, and activate Ret in the presence of either binding receptor. Although both ligands interact with both receptors, cells expressing GFR␣-1 bind GDNF more efficiently than neurturin, while cells expressing GFR␣-2 bind neurturin preferentially. Crosslinking and Ret activation data also suggest that while there is cross-talk, GFR␣-1 is the primary receptor for GDNF and GFR␣-2 exhibits a preference for neurturin. We have also cloned a cDNA that apparently codes for a third member of the GFR␣ receptor family. This putative receptor, designated GFR␣-3, is closely related in amino acid sequence and is nearly identical in the spacing of its cysteine residues to both GFR␣-1 and GFR␣-2. Analysis of the tissue distribution of GFR␣-1, GFR␣-2, GFR␣-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression. Consistent with a role in GDNF function, the GFR␣s and Ret are expressed in many of the same tissues, suggesting that GFR␣s mediate the action of GDNF family ligands in vivo.

An investigation was made as to whether studies have found journal clubs for physicians in training to be effective for improving patient. care, teaching critical appraisal skills, improving reading habits, increasing knowledge of clinical epidemiology and biostatistics, and increasing the use of medical literature in clinical practice. A literature search was undertaken using 10 databases and retrieval systems and hand searches of journals, conference proceedings and personal files. The rigor of studies meeting the inclusion criteria was analyzed using a protocol based on methods established by the Cochrane Collaboration. One randomized controlled trial found an improvement in knowledge of clinical epidemiology and biostaristics, reading habits, and the use of medical literature in practice, but no improvement in critical appraisal skills. Six less methodologically rigorous studies found possible improvement in critical appraisal skills. It is concluded that journal clubs may improve knowledge of clinical epidemiology and biostatistics, reading habits, and the use of medical literature in practice. A multi-center, randomized controlled trial of journal clubs is needed to assess whether journal clubs improve critical appraisal skills.

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