Src family protein-tyrosine kinases possess several modular domains important for regulation of catalytic activity and interaction with potential substrates. Here, we explore interactions between the SH2 domain of Hck, a Src family kinase, and substrates containing SH2 domain-binding sites. We have synthesized a series of peptide substrates containing a high affinity SH2 domain binding site, (phospho)Tyr-Glu-Glu-Ile. We show that the presence of this sequence in a peptide results in a dramatic increase in the phosphorylation rate of a second tyrosine located at the N terminus. Enhanced phosphorylation is not a consequence of stimulation of enzymatic activity by C-terminal tail displacement but is imparted instead by a 10-fold reduction in the K m of the phosphotyrosine-containing peptide when compared with a control. The isolated catalytic domain of the nonreceptor tyrosine kinase Abl does not show a preference for the pYEEI motif-containing peptide; however, the preference is restored when the SH2 domain of Src is introduced into Abl. Furthermore, enhanced phosphorylation is dependent on the distance between SH2 domain-binding site and phosphorylatable tyrosine, with the minimum distance requirement being seven amino acids. Reversing the orientation of the pYEEI motif with respect to the substrate sequence decreases phosphorylation by down-regulated Hck, but both orientations are utilized equally well by activated Hck. We discuss the possible implications of these results for processive phosphorylation of substrates in vivo by Src family kinases.There are presently nine identified members of the Src family of non-receptor tyrosine kinases. These enzymes are widely expressed in many tissues and are involved in the conversion of extracellular signals into cellular responses (see Ref. 1 for review). The primary structure of Src family kinases reveals a highly modular organization shared among all members. In addition to the kinase catalytic domain that is responsible for enzymatic activity, Src family kinases possess noncatalytic modules termed Src homology domains (SH2 and SH3). SH2 and SH3 domains mediate specific intramolecular and intermolecular interactions that are important for signal transduction; SH2 domains recognize short peptide motifs containing phosphotyrosine, and SH3 domains bind to proline-rich sequences (2, 3).For Src family kinases, SH2 and SH3 domains have both a negative and a positive regulatory role in tyrosine kinase activity. The negative regulatory role arises from intramolecular contacts between the SH2 and SH3 domains and the tyrosine kinase catalytic domain. The structural basis for repression of catalytic activity has recently been elucidated by crystal structures of the down-regulated forms of Src and Hck (4, 5). Phosphorylation of Src family kinases at a C-terminal regulatory site by another protein kinase (designated Csk) leads to inhibition. This inhibition is caused by an intramolecular interaction between the phosphorylated tail and the SH2 domain (6 -9). A polyproline type II h...

It is difficult to fully assess an agitated patient, and the complete psychiatric evaluation usually cannot be completed until the patient is calm enough to participate in a psychiatric interview. Nonetheless, emergency clinicians must perform an initial mental status screening to begin this process as soon as the agitated patient presents to an emergency setting. For this reason, the psychiatric evaluation of the agitated patient can be thought of as a 2-step process. First, a brief evaluation must be aimed at determining the most likely cause of agitation, so as to guide preliminary interventions to calm the patient. Once the patient is calmed, more extensive psychiatric assessment can be completed. The goal of the emergency assessment of the psychiatric patient is not necessarily to obtain a definitive diagnosis. Rather, ascertaining a differential diagnosis, determining safety, and developing an appropriate treatment and disposition plan are the goals of the assessment. This article will summarize what components of the psychiatric assessment can and should be done at the time the agitated patient presents to the emergency setting. The complete psychiatric evaluation of the patient whose agitation has been treated successfully is beyond the scope of this article and Project BETA (Best practices in Evaluation and Treatment of Agitation), but will be outlined briefly to give the reader an understanding of what a full psychiatric assessment would entail. Other issues related to the assessment of the agitated patient in the emergency setting will also be discussed.

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OBJECTIVES-To identify factors associated with sustained benzodiazepine use in older adults DESIGN-12-year cohort studySETTING-Community-based epidemiologic survey. PARTICIPANTS-1,342 individuals aged 65+ yearsMEASUREMENTS-Demographics, medication use, depressive symptoms, sleep complaints, alcohol use, and smoking, assessed at two-year intervals; descriptive analysis to characterize benzodiazepine users and identify factors associated with sustained benzodiazepine use (use at two consecutive waves); longitudinal lag-time analysis to determine characteristics that predicted sustained use. RESULTS-Initially, 5.5 % of men and 9.8 % of women were using benzodiazepines. Users were significantly more likely than non-users to be women, less educated, report more depressive and anxiety symptoms, use more prescription medications, have lower self-rated health, have difficulty maintaining sleep, and less likely to consume alcohol. Approximately 50%, 44%, and 25% of these users aged 65-74. 75-84, and 85+ were sustained users at follow-up. Being female, using two or more non-benzodiazepine prescription medications, and smoking were independently associated with subsequent sustained benzodiazepine use.