The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested. N itric oxide (NO), a ubiquitous signaling molecule, is currently one of the most intensely studied small molecules in biology because of its involvement in numerous biological events such as vasodilation, neurotransmission, and the immune response. The isozymes of NO synthase (NOS) that produce NO are dimeric multidomain polypeptides consisting of three main components: a heme-containing catalytic oxygenase domain (NOSoxy), a calmodulin binding linker, and a NADPH reductase domain. NOS transforms L-arginine to citrulline and NO in two sequential steps consuming oxygen and electrons (1). The cofactor tetrahydrobiopterin bound at the interface of the two oxygenase domains in the NOS dimer is required for NO synthesis (2, 3). In mammals, three NOS isoforms have been identified sharing 50-60% sequence identity, which differ in cellular distribution, regulation, and activity (1). Endothelial NOS (eNOS) regulates vascular tone and smooth muscle tension (4). Neuronal NOS (nNOS) produced NO functions as a diffusible neurotransmitter (5), whereas NO generated by inducible NOS (iNOS) generates cytotoxins with both protective and pathologic effects (1, 6). In line with NO's central biological role, there are a number of pathological processes associated with its over-or underproduction. For example, nNOS is implicated in stroke and migraine, and iNOS is implicated in septic shock, arthritis, and multiple sclerosis. The possibility of treating these and other conditions by inhibiting NOS has elicited intense efforts to identify or design NOS inhibitors. Because the three isoforms of NOS have unique roles in separate tissues, selective inhibition of one isozyme over the others is essential. In particular, it is important not to inhibit eNOS because of its critical role in maintaining vascular tone. Numerous inhibitors of NOS have been developed (7). The majority of the inhibitors contain amidino or ureido functional groups that mimic the guanidino group of the substrate L-arginine. The high level of amino acid conservation and striking...

DSAEK is an effective treatment of endothelial dysfunction. Surgical technique is important to limit endothelial cell loss and prevent complications, such as graft dislocation. The injector device has several advantages over the trifold forceps technique, including decreased endothelial cell loss, graft dislocation rate, and graft failure rate, and it reduces the DSAEK learning curve. DSAEK graft injectors likely will have a role in the future of endothelial keratoplasty.

PurposeThere is limited evidence to inform the optimal follow-up schedule after cataract surgery. This study aims to determine whether a standardized question set can predict unexpected management changes (UMCs) at the postoperative week one (POW1) timepoint.SettingMassachusetts Eye and Ear, Harvard Medical School.DesignProspective cohort study.MethodsTwo-hundred-and-fifty-four consecutive phacoemulsification cases having attended an examination between postoperative days 5–14. A set of 7 ‘Yes’ or ‘No’ questions were administered to all participants by a technician at the POW1 visit. Patient answers along with perioperative patient information were recorded and analyzed. Outcomes were the incidence of UMCs at POW1.ResultsThe incidence of UMCs was zero in uneventful cataract cases with unremarkable history and normal postoperative day one exam if no positive answers were given with the question set demonstrating 100% sensitivity (p<0.0001). A test version with 5 questions was equally sensitive in detecting UMCs at POW1 after cataract surgery.ConclusionIn routine cataract cases with no positive answers to the current set of clinical questions, a POW1 visit is unlikely to result in a management change. This result offers the opportunity for eye care providers to risk-stratify patients who have had cataract surgery and individualize follow-up.