Although primary patency is low, excellent limb salvage rates can be achieved in patients with CLI through close follow-up and secondary interventions. These data, and the 12% annual death rate, validate PTA as first-line therapy in patients with CLI.

SummaryThe C-C chemokine receptor 5 (CCR5), a member of G-protein-coupled receptors, serves as a coreceptor for human immunodeficiency virus type 1 (HIV-1). In the present study, we examined the interactions between CCR5 and novel CCR5 inhibitors containing the spirodiketopiperazine (SDP) scaffold, AK530 and AK317, both of which were lodged in the hydrophobic cavity located between the upper transmembrane domain and the second extracellular loop (ECL2) of CCR5. Although substantial differences existed between the two inhibitors: AK530 had 10-fold greater CCR5-binding affinity (K D : 1.4 nM) than AK317 (16.7 nM), their antiviral potency was virtually identical (IC 50 : 2.1 and 1.5 nM, respectively). Molecular dynamics simulations for inhibitor-unbound CCR5 showed hydrogen bond interactions among transmembrane residues Y108, E283, and Y251, which were crucial for HIV-1-gp120/sCD4 complex binding and HIV-1 fusion. Indeed, AK530 and AK317, when bound to CCR5, disrupted these inter-helix hydrogen bond interactions, a salient molecular mechanism enabling allosteric inhibition. Mutagenesis and structural analysis showed that ECL2 consists of a part of the hydrophobic cavity for both inhibitors, although AK317 is more tightly engaged with ECL2 than AK530, explaining their similar anti-HIV-1 potency despite the difference in K D values. We also found that amino acid residues in the β-hairpin structural motif of ECL2 are critical for HIV-1-elicited fusion and the binding of the SDP-based inhibitors to CCR5. The direct ECL2-engaging property of the inhibitors likely produces an ECL2 conformation, which HIV-1 gp120 cannot bind to, but also prohibits HIV-1 from utilizing the "inhibitor-bound" CCR5 for cellular entry, a mechanism of HIV-1's resistance to CCR5 inhibitors. The data should not only help delineate the dynamics of CCR5 following inhibitor binding but also aid in designing CCR5 inhibitors that are more potent against HIV-1 and prevent or delay the emergence of resistant HIV-1 variants.

Scaphoid fractures are among the most common hand fractures in adults. The geometry of the scaphoid as it relates to its retrograde blood supply renders it particularly prone to avascular necrosis and other fracture complications. Though there has been long-standing debate over the optimal method of diagnosing scaphoid fractures, the best and most cost-effective methods combine clinical exam with other imaging modalities such as navicular view plain films, CT, and MRI for particularly questionable presentations. Once a scaphoid fracture is diagnosed, it should be followed by an orthopaedic surgeon and treated with cast immobilization or operative management in the case of displaced fractures. Fractures should be followed to monitor healing progress in order to ensure the eventual development of bridging bone across the fracture line, usually best appreciated on CT. Proper treatment of scaphoid fractures and assessment of fracture healing can minimize the occurrence of non-unions and associated arthritic changes.