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PURPOSE: To analyze the feasibility of combining computer-assisted 3-dimensional planning with patient-specific drill guides and to evaluate this technology's surgical outcomes for distal radius intra-articular malunions. METHODS: Six symptomatic patients with intra-articular malunions of the distal radius with a stepoff of more than 2 mm were treated with an outside-in corrective osteotomy. The described cases consist of 2 malunited volar Barton fractures, 2 radial styloid fractures, 1 AOtype C1 fracture, and 1 die-punch fracture. The osteotomies were guided by 3-dimensionally generated aiming guides that allowed precise cutting and the reduction of up to 2 fragments. All 6 patients were examined clinically and radiologically after 1 year. The surgical outcomes were quantitatively analyzed by comparing the preoperative and postoperative computed tomographic data. RESULTS: In all 6 cases, the osteotomies were consolidated 8 weeks postoperatively. After 1 year, 4 patients were pain-free, 1 had mild pain, and 1 experienced moderate pain during heavy work. Wrist motion and grip strength were improved in all patients. The postoperative radiographs showed no articular stepoff or degenerative changes. CONCLUSIONS: Patient-specific aiming guides provided a reliable method to correct intraarticular malunions of the distal radius. This technique allows the surgeon to safely perform difficult intra-articular osteotomies and may help limit the need for salvage procedures such as partial or complete wrist arthrodesis. To analyze the feasibility of combining computer-assisted 3-dimensional planning with patient-7 specific drill guides and to evaluate its surgical outcomes for distal radius intra-articular malunions. 8 9 Methods: 10Six symptomatic patients with intra-articular malunions of the distal radius with a step-off of more 11 than 2 mm were treated with an outside-in corrective osteotomy. The described cases consist of 2 12 malunited volar Barton fractures, 2 radial styloid fractures, one AO-type C1 fracture, and 1 die-punch 13 fracture. The osteotomies were guided by 3-dimensionally generated aiming guides that allowed 14 precise cutting and the reduction of up to 2 fragments. All 6 patients were examined clinically and 15 radiologically after 1 year. The surgical outcomes were quantitatively analyzed by comparing the pre-16 and postoperative computed tomographic data. 17 18 Results: 19In all 6 cases, the osteotomies were consolidated 8 weeks postoperatively. After 1 year, 4 patients 20 were pain-free, one had mild pain, and one experienced moderate pain during heavy work. Wrist 21 motion and grip strength were improved in all patients. The postoperative radiographs showed no 22 articular step-off or degenerative changes. 23 24 Discussion: 25Patient-specific aiming guides provided a reliable method to correct intra-articular malunions of the 26 distal radius. This technique allows the surgeon to safely perform difficult intra-articular osteotomies 27 and may help limit the need for salvage procedures such a...

The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited during cell stress signaling. Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of the mitochondrion-dependent apoptotic pathway resulting in programmed cell death. Here we report the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-Å resolution. Compared with other caspases, significant structural differences prevail in the active site region and the dimer interface. The structure reveals the hydrophobic properties of the S5 specificity pocket, which is unique to caspase-2, and provides the details of the inhibitorprotein interactions in subsites S1-S4. These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and analytical use. Another unique feature of caspase-2 is a disulfide bridge at the dimer interface, which covalently links the two monomers. Consistent with this finding, caspase-2 exists as a (p19/p12) 2 dimer in solution, even in the absence of substrates or inhibitors. The intersubunit disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other long prodomain caspases exist as monomers in solution, and dimer formation is driven by ligand binding. Therefore, the central disulfide bridge appears to represent a novel way of dimer stabilization in caspases.

Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network.

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Congenital or posttraumatic bone deformity may lead to reduced range of motion, joint instability, pain, and osteoarthritis. The conventional joint-preserving therapy for such deformities is corrective osteotomy-the anatomical reduction or realignment of bones with fixation. In this procedure, the bone is cut and its fragments are correctly realigned and stabilized with an implant to secure their position during bone healing. Corrective osteotomy is an elective procedure scheduled in advance, providing sufficient time for careful diagnosis and operation planning. Accordingly, computer-based methods have become very popular for its preoperative planning. These methods can improve precision not only by enabling the surgeon to quantify deformities and to simulate the intervention preoperatively in three dimensions, but also by generating a surgical plan of the required correction. However, generation of complex surgical plans is still a major challenge, requiring sophisticated techniques and profound clinical expertise. In addition to preoperative planning, computer-based approaches can also be used to support surgeons during the course of interventions. In particular, since recent advances in additive manufacturing technology have enabled cost-effective production of patient-and intervention-specific osteotomy instruments, customized interventions can thus be planned for and performed using such instruments. In this chapter, state of the art and future perspectives of computer-assisted deformity-correction surgery of the upper and lower extremities are presented. We elaborate on the benefits and pitfalls of different approaches based on our own experience in treating over 150 patients with three-dimensional preoperative planning and patient-specific instrumentation.

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Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C) HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins—high physical stability, specificity and low production costs—with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.