G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations.

G551D is a major disease-associated gating mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP- and phosphorylation-dependent chloride channel. G551D causes severe cystic fibrosis (CF) disease by disrupting ATP-dependent channel opening; however, whether G551D affects phosphorylation-dependent channel activation is unclear. Here, we use macropatch recording and Ussing chamber approaches to demonstrate that G551D impacts on phosphorylation-dependent activation of CFTR, and PKA-mediated phosphorylation regulates the interaction between the x-loop in nucleotide-binding domain 2 (NBD2) and cytosolic loop (CL) 1. We show that G551D not only disrupts ATP-dependent channel opening but also impairs phosphorylation-dependent channel activation by largely reducing PKA sensitivity consistent with the reciprocal relationship between channel opening/gating, ligand binding, and phosphorylation. Furthermore, we identified two novel GOF mutations: D1341R in the x-loop near the ATP-binding cassette signature motif in NBD2 and D173R in CL1, each of which strongly increased PKA sensitivity both in the wild-type (WT) background and when introduced into G551D-CFTR. When D1341R was combined with a second GOF mutation (e.g., K978C in CL3), we find that the double GOF mutation maximally increased G551D channel activity such that VX-770 had no further effect. We further show that a double charge-reversal mutation of D1341R/D173R-CFTR exhibited similar PKA sensitivity when compared with WT-CFTR. Together, our results suggest that charge repulsion between D173 and D1341 of WT-CFTR normally inhibits channel activation at low PKA activity by reducing PKA sensitivity, and negative allostery by the G551D is coupled to reduced PKA sensitivity of CFTR that can be restored by second GOF mutations.

Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.

In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating.

Long-range coupling between the extracellular gates and the intracellular ATP binding domains of multidrug resistance protein pumps and cystic fibrosis transmembrane conductance regulator channels.

The ABCC transporter subfamily includes pumps, the long and short multidrug resistance proteins (MRPs), and an ATP-gated anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). We show that despite their thermodynamic differences, these ABCC transporter subtypes use broadly similar mechanisms to couple their extracellular gates to the ATP occupancies of their cytosolic nucleotide binding domains. A conserved extracellular phenylalanine at this gate was a prime location for producing gain of function (GOF) mutants of a long MRP in yeast (Ycf1p cadmium transporter), a short yeast MRP (Yor1p oligomycin exporter), and human CFTR channels. Extracellular gate mutations rescued ATP binding mutants of the yeast MRPs and CFTR by increasing ATP sensitivity. Control ATPase-defective MRP mutants could not be rescued by this mechanism. A CFTR double mutant with an extracellular gate mutation plus a cytosolic GOF mutation was highly active (single-channel open probability >0.3) in the absence of ATP and protein kinase A, each normally required for CFTR activity. We conclude that all 3 ABCC transporter subtypes use similar mechanisms to couple their extracellular gates to ATP occupancy, and highly active CFTR channels that bypass defects in ATP binding or phosphorylation can be produced.

An electrostatic interaction at the tetrahelix bundle promotes phosphorylation-dependent cystic fibrosis transmembrane conductance regulator (CFTR) channel opening.

The CFTR channel is an essential mediator of electrolyte transport across epithelial tissues. CFTR opening is promoted by ATP binding and dimerization of its two nucleotide binding domains (NBDs). Phosphorylation of its R domain (e.g. by PKA) is also required for channel activity. The CFTR structure is unsolved but homology models of the CFTR closed and open states have been produced based on the crystal structures of evolutionarily related ABC transporters. These models predict the formation of a tetrahelix bundle of intracellular loops (ICLs) during channel opening. Here we provide evidence that residues E267 in ICL2 and K1060 in ICL4 electrostatically interact at the interface of this predicted bundle to promote CFTR opening. Mutations or a thiol modifier that introduced like charges at these two positions substantially inhibited ATP-dependent channel opening. ATP-dependent activity was rescued by introducing a second site gain of function (GOF) mutation that was previously shown to promote ATP-dependent and ATP-independent opening (K978C). Conversely, the ATP-independent activity of the K978C GOF mutant was inhibited by charge- reversal mutations at positions 267 or 1060 either in the presence or absence of NBD2. The latter result indicates that this electrostatic interaction also promotes unliganded channel opening in the absence of ATP binding and NBD dimerization. Charge-reversal mutations at either position markedly reduced the PKA sensitivity of channel activation implying strong allosteric coupling between bundle formation and R domain phosphorylation. These findings support important roles of the tetrahelix bundle and the E267-K1060 electrostatic interaction in phosphorylation-dependent CFTR gating.

Conserved allosteric hot spots in the transmembrane domains of cystic fibrosis transmembrane conductance regulator (CFTR) channels and multidrug resistance protein (MRP) pumps.

ATP-binding cassette (ABC) transporters are an ancient family of transmembrane proteins that utilize ATPase activity to move substrates across cell membranes. The ABCC subfamily of the ABC transporters includes active drug exporters (the multidrug resistance proteins (MRPs)) and a unique ATP-gated ion channel (cystic fibrosis transmembrane conductance regulator (CFTR)). The CFTR channel shares gating principles with conventional ligand-gated ion channels, but the allosteric network that couples ATP binding at its nucleotide binding domains (NBDs) with conformational changes in its transmembrane helices (TMs) is poorly defined. It is also unclear whether the mechanisms that govern CFTR gating are conserved with the thermodynamically distinct MRPs. Here we report a new class of gain of function (GOF) mutation of a conserved proline at the base of the pore-lining TM6. Multiple substitutions of this proline promoted ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-ß,γ-imidodiphosphate (AMP-PNP). TM6 proline mutations exhibited additive GOF effects when combined with a previously reported GOF mutation located in an outer collar of TMs that surrounds the pore-lining TMs. Each TM substitution allosterically rescued the ATP sensitivity of CFTR gating when introduced into an NBD mutant with defective ATP binding. Both classes of GOF mutations also rescued defective drug export by a yeast MRP (Yor1p) with ATP binding defects in its NBDs. We conclude that the conserved TM6 proline helps set the energy barrier to both CFTR channel opening and MRP-mediated drug efflux and that CFTR channels and MRP pumps utilize similar allosteric mechanisms for coupling conformational changes in their translocation pathways to ATP binding at their NBDs.

Converting nonhydrolyzable nucleotides to strong cystic fibrosis transmembrane conductance regulator (CFTR) agonists by gain of function (GOF) mutations.

Cystic fibrosis transmembrane conductance regulator (CFTR) is the only ligand-gated ion channel that hydrolyzes its agonist, ATP. CFTR gating has been argued to be tightly coupled to its enzymatic activity, but channels do open occasionally in the absence of ATP and are reversibly activated (albeit weakly) by nonhydrolyzable nucleotides. Why the latter only weakly activates CFTR is not understood. Here we show that CFTR activation by adenosine 5'-O-(thiotriphosphate) (ATPγS), adenosine 5'-(ß,γ-imino)triphosphate (AMP-PNP), and guanosine 5'-3-O-(thio)triphosphate (GTPγS) is enhanced substantially by gain of function (GOF) mutations in the cytosolic loops that increase unliganded activity. This enhancement correlated with the base-line nucleotide-independent activity for several GOF mutations. AMP-PNP or ATPγS activation required both nucleotide binding domains (NBDs) and was disrupted by a cystic fibrosis mutation in NBD1 (G551D). GOF mutant channels deactivated very slowly upon AMP-PNP or ATPγS removal (τdeac ∼ 100 s) implying tight binding between the two NBDs. Despite this apparently tight binding, neither AMP-PNP nor ATPγS activated even the strongest GOF mutant as strongly as ATP. ATPγS-activated wild type channels deactivated more rapidly, indicating that GOF mutations in the cytosolic loops reciprocally/allosterically affect nucleotide occupancy of the NBDs. A GOF mutation substantially rescued defective ATP-dependent gating of G1349D-CFTR, a cystic fibrosis NBD2 signature sequence mutant. Interestingly, the G1349D mutation strongly disrupted activation by AMP-PNP but not by ATPγS, indicating that these analogs interact differently with the NBDs. We conclude that poorly hydrolyzable nucleotides are less effective than ATP at opening CFTR channels even when they bind tightly to the NBDs but are converted to stronger agonists by GOF mutations.

Can an integrated orthotic and rehabilitation program decrease pain and improve function after lower extremity trauma?

BACKGROUND: Patients with severe lower extremity trauma have significant disability 2 years after injury that worsens by 7 years. Up to 15% seek late amputation. Recently, an energy-storing orthosis demonstrated improved function compared with standard orthoses; however, the effect when integrated with rehabilitation over time is unknown. QUESTIONS/PURPOSES: (1) Does an 8-week integrated orthotic and rehabilitation initiative improve physical performance, pain, and outcomes in patients with lower extremity functional deficits or pain? (2) Is the magnitude of recovery different if enrolled more than 2 years after their injury versus earlier? (3) Does participation decrease the number considering late amputation? METHODS: We prospectively evaluated 84 service members (53 less than and 31 > 2 years after injury) who enrolled in the initiative. Fifty-eight sustained fractures, 53 sustained nerve injuries with weakness, and six had arthritis (there was some overlap in the patients with fractures and nerve injuries, which resulted in a total of > 84). They completed 4 weeks of physical therapy without the orthosis followed by 4 weeks with it. Testing was conducted at Weeks 0, 4, and 8. Validated physical performance tests and patient-reported outcome surveys were used as well as questions pertaining to whether patients were considering an amputation. RESULTS: By 8 weeks, patients improved in all physical performance measures and all relevant patient-reported outcomes. Patients less than and greater than 2 years after injury improved similarly. Forty-one of 50 patients initially considering amputation favored limb salvage at the end of 8 weeks. CONCLUSIONS: We found this integrated orthotic and rehabilitation initiative improved physical performance, pain, and patient-reported outcomes in patients with severe, traumatic lower extremity deficits and that these improvements were sustained for > 2 years after injury. Efforts are underway to determine whether the Return to Run clinical pathway with the Intrepid Dynamic Exoskeletal Orthosis (IDEO) can be successfully implemented at additional military centers in patients > 2 years from injury while sustaining similar improvements in patient outcomes. The ability to translate this integrated orthotic and rehabilitation program into the civilian setting is unknown and warrants further investigation.

ATP-independent CFTR channel gating and allosteric modulation by phosphorylation.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel, an ATP binding cassette (ABC) transporter. CFTR gating is linked to ATP binding and dimerization of its two nucleotide binding domains (NBDs). Channel activation also requires phosphorylation of the R domain by poorly understood mechanisms. Unlike conventional ligand-gated channels, CFTR is an ATPase for which ligand (ATP) release typically involves nucleotide hydrolysis. The extent to which CFTR gating conforms to classic allosteric schemes of ligand activation is unclear. Here, we describe point mutations in the CFTR cytosolic loops that markedly increase ATP-independent (constitutive) channel activity. This finding is consistent with an allosteric gating mechanism in which ligand shifts the equilibrium between inactive and active states but is not essential for channel opening. Constitutive mutations mapped to the putative symmetry axis of CFTR based on the crystal structures of related ABC transporters, a common theme for activating mutations in ligand-gated channels. Furthermore, the ATP sensitivity of channel activation was strongly enhanced by these constitutive mutations, as predicted for an allosteric mechanism (reciprocity between protein activation and ligand occupancy). Introducing constitutive mutations into CFTR channels that cannot open in response to ATP (i.e., the G551D CF mutant and an NBD2-deletion mutant) substantially rescued their activities. Importantly, constitutive mutants that opened without ATP or NBD2 still required R domain phosphorylation for optimal activity. Our results confirm that (i) CFTR gating exhibits features of protein allostery that are shared with conventional ligand-gated channels and (ii) the R domain modulates CFTR activity independent of ATP-induced NBD dimerization.

A unified view of cystic fibrosis transmembrane conductance regulator (CFTR) gating: combining the allosterism of a ligand-gated channel with the enzymatic activity of an ATP-binding cassette (ABC) transporter.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ion channel in that its gating is coupled to an intrinsic enzymatic activity (ATP hydrolysis). This enzymatic activity derives from the evolutionary origin of CFTR as an ATP-binding cassette transporter. CFTR gating is distinct from that of a typical ligand-gated channel because its ligand (ATP) is usually consumed during the gating cycle. However, recent findings indicate that CFTR gating exhibits allosteric properties that are common to conventional ligand-gated channels (e.g. unliganded openings and constitutive mutations). Here, we provide a unified view of CFTR gating that combines the allosterism of a ligand-gated channel with its unique enzymatic activity.

Thermally unstable gating of the most common cystic fibrosis mutant channel (ΔF508): "rescue" by suppressor mutations in nucleotide binding domain 1 and by constitutive mutations in the cytosolic loops.

Most cystic fibrosis (CF) cases are caused by the ΔF508 mutation in the CF transmembrane conductance regulator (CFTR), which disrupts both the processing and gating of this chloride channel. The cell surface expression of ΔF508-CFTR can be "rescued" by culturing cells at 26-28 °C and treating cells with small molecule correctors or intragenic suppressor mutations. Here, we determined whether these various rescue protocols induce a ΔF508-CFTR conformation that is thermally stable in excised membrane patches. We also tested the impact of constitutive cytosolic loop mutations that increase ATP-independent channel activity (K978C and K190C/K978C) on ΔF508-CFTR function. Low temperature-rescued ΔF508-CFTR channels irreversibly inactivated with a time constant of 5-6 min when excised patches were warmed from 22 °C to 36.5 °C. A panel of CFTR correctors and potentiators that increased ΔF508-CFTR maturation or channel activity failed to prevent this inactivation. Conversely, three suppressor mutations in the first nucleotide binding domain rescued ΔF508-CFTR maturation and stabilized channel activity at 36.5 °C. The constitutive loop mutations increased ATP-independent activity of low temperature-rescued ΔF508-CFTR but did not enhance protein maturation. Importantly, the ATP-independent activities of these ΔF508-CFTR constructs were stable at 36.5 °C, whereas their ATP-dependent activities were not. Single channel recordings of this thermally stable ATP-independent activity revealed dynamic gating and unitary currents of normal amplitudes. We conclude that: (i) ΔF508-CFTR gating is highly unstable at physiologic temperature; (ii) most rescue protocols do not prevent this thermal instability; and (iii) ATP-independent gating and the pore are spared from ΔF508-induced thermal instability, a finding that may inform alternative treatment strategies.

Management of posttraumatic osteoarthritis with an integrated orthotic and rehabilitation initiative.

Posttraumatic osteoarthritis affects approximately 5.6 million Americans annually. Those affected are typically younger and more active than persons with primary osteoarthritis. Arthrodesis is the typical management option for persons with end-stage ankle and subtalar posttraumatic arthritis. Arthroplasty is typically reserved for elderly persons. The functional limitations resulting from any of these strategies make treatment of this young population challenging. Combat wounds frequently lead to severe lower extremity injuries. We present a series of patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint after combat trauma. They were treated at our institution with an integrated orthotic and rehabilitation initiative called the Return To Run clinical pathway. This clinical pathway may serve as an alternative or adjunct to arthrodesis and arthroplasty for young patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint.

Quantification of posterior ankle exposure through an achilles tendon-splitting versus posterolateral approach.

BACKGROUND: The optimal surgical exposure to the posterior ankle for trauma and reconstruction is a source of debate. We hypothesized that the Achilles tendon-splitting approach would provide greater exposure to the posterior ankle than the posterolateral approach. METHODS: Forty surgical approaches were performed from twenty fresh-frozen cadavers. Achilles tendon-splitting and posterolateral approaches were performed using a randomized crossover design for surgical sequence. Six landmarks (medial malleolus, ankle joint, subtalar joint, incisura fibularis, lateral malleolus and medial gutter) were identified by direct visualization or palpation. A calibrated digital photograph was taken and Image J (http://rsb.info.nih.gov/ij/) was used to calculate the surface area of the distal tibia and talus exposed in neutral and dorsiflexion. RESULTS: Using a posterolateral approach, the average distal tibia exposed was 11.3cm(2) in neutral and 10.2 cm(2) in dorsiflexion. The average talus exposed was 2.0 cm(2) in neutral and 2.4 cm(2) in dorsiflexion. Using an Achilles tendon-splitting approach, the average exposed distal tibia was 33% more (15.0 cm(2)) in neutral and 43% more (14.6 cm(2)) in dorsiflexion. The average talus exposed was 47% more (3.0 cm(2)) in neutral and 76% more (4.2 cm(2)) in dorsiflexion. All increases in exposure were statistically significant. The medial malleolus was visualized in 19 tendon-splitting and six posterolateral approaches. The medial gutter was visualized in 20 tendon-splitting and 13 posterolateral approaches. These differences were statistically significant. All other landmarks could be visualized through both approaches. CONCLUSION: The Achilles tendon-splitting approach provided significantly greater exposure of the posterior distal tibia and talus compared to the posterolateral approach. CLINICAL RELEVANCE: Prospective studies will help determine if the tendon-splitting approach is a safe and clinically useful approach for surgeries in which direct access to the entire posterior ankle and subtalar joint are required.

Quantal release of free radicals during exocytosis of phagosomes.

Secretion of lysosomes and related organelles is important for immune system function. High-resolution membrane capacitance techniques were used to track changes in membrane area in single phagocytes during opsonized polystyrene bead uptake and release. Secretagogue stimulation of cells preloaded with beads resulted in immediate vesicle discharge, visualized as step increases in capacitance. The size of the increases were consistent with phagosome size. This hypothesis was confirmed by direct observation of dye release from bead-containing phagosomes after secretagogue stimulation. Capacitance recordings of exocytosis were correlated with quantal free radical release, as determined by amperometry. Thus, phagosomes undergo regulated secretion in macrophages, one function of which may be to deliver sequestered free radicals to the extracellular space.

Incidence of osteochondral lesions of the talus in the United States military.

BACKGROUND: Osteochondral lesion of the talus (OCLT) is frequently described as an uncommon diagnosis; however, little is known of its incidence. In light of increased awareness combined with the continued evolution of radiologic and treatment modalities, more attention has been given to this diagnosis. Serving a young, athletic population with unique occupational requirements, we have perceived an increase in the diagnosis of OCLTs. The goal of this study was to determine the incidence of OCLTs in an active duty military population, as well as demographic risk factors for OCLTs. METHODS: We performed a query of the Defense Medical Epidemiology Database (DMED) of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for OCLTs which in the Armed Forces Health Longitudinal Technology Application (AHLTA) system is uniquely assigned the code 732.5. An overall injury incidence was calculated, in addition to multivariate analysis to determine independent risk factors among the following demographic considerations: gender, race, rank, branch of military service, and age. Year of diagnosis was also considered. RESULTS: The overall incidence rate for the 10-year period (1999 to 2008) was 27 OCLTs per 100,000 person-years. Significant demographic risk factors were female gender, white race, enlisted rank, service in the Army and Marines, and age greater than 20 years. Incidence rate was 16 per 100,000 in 2002, with steady annual increases resulting in an incidence rate of 56 per 100,000 person-years in 2008, corresponding to the years of active involvement in global combat operations. CONCLUSION: The incidence of OCLTs in the active duty military population was higher with female gender, white race, enlisted rank, increased age, and Army or Marine service.

"March fractures" on a female military recruit.

Stress fractures are caused by repetitive low-impact activities. It is important to have a high index of suspicion in diagnosing and treating stress fractures early for remodeling to occur. This is a case report of a 19-year-old female military recruit with stress fractures of the right foot. The patient had an extended non-weight-bearing treatment that eventually had a successful outcome after allowing the fracture to heal by starting the patient on weight-bearing activities and a "walk-to-run" program. Treatment points in managing stress fractures including female-specific issues are also discussed.

Partial foot amputations in the combat wounded.

Throughout the current conflicts in Afghanistan and Iraq, there have been more than 1100 combat-related major limb amputations, with approximately 80% involving the lower extremity. There is, however, a paucity of data regarding the number of amputations below the level of the ankle. Although not as common, partial foot amputations, in the appropriate setting, offer a way to improve function and decrease energy consumption when compared to proximal amputations. Sound surgical tenets are prerequisite for successful outcomes when performing a distal amputation. Maintaining a robust soft tissue envelope allowing for tension-free wound closure is paramount in determining the feasibility of a partial foot amputation. Careful consideration of tendon balancing is also of utmost importance in avoiding common complications of contracture and deformity. Partial foot amputations present a viable surgical option for successful outcomes and maximization of patient function in the combat injured when certain criteria are met.

Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechanisms.

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CFTR chloride channel. Wild type and mutant CFTR channels can be activated by curcumin, a well tolerated dietary compound with some appeal as a prospective CF therapeutic. However, we show here that curcumin has the unexpected effect of cross-linking CFTR polypeptides into SDS-resistant oligomers. This effect occurred for CFTR channels in microsomes as well as in intact cells and at the same concentrations that are effective for promoting CFTR channel activity (5-50 mum). Both mature CFTR polypeptides at the cell surface and immature CFTR protein in the endoplasmic reticulum were cross-linked by curcumin, although the latter pool was more susceptible to this modification. Curcumin cross-linked two CF mutant channels (Delta F508 and G551D) as well as a variety of deletion constructs that lack the major cytoplasmic domains. In vitro cross-linking could be prevented by high concentrations of oxidant scavengers (i.e. reduced glutathione and sodium azide) indicating a possible oxidation reaction with the CFTR polypeptide. Importantly, cyclic derivatives of curcumin that lack the reactive beta diketone moiety had no cross-linking activity. One of these cyclic derivatives stimulated the activities of wild type CFTR channels, Delta 1198-CFTR channels, and G551D-CFTR channels in excised membrane patches. Like the parent compound, the cyclic derivative irreversibly activated CFTR channels in excised patches during prolonged exposure (>5 min). Our results raise a note of caution about secondary biochemical effects of reactive compounds like curcumin in the treatment of CF. Cyclic curcumin derivatives may have better therapeutic potential in this regard.

Return to duty rate of amputee soldiers in the current conflicts in Afghanistan and Iraq.

BACKGROUND: The purpose of this study was to determine the percentage of amputee soldiers who sustained their injury during the current conflicts in Afghanistan and Iraq and have returned to duty. In addition, the authors plan to identify the factors that influence the amputee's likelihood to return to duty. METHODS: The computerized records of amputee soldiers who presented to the Physical Evaluation Board between October 1, 2001 and June 1, 2006 were reviewed. This data were crossreferenced with the Military Amputee Database. The following variables were extracted: age, gender, pay grade, amputation level, and final disposition. RESULTS: During the period reviewed, there were 395 major limb amputees that met inclusion criteria. Of those, 65 returned to active duty (16.5%). The average age of amputees returning to duty was more than 4 years older than those who separated from the service (31.4 vs. 27.2), p < 0.0001. Officers and senior enlisted personnel returned to duty at a higher rate (35.3% and 25.5%, respectively) when compared with junior enlisted personnel (7.0%), p < 0.0001. Those with multiple extremity amputations have the lowest return to duty rate at 3%, when compared with the overall return to duty rate for single extremity amputees (20%), p < 0.0001. CONCLUSION: During the 1980s, 11 of 469 amputees returned to active duty (2.3%). The number of amputees returning to duty has increased significantly, from 2.3% to 16.5%, due to advancements in combat casualty care and the establishment of centralized amputee centers.

Reverse sural artery flap for reconstruction of blast injuries of the foot and ankle.

BACKGROUND: The reverse sural artery fasciocutaneous flap is a versatile soft tissue coverage procedure for traumatic soft tissue defects of the distal tibia, ankle, and foot. War-related blast injuries represent a unique injury mechanism. There are no reports on use of this reconstructive flap in treating highly contaminated war-related musculoskeletal trauma of the foot and ankle. The current study presents results using this soft tissue coverage procedure in a subacute fashion to treat a population of war-related blast injuries. MATERIALS AND METHODS: A retrospective chart study was performed to assess outcomes of ten consecutive patients with severe lower extremity musculoskeletal trauma requiring soft tissue coverage using reverse sural artery fasciocutaneous flaps. Average patient age was 27.2 years. All injuries occurred between 2003 and 2008 as a result of severe war-related blast injuries. RESULTS: All ten patients sustained Gustilo Type IIIB open fractures within the zones of injuries secondary to high energy blasts. Average time to flap coverage was 37 (range, 18 to 112) days post-injury. All ten flaps were well-healed at 12 weeks postoperatively. Major complications included one nonunion, three deep infections with chronic osteomyelitis, and three late elective amputations unrelated to the viability of the flap. CONCLUSION: In appropriately selected patients with significant open bony and soft tissue trauma to the foot and ankle, the reverse sural artery fasciocutaneous flap should be considered as a viable first option for soft tissue coverage, even in cases of subacute coverage. Early coverage is preferable in cases of severe contamination and soft tissue destruction, but late coverage of distal lower extremity defects with a sural artery flap is possible with good outcomes.

Minimally invasive shortening humeral osteotomy to salvage a through-elbow amputation.

OBJECTIVE: Determine the efficacy of a novel surgical technique to salvage a through-elbow amputation and avoid revision transhumeral amputation. METHODS: A 23-year-old soldier presented after sustaining a through-elbow amputation in a close-range blast injury with inadequate soft tissues to obtain closure over the distal humerus. A 2-cm anterior incision was made and a shortening osteotomy with percutaneous submuscular osteosynthesis was done. A myodesis was performed and a tension-free primary closure of the soft tissue envelope obtained. RESULTS: At 3 months postoperatively the osteotomy and soft tissue envelope were healed. At 2-year follow-up the patient reports using a body-powered prosthesis for ADLs and recreational hobbies, citing excellent rotational control and ease of prosthetic suspension. CONCLUSION: Minimally invasive shortening humeral osteotomy in the setting of a through-elbow amputation is a safe and effective procedure, which allows primary soft tissue closure, prevents the need for more proximal amputation, and allows for ease of prosthetic fitting and suspension.