Cement Spacer Formed in a 3D-Printed Mold for Endoprosthetic Reconstruction of an Infected Sarcomatous Radius: A Case Report.

CASE: The ulcerated recurrent clear cell sarcoma of the forearm with bony invasion of the radius needed an uncontaminated resection and control of infection. A mold was printed based on CT-reconstructed 3D models of the patient's anatomy to create an antibiotic-loaded cement spacer as endoprosthetic replacement used in combination with soft-tissue reconstruction and systemic antibiotics. CONCLUSION: This then undescribed novel technique allowed for fast local recovery of the patient's hand function and return to work. In selected cases, such an anatomically formed spacer may be preferred for faster functional recovery and longer intervals before definitive reconstruction is possible.

Benefits of Additional Procedures for Metacarpophalangeal Hyperextension on Simple Trapeziectomy in Thumb Basal Osteoarthritis: A Biomechanical Cadaver Study.

Background: Patients with advanced osteoarthritis of the first carpometacarpal joint (CMC-1) may develop hyperextension of the first metacarpophalangeal joint (MCP-1). No clear clinical benefice has been reported consecutively to the surgical treatment of the MCP-hyperextension combined to a trapeziectomy. The reason of the missing benefit may be due to changes in the thumb position impairing the thumb stability secondary to the surgical procedures. We assessed changes in the transmission of forces at the thumb's end phalanx following a trapeziectomy combined with the surgical adjustment of the hyperextension of the MCP-1-joint in a biomechanical investigation using cadavers. Methods: The thumb muscles were loaded with nylon cables connected to a tension meter in 8 forearm cadavers. A 6-axis force sensor assessed the termino-lateral key-pinch orthogonal strength vectors at the level of the thumb distal phalanx prior to any surgery, and following a simple trapeziectomy, a trapeziectomy combined to a MCP-1-capsulodesis and the transfer of the extensor pollicis brevis over the metacarpal-1 head, or to an MCP-1-arthrodesis. Results: Combination of the trapeziectomy with the MCP-1- joint palmar capsulodesis and EPB-transfer or with a MCP-arthrodesis in neutral pronation-supination resulted in a significant shift of the thumb in pronation-abduction with respect to the preoperative assessment. The lowest shift was achieved when performing the arthrodesis in 20° supination or by overloading of the adductor pollicis. Conclusions: Combining the trapeziectomy with surgeries addressing the MCP-1-joint hyperextension induced a shift of the thumb in pronation-abduction that could impair the key-pinch stability. When considering additional procedures for MCP-1-joint hyperextension deformities, it should be recommended to fix the EPB-tendon on the radial aspect of the metacarpal head if a tendon transfer is considered, otherwise the MCP joint arthrodesis should be performed in supinated position, in order to achieve lateral key-pinch stability.

Allergen cross-reactivity in allergic rhinitis and oral-allergy syndrome: a bioinformatic protein sequence analysis.

BACKGROUND: Clinical allergy cross-reactivity that is seen with related inhalant allergens or between unrelated inhalant allergens and foods in oral allergy syndrome (OAS) remains poorly understood. The goal of this study is to determine whether clinical cross-reactivity can be identified from primary protein sequences in allergy epitopes and food proteins. METHODS: High-throughput analysis was performed by assembling all known allergy epitopes within the Immune Epitope Database (IEDB; http://www.iedb.org) for 5 common species from 5 inhalant allergen subclasses and comparing their protein sequences to each other, as well as to sequences of intact proteins from known cross-reactive foods in the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI) protein database (http://www.uniprot.org) that have been implicated in OAS. Computational methods were employed to allow for exact matching, gaps, and similar amino acids using multiple algorithms. A phylogenetic tree was created to determine evolutionary relationships between cross-reactive epitopes in OAS. RESULTS: Twenty-three common inhalant allergens had 4429 unique epitopes; the 19 foods implicated in OAS had 9497 protein sequences. The Basic Local Alignment Search Tool (BLAST) algorithm identified interclass and intraclass sequence similarities for the 5 inhalant allergy classes with high similarity for mites, grasses, and trees. Analysis of OAS proteins identified 104 matches to inhalant allergy epitopes that are known to cross-react. The phylogenetic tree displayed relationships that mostly followed organism phylogeny. CONCLUSION: Use of primary protein sequences was successful in explaining clinical allergy cross-reactivity. Clinical correlation is needed for use of these epitopes as diagnostic or therapeutic entities for patients with cross-reactive allergic disease.

A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment.

RATIONALE: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function. OBJECTIVES: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy. METHODS: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays. MEASUREMENTS AND MAIN RESULTS: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts. CONCLUSIONS: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.

Physeal distraction for joint preservation in malignant metaphyseal bone tumors in children.

BACKGROUND: Physeal distraction facilitates metaphyseal bone tumor resection in children and preserves the adjacent joint. The technique was first described by Cañadell. Tumor resection procedures allowing limb-sparing reconstruction have been used increasingly in recent years without compromising oncologic principles. QUESTIONS/PURPOSES: We report our results with Cañadell's technique by assessing tumor control, functional outcome, and complications. METHODS: Six consecutive children with primary malignant metaphyseal bone tumors underwent physeal distraction as a part of tumor resection. Tumor location was the distal femur in four patients, the proximal humerus in one patient, and the proximal tibia in one patient. The functional outcome was evaluated after a minimum of 18 months (median, 62 months; range, 18-136 months) using the Musculoskeletal Tumor Society (MSTS) score and the Toronto Extremity Salvage Score (TESS). RESULTS: At latest followup, five patients were alive and disease-free and one had died from metastatic disease. All tumor resections resulted in local control; there were no local recurrencies. The mean MSTS score was 79% (range, 53%-97%) and corresponding mean TESS was 83% (range, 71%-92%). In one case, postoperative infection required amputation of the proximal lower leg. All physeal distractions were successful except for one patient in whom distraction resulted in rupturing into the tumor. This situation was salvaged by transepiphyseal resection. CONCLUSIONS: We consider Cañadell's technique a useful tool in the armamentarium to treat children with malignant tumors that are in close proximity to an open physis. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Slowing down downhill folding: a three-probe study.

The mutant Tyr22Trp/Glu33Tyr/Gly46Ala/Gly48Ala of lambda repressor fragment lambda(6-85) was previously assigned as an incipient downhill folder. We slow down its folding in a cryogenic water-ethylene-glycol solvent (-18 to -28 degrees C). The refolding kinetics are probed by small-angle x-ray scattering, circular dichroism, and fluorescence to measure the radius of gyration, the average secondary structure content, and the native packing around the single tryptophan residue. The main resolved kinetic phase of the mutant is probe independent and faster than the main phase observed for the pseudo-wild-type. Excess helical structure formed early on by the mutant may reduce the formation of turns and prevent the formation of compact misfolded states, speeding up the overall folding process. Extrapolation of our main cryogenic folding phase and previous T-jump measurements to 37 degrees C yields nearly the same refolding rate as extrapolated by Oas and co-workers from NMR line-shape data. Taken together, all the data consistently indicate a folding speed limit of approximately 4.5 micros for this fast folder.

Reaching the protein folding speed limit with large, sub-microsecond pressure jumps.

Biomolecules are highly pressure-sensitive, but their dynamics upon return to ambient pressure are often too fast to observe with existing approaches. We describe a sample-efficient method capable of large and very fast pressure drops (<1 nanomole, >2,500 atmospheres and <0.7 microseconds). We validated the method by fluorescence-detected refolding of a genetically engineered lambda repressor mutant from its pressure-denatured state. We resolved barrierless structure formation upon return to ambient pressure; we observed a 2.1 +/- 0.7 microsecond refolding time, which is very close to the 'speed limit' for proteins and much faster than the corresponding temperature-jump refolding of the same protein. The ability to experimentally perform a large and very fast pressure drop opens up a new region of the biomolecular energy landscape for atomic-level simulation.

A one-dimensional free energy surface does not account for two-probe folding kinetics of protein alpha(3)D.

We present fluorescence-detected measurements of the temperature-jump relaxation kinetics of the designed three-helix bundle protein alpha(3)D taken under solvent conditions identical to previous infrared-detected kinetics. The fluorescence-detected rate is similar to the IR-detected rate only at the lowest temperature where we could measure it (326 K). The fluorescence-detected rate decreases by a factor of 3 over the 326-344 K temperature range, whereas the IR-detected rate remains nearly constant over the same range. To investigate this probe dependence, we tested an extensive set of physically reasonable one-dimensional (1D) free energy surfaces by Langevin dynamics simulation. The simulations included coordinate- and temperature-dependent roughness, diffusion coefficients, and IR/fluorescence spectroscopic signatures. None of these can reproduce the IR and fluorescence data simultaneously, forcing us to the conclusion that a 1D free energy surface cannot accurately describe the folding of alpha(3)D. This supports the hypothesis that alpha(3)D has a multidimensional free energy surface conducive to downhill folding at 326 K, and that it is already an incipient downhill folder with probe-dependent kinetics near its melting point.

Reconstruction of Large Diaphyseal Defects of the Femur and the Tibia with Autologous Bone.

Post-traumatic segmental bone defects of the femur and the tibia above the critical size require special attention because conventional bone grafts result in high rates of nonunion. The biological and biomechanical aspects of this challenging surgery, as well as ongoing refinements to achieve mechanically stable bone healing with correct bone alignment are reviewed. Choosing the best appropriate method is mainly dependent on both the location and etiology of the bone defect. Three patients with successful bone reconstruction using two-stage reconstruction with cancellous bone graft, double-barrel free vascularized fibula transfer and distraction osteogenesis are described. Advantages and disadvantages of these methods are discussed in accordance with recent literature.

Rotationplasty (Borggreve/Van Nes and modifications) as an alternative to amputation in failed reconstructions after resection of tumours around the knee joint.

Failure of reconstructions as a result of infective or aseptic loosening and massive bone loss may make amputation necessary. If neurovascular structures can be preserved to keep a functional foot, rotationplasty may be considered an option. Four patients treated for malignant bone tumours (two osteosarcomas, one Ewing sarcoma, and one malignant fibrous histiocytoma) of the proximal tibia and distal femur (n=2 each) at the ages of 13 to 21 years had reconstructions that failed 3, 4, 5, and 15 years later. In three patients the cause was intractable infection, and in one loosening with shortening and deficiency of the extensor mechanism. The patients had the option to contact patients who had had rotationplasty as the primary procedure for tumours or severe femoral deficiencies. In two patients an AI-type rotationplasty was done, in one a type AII rotationplasty, and in the fourth a modification with shortening of the lower leg but retention of the knee joint. There were no postoperative complications such as persisting infections, fractures, or pseudarthrosis. All patients are active and are able to go alpine skiing or snowboarding. The main advantage of procedures in which a sensory-motor functional foot is retained is to avoid neuroma pain or phantom sensations. The foot allows for active knee movement of the orthoprosthesis and full weight bearing. It is of great psychological help for the patients to have contact during the decision-making with patients who have had similar procedures. It should be considered as an alternative to amputation.

Extra-articular en bloc resection of the talocrural and the talocalcaneonavicular joints for primary malignant synovial tumour (myxoinflammatory fibroblastic sarcoma).

A 13-year-old boy presented with a diagnosis of intra-articular myxoinflammatory fibroblastic sarcoma of the ankle. There had been no previous description of a sarcoma arising directly from the synovium of the ankle and limb salvage for malignant tumours of the ankle has rarely been reported. We treated him by peritalar extra-articular resection, and draw attention to this rare tumour and to a technique of limb-sparing resection of the ankle joint.

Results of treatment of malignant soft tissue tumours in the groin.

Soft tissue sarcomas of the inguinal region are a challenge with regard to achieving clear margins, reconstruction of the femoral vessels, and soft tissue coverage. Six men aged 39 to 48 years and one woman of 56 were treated for soft tissue sarcomas of the groin. All patients were treated with local en bloc resections including the femoral artery, vein, and nerve. In two patients the soft tissue defect was covered primarily with an ipsilateral rectus abdominis muscle flap, in two others (because of wound dehiscence) coverage was achieved with the opposite rectus abdominis muscle pedicle flap as we were afraid of closure of the ipsilateral deep epigastric vessels. In the others local measures were sufficient, however, wound healing was usually delayed. Histopathological examination showed tumour-free margins in each case. One patient developed a local recurrence, but had had no radiotherapy because of problems with wound healing. A high rate of local tumour control in soft tissue sarcomas of the inguinal region can be achieved with the combination of surgical resection and radiotherapy. No compromise should be made with aggressive soft tissue coverage to protect the vascular reconstruction, control wound healing after neoadjuvant radiotherapy, or allow immediate adjuvant radiotherapy. At primary wound closure we would generally use an ipsilaterally distally pedicled rectus abdominis muscle flap if the deep epigastric vessels can be preserved or - if the ipsilateral vessels need be resected to achieve clearance of tumour - use a contralateral flap.

Correction of forearm malunion guided by the preoperative complaint.

UNLABELLED: Diaphyseal malunion of the forearm may cause loss of pronation and supination, a painful distal radioulnar joint, and aesthetic problems. Seventeen patients (10 males, seven females; mean age, 20.6 +/- 9.3 years) were operated on because of symptomatic malunion after a pediatric forearm fracture. Six patients had predominant loss of pronation (Group 1), four had predominant loss of supination (Group 2), and seven had a painful distal radioulnar joint (Group 3). An osteotomy of the radius was performed in seven patients and of both forearm bones in 10. All patients were available for clinical and radiologic assessments at a minimum followup of 6 months (mean +/- standard deviation, 3.7 +/- 2.3 years; range, 0.5-9.9 years). Release of the contracted interosseous membrane frequently was necessary for patients in Groups 1 and 2 to allow for correction and did not result in weakness, instability of the distal radioulnar joint, or synostosis. The overall improvement in range of motion after osteotomies for patients with a supination deficit was much better than in those with a pronation deficit. All patients in Group 3 gained a pain-free and stable distal radioulnar joint and their range of motion was unchanged. Therefore, ability to improve overall range of motion through forearm osteotomies is dependent on the patients' preoperative complaint. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Simulation-based fitting of protein-protein interaction potentials to SAXS experiments.

We present a new method for computing interaction potentials of solvated proteins directly from small-angle x-ray scattering data. An ensemble of proteins is modeled by Monte Carlo or molecular dynamics simulation. The global x-ray scattering of the whole model ensemble is then computed at each snapshot of the simulation, and averaged to obtain the x-ray scattering intensity. Finally, the interaction potential parameters are adjusted by an optimization algorithm, and the procedure is iterated until the best agreement between simulation and experiment is obtained. This new approach obviates the need for approximations that must be made in simplified analytical models. We apply the method to lambda repressor fragment 6-85 and fyn-SH3. With the increased availability of fast computer clusters, Monte Carlo and molecular dynamics analysis using residue-level or even atomistic potentials may soon become feasible.

Multiple subungual soft tissue metastases from a chondrosarcoma.

Chondrosarcoma metastasises to the lungs and from there to other organs. A patient with several metastases in the soft tissues of the fingers and toes had previously been treated for a chondrosarcoma of the foot. Subungual metastases of chondrosarcoma are unusual and there is no evidence based treatment. We therefore treated the lesion of the finger by total resection of the nail (RO).

Bioengineering of a composite nerve graft for peripheral nerve reconstruction.

Engineering of nerve graft substitutes is challenging because of the complex cell and tissue interactions leading to successful nerve regeneration. Moreover cells in contrast to the extracellular nerve matrix are rejected by the immune system. We have developed ofa non-immunogenic nerve scaffold that can be seeded with autogenous Schwann cells prior to implantation in patients suffering extensive peripheral nerve lesions.

Pedicled vascularized rib transfer for reconstruction of clavicle nonunions with bony defects: anatomical and biomechanical considerations.

BACKGROUND: Clavicular nonunions with large bony defects, although rare, are difficult to treat and often result from multiple failed attempts at surgical management. Reconstruction using vascularized bone graft is the accepted standard in cases of large osseous defects. METHODS: An anatomical vascular corrosion study with cadaveric dissections and finite element analyses was designed to assess the feasibility of clavicular reconstruction with a musculo-osteous graft interposition based on a pedicled serratus anterior flap. RESULTS: Rib vascularization through the serratus anterior was demonstrated, so that the thoracic branch of the thoracodorsal artery can been considered a secondary blood supply for the seventh and eighth ribs. Single and double pedicled rib transfers allowed for reconstruction with as much as 8 cm of bone loss. The maximal stress found in the single-rib reconstruction interfaces was located at the medial contact of the plate with the clavicle. It was 2.7-fold higher than the maximal stress of the medial bow of the intact clavicle. Conversely, the double-rib reconstruction had improved mechanical resistance. A case report using a single-rib transfer supported the biomechanical study by showing that the maximal risk of material loosening was located at the medial bone interface. CONCLUSIONS: Double vascularized rib transfer as part of a serratus anterior flap should be used instead of single-rib transfer to reconstruct large clavicle defects. This technique is reproducible and does not require microvascular anastomoses. Therefore, it has potential advantages over free fibula transfer.

Fluoroscopic and magnetic resonance cross-sectional imaging assessments of radial and ulnar torsion profiles in volunteers.

PURPOSE: Planning an osteotomy to correct rotational malunions of the forearm is difficult because the uninvolved side is the only available reference to assess radial and ulnar torsions. This study was designed to compare the reliability of 2 methods for the determination of the torsion profile of both forearm bones and to assess side differences further in volunteers. METHODS: Fluoroscopy in combination with goniometry and magnetic resonance (MR) cross-sectional imaging were used to determine torsion profiles of the radius and the ulna in 24 asymptomatic volunteers. Interrater and interside reliabilities were assessed. RESULTS: For the radius, interclass correlation coefficients were less than 0.65 with fluoroscopy and greater than 0.80 with magnetic resonance imaging (MRI). For the ulna, both methods had an interclass correlation coefficient of greater than 0.90. Maximum side-to-side differences assessed with fluoroscopy and MRI were 25 degrees and 34.5 degrees for the radius and 20 degrees and 32 degrees for the ulna, respectively. There were no statistical differences between sides using both methods for both forearm bones. CONCLUSIONS: Fluoroscopy coupled with goniometry is a valuable method for assessing the torsion profile of the ulna. MR cross-sectional imaging is better to assess the torsion profile of the radius; however, a side difference in torsion profile of up to 35 degrees for the radius and of up to 20 degrees for the ulna should be considered physiologic. Hence, only side differences greater than these limits may serve as an indication for an axial osteotomy in the clinical setting.