Treatment of complex fractures of the distal radius: a prospective randomised comparison of external fixation 'versus' locked volar plating

The traditional treatment of severely impacted fractures of the distal radius involves bridging external fixation and maintaining reduction by applying continuous traction. The recent technique using fixed-angle screws within volar plates is reported restore the radial length and the articular profile whilst avoiding joint distraction. It is also believed to produce better and quicker clinical results. To test these claims, we carried out a randomised controlled comparison of the efficiency of external fixation (EF) \u27versus\u27 open reduction and internal fixation (ORIF) in treating severely impacted fractures of the distal radius. A total of 39 patients were treated with EF, eventually associated with percutaneous pinning, whereas 36 underwent ORIF with a locked volar plate. There was no significant difference in the two groups with regard to changes in the ulnar variance. Articular reduction was poor in two patients in the EF group with residual step-offs exceeding 2mm; another patient of the EF group suffered a secondary loss of reduction, healing with a severe articular malunion (>2mm). By contrast, articular reduction was satisfactory in all the patients of the ORIF group. The clinical results on the Green and O\u27Brien rating were significantly better in the ORIF group than in the EF group (p<0.01 at 6 weeks, p<0.05 at 6 months). Nevertheless, open reduction and volar plating did not yield better subjective results than EF. However, although not statistically significant, patients treated by ORIF seemed to resume their usual activities quicker than those treated with EF, suggesting that this technique may be adapted to a greater extent in the case of active, young individuals

Clinical and radiological outcomes of a cohort of 9 patients with anatomical fractures of the cuboid treated by locking plate fixation

INTRODUCTION: Cuboid fractures are very rare. Hence, their treatment has not been standardized. Advances in imaging techniques, particularly three-dimensional computed tomography (3D CT), and the introduction of cuboid-specific plates has improved the care of these injuries. The aim of this study was to determine the radiological and clinical outcomes of anatomical reconstruction of comminuted cuboid fractures with a locking plate. HYPOTHESIS: Fixation of comminuted cuboid fractures with a cuboid-specific locking plate leads to stable anatomical reduction and good functional outcomes. MATERIAL AND METHODS: This was a retrospective study of 9 consecutive cases of comminuted cuboid fracture treated at a single hospital between January 2009 and December 2015. A 3D CT scan was performed preoperatively with subtraction of the posterior tarsal bone to allow the articular facets to be viewed and analyzed. Fracture fixation was done with a Locking Cuboid Plate (DePuy Synthes™). Associated lesions in the foot were treated during the same procedure. The patients were reviewed by an independent observer who performed a clinical examination, and determined the AOFAS and Maryland Foot Score. The success of the reconstruction was determined by comparing the parameters on weight-bearing X-rays views between the fixed and non-operated cuboid. RESULTS: The mean follow-up was 4.1 years (range 1-6). The Maryland Foot Score was 93.1 [86-100] and the AOFAS was 91.9 [82-100]. The reconstruction was anatomical and long lasting in all 9 cases. There was no foot misalignment in the frontal plane, based on the radiographs (hindfoot axis 5.5° [0-9]). The mean Djian-Annonier angle was 123.9° [108-130]. CONCLUSION: Cuboid fractures can be treated effectively through appropriate imaging and with a cuboid-specific locking plate as evidenced by very good midterm clinical and radiological outcomes in this study. LEVEL OF EVIDENCE: IV Retrospective study

Isolated interfragmentary compression for nonunion of humeral shaft fractures initially treated by nailing: A preliminary report of seven cases

Introduction Plating with bone grafting is considered the gold standard treatment for nonunion of humeral shaft fractures. However, this complex procedure involves multiple risks. The aim of this study is to evaluate an alternative treatment using isolated axial interfragmentary compression for the dynamisation of humeral shaft nonunion after retrograde locked nailing. Materials and methods Between January 2000 and May 2009, 124 humeral shaft fractures were treated in our trauma department with retrograde locked nailing using the unreamed humeral nail (UHN®, Synthes, Paoli, PA, USA). Nonunion occurred in seven patients (5.6%) – five females and two males, mean age 44 years (range: 17–73 years). The nonunion was treated by applying isolated secondary interfragmentary compression. Mean follow-up was 43 months (range: 8–74 months). The Rommens score and the disabilities of the arm, shoulder and hand (DASH) score were used to evaluate the global functioning of the upper limb. Results The compression procedure was successful in all seven cases. In each case, the union occurred without any complications in 3–5 months. The mean DASH score was 25/100 (range: 8.3–60.8/100). The Rommens score was judged excellent for five of the seven patients but two were rated moderate. One of these suffered from complex regional pain syndrome type II since the fracture, and another developed a stiff shoulder 6 months after trauma. Conclusion Isolated secondary interfragmentary compression appears to be a simple and successful procedure in cases of humeral nonunion

Correlations of differentially expressed gap junction connexins cx26, cx30, cx32, cx43 and cx46 with breast cancer progression and prognosis.

BACKGROUND AND AIMS: Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers. MATERIALS AND METHODS: Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models. RESULTS: The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively. CONCLUSION: Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers

Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion

Isolation of Proteinase K-Sensitive Prions Using Pronase E and Phosphotungstic Acid

Disease-related prion protein, PrPSc, is classically distinguished from its normal cellular precursor, PrPC, by its detergent insolubility and partial resistance to proteolysis. Molecular diagnosis of prion disease typically relies upon detection of protease-resistant fragments of PrPSc using proteinase K, however it is now apparent that the majority of disease-related PrP and indeed prion infectivity may be destroyed by this treatment. Here we report that digestion of RML prion-infected mouse brain with pronase E, followed by precipitation with sodium phosphotungstic acid, eliminates the large majority of brain proteins, including PrPC, while preserving >70% of infectious prion titre. This procedure now allows characterization of proteinase K-sensitive prions and investigation of their clinical relevance in human and animal prion disease without being confounded by contaminating PrPC

Finite Element Analysis of Osteosynthesis Screw Fixation in the Bone Stock: An Appropriate Method for Automatic Screw Modelling

The use of finite element analysis (FEA) has grown to a more and more important method in the field of biomedical engineering and biomechanics. Although increased computational performance allows new ways to generate more complex biomechanical models, in the area of orthopaedic surgery, solid modelling of screws and drill holes represent a limitation of their use for individual cases and an increase of computational costs. To cope with these requirements, different methods for numerical screw modelling have therefore been investigated to improve its application diversity. Exemplarily, fixation was performed for stabilization of a large segmental femoral bone defect by an osteosynthesis plate. Three different numerical modelling techniques for implant fixation were used in this study, i.e. without screw modelling, screws as solid elements as well as screws as structural elements. The latter one offers the possibility to implement automatically generated screws with variable geometry on arbitrary FE models. Structural screws were parametrically generated by a Python script for the automatic generation in the FE-software Abaqus/CAE on both a tetrahedral and a hexahedral meshed femur. Accuracy of the FE models was confirmed by experimental testing using a composite femur with a segmental defect and an identical osteosynthesis plate for primary stabilisation with titanium screws. Both deflection of the femoral head and the gap alteration were measured with an optical measuring system with an accuracy of approximately 3 µm. For both screw modelling techniques a sufficient correlation of approximately 95% between numerical and experimental analysis was found. Furthermore, using structural elements for screw modelling the computational time could be reduced by 85% using hexahedral elements instead of tetrahedral elements for femur meshing. The automatically generated screw modelling offers a realistic simulation of the osteosynthesis fixation with screws in the adjacent bone stock and can be used for further investigations

Prion Protein Is a Key Determinant of Alcohol Sensitivity through the Modulation of N-Methyl-D-Aspartate Receptor (NMDAR) Activity

The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP−/−) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP−/− mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP−/− mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP−/− mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions

Protease-Sensitive Conformers in Broad Spectrum of Distinct PrPSc Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate

The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrPSc) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrPSc, we identified an extensive array of PrPSc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrPSc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrPSc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrPSc suggests that these conformers play an important role in the pathogenesis of sCJD

A New Method for the Characterization of Strain-Specific Conformational Stability of Protease-Sensitive and Protease-Resistant PrPSc

Although proteinacious in nature, prions exist as strains with specific self-perpetuating biological properties. Prion strains are thought to be associated with different conformers of PrPSc, a disease-associated isoform of the host-encoded cellular protein (PrPC). Molecular strain typing approaches have been developed which rely on the characterization of protease-resistant PrPSc. However, PrPSc is composed not only of protease-resistant but also of protease-sensitive isoforms. The aim of this work was to develop a protocol for the molecular characterization of both, protease-resistant and protease-sensitive PrPSc aggregates. We first set up experimental conditions which allowed the most advantageous separation of PrPC and PrPSc by means of differential centrifugation. The conformational solubility and stability assay (CSSA) was then developed by measuring PrPSc solubility as a function of increased exposure to GdnHCl. Brain homogenates from voles infected with human and sheep prion isolates were analysed by CSSA and showed strain-specific conformational stabilities, with mean [GdnHCl]1/2 values ranging from 1.6 M for MM2 sCJD to 2.1 for scrapie and to 2.8 M for MM1/MV1 sCJD and E200K gCJD. Interestingly, the rank order of [GdnHCl]1/2 values observed in the human and sheep isolates used as inocula closely matched those found following transmission in voles, being MM1 sCJD the most resistant (3.3 M), followed by sheep scrapie (2.2 M) and by MM2 sCJD (1.6 M). In order to test the ability of CSSA to characterise protease-sensitive PrPSc, we analysed sheep isolates of Nor98 and compared them to classical scrapie isolates. In Nor98, insoluble PrPSc aggregates were mainly protease-sensitive and showed a conformational stability much lower than in classical scrapie. Our results show that CSSA is able to reveal strain-specified PrPSc conformational stabilities of protease-resistant and protease-sensitive PrPSc and that it is a valuable tool for strain typing in natural hosts, such as humans and sheep