Distal humerus fractures in patients over 65: Complications

SummaryIntroductionFractures of the distal humerus in patients over the age of 65 remain a therapeutic challenge. Treatment options include conservative treatment, internal fixation or total elbow arthroplasty. The complications of these different treatment options were evaluated in a multicentre study.Materials and methodsFour hundred and ninety-seven medical records were evaluated. A retrospective study was performed in 410 cases: 34 received conservative treatment, 289 internal fixation and 87 underwent total elbow arthroplasty. A prospective study was performed in 87 cases: 22 received conservative treatment, 53 internal fixation, and 12 underwent total elbow arthroplasty. Patients were evaluated after at least 6 months follow-up.ResultsThe rate of complications was 30% in the retrospective study and 29% in the prospective study. The rate of complications in the conservative treatment group was 60%, and the main complication was essentially malunion. The rate of complications was 44% in the internal fixation group and included neuropathies, mechanical failure or wound dehiscence. Although complications only developed in 23% of total elbow arthroplasties, they were often more severe than those following other treatments.DiscussionComplications develop in one out of three patients over 65 with distal humerus fractures. Three main types of complications were identified. Neuropathies especially of the ulnar nerve, especially during arthroplasty, must always be identified, the nerve requiring isolation and transposition. Bone complications, due principally to mechanical failure, were found following internal fixation. Despite technical progress, care must be taken not to favor excessive utilization of this treatment option in complex fractures on fragile bone. Although there were relatively fewer complications with total elbow arthroplasty they were more difficult to treat. Ossifications were frequent whatever the surgical option and can jeopardize the functional outcome.Level of evidenceLevel IV

Temporary opening of the blood-brain barrier with the nitrone compound OKN-007

The blood-brain barrier (BBB) is usually impermeable to several drugs, which hampers treatment of various brain-related diseases/disorders. There have been several approaches to open the BBB, including intracarotid infusion of hyperosmotic concentrations of arabinose, mannitol, oleic or linoleic acids, or alkylglycerols, intravenous infusion of bradykinin B2, administration of a fragment of the ZO toxin from vibrio cholera, targeting specific components of the tight junctions (e.g. claudin-5) with siRNA or novel peptidomimetic drugs, or the use of ultrasound with microbubbles. We propose the use of a low molecular weight (MW), nitrone-type compound, OKN-007, which can temporarily open up the BBB for 1-2 hours. Gadolinium (Gd)-based compounds assessed ranged in MW from 546 (Gd-DTPA) to 465 kDa (beta-galactosidase Gd DOTA). We also included an albumin-based CA (albumin-Gd-DTPA-biotin) for assessment, as well as an antibody (Ab) against a neuron-specific biomarker conjugated to Gd-DOTA (anti-EphB2-Gd-DOTA). For the anti-EphB2 (goat Ab)-Gd-DOTA assessment, we utilized an anti goat Ab conjugated with horse radish peroxidase (HRP) for confirmation of the presence of the anti-EphB2-Gd-DOTA probe. In addition, a Cy5 labeled anti-EphB2 Ab was co-administered with the anti-EphB2-Gd-DOTA probe, and assessed ex vivo. This study demonstrates that OKN-007 may be able to temporarily open up the BBB to augment the delivery of various compounds ranging in MW from as small as similar to 550 to as large as similar to 470 kDa. This compound is an investigational new drugfor glioblastoma (GBM) therapy in clinical trials. The translational capability for human use to augment the delivery of non-BBB-permeable drugs is extremely high

Treatment of the fixation surface improves glenoid prosthesis longevity in-vitro

Many commercial cemented glenoid components claim superior fixation designs and increased survivability. However, both research and clinical studies have shown conflicting results and it is unclear whether these design variations do improve loosening rates. Part of the difficulty in investigating fixation failure is the inability to directly observe the fixation interface, a problem addressed in this study by using a novel experimental set-up.Cyclic loading-displacement tests were carried out on 60 custom-made glenoid prostheses implanted into a bone substitute. Design parameters investigated included treatment of the fixation surface of the component resulting in different levels of back-surface roughness, flat-back versus curved-back, keel versus peg and more versus less conforming implants. Visually-observed failure and ASTM-recommended rim-displacements were recorded throughout testing to investigate fixation failure and if rim displacement is an appropriate measure of loosening. Roughening the implant back (Ra > 3 µm) improved resistance to failure (P < 0.005) by an order of magnitude with the rough and smooth groups failing at 8712 ± 5584 cycles (mean ± SD) and 1080 ± 1197 cycles, respectively. All other design parameters had no statistically significant effect on the number of cycles to failure. All implants failed inferiorly and 95 % (57/60) at the implant/cement interface. Rim-displacement correlated with visually observed failure. The most important effect was that of roughening the implant, which strengthened the polyethylene-cement interface. Rim-displacement can be used as an indicator of fixation failure, but the sensitivity was insufficient to capture subtle effects.Level of Evidence: Basic Science Study, Biomechanical Analysis

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies