Is fixation of the medial malleolus necessary in unstable ankle fractures?

INTRODUCTION: It is unclear whether the medial malleolus in unstable bi- and tri- malleolar ankle fractures without medial talar displacement should be addressed surgically. This study reviews a fixation protocol for the medial malleolar component of unstable bi- or tri- malleolar ankle fractures. MATERIALS AND METHODS: Two hundred fifty-seven patients who sustained bi- (AO/OTA 44-B2) or tri- (AO/OTA 44-B3) malleolar ankle fractures between January 2005 and August 2019 at two Level 1 trauma centers were retrospectively identified. Medial malleolar fractures were defined as anterior, supra or intercollicular fractures based on the exit of the posterior fracture line. Fixation of the medial malleolar component was performed based on surgical algorithm. Only large or significantly displaced medial malleolar fractures were fixed if the soft tissues were amenable. Primary outcome measure was the presence of medial-sided ankle pain after operative or non-operative treatment of the medial malleolar fracture after a minimum follow up of 6 months. Presence of pain was defined by a pain score of 3 or higher on a 10-point VAS pain score at the site of the medial malleolar fracture. RESULTS: Significantly more patients in the supracollicular group reported the presence of pain when this type was not fixed versus fixed (28 vs 14%, p = 0.0094). Significantly more patients in the anterior collicular subgroup reported the presence of pain when this type was fixed versus not fixed (40 vs 10%, p = 0.0438). There was no difference in the number of patients reporting pain in the intercollicular group when comparing those who were fixed versus not fixed, (21 vs 22%, p = 1.000). CONCLUSIONS: When examining post-operative pain, not all medial malleolar fractures require fixation when appropriately selected based on fracture pattern. Only 10% of patients with anterior collicular fractures reported pain after non operative management. Unsurprisingly, more patients in the supracollicular fractures reported pain without surgery compared to with surgery. Fracture pattern should be considered in the treatment algorithm for the medial malleolar component in bi- and tri- malleolar fractures.

Low Level of Evidence and Methodologic Quality of Clinical Outcome Studies on Cartilage Repair of the Ankle.

PURPOSE: To examine the level of evidence and methodologic quality of studies reporting surgical treatments for osteochondral lesions of the ankle. METHODS: A search was performed using the PubMed/Medline, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Cochrane databases for all studies in which the primary objective was to report the outcome after surgical treatment of osteochondral lesions of the ankle. Studies reporting outcomes of microfracture, bone marrow stimulation, autologous osteochondral transplantation, osteochondral allograft transplantation, and autologous chondrocyte implantation were the focus of this analysis because they are most commonly reported in the literature. Two independent investigators scored each study from 0 to 100 based on 10 criteria from the modified Coleman Methodology Score (CMS) and assigned a level of evidence using the criteria established by the Journal of Bone and Joint Surgery. Data were collected on the study type, year of publication, number of surgical procedures, mean follow-up, preoperative and postoperative American Orthopaedic Foot & Ankle Society score, measures used to assess outcome, geography, institution type, and conflict of interest. RESULTS: Eighty-three studies reporting the results of 2,382 patients who underwent 2,425 surgical procedures for osteochondral lesions of the ankle met the inclusion criteria. Ninety percent of studies were of Level IV evidence. The mean CMS for all scored studies was 53.6 of 100, and 5 areas were identified as methodologically weak: study size, type of study, description of postoperative rehabilitation, procedure for assessing outcome, and description of the selection process. There was no significant difference between the CMS and the type of surgical technique (P = .1411). A statistically significant patient-weighted correlation was found between the CMS and the level of evidence (r = -0.28, P = .0072). There was no statistically significant patient-weighted correlation found between the CMS and the institution type (r = 0.05, P = .6480) or financial conflict of interest (r = -0.16, P = .1256). CONCLUSIONS: Most studies assessing the clinical outcomes of cartilage repair of the ankle are of a low level of evidence and of poor methodologic quality. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies.

A phospholipase C-γ1-independent, RasGRP1-ERK-dependent pathway drives lymphoproliferative disease in linker for activation of T cells-Y136F mutant mice.

Mice expressing a germline mutation in the phospholipase C-γ1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-θ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting.

Formation of covalently bonded polycyclic hydrocarbon ions by intracluster polymerization of ionized ethynylbenzene clusters.

Here we report a detailed study aimed at elucidating the mechanism of intracluster ionic polymerization following the electron impact ionization of van der Waals clusters of ethynylbenzene (C8H6)n generated by a supersonic beam expansion. The structures of the C16H12, C24H18, C32H24, C40H30, and C48H36 radical cations resulting from the intracluster ion-molecule addition reactions have been investigated using a combination of mass-selected ion dissociation and ion mobility measurements coupled with theoretical calculations. Noncovalent structures can be totally excluded primarily because the measured fragmentations cannot result from noncovalent structures, and partially because of the large difference between the measured collision cross sections and the calculated values corresponding to noncovalent ion-neutral complexes. All the mass-selected cluster ions show characteristic fragmentations of covalently bonded molecular ions by the loss of stable neutral fragments such as CH3, C2H, C6H5, and C7H7. The population of the C16H12 dimer ions is dominated by structural isomers of the type (C6H5)-C≡C-CH(•+)CH-(C6H5), which can grow by the sequential addition of ethynylbenzene molecules, in addition to some contributions from cyclic isomers such as the 1,3- or 1,4-diphenyl cyclobutadiene ions. Similarly, two major covalent isomers have been identified for the C24H18 trimer ions: one that has a blocked cyclic structure assigned to 1,2,4- or 1,3,5-triphenylbenzene cation, and a second isomer of the type (C6H5)-C≡C-C(C6H5)═CH-CH(•+)CH-(C6H5) where the covalent addition of further ethynylbenzene molecules can occur. For the larger ions such as C32H24, C40H30, and C48H36, the major isomers present involve the growing oligomer sequence (C6H5)-C≡C-[C(C6H5)═CH]n-CH(•+)CH-(C6H5) with different locations and orientations of the phenyl groups along the chain. In addition, the larger ions contain another family of structures consisting of neutral ethynylbenzene molecules associated with the blocked cyclic isomer ions such as the diphenylcyclobutadiene and triphenylbenzene cations. Low-energy dissociation channels corresponding to evaporation of ethynylbenzene molecules weakly associated with the covalent ions are observed in the large clusters in addition to the high-energy channels corresponding to fragmentation of the covalently bonded ions. However, in small clusters only high-energy dissociation channels are observed corresponding to the characteristic fragmentation of the molecular ions, thus providing structural signatures to identify the product ions and establish the mechanism of intracluster ionic polymerization.

Targeted Sos1 deletion reveals its critical role in early T-cell development.

Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre-T-cell receptor (pre-TCR)- but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR-stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.

Nuclear Medicine Scans in Total Joint Replacement.

¼: A 3-phase bone scan is a potential first-line nuclear medicine study for pain after total joint arthroplasty (TJA) when there is concern for periprosthetic joint infection or aseptic loosening. ¼: In patients who have a positive bone scintigraphy result and suspected infection of the joint, but where aspiration or other studies are inconclusive, labeled leukocyte scintigraphy with bone marrow imaging may be of benefit. ¼: Magnetic resonance imaging (MRI), while not a nuclear medicine study, also shows promise and has the advantage of providing information about the soft tissues around a total joint replacement. ¼: Radiotracer uptake patterns in scintigraphy are affected by the prosthesis (total knee arthroplasty [TKA] versus total hip arthroplasty [THA]) and the use of cement. ¼: Nuclear medicine scans may be ordered 1 year postoperatively but may have positive findings that are due to normal physiologic bone remodeling. Nuclear studies may be falsely positive for up to 2 years after TJA. ¼: Single-photon emission computed tomography (SPECT) combined with computed tomography (CT) (SPECT/CT), fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT, and MRI show promise; however, more studies are needed to better define their role in the diagnostic workup of pain after TJA.

Platelet-rich plasma increases transforming growth factor-beta1 expression at graft-host interface following autologous osteochondral transplantation in a rabbit model.

AIM: To explore the effect of platelet-rich plasma on protein expression patterns of transforming growth factor-beta1 (TGF-ß1) in cartilage following autologous osteochondral transplantation (AOT) in a rabbit knee cartilage defect model. METHODS: Twelve New Zealand white rabbits received bilateral AOT. In each rabbit, one knee was randomized to receive an autologous platelet rich plasma (PRP) injection and the contralateral knee received saline injection. Rabbits were euthanized at 3, 6 and 12 wk post-operatively. Articular cartilage sections were stained with TGF-ß1 antibody. Histological regions of interest (ROI) (left, right and center of the autologous grafts interfaces) were evaluated using MetaMorph. Percentage of chondrocytes positive for TGF-ß1 was then assessed. RESULTS: Percentage of chondrocytes positive for TGF-ß1 was higher in PRP treated knees for selected ROIs (left; P = 0.03, center; P = 0.05) compared to control and was also higher in the PRP group at each post-operative time point (P = 6.6 × 10(-4), 3.1 × 10(-4) and 7.3 × 10(-3) for 3, 6 and 12 wk, respectively). TGF-ß1 expression was higher in chondrocytes of PRP-treated knees (36% ± 29% vs 15% ± 18%) (P = 1.8 × 10(-6)) overall for each post-operative time point and ROI. CONCLUSION: Articular cartilage of rabbits treated with AOT and PRP exhibit increased TGF-ß1 expression compared to those treated with AOT and saline. Our findings suggest that adjunctive PRP may increase TGF-ß1 expression, which may play a role in the chondrogenic effect of PRP in vivo.

The ability of Sos1 to oligomerize the adaptor protein LAT is separable from its guanine nucleotide exchange activity in vivo.

The activation of the small guanosine triphosphatase Ras by the guanine nucleotide exchange factor (GEF) Sos1 (Son of Sevenless 1) is a central feature of many receptor-stimulated signaling pathways. In developing T cells (thymocytes), Sos1-dependent activation of extracellular signal-regulated kinase (ERK) is required to stimulate cellular proliferation and differentiation. We showed that in addition to its GEF activity, Sos1 acted as a scaffold to nucleate oligomerization of the T cell adaptor protein LAT (linker for activation of T cells) in vivo. The scaffold function of Sos1 depended on its ability to bind to the adaptor protein Grb2. Furthermore, the GEF activity of Sos1 and the Sos1-dependent oligomerization of LAT were separable functions in vivo. Whereas the GEF activity of Sos1 was required for optimal ERK phosphorylation in response to T cell receptor (TCR) stimulation, the Sos1-dependent oligomerization of LAT was required for maximal TCR-dependent phosphorylation and activation of phospholipase C-γ1 and Ca(2+) signaling. Finally, both of these Sos1 functions were required for early thymocyte proliferation. Whereas transgenic restoration of either the GEF activity or the LAT oligomerization functions of Sos1 alone failed to rescue thymocyte development in Sos1-deficient mice, simultaneous reconstitution of these two signals in the same cell restored normal T cell development. This ability of Sos1 to act both as a RasGEF and as a scaffold to nucleate Grb2-dependent adaptor oligomerization may also occur in other Grb2-dependent pathways, such as those activated by growth factor receptors.

Deconstructing Ras signaling in the thymus.

Thymocytes must transit at least two distinct developmental checkpoints, governed by signals that emanate from either the pre-T cell receptor (pre-TCR) or the TCR to the small G protein Ras before emerging as functional T lymphocytes. Recent studies have shown a role for the Ras guanine exchange factor (RasGEF) Sos1 at the pre-TCR checkpoint. At the second checkpoint, the quality of signaling through the TCR is interrogated to ensure the production of an appropriate T cell repertoire. Although RasGRP1 is the only confirmed RasGEF required at the TCR checkpoint, current models suggest that the intensity and character of Ras activation, facilitated by both Sos and RasGRP1, will govern the boundary between survival (positive selection) and death (negative selection) at this stage. Using mouse models, we have assessed the independent and combined roles for the RasGEFs Sos1, Sos2, and RasGRP1 during thymocyte development. Although Sos1 was the dominant RasGEF at the pre-TCR checkpoint, combined Sos1/RasGRP1 deletion was required to effectively block development at this stage. Conversely, while RasGRP1 deletion efficiently blocked positive selection, combined RasGRP1/Sos1 deletion was required to block negative selection. This functional redundancy in RasGEFs during negative selection may act as a failsafe mechanism ensuring appropriate central tolerance.