Tibial Tubercle Osteotomy and Medial Patellofemoral Ligament Imbrication for Patellar Instability Due to Trochlear Dysplasia.

BackgroundThe treatment of patellar instability in the setting of trochlear dysplasia is challenging.Purpose/hypothesisThe purpose of this study was to evaluate outcomes for the treatment of recurrent patellar dislocations due to trochlear dysplasia using anteromedialization tibial tubercle osteotomy combined with medial patellofemoral ligament (MPFL) imbrication. We hypothesized that the treatment of patellar instability with tibial tubercle osteotomy and MPFL imbrication would result in improved patient satisfaction and decrease patellar instability events in patients with prior instability and trochlear dysplasia.Study designCase series; Level of evidence, 4.MethodsWe performed a retrospective analysis of patients who underwent MPFL imbrication and concomitant anteromedialization tibial tubercle osteotomy for recurrent patellofemoral instability at a single institution. The minimum follow-up was 1 year. Patient demographic information including age at the time of surgery, sex, body mass index (BMI), tibial tubercle-trochlear groove (TT-TG) distance, and grade of trochlear dysplasia was collected along with relevant operative data. Postoperatively, recurrent dislocation events as well as Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index, and Kujala scores were collected, and satisfaction was ascertained by asking patients whether they would undergo the procedure again.ResultsA total of 37 knees from 31 patients (23 female) with a mean follow-up of 3.8 years (range, 1-8.9 years) were included. The mean patient age was 28.8 years (range, 14-45 years), the mean BMI was 24 kg/m2 (range, 20-38 kg/m2), and the mean preoperative TT-TG distance was 18.9 mm (range, 8.4-32.4 mm). Two knees were classified as low-grade trochlear dysplasia (Dejour A) and 35 as high-grade trochlear dysplasia (Dejour B-D). At final follow-up, patients reported mean KOOS subscale scores of 86.5 (Pain), 79.8 (Symptoms), 93.9 (Activities of Daily Living), 74.3 (Sports/Recreation), and 61.9 (Quality of Life), as well as a mean Kujala score of 81.3. Mean patient satisfaction was 8.3 of 10. The majority of knees (86.5%; 32/37) remained stable without recurrent instability after this procedure, while 13.5% (5 knees) suffered a recurrent dislocation, with 2 requiring revision surgery. Eight knees (21.6%) underwent subsequent hardware removal.ConclusionAnteromedialization tibial tubercle osteotomy with MPFL imbrication can improve recurrent patellofemoral instability and provide significant clinical benefit to patients with trochlear dysplasia

The spatial distribution of galaxies of different spectral types in the massive intermediate-redshift cluster MACSJ0717.5+3745

We present the results of a wide-field spectroscopic analysis of the galaxy population of the massive cluster MACSJ0717.5+3745 and the surrounding filamentary structure (z=0.55), as part of our systematic study of the 12 most distant clusters in the MACS sample. Of 1368 galaxies spectroscopically observed in this field, 563 are identified as cluster members; of those, 203 are classified as emission-line galaxies, 260 as absorption-line galaxies, and 17 as E+A galaxies (defined by $\frac{H_{\delta}+H_{\gamma}}{2}>6$\AA and no detection of [OII] and $H_{\beta}$ in emission). The variation of the fraction of emission- and absorption-line galaxies as a function of local projected galaxy density confirms the well-known morphology-density relation, and becomes flat at projected galaxy densities less than $\sim 20Mpc^{-2}. Interestingly, 16 out of 17 E+A galaxies lie (in projection) within the ram-pressure stripping radius around the cluster core, which we take to be direct evidence of ram-pressure stripping being the primary mechanism that terminates star-formation in the E+A population of galaxy clusters. This conclusion is supported by the rarity of E+A galaxies in the filament which rules out galaxy mergers as the dominant driver of evolution for E+A galaxies in clusters. In addition, we find the 42 e(a) and 27 e(b) member galaxies, i.e., the dusty-starburst and starburst galaxies respectively, to be spread out across almost the entire study area. Their spatial distribution, which shows a strong preference for the filament region, suggests that starbursts are triggered in relatively low-density environments as galaxies are accreted from the field population.Comment: 16 pages, 15 figures, accepted by Ap

Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Gravitino constraints on models of neutrino masses and leptogenesis

In the supersymmetric extensions of the standard model, neutrino masses and leptogenesis requires existence of new particles. We point out that if these particles with lepton number violating interactions have standard model gauge interactions, then they may not be created after reheating because of the gravitino problem. This will rule out all existing models of neutrino masses and leptogenesis, except the one with right-handed singlet neutrinos.Comment: 12 pages latex file with one postscript figur

Superconformal Flavor Simplified

A simple explanation of the flavor hierarchies can arise if matter fields interact with a conformal sector and different generations have different anomalous dimensions under the CFT. However, in the original study by Nelson and Strassler many supersymmetric models of this type were considered to be 'incalculable' because the R-charges were not sufficiently constrained by the superpotential. We point out that nearly all such models are calculable with the use of a-maximization. Utilizing this, we construct the simplest vector-like flavor models and discuss their viability. A significant constraint on these models comes from requiring that the visible gauge couplings remain perturbative throughout the conformal window needed to generate the hierarchies. However, we find that there is a small class of simple flavor models that can evade this bound.Comment: 43 pages, 1 figure; V3: small corrections and clarifications, references adde

An initial event in insect innate immune response: structural and biological studies of interactions between β-1,3-glucan and the N-terminal domain of β-1,3-glucan recognition protein

In response to invading microorganisms, insect β-1,3-glucan recognition protein (βGRP), a soluble receptor in the hemolymph, binds to the surfaces of bacteria and fungi and activates serine protease cascades that promote destruction of pathogens by means of melanization or expression of antimicrobial peptides. Here we report on the NMR solution structure of the N-terminal domain of βGRP (N-βGRP) from Indian meal moth (Plodia interpunctella), which is sufficient to activate the prophenoloxidase (proPO) pathway resulting in melanin formation. NMR and isothermal calorimetric titrations of N-βGRP with laminarihexaose, a glucose hexamer containing β-1,3 links, suggest a weak binding of the ligand. However, addition of laminarin, a glucose polysaccharide (~ 6 kDa) containing β-1,3 and β-1,6 links that activates the proPO pathway, to N-βGRP results in the loss of NMR cross-peaks from the backbone 15N-1H groups of the protein, suggesting the formation of a large complex. Analytical ultra centrifugation (AUC) studies of formation of N-βGRP:laminarin complex show that ligand-binding induces sel-fassociation of the protein:carbohydrate complex into a macro structure, likely containing six protein and three laminarin molecules (~ 102 kDa). The macro complex is quite stable, as it does not undergo dissociation upon dilution to sub-micromolar concentrations. The structural model thus derived from the present studies for N-βGRP:laminarin complex in solution differs from the one in which a single N-βGRP molecule has been proposed to bind to a triple helical form of laminarin on the basis of an X-ray crystallographic structure of N-βGRP:laminarihexaose complex [Kanagawa, M., Satoh, T., Ikeda, A., Adachi, Y., Ohno, N., and Yamaguchi, Y. (2011) J. Biol. Chem. 286, 29158-29165]. AUC studies and phenoloxidase activation measurements carried out with the designed mutants of N-βGRP indicate that electrostatic interactions involving Asp45, Arg54, and Asp68 between the ligand-bound protein molecules contribute in part to the stability of N-βGRP:laminarin macro complex and that a decreased stability is accompanied by a reduced activation of the proPO pathway. Increased β-1,6 branching in laminarin also results in destabilization of the macro complex. These novel findings suggest that ligand-induced self-association of βGRP:β-1,3-glucan complex may form a platform on a microbial surface for recruitment of downstream proteases, as a means of amplification of the initial signal of pathogen recognition for the activation of the proPO pathway

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome

Software defect prediction: do different classifiers find the same defects?

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.During the last 10 years, hundreds of different defect prediction models have been published. The performance of the classifiers used in these models is reported to be similar with models rarely performing above the predictive performance ceiling of about 80% recall. We investigate the individual defects that four classifiers predict and analyse the level of prediction uncertainty produced by these classifiers. We perform a sensitivity analysis to compare the performance of Random Forest, Naïve Bayes, RPart and SVM classifiers when predicting defects in NASA, open source and commercial datasets. The defect predictions that each classifier makes is captured in a confusion matrix and the prediction uncertainty of each classifier is compared. Despite similar predictive performance values for these four classifiers, each detects different sets of defects. Some classifiers are more consistent in predicting defects than others. Our results confirm that a unique subset of defects can be detected by specific classifiers. However, while some classifiers are consistent in the predictions they make, other classifiers vary in their predictions. Given our results, we conclude that classifier ensembles with decision-making strategies not based on majority voting are likely to perform best in defect prediction.Peer reviewedFinal Published versio