Arthroscopic Optical Coherence Tomography in Diagnosis of Early Arthritis

Osteoarthritis (OA) is a progressive, debilitating disease that is increasing in prevalence. The pathogenesis of OA is likely multifactorial but ultimately leads to progressive breakdown of collagen matrix and loss of chondrocytes. Current clinical modalities employed to evaluate cartilage health and diagnose osteoarthritis in orthopaedic surgery include, radiography, MRI, and arthroscopy. While these assessment methods can show cartilage fissuring and loss, they are limited in ability to diagnose cartilage injury and degeneration prior breakdown of the articular surface. An improved clinical ability to detect subsurface cartilage pathology is important for development and testing of chondroprotective and chondrorestorative treatments because the pathological changes following surface breakdown are generally considered to be irreversible. Optical Coherence Tomography (OCT), is a novel, non-destructive imaging technology capable of near-real time cross-sectional images of articular cartilage at high resolutions comparable to low power histology. This review discusses a series of bench to bedside studies supporting the potential use of OCT for enhanced clinical diagnosis and staging of early cartilage injury and degeneration. OCT was also found to be useful as a translations research tool to assist in clinical evaluation of novel quantitative MRI technologies for non-invasive evaluation of articular cartilage

The evolution of research on collaborative learning

For many years, theories of collaborative learning tended to focus on how individuals function in a group. More recently, the focus has shifted so that the group itself has become the unit of analysis. In terms of empirical research, the initial goal was to establish whether and under what circumstances collaborative learning was more effective than learning alone. Researchers controlled several independent variables (size of the group, composition of the group, nature of the task, communication media, and so on). However, these variables interacted with one another in a way that made it almost impossible to establish causal links between the conditions and the effects of collaboration. Hence, empirical studies have more recently started to focus less on establishing parameters for effective collaboration and more on trying to understand the role which such variables play in mediating interaction. In this chapter, we argue that this shift to a more process-oriented account requires new tools for analysing and modelling interactions

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer

Adaptive genetic markers discriminate migratory runs of Chinook salmon (Oncorhynchus tshawytscha) amid continued gene flow

Neutral genetic markers are routinely used to define distinct units within species that warrant discrete management. Human-induced changes to gene flow however may reduce the power of such an approach. We tested the efficiency of adaptive versus neutral genetic markers in differentiating temporally divergent migratory runs of Chinook salmon (Oncorhynchus tshawytscha) amid high gene flow owing to artificial propagation and habitat alteration. We compared seven putative migration timing genes to ten microsatellite loci in delineating three migratory groups of Chinook in the Feather River, CA: offspring of fall-run hatchery broodstock that returned as adults to freshwater in fall (fall run), spring-run offspring that returned in spring (spring run), and fall-run offspring that returned in spring (FRS). We found evidence for significant differentiation between the fall and federally listed threatened spring groups based on divergence at three circadian clock genes (OtsClock1b, OmyFbxw11, and Omy1009UW), but not neutral markers. We thus demonstrate the importance of genetic marker choice in resolving complex life history types. These findings directly impact conservation management strategies and add to previous evidence from Pacific and Atlantic salmon indicating that circadian clock genes influence migration timing.Keywords: conservation genetics, ecological genetics, captive populations, conservation biology, life history evolution, hybridization, population genetics, fisheries managemen

The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin

SHIP-2 is a phosphoinositidylinositol 3,4,5 trisphosphate (PtdIns[3,4,5]P3) 5-phosphatase that contains an NH2-terminal SH2 domain, a central 5-phosphatase domain, and a COOH-terminal proline-rich domain. SHIP-2 negatively regulates insulin signaling. In unstimulated cells, SHIP-2 localized in a perinuclear cytosolic distribution and at the leading edge of the cell. Endogenous and recombinant SHIP-2 localized to membrane ruffles, which were mediated by the COOH-terminal proline–rich domain. To identify proteins that bind to the SHIP-2 proline–rich domain, yeast two-hybrid screening was performed, which isolated actin-binding protein filamin C. In addition, both filamin A and B specifically interacted with SHIP-2 in this assay. SHIP-2 coimmunoprecipitated with filamin from COS-7 cells, and association between these species did not change after epidermal growth factor stimulation. SHIP-2 colocalized with filamin at Z-lines and the sarcolemma in striated muscle sections and at membrane ruffles in COS-7 cells, although the membrane ruffling response was reduced in cells overexpressing SHIP-2. SHIP-2 membrane ruffle localization was dependent on filamin binding, as SHIP-2 was expressed exclusively in the cytosol of filamin-deficient cells. Recombinant SHIP-2 regulated PtdIns(3,4,5)P3 levels and submembraneous actin at membrane ruffles after growth factor stimulation, dependent on SHIP-2 catalytic activity. Collectively these studies demonstrate that filamin-dependent SHIP-2 localization critically regulates phosphatidylinositol 3 kinase signaling to the actin cytoskeleton

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46;p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52;p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment

Techniques, Clinical Applications and Limitations of 3D Reconstruction in CT of the Abdomen

Enhanced z-axis coverage with thin overlapping slices in breath-hold acquisitions with multidetector CT (MDCT) has considerably enhanced the quality of multiplanar 3D reconstruction. This pictorial essay describes the improvements in 3D reconstruction and technical aspects of 3D reconstruction and rendering techniques available for abdominal imaging. Clinical applications of 3D imaging in abdomen including liver, pancreaticobiliary system, urinary and gastrointestinal tracts and imaging before and after transplantation are discussed. In addition, this article briefly discusses the disadvantages of thin-slice acquisitions including increasing numbers of transverse images, which must be reviewed by the radiologist

Improbability mapping: a metric for satellite-detection of submarine volcanic eruptions

Submarine volcanic eruptions can result in both real and apparent changes in marine algal communities, e.g., increases in phytoplankton biomass and/or growth rates that can cover thousands of square kilometers. Satellite ocean color monitoring detects these changes as increases in chlorophyll and particulate backscattering. Detailed, high resolution analysis is needed to separate the optical effects of volcanic products from the response of the marine algal community. It is possible to calculate an index, which maps the magnitude of improbable change (relative to long term average conditions) following known volcanic eruptions by using low resolution, initial estimates of chlorophyll and backscatter along with an archived history of satellite data. We apply multivariate probability analysis to changes in global satellite ocean chlorophyll and particulate backscatter data to create a new metric for observing apparent biological responses to submarine eruptions. Several examples are shown, illustrating the sensitivity of our improbability mapping index to known submarine volcanic events, yielding a potentially robust method for the detection of new events in remote locations.Keywords: Improbability mapping index, Submarine volcanic eruptions, Satellite detectio