Femoral Cartilage Ultrasound Echo Intensity Associates with Arthroscopic Cartilage Damage

This study compared quantitative cartilage ultrasound metrics between people with (n = 12) and without (n = 12) arthroscopic cartilage damage after anterior cruciate ligament injury (age, 24.9 ± 3.7 y; sex, 33% female, 67% male; days since injury = 50 ± 52). A transverse suprapatellar ultrasound assessment imaged the femoral cartilage in participants’ injured knees before a clinical arthroscopy. A custom program automatically separated a manual cartilage segmentation into standardized medial and lateral femoral regions and calculated mean thickness (i.e., cross-sectional area/length of cartilage-bone interface), mean echo intensity and echo-intensity heterogeneity. An orthopedic surgeon assessed arthroscopic cartilage damage in the medial and lateral femoral condyles using the Outerbridge grading system (cartilage damage = Outerbridge ≥ 1). Separate logistic regressions for medial and lateral femoral cartilage were used to determine the association between each ultrasound metric and arthroscopic cartilage damage. In medial femoral cartilage, for every 1 standard deviation decrease in echo-intensity mean and heterogeneity, there is, respectively, a 91% (adjusted odds ratio, 0.09; 95% confidence interval, 0.01–0.69) and 97% (adjusted odds ratio, 0.03; 95% confidence interval, 0.002–0.50) increase in the odds of having arthroscopic cartilage damage. Lateral cartilage ultrasound metrics are not associated with lateral arthroscopic cartilage damage. This study provides preliminary evidence that femoral cartilage ultrasound echo intensity is a non-invasive measure associated with medial femoral cartilage health after anterior cruciate ligament injury.     

Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis

Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.     

Matrix detachment and proteasomal inhibitors diminish Sulf-2 expression in breast cancer cell lines and mouse xenografts

Sulfatase 2 (Sulf-2) has been previously shown to be upregulated in breast cancer. Sulf-2 removes sulfate moieties on heparan sulfate proteoglycans which in turn modulate heparin binding growth factor signaling. Here we report that matrix detachment resulted in decreased Sulf-2 expression in breast cancer cells and increased cleavage of poly ADP-ribose polymerase. Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells. In an attempt to identify Sulf-2 specific inhibitor, we found that proteasomal inhibitors such as MG132, Lactacystin and Bortezomib treatment abolished Sulf-2 expression in multiple breast cancer cell lines. Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo. Finally, our immunohistochemistry analysis of Sulf-2 expression in cohort of patient derived breast tumors indicates that Sulf-2 is significantly upregulated in autologous metastatic lesions compared to primary tumors (p < 0.037, Pearson correlation, Chi-Square analysis). In all, our data suggest that Sulf-2 might play an important role in breast cancer progression from ductal carcinoma in situ into an invasive ductal carcinoma potentially by resisting cell death.     

Does like attract like? Exploring the relationship between errors and representational structure in connectionist networks

Many cognitive psychological studies assume that error probabilities reflect the structure of cognitive representations (e.g., if the representations of two lexical items overlap, they are more likely to interact in a word exchange error than are two lexical items with nonoverlapping representations). However, since errors directly reflect the properties of neurobiological structures and processes, this assumption rests on the correspondence between cognitive and neurobiological elements. Analytical and simulation studies of connectionist networks are used to examine the consequences of different cognitive-neurobiological relationships (e.g., localist vs. distributed representations) for effects of representational structure on error probabilities. The results reveal that such effects are influenced by the nature of the relationship between network and cognitive representations. While errors on localist network representations always reflect the degree to which cognitive representations overlap, distributed representations only do so under specific conditions. Furthermore, the effects of cognitive representational structure on error probabilities are shown to be stronger under localist than under distributed representations.