Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway.

Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.This article has an associated First Person interview with the first author of the paper.

Association Between CT Angiogram Collaterals and CT Perfusion in Delayed Time Windows for Large Vessel Occlusion Ischemic Strokes.

OBJECTIVES: Recent endovascular trials have established the use of CT perfusion (CTP) in endovascular treatment selection for patients with large vessel occlusions (LVO). However, the relationship between CTP and collateral circulation is unclear in delayed time windows. We explored the relationship between CT Angiogram (CTA) collaterals and CTP parameters in delayed time windows (6-24 hours). MATERIALS AND METHODS: We utilized a single institutional, retrospective stroke registry of consecutive patients between May 2016 and May 2018 with anterior LVO with CTA and CTP imaging within 6-24 hours of stroke onset. We graded baseline collaterals on single phase CTA using modified Tan collateral score (0-3) and dichotomized into good (2-3) and poor (0-1) collaterals. We recorded automated CTP parameters, including estimated ischemic core (cerebral blood flow (CBF)<30%), penumbra (Tmax>6 s), and mismatch ratio. We used Mann-Whitney test and linear regression to assess associations. RESULTS: We included 48 patients with median age of 62 years (IQR= 52-72), median core of 17.5 mL (IQR=0-47), and median penumbra of 117.5 mL (IQR= 62-163.5). Patients with good collaterals had smaller median core (0 mL, IQR=0-12 mL vs. 40.5 mL, IQR=15-60 mL) (p < 0.001), smaller median penumbra (83.5 mL, IQR=43-135 mL vs. 142.5 mL, IQR=77-190 mL) (p = 0.04), larger median mismatch ratio (13.7, IQR=5.7-58.0 vs. 3.1, IQR=2.1-5.0) (p < 0.001), and lower median hypoperfusion intensity ratio (0.23, IQR=0-0.44 vs. 0.52, IQR=0.45-0.63) (p < 0.001) than patients with poor collaterals. CONCLUSIONS: In delayed time window LVO patients, good CTA collaterals are significantly associated with smaller CTP core, smaller penumbra, larger mismatch ratio, and lower hypoperfusion intensity ratio. CTA collateral assessment could be a potential valuable surrogate to perfusion imaging, particularly in stroke centers where CTP is unavailable.

Correlation of Alberta Stroke Program Early Computed Tomography Score With Computed Tomography Perfusion Core in Large Vessel Occlusion in Delayed Time Windows.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) and CT perfusion (CTP) are commonly used to predict the ischemic core in acute ischemic strokes. CT angiography source images (CTA-SI) can also provide additional information to identify the extent of ischemia. Our objective was to investigate the correlation of noncontrast CT (NCCT) ASPECTS and CTA-SI ASPECTS with CTP core volumes. METHODS: We utilized a single institutional, retrospective registry of consecutive patients with acute ischemic stroke with large vessel occlusion between May 2016 and May 2018. We graded ASPECTS both on baseline NCCT and CTA-SI and measured CTP core using automated RAPID software (cerebral blood flow <30%). We used Spearman's correlation coefficients to evaluate the correlation between continuous variables. RESULTS: A total of 52 patients fit the inclusion criteria of large vessel occlusion in 6 to 24 hours and baseline imaging work up of NCCT, CTA, and CTP. The median age was 63 (interquartile range=53.5-75) and 38.46% were female. The median NCCT ASPECTS was 7 (interquartile range=6-9), CTA-SI ASPECTS was 5 (interquartile range=4-7), and CTP core was 14.5 mL (interquartile range=0-46 mL). There was a moderate correlation between NCCT ASPECTS and CTP core (rs=-0.55, P<0.0001) and between CTA-SI ASPECTS and CTP core (rs=-0.50, P=0.0002). The optimal NCCT ASPECTS cutoff score to detect CTP core ≤70 mL was ≥6 (sensitivity, 0.84; specificity, 0.57; positive predictive value, 0.93; negative predictive value, 0.36) and the optimal CTA-SI ASPECTS was ≥5 (sensitivity, 0.76; specificity, 0.71; positive predictive value, 0.94; negative predictive value, 0.31). CONCLUSIONS: There was a moderate correlation between NCCT and CTA-SI ASPECTS in predicting CTP defined ischemic core in delayed time windows. Further studies are needed to determine if NCCT and CTA imaging could be used for image-based patient selection when CTP imaging is not available.

Accuracy of CT perfusion-predicted core in the late window.

BACKGROUND AND PURPOSE: Recent endovascular trials have spurred a paradigm shift toward routine use of CT perfusion (CTP) for decision-making in acute ischemic stroke. CTP use in the late window, however, remains under evaluation. Our objective was to assess the accuracy of CTP-predicted core in the late window. METHODS: In a retrospective review of our prospectively identified stroke registry at a single, comprehensive stroke center, we included patients with anterior large vessel occlusions presenting within the 6-24 h window who underwent baseline CTP evaluation and achieved TICI2b or TICI3 reperfusion on endovascular treatment. We recorded baseline CTP-predicted core volumes at relative cerebral blood flow (CBF) thresholds of <30% <34%, and <38% using RAPID software. Final infarct volumes (FIV) were calculated using follow up MRI and CT, obtained within 72 h after stroke onset. RESULTS: Of the eligible patients, 134 met our inclusion criteria. Mean FIV was 39.5 (SD 49.6). Median CTP to reperfusion time was 93.5 min. Median absolute differences between CTP-predicted core and FIV were 14.7, 14.9, and 16.0 ml at <30%, <34%, and <38%, respectively. Correlation between CTP-predicted ischemic cores and FIV was moderate and statistically significant at all thresholds: r = 0.43 (p <0.001), r = 0.43 (p <0.001), and r = 0.42 (p <0.001) at the <30%, <34%, and <38% cutoffs, respectively. CONCLUSION: CTP cores in the 6-24 h period underestimate FIV, especially with larger infarcts. CTP-predicted core volumes in the late window show moderate positive correlation with FIV.

Direct evidence of acid-base interactions in gecko adhesion.

While it is generally accepted that van der Waals (vdW) forces govern gecko adhesion, several studies indicate contributions from non-vdW forces and highlight the importance of understanding the adhesive contact interface. Previous work hypothesized that the surface of gecko setae is hydrophobic, with nonpolar lipid tails exposed on the surface. However, direct experimental evidence supporting this hypothesis and its implications on the adhesion mechanism is lacking. Here, we investigate the sapphire-setae contact interface using interface-sensitive spectroscopy and provide direct evidence of the involvement of acid-base interactions between polar lipid headgroups exposed on the setal surface and sapphire. During detachment, a layer of unbound lipids is left as a footprint due to cohesive failure within the lipid layer, which, in turn, reduces wear to setae during high stress sliding. The absence of this lipid layer enhances adhesion, despite a small setal-substrate contact area. Our results show that gecko adhesion is not exclusively a vdW-based, residue-free system.