Citations

Myxomatous mitral valve disease (MMVD) is associated with increases in valvular fibrosis, matrix remodeling, and transforming growth factor beta (TGF β) signaling. While interleukin 10 (IL‐10) can suppress tissue fibrosis and matrix metalloproteinase (MMP) expression, its role in MMVD is unknown. We tested the hypotheses that reduced IL‐10 expression contributes to increased tissue fibrosis in MMVD, and that IL‐10 tonically suppresses TGF‐β signaling in normal mitral valves. We used qRT‐PCR to measure expression of IL10, TGF‐β1, MMP 2 and 9, and connective tissue growth factor (CTGF) in normal and myxomatous human mitral valves and in mitral and tricuspid valves from wild‐type and IL‐10 knockout mice. IL‐10 expression was significantly reduced in human myxomatous valves compared to normal valves (53± 12%), and was associated with increases in TGFβ, CTGF, and MMP2. Mitral valve gene expression patterns in IL‐10 −/− mice favored fibrosis and matrix remodeling compared to wild‐type littermates, with increases in TGF β (132±7%), CTGF (154±3%), and MMP9 (259±7%) (p< 0.05 for all), but not MMP2. Interestingly, expression of these genes was not altered in tricuspid valves from IL‐10 −/− mice. Collectively, these data are the first to show that IL‐10 tonically suppresses TGF β signaling in normal mitral valves and that deficiency of IL‐10 is likely to contribute to fibrosis and matrix remodeling in MMVD. NHLBI

Myxomatous mitral valve disease is characterized by fibrosis and matrix degradation and increases in transforming growth factor beta‐1 (TGFbeta‐1). Little is known, however, about changes in molecules that regulate TGFbeta‐1 signaling in myxomatous valves. Thus, we tested the hypothesis that TGFbeta‐1 promotes valvular fibrosis and matrix remodeling in myxomatous valves through canonical Smad2 signaling and permissive reductions in Smad inhibitors. Expression of TGFbeta‐1, TGFbeta‐1 target genes (connective tissue growth factor, matrix metalloproteinases 2/9), E3 ubiquitin‐protein ligases (Smurf 1/2, which degrade Smad2), and NAD(P)H oxidase catalytic subunits (Nox 2, 4, and 5) was measured using quantitative real‐time RT‐PCR. Phospho‐Smad2 levels were measured using western blotting. TGFbeta‐1 expression was higher in myxomatous valves (138.3 ± 12.5% of control, n = 24 per group; p < 0.05), while CTGF and MMP2 were increased by 5‐ and 2‐fold, respectively. Surprisingly, phospho‐Smad2 levels were unchanged between myxomatous and control tissue due to selective increases in Smurf2 expression in myxomatous valve tissue (165.2 ± 17.7% of control, p < 0.05), as Smurf1 expression was unchanged. Expression of Nox2 and Nox4—which can drive pro‐fibrotic and matrix remodeling gene expression in other tissues—were significantly elevated in myxomatous valves (211 ± 44% and 224 ± 35 % of control, respectively; p < 0.05). In conclusion, our data suggest that canonical TGFbeta‐1/Smad2 signaling is not required for progression of myxomatous valve disease, and that reducing Nox2‐and Nox4‐derived reactive oxygen species may be a novel intervention to slow progression of fibrosis and matrix remodeling in myxomatous valves.

Abstract As capabilities for endovascular treatment of intracranial vascular pathologies continue to expand, the need for access to the distal internal carotid artery with rigid support catheter systems continues to increase. One of the dominant factors limiting this access is patient anatomy, specifically vessel tortuosity. Increased tortuosity of the carotid siphon is a frequently encountered anatomic variant and may complicate endovascular procedures in adults and children. 1,2 Failed attempts to navigate the carotid siphon with a distal access catheter carry a risk of vessel injury and treatment failure. For this reason, techniques that aid in supporting safe advancement of a distal access catheter across a tortuous carotid siphon are essential. 3,4 In this video, we demonstrate 2 ways in which this may be accomplished. The first technique uses a larger diameter microcatheter, such as the AXS Offset catheter (Stryker, Kalamazoo, Michigan), to increase support for the distal access catheter, while the second uses a buddy wire technique to accomplish this increased support. Both of these techniques can help increase the safety of navigating a tortuous carotid siphon and increase the likelihood of successful treatment. The procedures shown were performed with the informed consent of the patients.

Objectives: Mood disorders in youth are associated with social and academic impairment, and difficulties within the family system. Engagement in sleep hygiene, and family- and technology-based treatment models can address these impairments. The current study evaluates changes in functioning for youth who participated in a family-based partial hospitalization program (PHP) for mood disorders. Child and parent views of the importance and application of sleep hygiene and utilization of technology-based interventions were also evaluated. Methods: 474 youth diagnosed with a primary mood disorder and their caregivers participated in a family-based PHP that addressed the role of sleep hygiene, technology use for symptom management, and components of evidence-based treatments in ameliorating mood disorders. Participants were evaluated 1-, 3-, and 6-month following treatment. Results: Participants demonstrated improved functioning in social, home, and school domains. The majority of participants and parents found the sleep hygiene content and application important or very important as a component of treatment. Parents were significantly more likely than youth to be interested in using technology to access after care resources. Conclusions: Findings revealed significantly less impairment in functioning at follow-up. Parents and youth reported interest in sleep hygiene strategies as part of a comprehensive treatment for mood disorders as well as the use of technology-based resources to assist with treatment. Limitations include sample demographics and follow-up sample size.

333 Background: Hepatitis B is a cause of hepatocellular carcinoma (HCC) globally, irrespective of viral loads. Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation, and has implications in early diagnosis and treatment. Methods: We employed our Search, Tag, Analyze, Resource (STARGEO) platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples. We present the results from the meta-analysis in Ingenuity Pathway Analysis. Results:Our analysis revealed LXR/RXR activation, LPS-IL-1 mediation inhibition of RXR, and FXR/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene RABL6. The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. Additionally, HOXA10 was a top upstream regulator and was strongly upregulated in our analysis. While described in other cancer, HOXA10 has not been well documented in HBV-related HCC and our causal analysis suggests it mediates pathogenesis through downregulation of tumor suppressors and its protective effect from oxidative stress. Conclusions: This meta-analysis describes possible role of viral regulatory proteins such as RABL6 and HOXA10 in the pathogenesis of HBV -related HCC. Further prospective studies are needed to confirm our findings.

Few studies have documented relationships between endovascular therapy, duplex ultrasonography (DUS), post-thrombotic syndrome (PTS), and quality of life (QOL). The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial randomized 692 patients with acute proximal deep vein thrombosis (DVT) to receive anticoagulation or anticoagulation plus pharmacomechanical catheter-directed thrombolysis (PCDT). Compression DUS was obtained at baseline, 1 month and 12 months. Reflux DUS was obtained at 12 months in a subset of 126 patients. Clinical outcomes were collected over 24 months. At 1 month, patients who received PCDT had less residual thrombus compared to Control patients, evidenced by non-compressible common femoral vein (CFV) (21% vs 35%, p < 0.0001), femoral vein (51% vs 70%, p < 0.0001), and popliteal vein (61% vs 74%, p < 0.0001). At 12 months, in the ultrasound substudy, valvular reflux prevalence was similar between groups (85% vs 91%, p = 0.35). CFV non-compressibility at 1 month was associated with higher rates of any PTS (61% vs 46%, p < 0.001), a higher incidence of moderate-or-severe PTS (30% vs 19%, p = 0.003), and worse QOL (difference 8.2 VEINES-QOL (VEnous INsufficiency Epidemiological and Economic Study on Quality of Life) points; p = 0.004) at 24 months. Valvular reflux at 12 months was associated with moderate-or-severe PTS at 24 months (30% vs 0%, p = 0.01). In summary, PCDT results in less residual thrombus but does not reduce venous valvular reflux. CFV non-compressibility at 1 month is associated with more PTS, more severe PTS, and worse QOL at 24 months. Valvular reflux may predispose to moderate-or-severe PTS. ClinicalTrials.gov Identifier NCT00790335.