Regulation of Yes-Associated Protein by Laminar Flow.

BACKGROUND: The cells lining the endothelium of blood vessels are recognized as playing critical roles in vascular health and disease. The mechanisms that regulate endothelial cells (ECs) proliferation and release of mediators remain poorly understood but represent a potential source of disease modulation. Actin-cytoskeleton remodeling and cell shape have been suggested as key regulators of phosphorylation of yes-associated protein (YAP) which controls cellular growth and proliferation. Because different types of flow have been shown to affect cell shape and cytoskeleton differently, we hypothesized that the level of phosphorylated yes-associated protein (pYAP; serine 127) decreases in EC exposed to pulsatile uniform flow or steady laminar flow, whereas exposure to pulsatile disturbed flow causes an increase or no change. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to pulsatile uniform flow, pulsatile disturbed flow, or steady laminar flow and analyzed by immunoblotting. RESULTS: Exposure of HUVECs to steady laminar flow caused a significant decrease in the levels of pYAP (69.7 + 2.6%, P < 0.05), whereas total YAP levels remained nearly unchanged. Conversely, exposure to either pulsatile uniform or disturbed flow caused a significant decrease in the levels of both pYAP (63.2 + 10.9% and 69.8 + 11.9%, respectively; P < 0.05) and total YAP (57.1 + 17.8% and 58.4 + 16.3%, respectively; P < 0.05). Addition of MG132, a ubiquitin-proteasome system inhibitor, failed to significantly inhibit the decrease in the levels of total YAP in HUVECs exposed to either pulsatile uniform or disturbed flow. CONCLUSIONS: Flow causes a decrease in pYAP. The observed decrease in total YAP levels with pulsatile flow is due to degradation via a proteasome-independent mechanism. This may be a potential target for intervention for disease states such as atherosclerosis and intimal hyperplasia.

Increased Odds of Melanoma: Parkinson's Disease, Essential Tremor, Dystonia versus Controls.

OBJECTIVE: Patients with Parkinson's disease (PD) have an increased risk of melanoma, although the mechanisms are unclear. We are unaware of studies that have assessed the association between other movement disorders, such as essential tremor (ET) and dystonia, and melanoma. In this study, we assessed the association between ET, PD, dystonia and cancer (esp. melanoma). METHODS: One hundred and eight PD cases, 139 ET cases, and 54 dystonia cases, and 124 controls were enrolled in a research study of the epidemiology of movement disorders (total n = 425). The groups were frequency matched on age and gender. Cancer diagnoses were made based on self-reports. Melanoma diagnoses were further validated. RESULTS: The prevalence of melanoma was higher in PD cases than controls (13.9 vs. 1.6%, p < 0.001), and was marginally higher in ET cases (5.8%, p = 0.08) and dystonia cases (7.4%, p = 0.06) than controls. In adjusted logistic regression models, the odds of melanoma was 7.09-9.84 times higher in PD cases than controls (p values 0.01-0.003), 3.73-4.10 times higher in ET cases than controls (p values 0.08-0.10), and 4.88-5.27 times higher in dystonia cases than controls (p values 0.06-0.07). CONCLUSION: The links between neurological disorders and melanoma, long-known, may not be specific to PD and may extend to other movement disorders.

Statin Use and Its Association with Essential Tremor and Parkinson's Disease.

BACKGROUND: Statins have potent anti-inflammatory and immunomodulating effects, and may have neuroprotective properties in patients with Parkinson's disease (PD). There are no studies about the use of statins in the related tremor disorder, essential tremor (ET). We determined whether statin use differed in ET cases vs. controls and PD cases vs. METHODS: One hundred and thirty nine ET cases, 108 PD cases, and 124 controls participated in a research study of the epidemiology of movement disorders. They were frequency matched based on age and gender. Statin use was assessed by self-report. RESULTS: In adjusted logistic regression analyses, statin use (current or ever) was inversely associated with PD (ORs 0.56-0.63), with marginal values (p values = 0.07-0.187). In similar adjusted models, ET was not associated with statin use (p values = 0.45-0.50). However, ET was inversely associated with longer-term statin use (adjusted OR 0.27, p values = 0.04-0.048). CONCLUSIONS: We observed a marginally significant inverse association between PD and statin use. Although in primary analyses we found no evidence that statin use was protective in ET, there was an inverse association in analyses that assessed longer term use of statins. Further observational studies are warranted.

Systemic Inflammatory Disease and Its Association With Type II Endoleak and Late Interventions After Endovascular Aneurysm Repair.

IMPORTANCE: Abdominal aortic aneurysms are associated with chronic inflammation within the aortic wall, and previous studies have suggested that chronic inflammation may be a consequence of a dysregulated and persistent autoimmune response. Persistent aortic remodeling after aneurysm repair could place the patient at risk for endoleak or sac rupture. OBJECTIVE: To determine whether patients with systemic inflammatory disease and large aneurysms have persistent aortic remodeling after endovascular aneurysm repair (EVAR). DESIGN, SETTING, AND PARTICIPANTS: The records of all patients who underwent EVAR between July 2002 and June 2011 at the Veterans Affairs Connecticut Healthcare System were included in this retrospective review. Patients were considered to have a systemic inflammatory disease when confirmed by a referring specialist. Post-EVAR surveillance was performed by yearly imaging. INTERVENTION: Endovascular aneurysm repair. MAIN OUTCOMES AND MEASURES: Significant endoleak, defined as endoleak and sac diameter increase of 0.5 cm or greater. RESULTS: A total of 51 of 79 patients (65%) had a systemic inflammatory disease. These patients had similar comorbid conditions compared with patients without inflammation but significantly greater numbers of major postoperative complications after EVAR (23.5% vs 3.6%; P = .02) and overall postoperative complications after EVAR (27.5% vs 7.1%; P = .03). Patients with a history of systemic inflammatory disease developed more endoleaks (45.1% vs 17.9%; P = .02) and late sac expansion (51.0% vs 21.4%; P = .01) and required more interventions (21.6% vs 3.6%; P = .03) during long-term follow-up. Systemic inflammatory disease was significantly associated with significant endoleak (odds ratio, 5.18; 95% CI, 1.56-17.16; P = .007). CONCLUSIONS AND RELEVANCE: Patients with systemic inflammatory disease are at high risk for postoperative complications, type II endoleak, sac expansion, and additional interventions after EVAR. Additional strategies for improving the efficacy of EVAR in these patients may be warranted.

New modalities in the chronic ischemic diabetic foot management.

The diabetic population is increasing worldwide at a staggering rate. Diabetic foot ulcers are a major contributor to nontraumatic lower limb amputations and peripheral arterial disease is one of main contributing pathophysiologic causes of diabetic ulcers. The dire need to reduce complication and wound healing recovery period of the chronic ischemic diabetic foot (CIDF) is indispensable to limb salvage and improvement of quality of life of patients with CIDF. This article discusses newer modalities that have been proposed to improve CIDF efficiently, safely, and effectively either alone or as adjuvants to conventional therapy.

Effect of pulsatile and continuous flow on yes-associated protein.

Yes-associated protein (YAP) is a mechanosignaling protein that relays mechanical information to the nucleus by changing its level of phosphorylation. We hypothesize that different flow patterns show differential effect on phosphorylated YAP (pYAP) (S127) and total YAP and could be responsible for flow dependent localization of atherosclerosis. Confluent human umbilical vein endothelial cells (HUVECs) seeded on fibronectin-coated glass slides were exposed to continuous forward flow (CFF) and pulsatile forward flow (PFF) using a parallel plate flow chamber system for 30 minutes. Cell lysates were prepared and immunoblotted to detect the levels of phosphorylated YAP and total YAP. HUVECs exposed to both PFF and CFF showed a mild decrease in the levels of both pYAP (S127) and total YAP. While the levels of pYAP (S127) decreased to 87.85 and 85.21% of static control with PFF and CFF, respectively, the levels of total YAP significantly decreased to 91.31 and 92.27% of static control. No significant difference was seen between CFF and PFF on their effect on pYAP (S127), but both conditions resulted in a significant decrease in total YAP at 30 minutes. The results of this experiment show that the possible effect of different types of flow on YAP is not induced before 30 minutes. Experiments exposing endothelial cells to various types of flow for longer duration of time could help to elucidate the role of YAP in the pathogenesis of atherosclerosis.