Endothelial cells transduce mechanical forces from blood flow into intracellular signals required for vascular homeostasis. Here we show that endothelial NOTCH1 is responsive to shear stress, and is necessary for the maintenance of junctional integrity, cell elongation, and suppression of proliferation, phenotypes induced by laminar shear stress. NOTCH1 receptor localizes downstream of flow and canonical NOTCH signaling scales with the magnitude of fluid shear stress. Reduction of NOTCH1 destabilizes cellular junctions and triggers endothelial proliferation. NOTCH1 suppression results in changes in expression of genes involved in the regulation of intracellular calcium and proliferation, and preventing the increase of calcium signaling rescues the cell–cell junctional defects. Furthermore, loss of Notch1 in adult endothelium increases hypercholesterolemia-induced atherosclerosis in the descending aorta. We propose that NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries, where it integrates responses to laminar shear stress and regulates junctional integrity through modulation of calcium signaling.

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Multimodality imaging based on complementary detection principles has broad clinical applications and promises to improve the accuracy of medical diagnosis. This means that a tracer particle advantageously incorporates multiple functionalities into a single delivery vehicle. In the present work, we explore a unique combination of MRI and photoacoustic tomography (PAT) to detect picomolar concentrations of nanoparticles. The nanoconstruct consists of ferromagnetic (Co) particles coated with gold (Au) for biocompatibility and a unique shape that enables optical absorption over a broad range of frequencies. The end result is a dual-modality probe useful for the detection of trace amounts of nanoparticles in biological tissues, in which MRI provides volume detection, whereas PAT performs edge detection.dual-modality imaging ͉ ferromagnetic nanoparticle ͉ molecular imaging ͉ MRI contrast ͉ photoacoustic tomography W e have synthesized nanoparticles for dual-modality (1-7)MRI and photoacoustic tomography (PAT). The incorporation of MRI and PAT into a single probe offers the unique possibility of combining the complementary strategies of contrastbased volume imaging and edge detection. Our nanoconstruct consists of zero-valence ferromagnetic cobalt (Co) particles (8) with a gold (Au) coating for biocompatibility and a unique shape rendering increased optical absorption over a broad range of frequencies (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). This research theme follows the rapid developments in nanotechnology, diagnostic radiology, and targeted molecular imaging (20), whereby nanoparticulate contrast agents, with the desirable properties of high chemical specificity, biocompatibility, and a reasonable half-life, are administered within a specific region of interest. In nanoparticle-based imaging studies, higher particle concentrations lead to better signal-to-noise contrasts, but this also poses a tradeoff with the toxicity. Therefore, one of the most important parameters when developing particle-based contrast is the safest and lowest nanoparticle concentration that offers sufficient contrast sensitivity.In MRI, magnetic materials such as gadolinium chelates and magnetic nanoparticles are often used (21-23) to enhance image contrast. The magnetic nanoparticles are passivated by biocompatible coatings such as dextrin, citrate, polystyrene/divinylbenzene, and elemental gold. These coatings also detoxify the particles, resulting in enhanced lifetimes in vivo. Typical examples of magnetic nanoparticulate core-shell configurations include magnetitedextrin, magnetite-silica (24) and iron-gold (25).Laser-based PAT (9-19) is a hybrid imaging modality [see supporting information (SI) Fig. S1]. It uses a pulsed laser source to illuminate a biological sample. Light absorption by the tissue results in a transient temperature rise on the order of 10 mK. The rapid thermoelastic expansion excites ultrasonic waves that are measured by using broadband ultrasonic transducers conformally arranged around the sample. Finally, a modif...

Idiopathic noncirrhotic portal hypertension is a heterogeneous group of diseases characterized by portal hypertension in the absence of cirrhosis. The efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) in this population are unknown. The charts of patients with idiopathic noncirrhotic portal hypertension undergoing TIPS in seven centers between 2000 and 2014 were retrospectively reviewed. Forty-one patients were included. Indications for TIPS were recurrent variceal bleeding (n 5 25) and refractory ascites (n 5 16). Patients were categorized according to the presence (n 5 27) or absence (n 5 14) of significant extrahepatic comorbidities. Associated conditions were hematologic, prothrombotic, neoplastic, immune, and exposure to toxins. During follow-up (mean 27 6 29 months), variceal rebleeding occurred in 7/25 (28%), including three with early thrombosis of the stent. Post-TIPS overt hepatic encephalopathy was present in 14 patients (34%). Eleven patients died, five due the liver disease or complications of the procedure and six because of the associated comorbidities. The procedure was complicated by hemoperitoneum in four patients (10%), which was fatal in one case. Serum creatinine (P 5 0.005), ascites as indication for TIPS (P 5 0.04), and the presence of significant comorbidities (P 5 0.01) at the time of the procedure were associated with death. Mortality was higher in patients with significant comorbidities and creatinine 100 lmol/L (P < 0.001). Conclusion: In patients with idiopathic noncirrhotic portal hypertension who have normal kidney function or do not have severe extrahepatic conditions, TIPS is an excellent option to treat severe complications of portal hypertension. (HEPATOLOGY 2016;64:224-231) I diopathic noncirrhotic portal hypertension (INCPH) is a heterogeneous group of rare diseases characterized by portal hypertension (PHT) without cirrhotic changes, without a cause of chronic liver disease, and without venous obstruction.(1,2) Various histologic changes may be present, including nodular regenerative hyperplasia, hepatoportal sclerosis or obliterative portal venopathy, sinusoidal dilatation, and Abbreviations: HE, hepatic encephalopathy; INCPH, idiopathic noncirrhotic portal hypertension; PHT, portal hypertension; PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt.

A 125Te NMR study of bismuth telluride nanoparticles as a function of particle size revealed that the spin-lattice relaxation is enhanced below 33 nm, accompanied by a transition of NMR spectra from the single to the bimodal regime. The satellite peak features a negative Knight shift and higher relaxivity, consistent with core polarization from p-band carriers. Whereas nanocrystals follow a Korringa law in the range 140-420 K, micrometer particles do so only below 200 K. The results reveal increased metallicity of these nanoscale topological insulators in the limit of higher surface-to-volume ratios.

The present series demonstrates that bleeding from ectopic varices, a challenging clinical problem, can be managed safely by TIPS placement with low rebleeding and good survival rates.

Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years) with cirrhosis (seven alcoholics and 11 nonalcoholics) who underwent transjugular intrahepatic portosystemic shunt (TIPS) placement before antrectomy (n=5), colectomy (n=10), small-bowel resection (n=1), pancreatectomy (n=1) and nephrectomy (n=1). TIPS was performed a mean (+/-SD) of 72+/-21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4+/-3.9 mmHg to 8.4+/-3.4 mmHg. Cirrhotic patients (n=17) who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2). No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88%) or one-year (54% versus 63%) cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.

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