Effect of Shear Stress Direction on Endothelial Function and eNOS Phosphorylation in Soleus Feed Arteries

Blood flow feeding tissues and organs is closely regulated in order to meet metabolic and functional needs. Control of blood flow is accomplished by regulating the diameter of the arteries and arterioles feeding different organs. Several neural, hormonal, chemical and mechanical mechanisms contribute to the constriction and dilation of arteries. Shear stress, the frictional force created by streaming blood on the endothelial layer of arteries, is one of these mechanical mechanisms (1). Shear stress causes both acute and long term effects on endothelial cells (1,2,5). Blood in arteries typically flows away from the heart towards organs (causing antegrade shear stress) during cardiac contraction and briefly flows back toward the heart (causing retrograde shear stress) during cardiac filling. Retrograde flow occurs more often in some disease situations, and studies have shown that retrograde shear stress decreases endothelial cell function (3,4). The specific mechanisms for endothelial dysfunction are unknown, but altered mechanisms could include impaired cell signaling pathways. The most important endothelial cell dilatory signaling pathway is the production of nitric oxide (NO). Retrograde shear stress causes endothelial cells to secrete NO, and increased rates of shear stress cause increased expression and phosphorylation of nitric oxide synthase (eNOS). Regulatory phosphorylation of eNOS can potentially occur on at least four sites: Ser 1177, Ser 116, Ser 635 and Thr 497 (3). The most well characterized of these is Ser 1177, which is phosphorylated by a by PI3K/AKT shear dependent pathway. Regulating phosphorylation of eNOS is critical to endothelial health and maintaining cardiovascular equilibrium. Using rat soleus muscle feed arteries, we seek to determine the effects of changes in shear stress direction on both endothelial cell function and phosphorylation of eNOS at the Ser 1177 site

Predicting short-term disability progression in early multiple sclerosis: Added value of MRI parameters

Objective: Magnetic resonance imaging (MRI) and clinical parameters are associated with disease progression in multiple sclerosis (MS). The aim of this study was to investigate whether adding MRI parameters to a model with only clinical parameters could improve these associations. Methods: 89 patients (55 women) with recently diagnosed MS had clinical and MRI evaluation at baseline (time of diagnosis) and at follow-up after 2.2 years. Detailed clinical data were available, including disease type (relapse-onset or progressive-onset) and disability, as measured by the Expanded Disability Status Scale (EDSS). MRI parameters included Normalised Brain Volume (NBV) at baseline, percentage brain volume change (PBVC/year), T2- and T1-lesion loads and spinal cord abnormalities. Progression of disability (increase in EDSS of at least 1 point at follow-up) was the main outcome measure. For a model containing only clinical parameters, the added value of MRI parameters was tested using logistic regression. Results: PBVC/year and lesion loads at follow-up were significantly higher in the group with progression. Adding PBVC/year to a clinical model improved the model, indicating that MRI parameters added independent information (p<0.001). Conclusion: The rate of cerebral atrophy conveys added information for the progression of disability in patients with early MS, suggesting that clinical disability is determined by neurodegenerative changes as depicted by MRI

Precise wavefunction engineering with magnetic resonance

Controlling quantum fluids at their fundamental length scale will yield superlative quantum simulators, precision sensors, and spintronic devices. This scale is typically below the optical diffraction limit, precluding precise wavefunction engineering using optical potentials alone. We present a protocol to rapidly control the phase and density of a quantum fluid down to the healing length scale using strong time-dependent coupling between internal states of the fluid in a magnetic field gradient. We demonstrate this protocol by simulating the creation of a single stationary soliton and double soliton states in a Bose-Einstein condensate with control over the individual soliton positions and trajectories, using experimentally feasible parameters. Such states are yet to be realized experimentally, and are a path towards engineering soliton gases and exotic topological excitations.Comment: 8+ pages, 3 figures; revised parameters and added section about optimisation of adiabatic, finite-duration pulses and analytic resolution limi

Marketplace shrimp mislabeling in North Carolina

Seafood mislabeling occurs in a wide range of seafood products worldwide, resulting in public distrust, economic fraud, and health risks for consumers. We quantified the extent of shrimp mislabeling in coastal and inland North Carolina. We used standard DNA barcoding procedures to determine the species identity of 106 shrimp sold as “local” by 60 vendors across North Carolina. Thirty-four percent of the purchased shrimp was mislabeled, and surprisingly the percentage did not differ significantly between coastal and inland counties. One third of product incorrectly marketed as “local” was in fact whiteleg shrimp: an imported and globally farmed species native to the eastern Pacific, not found in North Carolina waters. In addition to the negative ecosystem consequences of shrimp farming (e.g., the loss of mangrove forests and the coastal buffering they provide), North Carolina fishers—as with local fishers elsewhere—are negatively impacted when vendors label farmed, frozen, and imported shrimp as local, fresh, and wild-caught

Neoadjuvant nivolumab and nivolumab plus ipilimumab induce (near-) complete responses in patients with head and neck squamous cell carcinoma:The IMCISION trial

BackgroundNivolumab (NIVO) alone or with ipilimumab (COMBO) immune checkpoint blockade (ICB) prior to curative surgery has shown promising results in multiple tumor types. We completed a phase Ib/II study with neoadjuvant NIVO or COMBO in resectable head and neck squamous cell carcinoma (HNSCC) and show safety, efficacy and correlative biomarker results.Methods32 stage II-IVB HNSCC patients indicated for curative (salvage) surgery were treated with NIVO (240mg, weeks 1&amp;3, N=6) or NIVO (240mg, weeks 1&amp;3) + IPI (1mg/kg, week 1, N=26) prior to surgery in week 5. Imaging was performed at baseline and week 4. AEs were reported in terms of CTCAE. Pathological response (pR) was defined as % change in viable tumor cells from baseline to on-treatment; ≥90% pR was considered (near-) complete response (pCR). WES and RNAseq were performed on paired tumor biopsies.Results32 (31 HPV-negative) patients started treatment (stage II n=3, III n=8, IVA-B n=11, recurrent disease n=10). 6 patients included with recurrent disease had had previous (C)RT. 1 patient discontinued ICB after one course due to patient’s preference. Surgery was not postponed in any patient. 3/32 patients did not undergo surgery: 1 due to unresectable PD and 2 due to reasons unrelated to ICB or disease. Grade 3-4 irAEs in 11/32 patients were well manageable. (Near-)pCR in the primary tumor was seen in 9/29 evaluable patients (31%). Another 31% of patients had 20-89% pR. At 14 months median FU, RFS for patients with (near-)pCR was 100%, significantly better than patients with &lt;90% pR (p=&lt;0.05). Metabolic response assessment with FDG-PET (week 4) was able to identify (near-)pCRs. A baseline AID/APOBEC-associated tumor mutational profile was correlated with (near)pCR (p=&lt;0.05). Finally, (near)pCR tumors were characterized by a decrease in hypoxia gene expression after ICB.ConclusionsNeoadjuvant ICB was feasible in HNSCC and induced (near)pCR in 31% of evaluable patients at time of surgery, which was accompanied by 100% RFS. Baseline AID/APOBEC-related mutations, on-treatment FDG-PET and resolution of hypoxia need future validation to discover their potential role as biomarkers for (near)pCR after ICB in HNSCC

Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis

Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis (MS) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents. In this study, we evaluate the rate of cerebral atrophy in a 6-month period, investigate the predictive and explanatory value of other magnetic resonance imaging (MRI) measures in relation to cerebral atrophy, and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS - Neurofilament as a Surrogate of Disease Progression

This work was supported by National MS Society (USA) under the Promise 2010 initiative and the MS Society of Great Britain and Northern Ireland as part of exploratory analysis for the UK MS Clinical Trial Network. VL is supported by Italian Minister of Health grant for young researcher 2008

Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis

Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment.Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ~0.3-0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = -0.36, p<0.005).The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability

Proton transport model in the ionosphere .1. Multistream approach of the transport equations

The suprathermal particles, electrons and protons, coming from the magnetosphere and precipitating into the high-latitude atmosphere are an energy source of the Earth's ionosphere. They interact with ambient thermal gas through inelastic and elastic collisions. The physical quantities perturbed by these precipitations, such as the heating rate, the electron production rate, or the emission intensities, can be provided in solving the kinetic stationary Boltzmann equation. This equation yields particle fluxes as a function of altitude, energy, and pitch angle. While this equation has been solved through different ways for the electron transport and fully tested, the proton transport is more complicated. Because of charge-changing reactions, the latter is a set of two-coupled transport equations that must be solved: one for protons and the other for H atoms. We present here a new approach that solves the multistream proton/hydrogen transport equations encompassing the collision angular redistributions and the magnetic mirroring effect. In order to validate our model we discuss the energy conservation and we compare with another model under the same inputs and with rocket observations. The influence of the angular redistributions is discussed in a forthcoming paper

Gray matter imaging in multiple sclerosis: what have we learned?

At the early onset of the 20th century, several studies already reported that the gray matter was implicated in the histopathology of multiple sclerosis (MS). However, as white matter pathology long received predominant attention in this disease, and histological staining techniques for detecting myelin in the gray matter were suboptimal, it was not until the beginning of the 21st century that the true extent and importance of gray matter pathology in MS was finally recognized. Gray matter damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Several studies subsequently demonstrated that the histopathology of gray matter lesions differs from that of white matter lesions. Unfortunately, imaging of pathology in gray matter structures proved to be difficult, especially when using conventional magnetic resonance imaging (MRI) techniques. However, with the recent introduction of several more advanced MRI techniques, the detection of cortical and subcortical damage in MS has considerably improved. This has important consequences for studying the clinical correlates of gray matter damage. In this review, we provide an overview of what has been learned about imaging of gray matter damage in MS, and offer a brief perspective with regards to future developments in this field