simvastatin and cognition in multiple sclerosis

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Multi-branch Convolutional Neural Network for Multiple Sclerosis Lesion Segmentation

In this paper, we present an automated approach for segmenting multiple sclerosis (MS) lesions from multi-modal brain magnetic resonance images. Our method is based on a deep end-to-end 2D convolutional neural network (CNN) for slice-based segmentation of 3D volumetric data. The proposed CNN includes a multi-branch downsampling path, which enables the network to encode information from multiple modalities separately. Multi-scale feature fusion blocks are proposed to combine feature maps from different modalities at different stages of the network. Then, multi-scale feature upsampling blocks are introduced to upsize combined feature maps to leverage information from lesion shape and location. We trained and tested the proposed model using orthogonal plane orientations of each 3D modality to exploit the contextual information in all directions. The proposed pipeline is evaluated on two different datasets: a private dataset including 37 MS patients and a publicly available dataset known as the ISBI 2015 longitudinal MS lesion segmentation challenge dataset, consisting of 14 MS patients. Considering the ISBI challenge, at the time of submission, our method was amongst the top performing solutions. On the private dataset, using the same array of performance metrics as in the ISBI challenge, the proposed approach shows high improvements in MS lesion segmentation compared with other publicly available tools.Comment: This paper has been accepted for publication in NeuroImag

Pharmacokinetics and antinociceptive effects of tramadol and its metabolite O-desmethyltramadol following intravenous administration in sheep

Although sheep are widely used as an experimental model for various surgical procedures there is a paucity of data on the pharmacokinetics and efficacy of analgesic drugs in this species. The aims of this study were to investigate the pharmacokinetics of intravenously (IV) administered tramadol and its active metabolite O-desmethyltramadol (M1) and to assess the mechanical antinociceptive effects in sheep. In a prospective, randomized, blinded study, six healthy adult sheep were given 4 and 6\u2009mg/kg tramadol and saline IV in a cross-over design with a 2-week wash-out period. At predetermined time points blood samples were collected and physiological parameters and mechanical nociceptive threshold (MNT) values were recorded. The analytical determination of tramadol and M1 was performed using high performance liquid chromatography. Pharmacokinetic parameters fitted a two- and a non-compartmental model for tramadol and M1, respectively. Normally distributed data were analysed by a repeated mixed linear model. Plasma concentration vs. time profiles of tramadol and M1 were similar after the two doses. Tramadol and M1 plasma levels decreased rapidly in the systemic circulation, with both undetectable after 6\u2009h following drug administration. Physiological parameters did not differ between groups; MNT values were not statistically significant between groups at any time point. It was concluded that although tramadol and M1 concentrations in plasma were above the human minimum analgesic concentration after both treatments, no mechanical antinociceptive effects of tramadol were reported. Further studies are warranted to assess the analgesic efficacy of tramadol in sheep

Evidence for Cortical Functional Changes in Patients With Migraine and White Matter Abnormalities on Conventional and Diffusion Tensor Magnetic Resonance Imaging

Background— In this study, we used functional MRI (fMRI) to investigate the pattern of cortical activations after a simple motor task in patients with migraine and white matter (WM) abnormalities on conventional MRI scans of the brain. We also investigated whether the extent of brain activations was correlated with WM structural pathology measured using diffusion tensor (DT) MRI. Methods— From 15 right-handed patients with migraine and 15 sex- and age-matched, right-handed healthy volunteers, we obtained the following: (1) fMRI (repetitive flexion-extension of the last 4 fingers of the right hand), (2) dual-echo turbo spin echo scans, and (3) pulsed-gradient spin-echo echo-planar sequence to calculate DT-MRI maps. fMRI analysis was performed using SPM99 and cluster detection. We measured the volume, the average mean diffusivity ( ), and the average fractional anisotropy of all lesions seen on the dual-echo scans. histograms of the normal-appearing WM were also produced. Results— Compared with healthy volunteers, migraine patients had a larger relative activation of the contralateral primary sensorimotor cortex ( P =0.01) and a rostral displacement of the supplementary motor area ( P =0.03). The shapes of the curves reflecting the time course for fMRI signal intensity changes were similar between migraine patients and controls for all of the cortical areas we studied. Compared with healthy subjects, migraine patients had significantly lower histogram peak height of the normal-appearing WM histogram ( P =0.02), which was found to be correlated with the extent of displacement of the supplementary motor area ( r =−0.80, P <0.001). Conclusions— This study suggests that functional cortical changes occur in patients with migraine and brain MRI abnormalities and that they might be secondary to the extent of subcortical structural damage

Deuterated polyethylene nanowire arrays for high-energy density physics

The interaction of intense, ultrashort laser pulses with ordered nanostructure arrays offers a path to the efficient creation of ultra-high-energy density (UHED) matter and the generation of high-energy particles with compact lasers. Irradiation of deuterated nanowires arrays results in a near-solid density environment with extremely high temperatures and large electromagnetic fields in which deuterons are accelerated to multi-megaelectronvolt energies, resulting in deuterium- deuterium (D-D) fusion. Here we focus on the method of fabrication and the characteristics of ordered arrays of deuterated polyethylene nanowires. The irradiation of these array targets with femtosecond pulses of relativistic intensity and joule-level energy creates a micro-scale fusion environment that produced 2×106 neutrons per joule, an increase of about 500 times with respect to flat solid CD2 targets irradiated with the same laser pulses. Irradiation with 8 J laser pulses was measured to generate up to 1.2 × 107 D-D fusion neutrons per shot.Fil: Capeluto, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. State University of Colorado - Fort Collins; Estados UnidosFil: Curtis, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Calvi, C.. State University of Colorado - Fort Collins; Estados UnidosFil: Hollinger, R.. State University of Colorado - Fort Collins; Estados UnidosFil: Shlyaptsev, V.N.. State University of Colorado - Fort Collins; Estados UnidosFil: Rocca, J.J.. State University of Colorado - Fort Collins; Estados Unido

Using the internet to seek information about genetic and rare diseases: A case study comparing data from 2006 and 2011

BACKGROUND: The Genetic and Rare Disease Information Center (GARD) is a major provider of Web-based information on genetic and rare diseases. Little is known about the type of Web-based information individuals seek about genetic and rare diseases or their reasons for seeking. OBJECTIVE: The objective of this paper is to describe the types of Web-based information sought about genetic and rare diseases and the reasons for seeking it from GARD by examining inquiries from 2006 and 2011. METHODS: There were 278 English-language email and Web-based inquiries posed to GARD by lay individuals (ie, patients, parents, and relatives), which were randomly selected from inquiries in 2006 (n=68) and 2011 (n=210) and examined using content analysis. RESULTS: Most often in both years, individuals sought basic disease information (51/68, 75.0% and 132/210, 62.8%; P=.067) and information about treatment (17/51, 33.3% and 62/132, 47.0%; P=.095). Specifically, inquirers requested information about their disease prognosis (6/51, 11.8% and 23/132, 17.4%; P=.347) and made requests for specialists (8/68, 11.8% and 31/210, 14.8%; P=.536). In both 2006 and 2011, a substantial subset of inquirers requested information related to undiagnosed symptoms, representing 16.2% (11/68) and 11.9% (25/210; P=.362) of inquiries, respectively. Inquirers were significantly more likely to have seen a health care provider before contacting GARD (99/210, 47.1% vs 20/68, 29.4%; P=.010) and to ask about clinical research studies in 2011 than in 2006 (24/210, 11.4% vs 2/68, 2.9%; P=.037). In the 2011 data set, the majority of the inquirers were women (201/210, 95.7%). In our 2006 sample, men were the majority source of inquiries (54/68, 79.4%). CONCLUSIONS: Findings from this study indicate that lay people contacting a genetic and rare disease information center most often seek information about disease prognosis, finding a specialist, and obtaining a diagnosis for symptoms. Unique characteristics of individuals searching the Internet for genetic and rare diseases information, includes a growing interest in participating in clinical research studies and a desire to supplement or better understand information discussed during a visit with a health care provider. These efforts represent advancements in patient self-advocacy

Brain Gray Matter Changes in Migraine Patients With T2-Visible Lesions

Background and Purpose— In migraine patients, functional imaging studies have shown changes in several brain gray matter (GM) regions. However, 1.5-T MRI has failed to detect any structural abnormality of these regions. We used a 3-T MRI scanner and voxel-based morphometry (VBM) to assess whether GM density abnormalities can be seen in patients with migraine with T2-visible abnormalities and to grade their extent. Methods— In 16 migraine patients with T2-visible abnormalities and 15 matched controls, we acquired a T2-weighted and a high-resolution T1-weighted sequence. Lesion loads were measured on T2-weighted images. An optimized version of VBM analysis was used to assess regional differences in GM densities on T1-weighted scans of patients versus controls. Statistical parametric maps were thresholded at P <0.001, uncorrected for multiple comparisons. Results— Compared with controls, migraine patients had areas of reduced GM density, mainly located in the frontal and temporal lobes. Conversely, patients showed increased periacqueductal GM (PAG) density. Compared with patients without aura, migraine patients with aura had increased density of the PAG and of the dorsolateral pons. In migraine patients, reduced GM density was strongly related to age, disease duration, and T2-visible lesion load ( r ranging from −0.84 to −0.73). Conclusions— Structural GM abnormalities can be detected in migraine patients with brain T2-visible lesions using VBM and a high-field MRI scanner. Such GM changes comprise areas with reduced and increased density and are likely related to the pathological substrates associated with this disease

Extreme ionization of heavy atoms in solid-density plasmas by relativistic second-harmonic laser pulses

Stripping heavy atoms in solid matter of most of their electrons requires the extreme conditions that exist in astrophysical plasmas, but are difficult to create in the laboratory1–3. Here we demonstrate solid-density gold plasmas with atoms stripped of up to 72 electrons (N-like Au72+) over large target depths. This record ionization is achieved by irradiating solid foils and near-solid-density nanowire arrays with highly relativistic (3 × 1021 W cm−2) second-harmonic femtosecond laser pulses of '10 J energy focused into a 1.6 µm spot. The short wavelength and high intensity enable the interaction to occur at a relativistic critical density4,5 of 1023 cm−3. Solid targets reach a higher average charge in 1- to 2-µm-thick layers, while the less dense nanowire plasmas are heated to much larger depths ('8 µm) by energetic electrons generated near the nanowire tips. Larger laser spots could result in solid Au plasmas ionized up to He-like.Fil: Hollinger, R.. State University of Colorado - Fort Collins; Estados UnidosFil: Wang, S.. State University of Colorado - Fort Collins; Estados UnidosFil: Wang, Y.. State University of Colorado - Fort Collins; Estados UnidosFil: Moreau, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Capeluto, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Song, H.. State University of Colorado - Fort Collins; Estados UnidosFil: Rockwood, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Bayarsaikhan, E.. State University of Colorado - Fort Collins; Estados UnidosFil: Kaymak, V.. Universitat Dusseldorf; AlemaniaFil: Pukhov, A.. Universitat Dusseldorf; AlemaniaFil: Shlyaptsev, V.N.. State University of Colorado - Fort Collins; Estados UnidosFil: Rocca, J.J.. State University of Colorado - Fort Collins; Estados Unido

Enhanced electron acceleration in aligned nanowire arrays irradiated at highly relativistic intensities

We report a significant enhancement in both the energy and the flux of relativistic electrons accelerated by ultra-intense laser pulse irradiation (>1 10 21 W cm-2) of near solid density aligned CD2 nanowire arrays in comparison to those from solid CD2 foils irradiated with the same laser pulses. Ultrahigh contrast femtosecond laser pulses penetrate deep into the nanowire array creating a large interaction volume. Detailed three dimensional relativistic particle-in-cell simulations show that electrons originating anywhere along the nanowire length are first driven towards the laser to reach a lower density plasma region near the tip of the nanowires, where they are accelerated to the highest energies. Electrons that reach the lower density plasma experience direct laser acceleration up to the dephasing length, where they outrun the laser pulse. This yields an electron beam characterized by a 3 higher electron temperature and an integrated flux 22.4 larger respect to foil targets. Additionally, the generation of >1 MeV photons were observed to increase up to 4.5.Fil: Moreau, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Hollinger, R.. State University of Colorado - Fort Collins; Estados UnidosFil: Calvi, C.. State University of Colorado - Fort Collins; Estados UnidosFil: Wang, S.. State University of Colorado - Fort Collins; Estados UnidosFil: Wang, Y.. State University of Colorado - Fort Collins; Estados UnidosFil: Capeluto, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Rockwood, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Curtis, A.. State University of Colorado - Fort Collins; Estados UnidosFil: Kasdorf, S.. State University of Colorado - Fort Collins; Estados UnidosFil: Shlyaptsev, V.N.. State University of Colorado - Fort Collins; Estados UnidosFil: Kaymak, V.. Universitat Dusseldorf; AlemaniaFil: Pukhov, A.. Universitat Dusseldorf; AlemaniaFil: Rocca, J.J.. State University of Colorado - Fort Collins; Estados Unido

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowedwith a cardioprotective effect againstmyocardial ischemic damage. Q1 inhibits angiotensin converting enzymeactivity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aimto overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6Mdoses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8 ÷ 10−6 M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OHwith ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension