\r\n\t- BMD measurement technology \r\n\t- Osteoporosis and fracture risk \r\n\t- Bone growth and remodeling
\r\n
\r\n\t \r\n\tThe submission is also open to any other original study related to these research topics.
",isbn:"978-1-83768-015-3",printIsbn:"978-1-83768-014-6",pdfIsbn:"978-1-83768-016-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"db1790f61fd55a35e85e10e8ed9cf756",bookSignature:"Dr. Abdelwahed Barkaoui",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11695.jpg",keywords:"Bone Densitometry Techniques, Computerized Tomography, Quantitative Ultrasound, Magnetic Resonance Imaging MRI, Bone Biomechanics Behavior, Testing and Modeling of Bone Fracture, Fracture Risk Assessment Tool, Mechanobiology of Bone Remodeling, Modeling of Bone Remodeling, Bone Mineral Density Evolution, Bone Growth, Bone Strength",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2022",dateEndSecondStepPublish:"June 7th 2022",dateEndThirdStepPublish:"August 6th 2022",dateEndFourthStepPublish:"October 25th 2022",dateEndFifthStepPublish:"December 24th 2022",remainingDaysToSecondStep:"17 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Barkaoui is the assistant director of the LERMA laboratory and coordinator of the Modelling & Simulation in Biomechanics & Biomaterials (MS2B) team. He was a member of the editorial board of several international scientific journals such as Frontiers in Bioengineering and Biotechnology “Biomechanics” (IF=5,9), BMC Musculoskeletal Disorders (IF:2.6), BMC Biomedical Engineering, a Series on Biomechanics. He is also the author of more than 60 publications in international journals, books, and conferences.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320631",title:"Dr.",name:"Abdelwahed",middleName:null,surname:"Barkaoui",slug:"abdelwahed-barkaoui",fullName:"Abdelwahed Barkaoui",profilePictureURL:"https://mts.intechopen.com/storage/users/320631/images/system/320631.jpg",biography:"Abdelwahed BARKAOUI is an Associate Professor of Mechanical Engineering at the International University of Rabat. He obtained his University habilitation from the University of Tunis El Manar-Tunisia in 2017 and his Ph.D. from the University of Orleans, France in 2012. He has a master\\'s degree in mechanics obtained from the INSA of Lyon, France, and an engineering diploma in electromechanics from ENI-Sfax, Tunisia. Currently, dr. BARKAOUI is the assistant director of the LERMA laboratory and coordinator of the Modelling & Simulation in Biomechanics & Biomaterials (MS2B) team. He is responsible for the mechanical discipline and coordinator of the ABET accreditation project at the Higher School of Energy Engineering. His research is focused on biomechanics, mechanobiology, and biomedical engineering. He was a member of the editorial board of several international scientific journals such as Frontiers in Bioengineering and Biotechnology “Biomechanics” (IF=5,9), BMC Musculoskeletal Disorders (IF:2.6), BMC Biomedical Engineering, Series on Biomechanics, as well as a reviewer for several international journals\nin the field of biomechanics and mechanical engineering. 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\n
1. Introduction
\n
Cardiovascular diseases are among the main causes of death in both men and women in the United States. Some of these diseases are caused or can be diagnosed by abnormal blood flow in a particular part of the cardiovascular system. For example, atherosclerosis consists of the narrowing of a blood vessel due to the gradual accumulation of lipids, inflammatory cells and connective tissue in the vessel wall [1]. This narrowing alters the local blood flow and may cause flow jets and/or turbulent flow. In these flow jets occur peaks of velocity that are significantly higher than those exhibited at a normal flow. Thus, knowledge of blood flow patterns in the human body is an important component in the research and diagnosis of certain cardiovascular diseases. Currently, two distinct approaches to the study and quantification of blood flow in the human body are available to researchers and clinicians: in-vivo direct measurements of the velocity field using velocity-encoded magnetic resonance imaging (MRI) or Doppler ultrasound.
\n
Doppler ultrasound is the gold standard for quantifying blood flow patterns in the clinical environment. The equipment is relatively small, cheap and portable, and is capable of producing measurements in real time with excellent temporal resolution. On the other hand, evaluation by ultrasound is inadequate when there is fat, air, bone, or surgical scar in the acoustic path. Moreover the equipment is strongly user-dependent, since flow measurements are inaccurate when the ultrasound beam cannot be properly aligned with the axis of flow [2, 3].
\n
MRI is capable of three-dimensional visualization of all aspects of a cardiac examination, such as the anatomy of the heart, features in the blood vessels, and also the quantification of velocity in any given vessel. Compared to ultrasound, magnetic resonance imaging does not have the same operator dependence, being able to accurately quantify the correct direction of flow, and does not have the same acoustic limitations related to bones, fat, air or surgical scars.
\n
The current gold standard for MRI flow quantification is phase contrast (PC) [4]. In this technique, a bipolar gradient is aligned to the flow axis to obtain a velocity measurement (approximately the mean [5]) for each voxel of the image. Despite its unrestricted use, phase contrast has some limitations. Phase contrast technique suffers from partial-volume effects when a wide distribution of velocities is contained within a single voxel [6]. This is particularly problematic when flow is turbulent and/or complex (e.g., flow jets due to stenosis) or at the interface between blood and vessel wall (viscous sublayer). This issue is typically addressed by increasing the spatial resolution, which dramatically affects the signal-to-noise ratio (SNR) and increases the scan time. Therefore, PC may be inadequate for estimating the peak velocity of stenotic flow jets and for assessing wall shear rate.
\n
Fourier velocity encoded (FVE) MRI [7] is a magnetic resonance velocity quantification technique which is as an alternative to phase contrast imaging, since real-time FVE is the MRI equivalent to spectral-Doppler ultrasound [8]. In this technique, the acquired measurements have a considerably higher signal-to-noise ratio than those acquired with phase contrast, due to its high-dimensional data set and also to its larger voxels. In addition, different from PC data, FVE does not suffer from partial volume effects, since for each voxel a velocity distribution is measured. So this technique can accurately diagnose vessels stenosis on low spatial resolution. The data set measured with this technique is usually obtained with very low spatial resolution. This is due to restrictions associated with its high dimensionality, which can lead to long acquisitions time. Thus, FVE is not a popular technique in the clinical environment that requires exams to be performed as fast as possible. On the other hand, it has been shown that the FVE acquisition can be accelerated. For example, FVE acquisition using rapid spiral sampling in \n\nk\n\n-space is a fast and reliable alternative to accurately measure velocity peaks in blood flow jets or to obtain hemodynamic parameters [9].
\n
In this context, this chapter deals with two aspects of the FVE MRI technique: acceleration and estimation of velocity map. First, are introduced six different important acceleration techniques that can be applied to FVE acquisition and are related to the use of variable-density sampling, which may be used along spatial k-space and velocity k-space, partial Fourier acquisition along velocity k-space, temporal acceleration methods such as UNFOLD and k-t BLAST, parallel imaging methods and compressive sampling.
\n
Finally, since FVE does not provide the actual velocity map associated with the flow, is proposed a novel method to velocity maps estimation with high spatial resolution from low-resolution FVE data. The proposed method is based on the mathematical model of the FVE distribution, \n\ns\n\nx\ny\nv\n\n\n, and involves solving a PDE-constrained optimization related to the Navier-Stokes equation.
\n
\n
\n
2. Magnetic resonance flow imaging
\n
MRI is a modality uniquely capable of imaging all aspects of cardiovascular disease, and is a potential “one-stop shop” for cardiovascular health assessment. MRI can generate cross-sectional images in any plane (including oblique planes), and can also measure blood flow. The image acquisition is based on using strong magnetic fields and non-ionizing radiation in the radio frequency range, which are harmless to the patient. MR is used to image hydrogen nuclei, because of its abundance in the human body. Spinning charged particles (or “spins”), such as hydrogen nuclei, act like a tiny bar magnet, presenting a very small magnetic field, emanating from the south pole to the north pole. In this section we introduce the mathematical formalism of MR imaging and flow imaging.
\n
\n
2.1. Mathematical formalism
\n
The acquired MR signal \n\ns\n\nt\n\n\n at a particular time instant corresponds to a sample of the Fourier transform \n\nM\n\n\nk\nx\n\n\nk\ny\n\n\n\n of the excited magnetization \n\nm\n\nx\ny\n\n\n:
The Fourier coordinates \n\n\nk\nx\n\n\n and \n\n\nk\ny\n\n\n vary with time, according to the zeroth moment of the readout gradients \n\n\nG\nx\n\n\n and \n\n\nG\ny\n\n\n:
where \n\n\n\n\nG\n→\n\n\nr\n\n\n is the oblique gradient resulting from the combination of the \n\n\nG\nx\n\n\n, \n\n\nG\ny\n\n\n and \n\n\nG\nz\n\n\n gradients, and \n\n\nr\n→\n\n\n is its corresponding axis along which the linear variation in magnetic field intensity is realized.
\n
Given a spatial position function \n\n\n\nr\n→\n\n\n\n(t) and a magnetic field gradient \n\n\n\n\nG\n→\n\n\nr\n\n\nt\n\n\n, the magnetization phase is:
The basic principles of quantitative flow measurement using magnetic resonance were first proposed by Singer [10] and Hahn [11] in the late 1950s. However, clinical applications of MR flow quantification were not reported until the early 1980s [12, 13, 14, 15]. Current MR flow imaging methods are based on the fact that spins moving at a constant velocity accrue a phase proportional to the velocity times the first moment of the gradient waveform along the direction in which they are moving.
\n
For spins moving along the \n\n\nr\n→\n\n\n-axis with a constant velocity \n\n\nv\n→\n\n\n, and initial position \n\n\n\n\nr\n→\n\n\n0\n\n\n, we can write \n\n\nr\n→\n\n\nt\n\n=\n\n\n\nr\n→\n\n\n0\n\n+\n\n\nv\n→\n\n\nt\n\n. Rewriting Eq. (6), for \n\nt\n=\n\nt\n0\n\n\n:
where \n\n\n\n\nM\n→\n\n\n0\n\n\n and \n\n\n\n\nM\n→\n\n\n1\n\n\n are the zeroth and first moments of the \n\n\nr\n→\n\n\n-gradient waveform at the time of signal acquisitions (“echo time”, or “time to echo” (TE)), respectively. Thus, if a gradient with null zeroth moment is used (e.g., a bipolar gradient, aligned with \n\n\nv\n→\n\n\n), the phase accrued for a constant velocity spin is \n\nϕ\n=\nγ\n\n\n\nv\n→\n\n\n⋅\n\n\n\nM\n→\n\n\n1\n\n\n.
\n
Therefore, if a bipolar gradient waveform is played between the excitation and the readout, the phase measured in a pixel of the acquired image is directly proportional to the velocity of the spins contained within its corresponding voxel. However, factors other than flow (such as inhomogeneities of the magnetic field) may cause additional phase shifts that would cause erroneous interpretation of the local velocity [16].
\n
\n
2.2.1. Phase contrast
\n
The phase contrast method addresses the problem mentioned above by using two gradient-echo data acquisitions in which the first moment of the bipolar gradient waveform is varied between measurements [4]. So from Eq. (11) it is possible to obtain time-dependent velocity measures in all three spatial directions. Then for a fixed time and direction, e.g. velocity in \n\nz\n\n-axis, the through-plane velocity in each voxel is measured as:
where \n\n\nϕ\na\n\n\nx\ny\n\n\n and \n\n\nϕ\nb\n\n\nx\ny\n\n\n are the phase images acquired in each acquisition, and \n\n\nM\n1\na\n\n\n and \n\n\nM\n1\nb\n\n\n are the first moment of the bipolar gradients used in each acquisition.
\n
\n
\n
2.2.2. Fourier velocity encoding
\n
While phase contrast provides a single velocity measurement associated with each voxel, Fourier velocity encoding [7] provides a velocity histogram for each spatial location, which is a measurement of the velocity distribution within each voxel.
\n
FVE involves phase-encoding along a velocity dimension. Instead of only two acquisitions, as in phase contrast, multiple acquisitions are performed, and a bipolar gradient with a different amplitude (and first moment) is used in each acquisition. Eq. (11) can be rewritten as:
where \n\n\n\n\nk\n→\n\n\nv\n\n\n is the velocity frequency variable associated with \n\n\nv\n→\n\n\n, and is proportional to the first moment of \n\n\n\n\nG\n→\n\n\nr\n\n\nt\n\n\n:
Each voxel of the two-dimensional image is associated with a distribution of velocities. This three-dimensional function \n\nm\n\nx\ny\nv\n\n\n is associated with a three-dimensional Fourier space \n\nM\n\n\nk\nx\n\n\nk\ny\n\n\nk\nv\n\n\n\n. Thus, an extra dimension is added to k-space, and multiple acquisitions are required to cover the entire \n\n\nk\nx\n\n\n-\n\n\nk\ny\n\n\n-\n\n\nk\nv\n\n\n space (\nFigure 1\n). In order to move along \n\n\nk\nv\n\n\n, a bipolar gradient with the appropriate amplitude (and first moment) is played before the \n\n\nk\nx\n\n\n-\n\n\nk\ny\n\n\n readout gradients, in each acquisition. Placing the bipolar gradient along the \n\nz\n\n-axis will encode through-plane velocities. Placing the bipolar gradient along \n\nx\n\n or \n\ny\n\n will encode in-plane velocities. Oblique flow can be encoded using a combination of bipolar gradients along the \n\nx\n\n, \n\ny\n\n and \n\nz\n\n axes.
\n
Figure 1.
Spiral FVE k-space sampling scheme. The dataset corresponding to each temporal frame is a stack-of-spirals in \n\n\nk\nx\n\n‐\n\nk\ny\n\n‐\n\nk\nv\n\n\n space. Each spiral acquisition corresponds to a different \n\n\nk\nv\n\n\n encode level.
\n
Each acquisition along \n\n\nk\nv\n\n\n is called a velocity encode. The number of required velocity encodes depends on the desired velocity resolution and velocity field-of-view (the maximum range of velocities measured without aliasing). For example, to obtain a 25 cm/s resolution over a 600 cm/s field-of-view, 24 velocity encodes are needed. The spatial-velocity distribution, \n\nm\n\nx\ny\nv\n\n\n, is obtained by inverse Fourier transforming the acquired data, \n\nM\n\n\nk\nx\n\n\nk\ny\n\n\nk\nv\n\n\n\n. If cine imaging [17] is used, measurements are also time resolved, resulting in a four-dimensional dataset: \n\nm\n\nx\ny\nv\nt\n\n\n.
\n
\n
\n
\n
2.3. FVE signal model
\n
2DFT phase contrast provides two 2-dimensional functions, \n\nm\n\nx\ny\n\n\n and \n\n\nv\nz\n\n\nx\ny\n\n\n, the magnitude and velocity maps, respectively. For simplicity we are assuming that the through-plane velocity map is in the \n\nz\n\n direction. If these maps are measured with sufficiently high spatial resolution, and flow is laminar, one can assume that each voxel contains only one velocity, and therefore the spatial-velocity distribution associated with the object is approximately:
where \n\nδ\n\nv\n\n\n is the Dirac delta function.
\n
In 2DFT FVE, k-space data is truncated to a rectangular cuboid in \n\n\nk\nx\n\n\n-\n\n\nk\ny\n\n\n-\n\n\nk\nv\n\n\n space. The associated object domain spatial-velocity blurring can be modeled as a convolution of the true object distribution, \n\ns\n\nx\ny\nv\n\n\n, with \n\n\nsinc\n\n\n\nx\n/\nΔ\nx\n\n\n\n, \n\n\nsinc\n\n\n\ny\n/\nΔ\ny\n\n\n\n, and \n\n\nsinc\n\n\n\nv\n/\nΔ\nv\n\n\n\n, where \n\nΔ\nx\n\n and \n\nΔ\ny\n\n are the spatial resolutions along the \n\nx\n\n and \n\ny\n\n axes, respectively, and \n\nΔ\nv\n\n is the velocity resolution, as follows:
On the other hand, spiral FVE acquisitions follows a stack-of-spirals pattern in \n\n\nk\nx\n\n\n-\n\n\nk\ny\n\n\n-\n\n\nk\nv\n\n\n space (\nFigure 1\n), then k-space data is truncated to a cylinder, i.e., a circle along \n\n\nk\nx\n\n\n-\n\n\nk\ny\n\n\n (with diameter \n\n1\n/\nΔ\nr\n\n), and a rect function along \n\n\nk\nv\n\n\n (with width \n\n1\n/\nΔ\nv\n\n), where \n\nΔ\nr\n\n and \n\nΔ\nv\n\n are the prescribed spatial and velocity resolutions, respectively. Using the same approach we used for 2DFT FVE, the associated object domain spatial-velocity blurring in spiral FVE can be modeled as a convolution of the true object distribution, \n\ns\n\nx\ny\nv\n\n\n, with \n\n\njinc\n\n\n\n\n\n\nx\n2\n\n+\n\ny\n2\n\n\n\n/\nΔ\nr\n\n\n\n and \n\n\nsinc\n\n\n\nv\n/\nΔ\nv\n\n\n\n, resulting in:
where \n\n\njinc\n\n\nz\n\n=\n\nJ\n1\n\n\nπz\n\n/\n\n\n2\nz\n\n\n\n and \n\n\nJ\n1\n\n\nz\n\n\n is the Bessel function of the first kind and first order. These approaches for deriving FVE data from high-resolution velocity maps will be used for the map estimation purposes.
\n
\n
\n
\n
3. Acceleration of FVE
\n
FVE datasets are multidimensional, which makes this method particularly suitable for accelerated acquisition. Variable-density sampling may be used along spatial k-space, and also along velocity k-space. Partial Fourier acquisition along velocity k-space can be used to reduce scan time by nearly 50%. Temporal acceleration methods such as UNFOLD and k-t BLAST have been demonstrated with FVE. Parallel imaging methods have also been shown to work well with FVE. Also FVE is optimally suited for acquisition acceleration using compressed sensing. This section introduces each of these acceleration methods.
\n
\n
3.1. Variable-density sampling of spatial k-space
\n
Magnetic resonance imaging can be accelerated using variable-density sampling of k-space. This is typically implemented by using a sampling pattern that satisfies the Nyquist criterion at the low spatial frequencies, and undersamples the high spatial frequencies. In other words, the effective field-of-view (FOV) is varied from the desired FOV at the center of k-space to a reduced FOV at the periphery [18]. The general hypothesis is that artifacts from undersampling the periphery of k-space will be negligible, because the energy of high frequency components is typically much lower than that of low frequency components. Variable-density spirals can increase spatiotemporal resolution and improve accuracy in flow quantitation [19]. The spatial aliasing resulting from variable-density spiral sampling is incoherent, and, in the regions-of-interest (e.g., cardiac chambers, valves, great vessels), it typically originates from static or slow moving material located at the periphery of the spatial FOV (e.g., chest wall). FVE resolves the distribution of velocities within the voxel, thus moderate low-velocity aliasing artifacts generally do not affect one’s ability to calculate diagnostically important parameters—such as peak velocity and acceleration—from the time-velocity distribution.
\n
The use of variable-density spirals for acceleration of slice-selective FVE with spiral readouts is illustrated in \nFigure 2\n. A single-shot uniform-density spiral readout was replaced with a multi-shot variable-density spiral acquisition. The use of multi-shot acquisitions provides the possibility of multi-dimensional temporal acceleration, and allows reduction of readout duration and TR, which reduce off-resonance artifacts and temporal aliasing, respectively. The use of a shorter TR also allows improving the temporal resolution. The data in \nFigure 2a\n was obtained using a single-interleave 8 ms readout uniform-density spiral design [20, 21]. The variable-density design used three 4 ms spiral interleaves, and provided higher spatial resolution and reduced off-resonance artifacts, and thus better spatial localization of flow (\nFigure 2b\n) [9]. Some aliasing artifacts were observed in spatial domain (see asterisk), but these were not observed in the time-velocity distributions. A fully sampled reference is shown in \nFigure 2c\n, for comparison.
\n
Figure 2.
Effect of variable-density sampling of spatial k-space on image quality and spatial localization of flow: (a) uniform-density design; (b) variable-density design; (c) ground truth reference. Top row: spatial images from the first cardiac phase; center row: time-velocity distributions measured at the aortic valve; bottom row: time-velocity distributions measured in the descending aorta. The use of higher spatial resolution and shorter readout duration improves the spatial localization of flow, which is identified by the reduced signal from static material in the time-velocity histograms (see arrows). Some aliasing artifacts were observed in spatial domain (see asterisk), but these were not observed in the time-velocity distributions.
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3.2. Variable-density sampling of velocity k-space
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Variable-density sampling of velocity k-space was first demonstrated by DiCarlo et al. [22] using real-time FVE. Real-time FVE (also known as MR Doppler or one-shot FVE) [8, 23, 24, 25] utilizes cylindrical excitation to restrict the spatial field-of-view to a one-dimensional beam. An oscillating readout gradient simultaneously encodes spatial position and velocity along the axis of the beam. Variable-density sampling of velocity k-space has also been demonstrated using slice-selective FVE [26]. Variable-density sampling along the velocity dimension may be used to improve the velocity resolution and/or increase the velocity field-of-view. However, conventional non-Cartesian reconstruction methods such as gridding and direct Fourier transform (DrFT) do not adequately deal with the associated undersampling artifacts. Alternatively, reconstruction of variable-density FVE may be performed using variable-width sinc interpolation with dynamic field-of-view centering [26]. \nFigure 3\n illustrates the use of variable-density sampling along velocity k-space for accelerating slice-selective FVE [26]. The reconstruction scheme using variable-width sinc interpolation with dynamic field-of-view centering exhibits negligible aliasing artifacts compared to conventional gridding (see arrows). There is also no noticeable loss of velocity resolution compared with the small velocity FOV ground truth reference. Note the improvement in velocity resolution compared with the large FOV uniform-density result.
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Figure 3.
\nIn vivo demonstration of variable-density sampling of velocity k-space. Velocity distributions were measured using slice-selective spiral FVE at the aortic valve plane of a healthy volunteer using: (a) uniform-density sampling, large FOV; (b) uniform-density sampling, small FOV (ground truth); (c) variable-density sampling, reconstructed using conventional gridding; and (d) variable-density sampling, reconstructed using variable-width sinc interpolation with dynamic field-of-view centering. The reconstruction scheme using variable-width sinc interpolation with dynamic field-of-view centering reduces undersampling artifacts (arrows), and shows velocity resolution equivalent to that of the ground truth reference.
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\n
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3.3. Partial Fourier acquisition of velocity k-space
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Partial Fourier acquisition and reconstruction exploits the conjugate symmetry property of the Fourier transform of real-valued signals. The method involves acquiring slightly greater than one half of k-space, and synthesizing the missing data using a combination of conjugate synthesis and background phase correction. A narrow strip of k-space is acquired with symmetric coverage in order to estimate this smoothly-varying background phase. The fastest and most widely used method of partial Fourier reconstruction is homodyne detection [27]. Acquisition time in FVE can be reduced by 30–40% using partial Fourier acceleration along the velocity dimension. This consists in acquiring only slightly more than half of the \n\n\nk\nv\n\n\n encodings, and synthesizing the missing data using homodyne reconstruction. This has been successfully used in FVE for scan time reduction, without significant loss of velocity resolution. This approach has been demonstrated in studies with healthy volunteers [8, 20, 21] and patients [20, 21, 25, 28], and in phantom experiments [22]. The feasibility of reducing scan time in FVE using partial Fourier acquisition is illustrated in \nFigure 4\n. Up to 42% of the acquired data (along velocity k-space) was discarded and then synthesized using homodyne reconstruction. The results show 71 and 60% improvement in velocity resolution using this approach, when imaging the aortic valves of a healthy volunteer and of a patient with aortic stenosis. Partial Fourier performs well in both healthy volunteer and patient studies, and no significant loss of resolution or artifacts is noticed [20, 21].
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Figure 4.
Evaluation of partial k-space reconstruction along the velocity dimension, in aortic valve studies of a healthy volunteer (a–c) and a patient with aortic stenosis (d–f). Homodyne reconstruction performs well in both healthy volunteer (b) and patient (e) studies, improving the velocity resolution by 71 and 60%, respectively. Full k-space distributions with the same number of velocity-encode samples are shown for comparison (a,d), as well as the fully sampled datasets (c,f).
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3.4. Temporal acceleration
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In dynamic MRI, view sharing [29] is commonly used to increase the number of temporal frames. Artifacts and loss of temporal resolution due to view sharing can be avoided or corrected using temporal acceleration techniques, such as UNFOLD [30, 31] and k-t BLAST [32]. UNFOLD reduces scan time by making efficient use of k-t space, and can be very successful in the context of slice-selective FVE due to the high dimensionality of this imaging method. The use of UNFOLD for acceleration of FVE was first demonstrated by Macgowan and Madore [33], and further investigated by Carvalho and Nayak [9, 20, 21]. \nFigure 5\n illustrates an implementation of the UNFOLD method specially designed for slice-selective FVE with spiral readouts [9, 20, 21]. A view-ordering scheme that reduces overlap in v-f space was designed (v denotes the through-plane velocity dimension, and f denotes temporal frequency). \nFigure 2a\n shows the undersampled data in both \n\nv\n\n–\n\nf\n\n and \n\nv\n\n–\n\nt\n\n domains (where t denotes time). The aliasing signal is filtered using a two-dimensional filter (\nFigure 5a\n). This filter has a bandwidth of 107 Hz for velocities below \n\n±\n\n150 cm/s. For higher velocities, the bandwidth varies from 69 to 30 Hz. This results in effective temporal resolutions of 9.3 and 14.5–33.3 ms, respectively. The temporal resolution is lower for higher velocities, but this may prove unnoticeable, as the velocity distribution of high-velocity flow jets within large voxels is typically temporally smooth. For comparison, the temporal resolution with view sharing would be 50 ms for all velocities (\nFigure 5d\n). The remaining narrow-bandwidth aliasing components at \n\n±\n\n20 and \n\n±\n\n40 Hz are filtered using a tight zero-phase one-dimensional notch filter along the temporal dimension (\nFigure 5b\n). The final results show that this temporal acceleration scheme is capable of achieving 6-fold acceleration in multi-interleaf spiral FVE, without noticeable loss of temporal resolution, and without introducing significant artifacts (\nFigure 5c\n). View-sharing (\nFigure 5d\n), on the other hand, is equivalent to a moving-average low-pass filter, which reduces the temporal frequency bandwidth (dashed arrows), and causes loss of temporal resolution, perceived as blurring along time (circled).
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Figure 5.
Temporal acceleration compared with view sharing in (left) v-f space and (right) v-t space: (a) undersampled data; (b) with two-dimensional filtering; (c) with two-dimensional and notch filtering; and (d) with view sharing. The two-dimensional filter (dashed lines) removes a majority of the aliasing, and the notch filter (dotted line) removes the remaining aliasing signal (solid arrows). This approach removes aliasing components without noticeable loss of temporal resolution. View sharing reduces the temporal frequency bandwidth (dashed arrows) and causes temporal blurring (circles).
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3.5. Parallel imaging
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Spatial aliasing due to undersampling of slice-selective FVE can be reduced using parallel imaging methods such as SENSE [34] and SPIRiT [35]. Parallel imaging is an acceleration approach that uses data from multiple coils to reduce aliasing artifacts due to undersampling of spatial k-space [34]. Steeden et al. was able to accelerate slice-selective spiral FVE by a factor of four using SENSE [28]. Lyra-Leite et al. used two-dimensional and three-dimensional SPIRiT to accelerate slice-selective spiral FVE by factors of two and four, respectively [36, 37]. In the velocity distributions measured using slice-selective FVE, aliasing due to spatial undersampling typically results in increased signal at \n\nv\n=\n0\n\n cm/s, since the majority of the aliasing signal is associated with static material. \nFigure 6\n illustrates the use of two-dimensional SPIRiT to accelerate slice-selective spiral FVE by a factor of two [36]. SPIRiT is able to considerably reduce aliasing artifacts, while not introducing significant artifacts (see error images).
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Figure 6.
Time-velocity distributions from select voxels, reconstructed using twofold accelerated two-dimensional SPIRiT (center row), in comparison with the fully sampled reference (top row): (a) right external carotid artery; (b) right internal carotid artery; and (c) left carotid bifurcation.
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3.6. Compressive sensing
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Compressive sensing (CS) has been used in MRI [38] context for a while in different applications, such as fMRI images [39], PC-MRI velocity maps [40] and also FVE distributions [41, 42]. Basically, is a set of theories and methods that establish the conditions under which a signal can be reconstructed based on a limited number of linear measurements. It also states different procedures for signal reconstruction, provided that these conditions are properly met [43, 44, 45, 46]. For a successful image reconstruction using CS the desired image must satisfy three conditions: (1) must have a sparse representation in a known transform domain, (2) artifacts caused by k-space undersampling must be incoherent in the sparsifying transform domain and (3) must be reconstructed by a nonlinear method that enforces both sparsity of the image representation and consistency of the reconstruction with the acquired samples [38].
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FVE data is suitable for CS application, since the information contained in images with different velocity encodes is highly redundant differing only where flow occurs. Therefore, through spatial finite differencing operations FVE dataset have a sparse representation [38, 42].
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The original CS reconstruction problem is a NP-hard problem, generally of combinatorial complexity [46, 47, 48], and is not viable except for very low-dimensional cases. Thus, the original problem can be relaxed and a precise reconstruction can be achieved using the following non-linear constrained optimization problem:
where \n\n0\n<\np\n≤\n1\n\n, \n\nT\n\n is the sparsifying transform, \n\nM\n\n is the acquisition process matrix, \n\nf\n\n is the desired image, \n\ns\n\n is the acquired signal and
Usually in most CS applications the value of \n\np\n\n is set to \n\np\n=\n1\n\n, but it has been shown that for \n\n\nℓ\np\n\n\n-minimization (with \n\n0\n<\np\n<\n1\n\n) requires fewer measurements than \n\n\nℓ\n1\n\n\n [46]. In order to reconstruct MR data based on \n\n\nℓ\np\n\n\n-minimization, one can use the algorithm described by Miosso et al. [45].
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Other possible ways to enhance signal reconstruction in CS, both in terms of reducing the number of required measurements and in terms of improving image quality for a fixed number of measurements, include the use of support prior information extracted from structural knowledge, previous frames or previous slices [39, 46], and the use of information extracted using machine learning techniques [49, 50]. Other alternative optimization problems are also desired in the context of noisy measurements, in which case, for example, the equality constraint in Problem 19 is replaced by an inequality such as \n\n∥\nMf\n−\ns\n\n∥\n\nℓ\n2\n\n\n≤\nε\n\n, with \n\nε\n\n being a tolerance to noise [47, 48] — the higher the value of \n\nε\n\n, the higher the number of measurements required for reconstruction.
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In this context, has been shown by Marinelli et al. [51] and Hilbert et al. [42] that CS can also be used as an acceleration technique for FVE datasets and the acquisition can be made in time scale comparable to the gold standard phase contrast. So it is possible to obtain meaningful velocity spectra in small vessels in clinical time while regular phase contrast can provide only mean velocity maps [42].
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4. Estimating velocity maps from FVE distributions
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In this section will be discussed a methodology to estimate the velocity map based on the FVE velocity distribution. It has been shown in Section 2.3 that FVE velocity distribution signal model \n\n\ns\n̂\n\n\nx\ny\nv\n\n\n is related to the actual velocity map \n\n\nv\nz\n\n\nx\ny\n\n\n through the relation
where \n\nΨ\n\nx\ny\n\n\n is a point spread function associated with \n\nk\n\n-space truncation data. This provide a first relation between the FVE measured velocity distribution and the velocity map. On the other hand, blood can be ideally modeled as an incompressible Newtonian fluid. Then, blood flow can be predicted using the Navier-Stokes equation
where \n\nv\n=\n\n\nv\nx\n\n\nv\ny\n\n\nv\nz\n\n\n\n is the velocity vector, \n\nρ\n\n is the blood density, \n\nμ\n\n is the whole blood viscosity and \n\n\n∇\n2\n\n\n is the Laplacian differential operator. Then, ideally the desired velocity map must satisfy the flow physics model. Therefore, for a fixed instant of time, a velocity map can be estimated from a measured FVE dataset \n\nf\n\nx\ny\nv\n\n\n, with \n\nK\n\n velocity encodes, through the following PDE-constrained optimization problem
where \n\nx\n=\n\nx\ny\n\n\n is the position vector and \n\n\nv\nk\n\n\n is a velocity encode.
\n
In order to solve Eq. (23) the Navier-Stokes equation must be discretized. Since the interest here is in a proof-of-concept velocity map estimation based on only one component of the velocity vector, a bidimensional version of the physics model solver was used. Fluid is assumed incompressible, so the steady 2D Navier-Stokes-continuity dimensionless system of equations [52],
was discretized using the Finite Element Method [53], where \n\nRe\n\n is the Reynolds number [52], \n\nv\n=\n\nv\nx\n\ni\n+\n\nv\nz\n\nj\n∈\n\nIR\n2\n\n\n is the velocity field and \n\np\n\n is the pressure. Discretization is made using residues functions based on the governing equations’ weak form Gresho and Sani [53]
where \n\nϕ\n∈\nIR\n,\n\nΨ\n∈\n\nIR\n2\n\n\n are test functions, and \n\nσ\n=\n−\np\nI\n+\n\nRe\n\n−\n1\n\n\n\n\n∇\nv\n+\n∇\n\nv\nT\n\n\n\n\n the Newtonian stress tensor [52].
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Discretizatized equations are written as a linear system \n\nJc\n=\nr\n\n, where \n\nJ\n\n is a matrix given by the residues’ Jacobian, \n\nr\n\n is a vector given by the residues and \n\nc\n\n is the solution vector containing velocity and pressure. Now the minimization problem given by Eq. (23) can be written as
where \n\nc\n=\n\n\nv\nx\n\n\nv\nz\n\np\n\n\n is the solution vector written in a stacked form and \n\nm\n\n is a spin density map with high spatial resolution.
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In order to validate the proposed constrained optimization (Eq. (27)) an simple experiment was carried out. To do so, a FVE dataset was simulated from an acquired PC dataset, then the optimization was solved and finally the resultant velocity map was compared with the acquired PC velocity map qualitatively and quantitatively.
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First, high-spatial-resolution four-dimensional PC data of a pulsatile carotid flow phantom (Phantoms by Design, Inc., Bothell, WA) were obtained using a 3DFT SPGR pulse sequence. The scan parameters were: \n\n0.5\n×\n0.5\n×\n1\n\n mm\n\n\n\n\n3\n\n\n spatial resolution; field-of-view \n\n4.0\n×\n3.5\n×\n5.0\n\n cm\n\n\n\n\n3\n\n\n; TR 11.4 ms; flip angle 8.5°; temporal resolution 91.2 ms; VENC 50 cm/s; 40 min per scan; 9 NEX. The data were acquired on a GE Discovery MR750 3T system, with a 32-channel receive-only head coil array (Nova Medical, Inc., Wilmington, MA, USA). The through-slab (\n\nz\n\n) axis was oriented along the S/I direction. The phantom’s pulse cycle was set to 60 bpm. The velocity map for each spatial axis—\n\n\nu\npc\n\n,\n\n\n\n\n\nv\npc\n\n\n, and \n\n\nw\npc\n\n\n—was reconstructed using data from all channels of the receive coil array. The lumen was segmented by manually outlining the vessel borders from a stack of 2D axial images, obtained from the reconstructed 3D volume.
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Then simulated spiral FVE distributions were derived from the acquired phase contrast data using the signal model presented in Eq. (21). Simulated data was generated only for the through-axis velocity component (\n\n\nv\nz\n\n\n), and for a cardiac phase corresponding to the phantom’s mid-systole. The 9-NEX PC dataset was used in this process, so that the FVE distributions were computed from low-noise velocity maps (as in Carvalho et al. [54]). This is because FVE has considerably higher SNR than PC in general, due to its higher dimensionality and larger voxel size. Finally, two different spiral FVE distributions were obtained for each slice of the volume with \n\nΔ\nr\n\n = 2 mm spatial resolution: one using the proposed method and the other one using the method proposed by Rispoli and Carvalho [55]. The velocity resolution was set to \n\nΔ\nv\n=\n10\n\n cm/s, over a 120 cm/s velocity field-of-view.
\n
About the discretization of the Navier-Stokes equations, lumen manually outlined was used to define computational mesh and simulation grid was designed with 1.0 \n\n×\n\n 0.5 \n\n\nmm\n2\n\n\n element resolution using \n\n\nQ\n2\n\n/\n\nP\n\n−\n1\n\n\n\n elements. Phantom’s blood-mimicking fluid (with Reynolds number \n\nRe\n=\n110\n\n) was assumed to be Newtonian and incompressible. PC-MRI velocity profile was set at the inlet together with no-slip boundary condition.
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The optimization problem given by Eq. (27) was then solved using a alternating minimization technique [56]. Left side part was solved using a standard non-linear least squares algorithm and the physics model part of the optimization was solved using Newton’s method [53].
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\n\nFigure 7\n presents the results of the validation experiment using the phase contrast velocity map acquired at the pulsatile carotid flow phantom’s bifurcation. The velocity maps estimated from the simulated low spatial resolution FVE data are very similar (qualitatively) to the reference map. At first glance one can say that the velocity map obtained using the technique proposed by Rispoli and Carvalho [55] (\nFigure 7c\n) is more similar to the acquired PC-MRI velocity map. However the error images show that the velocity map obtained using the technique proposed in this work (\nFigure 7b\n) was more accurate than the one obtained with the other method (\nFigure 7c\n).
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Figure 7.
Validation experiment using a pulsatile carotid flow phantom: (a) reference phase contrast velocity map, measured at the phantom’s bifurcation; (b) velocity map estimated from the simulated low-resolution spiral FVE data with \n\nΔ\nr\n\n = 2 mm spatial resolution with the proposed method (and associated error percentages); and (c) velocity map estimated from the simulated low-resolution spiral FVE data with \n\nΔ\nr\n\n = 2 mm spatial resolution with the method proposed by Rispoli and Carvalho [55] (and associated error percentages).
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Moreover, a quantitative comparison was performed based on the signal-to-error ratio (SER). The acquired phase contrast velocity field, \n\n\nv\npc\n\n\n, was used as the ground-truth “signal”; consequently, the estimation error is the difference between the estimated velocity field, \n\n\nv\ne\n\n\n, and the ground-truth field, \n\n\nv\npc\n\n\n. Thus, the SER is calculated (in decibels) as:
Finally, the proposed method measured SER, relative to the PC reference, was 44.63 dB while the technique proposed in Rispoli and Carvalho [55] achieved 28.68 dB. Showing that the proposed optimization given by Eq. (27) is more consistent with the actual velocity map than the previous method proposed.
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These good results are important, meaning that FVE may potentially be a substitute of PC imaging, since it contains both a velocity distribution and also velocity map with considerably higher SNR and robustness to partial voluming.
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\n
\n
5. Conclusion
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In this chapter, was discussed approaches in order to make Fourier Velocity Encoding MRI more suitable for the clinical environment. FVE is a promising MRI technique capable of measuring blood flow in the blood vessels and estimating important biomarkers that are useful for understand and diagnose diseases. It provides a velocity distribution within a voxel instead of a mean velocity map like phase contrast but requires acceleration to be feasible in the clinical setting. So was discussed six different strategies that can reduce drastically the acquisition time. The acceleration techniques discussed are related to the use of variable-density sampling, which may be used along spatial k-space and velocity k-space, partial Fourier acquisition along velocity k-space, temporal acceleration methods such as UNFOLD and k-t BLAST, parallel imaging methods and compressive sensing.
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On the other hand, was proposed a novel method for estimating high-resolution velocity maps from low-resolution FVE measurements. This method is based on a PDE-constrained optimization that incorporates the FVE signal model and the Navier-Stokes equation. Results showed that it is possible to obtain highly accurate velocity maps from the FVE distributions. Finally, it can be concluded that FVE datasets can be acquired in time scale comparable to the gold standard phase contrast, it provides more velocity information, since it contains a velocity distribution, and also can provide the actual velocity map as long as a constrained-optimization problem to restore the velocity map is solved.
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\n\n',keywords:"Fourier velocity encoding, compressive sensing, variable-density sampling, parallel imaging, velocity map estimation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59370.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59370.xml",downloadPdfUrl:"/chapter/pdf-download/59370",previewPdfUrl:"/chapter/pdf-preview/59370",totalDownloads:984,totalViews:273,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:12,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"June 6th 2017",dateReviewed:"November 16th 2017",datePrePublished:null,datePublished:"March 14th 2018",dateFinished:"February 15th 2018",readingETA:"0",abstract:"Fourier velocity encoding (FVE) is an alternative to phase contrast imaging (PC). FVE provides considerably higher SNR than PC, due to its higher dimensionality and larger voxel sizes. Furthermore, FVE is robust to partial voluming, as it resolves the velocity distribution within each voxel. FVE data are usually acquired with low spatial resolution, due to scan-time restrictions associated with its higher dimensionality. FVE is capable of providing the velocity distribution associated with a large voxel, but does not directly provides a velocity map. Knowing the velocity distribution on a voxel is important for accurate diagnosis of stenosis in vessels on the scale of spatial resolution. Velocity maps, however, are useful for visualizing the actual blood flow through a vessel and can be used in different studies and diagnosis. In this context, this chapter deals with two aspects of the FVE MRI technique: acceleration and estimation of velocity map. First, are introduced six different acceleration techniques that can be applied to FVE acquisition. Methods such as variable-density sampling and compressive sampling. Then, is proposed a novel method to estimate velocity maps with high spatial resolution from low-resolution FVE data. Finally, it can be concluded that FVE datasets can be acquired in time scale comparable to PC, it contains more velocity information, since it resolves a velocity distribution within a voxel, and also provides an accurate estimation of the velocity map.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59370",risUrl:"/chapter/ris/59370",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications"},signatures:"Vinicius C. Rispoli, Joao L.A. Carvalho, Cristiano J. Miosso and\nFabiano A. Soares",authors:[{id:"36213",title:"Prof.",name:"Joao",middleName:null,surname:"Carvalho",fullName:"Joao Carvalho",slug:"joao-carvalho",email:"joaoluiz@pgea.unb.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"208686",title:"Dr.",name:"Vinicius",middleName:"Carvalho",surname:"Rispoli",fullName:"Vinicius Rispoli",slug:"vinicius-rispoli",email:"vrispoli@pgea.unb.br",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/208686/images/5451_n.jpg",institution:{name:"University of Brasília",institutionURL:null,country:{name:"Brazil"}}},{id:"209663",title:"Dr.",name:"Cristiano",middleName:null,surname:"Miosso",fullName:"Cristiano Miosso",slug:"cristiano-miosso",email:"jacques.unb@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"216170",title:"Dr.",name:"Fabiano",middleName:null,surname:"Soares",fullName:"Fabiano Soares",slug:"fabiano-soares",email:"soaresfabiano@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Magnetic resonance flow imaging",level:"1"},{id:"sec_2_2",title:"2.1. Mathematical formalism",level:"2"},{id:"sec_3_2",title:"2.2. Principles of MR flow imaging",level:"2"},{id:"sec_3_3",title:"2.2.1. Phase contrast",level:"3"},{id:"sec_4_3",title:"2.2.2. Fourier velocity encoding",level:"3"},{id:"sec_6_2",title:"2.3. FVE signal model",level:"2"},{id:"sec_8",title:"3. Acceleration of FVE",level:"1"},{id:"sec_8_2",title:"3.1. Variable-density sampling of spatial k-space",level:"2"},{id:"sec_9_2",title:"3.2. Variable-density sampling of velocity k-space",level:"2"},{id:"sec_10_2",title:"3.3. Partial Fourier acquisition of velocity k-space",level:"2"},{id:"sec_11_2",title:"3.4. Temporal acceleration",level:"2"},{id:"sec_12_2",title:"3.5. Parallel imaging",level:"2"},{id:"sec_13_2",title:"3.6. Compressive sensing",level:"2"},{id:"sec_15",title:"4. Estimating velocity maps from FVE distributions",level:"1"},{id:"sec_16",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\nManning WJ, Pennell DJ. Cardiovascular Magnetic Resonance. Elsevier; 2010\n'},{id:"B2",body:'\nHoskins PR. Accuracy of maximum velocity estimates made using Doppler ultrasound systems. The British Journal of Radiology. 1996;69(818):172-177\n'},{id:"B3",body:'\nWinkler AJ, Wu J. Correction of intrinsic spectral broadening errors in Doppler peak velocity measurements made with phased sector and linear array transducers. Ultrasound in Medicine & Biology. 1995;21(8):1029-1035\n'},{id:"B4",body:'\nO’Donnell M. NMR blood flow imaging using multiecho, phase contrast sequences. Medical Physics. 1985;12(1):59-64\n'},{id:"B5",body:'\nGonzales E, Carvalho J. Does phase contrast MRI provide the mean velocity of the spins within a voxel?. In: Proc, ISMRM, 22nd Annual Meeting; Milan; 2014. p. 2480\n'},{id:"B6",body:'\nTang C, Blatter DD, Parker DL. Accuracy of phase-contrast flow measurements in the presence of partial-volume effects. 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Magnetic Resonance in Medicine. 1993;30(3):393-398\n'},{id:"B24",body:'\nIrarrazabal P, Hu BS, Pauly JM, Nishimura DG. Spatially resolved and localized real-time velocity distribution. Magnetic Resonance in Medicine. 1993;30(2):207-212\n'},{id:"B25",body:'\nSantos JM, Kerr AB, Lee D, McConnell MV, Yang PC, Hu BS, Pauly JM. Comprehensive valve evaluation system. In: Proc, ISMRM, 15th Annual Meeting; Berlin; 2007. p. 2551\n'},{id:"B26",body:'\nCarvalho JLA, DiCarlo JC, Kerr AB, Nayak KS. Reconstruction of variable-density data in Fourier velocity encoding. In: Proc, ISMRM, 15th Annual Meeting; Berlin; 2007. p. 2514\n'},{id:"B27",body:'\nNoll DC, Nishimura DG, Macovski A. Homodyne detection in magnetic resonance imaging. IEEE Transactions on Medical Imaging. 2001;10(2):154-163\n'},{id:"B28",body:'\nSteeden JA, Jones A, Pandya B, Atkinson D, Taylor AM, Muthurangu V. High-resolution slice-selective Fourier velocity encoding in congenital heart disease using spiral SENSE with velocity unwrap. Magnetic Resonance in Medicine. 2012;67:1538-1546\n'},{id:"B29",body:'\nRiederer SJ, Tasciyan T, Farzaneh F, Lee JN, Wright RC, Herfkens RJ. MR fluoroscopy: Technical feasibility. Magnetic Resonance in Medicine. 1988;8(1):1-15\n'},{id:"B30",body:'\nMadore B, Glover GH, Pelc NJ. Unaliasing by Fourier-encoding the overlaps using the temporal dimension (UNFOLD), applied to cardiac imaging and fMRI. Magnetic Resonance in Medicine. 1999;42(5):813-828\n'},{id:"B31",body:'\nTsao J. On the UNFOLD method. Magnetic Resonance in Medicine. 2002;47(1):202-207\n'},{id:"B32",body:'\nTsao J, Boesiger P, Pruessmann KP. k-t BLAST and k-t SENSE: Dynamic MRI with high frame rate exploiting spatiotemporal correlations. Magnetic Resonance in Medicine. 2003;50(5):1031-1042\n'},{id:"B33",body:'\nMacgowan CK, Madore B. Application of UNFOLD to real-time Fourier velocity encoding. In: Proc, ISMRM, 14th Annual Meeting; Seattle; 2006. p. 872\n'},{id:"B34",body:'\nPruessmann KP, Weiger M, Bornert P, Boesiger P. Advances in sensitivity encoding with arbitrary k-space trajectories. Magnetic Resonance in Medicine. 2001;46(4):638-651\n'},{id:"B35",body:'\nLustig M, Pauly JM. SPIRiT: Iterative self-consistent parallel imaging reconstruction from arbitrary k-space. Magnetic Resonance in Medicine. 2010;64:457-471\n'},{id:"B36",body:'\nLyra-Leite DM, Carvalho JLA. Parallel imaging acceleration of spiral Fourier velocity encoded MRI using SPIRiT. In: Proc 34th International Conference, IEEE Engineering in Medicine and Biology Society; Seattle; 2012. pp. 416-419\n'},{id:"B37",body:'\nLyra-Leite DM, Nayak KS, Carvalho JLA. Acceleration of spiral Fourier velocity encoded MRI using 3D SPIRiT. In: Proc, ISMRM, 21st Annual Meeting; 2013. p. 1352\n'},{id:"B38",body:'\nLustig M, Donoho D, Santos J, Pauly J. Compressive sensing MRI. IEEE Signal Processing Magazine. 2008;25(2):72-82\n'},{id:"B39",body:'\nMiosso CJ, von Borries R, Pierluissi H. Compressive sensing with prior information: Requirements and probabilities of reconstruction in \n\n\nℓ\n1\n\n\n-minimization. IEEE Transactions on Signal Processing. 2013;61(9):2150-2164\n'},{id:"B40",body:'\nKwak Y, Nam S, Akçakaya M, Basha T, Goddu B, Manning W, Tarokh V, Nezafat R. Accelerated aortic flow assessment with compressed sensing with and without use of the sparsity of the complex difference image. Magnetic Resonance in Medicine. 2013;70(3):851-858\n'},{id:"B41",body:'\nGamper U, Boesiger P, Kozerke S. Compressed sensing in dynamic MRI. Magnetic Resonance in Medicine. 2008;59:365-373. DOI: 10.1002/mrm.21477\n'},{id:"B42",body:'\nHilbert F, Wech T, Hahn D, Köstler H. Accelerated radial Fourier-velocity encoding using compressed sensing. Zeitschrift für Medizinische Physik. 2014;24(3):190-200\n'},{id:"B43",body:'\nBaraniuk RG. Compressive sensing [lecture notes]. IEEE Signal Processing Magazine. 2007;24:118-121\n'},{id:"B44",body:'\nDonoho DL. Compressive sensing. IEEE Transactions on Information Theory. 2006;52(4):1289-1306\n'},{id:"B45",body:'\nMiosso CJ, von Borries R, Argaez M, Velazquez L, Quintero C, Potes CM. Compressive sensing reconstruction with prior information by iteratively reweighted least-squares. IEEE Transactions on Signal Processing. 2009;57(6):2424-2431\n'},{id:"B46",body:'\nMiosso CJ. Compressive sensing with prior information applied to magnetic resonance imaging [PhD thesis]. Department of Electrical and Computer Engineering, University of Texas at El Paso; 2010\n'},{id:"B47",body:'\nCandès EJ, Romberg J, Tao T. Stable signal recovery from incomplete and inaccurate measurements. Communications on Pure and Applied Mathematics. 2006;59(8):1207-1223\n'},{id:"B48",body:'\nCandès EJ, Romberg J, Tao T. Robust uncertainty principles: Exact signal reconstruction from highly incomplete frequency information. IEEE Transactions on Information Theory. 2006;52:489-509\n'},{id:"B49",body:'\nMousavi A, Patel AB, Baraniuk RG. A deep learning approach to structured signal recovery. In: 53rd Annual Allerton Conference on Communication, Control, and Computing (Allerton); 2015. pp. 1336-1343\n'},{id:"B50",body:'\nPalangi H, Ward R, Deng L. Distributed compressive sensing: A deep learning approach. IEEE Transactions on Signal Processing. 2016;64(17):4504-4518\n'},{id:"B51",body:'\nMarinelli L, Khare K, King K, Darrow R, Hardy C. Accelerated 2D Fourier-velocity encoded MRI using compressed sensing. In: Proc, ISMRM, 17th Annual Meeting; 2009. p. 2827\n'},{id:"B52",body:'\nChorin A, Marsden J. A Mathematical Introduction to Fluid Mechanics. Springer; 2000\n'},{id:"B53",body:'\nGresho P, Sani R. Incompressible Flow and the Finite Element Method. Wiley; 2000\n'},{id:"B54",body:'\nCarvalho JLA, Nielsen JF, Nayak KS. Feasibility of in vivo measurement of carotid wall shear rate using spiral Fourier velocity encoded MRI. Magnetic Resonance in Medicine. 2010;63(6):1537-1547\n'},{id:"B55",body:'\nRispoli VC, Carvalho JLA. Deriving high-resolution velocity maps from low-resolution Fourier velocity encoded MRI data. In: IEEE 10th International Symposium on Biomedical Imaging; 2013. pp. 334-337\n'},{id:"B56",body:'\nWang Y, Yang J, Yin W, Zhang Y. A new alternating minimization algorithm for total variation image reconstruction. SIAM Journal on Imaging Sciences. 2008;1(3):248-272\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Vinicius C. Rispoli",address:"vrispoli@pgea.unb.br",affiliation:'
'},{corresp:null,contributorFullName:"Cristiano J. Miosso",address:null,affiliation:'
University of Brasilia, Brazil
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University of Brasilia, Brazil
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1. Introduction
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The redox status of cells is crucial for normal physiological functioning; however, when the prooxidant activity overrides the antioxidative capacity (AOC), oxidative stress occurs. Chronic oxidative stress causes cytotoxicity and organ failure. As such, it is believed to play a role in many diseases, such as cardiovascular, thromboembolic and neurodegenerative disorders, as well as aging [1].
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In this review, we suggest that RBC, in addition to their primary role as oxygen and CO2 carriers, functions as redox modulators. Various RBC systems afford them with AOC that, in addition to balancing their own redox state, can provide antioxidative protection to the cellular and intercellular milieus throughout the body. Their vast number, mobility, and occurrence throughout the body and renewability make them good candidates for this function. A decrease in their number (anemia) or function may exacerbate the symptoms of many diseases by failing to neutralize oxidative stress. However, correcting anemia, e.g., by repeated RBC transfusions or by iron supplementation, may increase the iron load, which, in turn, causes oxidative stress. This situation suggests that the status of both iron and redox should be monitored during treatment, using RBC as bioindicators.
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2. Oxidative stress and its involvement in pathology
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The cellular redox status represents the balance between generation of free radicals, such as the reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the ability to detoxify them or to repair their resultant damage by antioxidants, such as the reduced glutathione (GSH), the major intracellular scavenger of ROS. ROS are generated in cells mainly during energy production: In the mitochondria, about 2% of the total oxygen (O2) consumption results in the free radical superoxide anion (O2−) [1]. While not particularly reactive, superoxide can act as a reductant toward divalent metal ions, mainly iron and copper, and can react with itself by spontaneous or enzymatic (e.g., by the reducing enzyme superoxide dismutase, SOD) dismutation to form hydrogen peroxide (H2O2). The latter is a mild oxidant, but in the presence of divalent metals, it can generate the reactive hydroxyl (˙OH) radical.
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In mature RBC, which are devoid of mitochondria, the hemoglobin (Hb) is the major source of ROS generation [2]. The heme iron, which is in the Fe(II) ferrous state in the oxygenated Hb, is oxidized to the Fe(III) ferric state in metHb—a reaction that normally occurs at a rate of about 3% of the Hb per day. This process results in the production of superoxide that in turn generates hydrogen peroxide and oxygen as products of dismutation by SOD [3]. The metHb is then restored back to oxyHb by the NADH-cytochrome b5 reductase [4].
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An additional pathway of oxygen to superoxide reduction is by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Phagocytic cells, such as polymorphonuclear (PMN) neutrophils and macrophages, have an NADPH oxidase complex that generates ROS as part of the innate immune response to infection. Non-phagocytic cells contain NADPH oxidases that generate ROS, at lower levels than phagocytes, for signaling responses [5]. ROS can also arise as the indirect by-product of enzymatic activities, such as that of monooxygenases (e.g., cytochrome P450) [6].
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RNS originate from the gaseous molecule nitric oxide (NO). The latter is synthesized by constitutive or inducible nitric oxide synthase enzymes by oxidation of L-arginine to L-citrulline. NO can react rapidly with the superoxide anion to form the oxidant peroxynitrite (ONOO−), nitrogen dioxide (NO2), nitroxyl (HNO), and nitrosonium cation (NO+) (for review see [7]).
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The cellular prooxidants are tightly controlled by restricting the magnitude and the location of their generation and by elaborating antioxidant mechanisms that scavenge their excess and correct their toxic consequences (for review see [1]). In addition to these intracellular antioxidant mechanisms, extracellular mechanisms function as well. For example, the blood serum contains many molecules with AOC such as bilirubin, albumin, ascorbic acid, as well as diet-derived antioxidants such as polyphenols.
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Under certain conditions, excess oxidants my override the AOC and generate a state of oxidative stress. This may occur due to external factors (e.g., certain food components, air pollution, sun exposure, environmental radiation, as well as radio- and chemotherapeutic regimes) or internal factors such as various pathological circumstances (e.g., inflammation, iron overload, Hb instability). Excess ROS react quickly with bio-molecules such as the DNA, proteins, and lipids, interfering with cellular functions. As such, even if it is not the primary etiology, oxidative stress is believed to mediate the symptoms of many diseases, such as cancer, atherosclerosis, diabetes, cardiovascular, thromboembolic and neurodegenerative disorders, as well as physiological aging [1].
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3. Hemolytic anemia
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We have studied oxidative stress in hemolytic anemias [8]. The anemia in these hereditary or acquired diseases is the result of augmented destruction (hemolysis) of mature RBC and their immature progenitors/precursors that is not balanced by compensatory overproduction. Among these diseases are: (I) The hemoglobinopathies—caused by mutations in the globin genes, leading to insufficient production (thalassemia) or production of aborted (sickle cell disease) globin chains [9]. (II) RBC membrane/cytoskeletal disorders such as hereditary spherocytosis, elliptocytosis, and stomatocytosis—caused by mutations in genes leading to abnormal RBC shape and propensity for hemolysis [10]. (III) Inherited enzymatic defects in RBC such as glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency. G6PD is a key enzyme of the pentose pathway (hexose monophosphate shunt) which supplies NADPH—a reducing agent that is important for the regulation of the redox state, especially in RBC [11]. Patients with G6PD deficiency exhibit hemolytic anemia in response to infection and certain medications or foods. (IV) Paroxysmal nocturnal hemoglobinuria—a clonal disease caused by an acquired somatic mutation in the phosphatidylinositol glycan complementation class A gene. This gene encodes the enzyme responsible for the first step in the production of the glycosylphosphatidylinositol anchor, by which various proteins are linked to the plasma membrane. In this disease, the mutation occurs in a hematopoietic stem cell and is expressed in its progeny, affecting various membrane proteins including the complement (C′) inhibitors: CD55 (decay-accelerating factor) which inhibits the C3 component of the C′, and CD59 (membrane inhibitor of reactive lysis) which inhibits terminal C′ components (C5b-9) from forming the hemolytic membrane pore [12]. This leads to hemolysis and platelet activation, leading to anemia and to venous thrombosis, respectively [13]. (V) Congenital dyserythropoietic anemias—a heterogeneous group of diseases characterized by anemia due to abnormalities of erythroid precursor cells and reduced erythropoiesis [14]. (VI) Autoimmune hemolytic anemia such as ABO mismatch transfusion reaction and severe idiopathic autoimmune hemolytic anemia—caused by autoantibodies against antigens expressed on the surface of RBC. Once formed, these antibodies bind to the surface of RBC marking them for destruction through C′-mediated lysis (intravascular hemolysis) and/or Fc-mediated phagocytosis (extravascular hemolysis). Autoimmune hemolytic anemia can occur alone, but is often seen in association with other autoimmune diseases, cancer, drug treatment, transfusion, and pregnancy. (VII) Myelodysplastic syndromes (MDS)—diverse conditions that involve ineffective production (dysplasia) of hematopoietic cells. The patients often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens, and the patient develops cytopenias due to progressive bone marrow failure. In about one third of patients, the disease transforms into acute myelogenous leukemia, usually within months to a few years.
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Although oxidative stress is not the primary etiology of these diseases, except for G6PD deficiency, it mediates their symptoms, including anemia, recurrent infections, and thromboembolic complications [8]. The main causes of oxidative stress in these diseases are: (I) Degradation of abnormal Hbs in the mature RBC and their precursors (in the hemoglobinopathies), leading to the production of hemichromes and eventually to release of heme and iron. (II) Iron overload caused by frequent blood transfusions and increased iron uptake [15]. Usually, iron uptake in the gut as well as its mobilization from storage cells, regulated by hepcidin, is downregulated by iron excess [16]. It these diseases, where the body attempts to compensate for the anemia by over production of new RBC (“ineffective erythropoiesis”), iron is in high demand. To ensure sufficient iron uptake, the developing erythroid progenitors produce factors that inhibit hepcidin production, thus overriding the regulating effect of hepcidin. (III) Iron-containing compounds (Hb and hemin) which are released by intravascular hemolysis can also add to the iron load and further aggravate the hemolysis [17]. In the absence of specific mechanisms for disposal of excess iron, under these conditions iron accumulates. Iron overload increases ROS generation by catalyzing the Haber-Weiss/Fenton biochemical reactions [3, 18].
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4. RBC as redox modulators
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The main function of RBC is oxygen transport, for which they have evolved efficient nonenzymatic and enzymatic antioxidative systems for protection against oxidizing substances to which they are exposed. The nonenzymatic systems include reduced glutathione, thioredoxin, ascorbic acid, and vitamin E. The most important antioxidant enzymes include SOD, thioredoxin reductase/peroxiredoxin system, catalase, glutathione peroxidase, glutathione reductase, plasma membrane oxidoreductases, and the metHb reductase/NADH/glycolysis system that maintains Hb in a Fe(II)-active form [19].
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Although these systems mainly serve the RBC own requirements, it seems that since they are produced in excess they can be utilized for antioxidant protection of other cells, at least under conditions of oxidative stress. This function may affect the intra- and extracellular milieus throughout the body, especially of cells in the circulation and in the perivascular tissues (endothelial cells).
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Several characteristics, in addition to their extra reducing power, make RBC ideal candidates to serve as redox mediators. These include their vast number, mobility, and occurrence throughout the body. The consequence of their antioxidative activity could be oxidative damage to the RBC themself, facilitating their erythrophagocytosis, degradation, and detoxification of their oxidized constituents by macrophages in reticuloendothelial systems, mainly the spleen and the liver. These damaged/old RBC are replaced by new RBC that are continuously formed in the bone marrow.
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A “bystander” effect of cells on the oxidative status of other neighboring cells has been described previously in other circumstances of oxidative stress induced by ionizing or photoradiation [20, 21].
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4.1 Proofs of the concept
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The concept of the RBC protective role was first introduced by Fazi et al. [22]. They showed that RBC are able to inactivate harmful xenobiotics, including 1-chloro-2,4-dinitrobenzene, by conjugation with glutathione and suggested that it may be possible to treat xenobiotic intoxication by transfusion of GSH-loaded RBC.
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Richards et al. have shown that RBC can protect endothelial cells from PMN- induced damage [23]. PMN exert their antibacterial effect by generating a burst of ROS (respiratory burst) in response to toxins released by phagocytosed bacteria. These ROS not only kill the bacteria but also damage the PMN themselves and other neighboring cells (inflammation). The respiratory burst can be reproduced in vitro by incubating PMN with phorbol myristate acetate (PMA). In their study, 51Cr-labeled endothelial cells were incubated with PMA-triggered PMN. Damage to the endothelial cells was measured by the release of 51Cr into the incubation medium. Adding RBC to the mixture reduced the damage dose-dependently. Analyzing the RBC following the incubation, revealed reduced levels of 2,3-diphosphoglyceric acid and glutathione, and increased levels of the oxidation products malondialdehyde and metHb. These results indicated that these RBC are under oxidative stress compared with RBC incubated alone or with non-triggered PMN. The authors suggested that RBC can provide antioxidant protection to other tissues in vivo [24].
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We have studied the effect of RBC on the oxidative status of other cells by measuring oxidative parameters by flow cytometry. Following pulse-labeling of cells with the probe 2′7′-dichlorodihydrofluorescindiacetate, their fluorescence was proportional to their ROS content. The increase in their fluorescence after washing indicated their rate of generation of ROS. In our experiments, the labeled cells were incubated with RBC derived from either normal donors or patients with β-thalassemia. Normal RBC had a dose-dependent decrease effect on ROS generation, while thalassemic RBC had a much inferior effect [25].
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It is well known that thalassemic RBC are under oxidative stress and contain more free iron load (the labile iron pool) than normal RBC [26]. To explore this condition on their AOC, RBC were exposed to agents that affect their oxidative stress or iron overload: normal RBC—to the oxidant hydrogen peroxide or to an iron source, ferric ammonium citrate, and thalassemic RBC—to the antioxidant N-acetyl cysteine or to the iron chelator, Desferal. The RBC were then mixed with the probe-labeled cells, and the kinetics of ROS generated by the labeled cells was monitored during incubation. The results indicated that oxidants and iron reduced the AOC of RBC (Figure 1).
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Figure 1.
The effects of iron overload and oxidative stress on the antioxidative capacity (AOC) of normal and thalassemia RBC. The human myeloid leukemia HL60 cells were labeled with 2′-7′-di-chlorofluorescein diacetate, washed, and then incubated with 6 × 106/ml RBC from normal or β-thalassemia donors (N = 6 each). Prior to incubation with cells, the RBC had been treated for 30 min: normal RBC with ferric ammonium citrate (FAC), 1 mM, and thalassemic RBC—with the iron chelator, Desferal, 5 mM—thus increasing and decreasing iron overload, respectively. Alternatively, normal RBC had been treated with the oxidant H2O2, 5 mM, and thalassemic RBCs—with the anti-oxidant N-acetyl cysteine (NAC), 5 mM—thus increasing and decreasing oxidative stress, respectively. The cells were then analyzed by a flow cytometer (FACS-caliburR; Becton-Dickinson, Immunofluorometry systems, Mountain View, CA, USA). The average (mean fluorescence channel) cellular green fluorescence (FL-1), reversely indicating the AOC, of 40,000 HL60 cells, was determined. In the analysis, RBC were excluded from HL60 cells by gating based on forward - and side-light scatter and fluorescence. The results indicate that the AOC of thalassemia RBC was significantly lower than that of normal RBC, and that iron and oxidants further decreased it, but it could be restored by iron chelation or antioxidants.
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4.2 RBC as oxidants
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Oxidative stress, being a common feature of many diseases, affects most cells of the body, including the RBC. These diseases involve RBC directly (e.g., thalassemia) or indirectly (e.g., diabetes) [27]. We have shown oxidative stress in RBC in all the hemolytic anemias [15]. Oxidative stress in RBC diminishing their own AOC, resulting in their short survival, but also reduces their ability to protect other cells. Under extreme conditions, this situation may turn the RBC into oxidative agents, rather than antioxidative agents.
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4.3 Probable mechanisms involved in redox protection of RBC
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Using artificial vesicles, it has been shown that while hydrogen peroxide readily crosses biological membranes, superoxide does it very slowly [28]. Vesicles made of RBC membranes allow superoxide to cross through and oxidize cytochrome c in the suspending medium within a time-frame consistent with its half-life time [29]. This transfer probably occurs via an anion channel since it was inhibited by stilbenes, which inhibit the exchange of anions across the membrane. Whether such outward flux actually occurs in intact RBC is doubtful. Since RBC contain a large amount of SOD [30], it seems unlikely that superoxide made within the RBC would escape both the spontaneous and enzymatic dismutations and diffuse across the membrane. In contrast, an inward flux could occur. The plasma contains comparatively little SOD [31], and superoxides generated outside the RBC might diffuse inward to be scavenged by the RBC-SOD. In this fashion, RBC might limit the damage inflicted by superoxides produced by blood phagocytes and vascular endothelial cells.
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Similarly, RBC provide a mechanism for inactivation of free NO [32]. NO liberated from endothelium may be taken up by RBC and inactivated by oxyHb that in turn is converted to metHb, while the NO is converted to nitrate to be secreted by the kidneys.
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Another RBC redox protective mechanism involves ascorbic acid (AA) (vitamin C) [33]. In humans, AA dietary intake is essential for maintaining plasma and tissue reductive capacity. It primarily functions to scavenge superoxide anion and singlet oxygen, but it also removes other ROS generated by protein-bound redox metals and xanthine oxidase. AA itself is oxidized to an AA radical and dehydro AA. Human RBC were suggested to possess a two-layered system of redox recycling of low concentrations of the AA radical under minimal oxidative stress and a backup system of recycling of large quantities of dehydro AA under increased oxidative stress. RBC accumulation of dehydro AA as a result of prooxidative conditions originates in part outside of the RBC during the two-electron oxidation of AA, which is subsequently transported reversibly in competition with glucose by the type 1 glucose transporters spanning the RBC membrane. Alternatively, dehydro AA may be lost altogether by degradation, removing a pool of potentially reversible oxidized AA. Experimental evidence suggests that recycling of AA by the RBC significantly add to the AOC of the blood [34].
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Still another potential RBC redox protective mechanism is through the release of antioxidants and antioxidative enzymes (e.g., SOD and catalase) following hemolysis. We have found that hemolysate inhibits ROS generation by cells (unpublished observation). This could also occur following shedding of membrane-bound vesicles during the maturation of erythroid precursors in the bone marrow and senescence of RBC in the circulation. Both processes are enhanced in hemolytic anemias by oxidative stress [35].
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Except for direct effects, RBC may affect other cells indirectly. For example, diet-derived antioxidant polyamines tend to attach to RBC membranes, resulting in a synergistic enhancement of their antioxidative activity [36].
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5. Pathological significance of RBC as redox modulators
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The redox-modulating activity of RBC could affect cells and their function throughout the body. We have studied their effect on platelets. Hemolytic anemia, such as thalassemia, is often associated with high incidence of thromboembolic complications (e.g., venous thrombosis and stroke) due to platelet hyperactivation and plasma hypercoagulation [37]. Platelet functioning depends on their redox state. They have an inherent ability to produce ROS by various pathways—as a by-product of the mitochondrial respiratory chain [38] and by the NADH/NADPH oxidase [for a review see [39]] produced mainly in the pentose cycle [40]. ROS, along with NO, adenosine, and prostacyclins, may play a profound role in the regulation of platelet activities [41]. Many studies demonstrated that their functioning during clot formation involves ROS; for example, platelet activators, such as thrombin, increase ROS generation [42, 43, 44].
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Oxidative stress in platelets may give rise to two pathological outcomes: (I) toxicity, resulting in thrombocytopenia and bleeding and (II) hyperactivation resulting in excess clot formation leading to thromboembolic complications. Exemplifying the latter is hydrogen peroxide that stimulates their oxidative stress [45], and affects their various functions: activation by: (I) arachidonic acid and collagen [46]; (II) thrombin and ADP [47, 48, 49]; (III) tyrosine phosphorylation of the platelet αIIbβ3, an independent platelet activation pathway, thereby enhancing their aggregation [50], as well as (IV) through scavenging of the platelet- or endothelium-derived NO—thereby decreasing its aggregation-inhibiting effect [51]. Superoxide can also contribute to late clot growth by increasing the bioavailability of ADP and subsequently recruiting additional platelets [49].
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Since platelets do not carry known specific inherent redox pathology, it is reasonable to attribute their oxidative stress, at least in part, to continuous exposure to oxidative insults from extra platelet sources, such as their environment, i.e., the blood plasma, and neighboring cells - blood cells and the vascular endothelium. We have shown that incubation of normal platelets with plasma from thalassemia patients, rather than with normal plasma, resulted in their oxidative stress and activation [52]. Potential plasma oxidants are iron-containing compounds such as non-transferrin-bound iron, ferritin, heme, or Hb, all of which are increased in thalassemia patients [47, 53]. Incubation of platelets with iron (ferric ammonium citrate), heme (hemin or heme arginate), or Hb stimulated their oxidative stress. Moreover, addition of the iron-chelator deferoxamine to thalassemic plasma reduced its effect on the platelets’ ROS [52].
\n
Interestingly, thalassemic RBC also increased normal platelet oxidative status. In contrast, normal RBC, unless treated with oxidants, decreased it [54]. These results suggest that thalassemic RBC, having a higher than normal ROS level, mediate oxidative stress in platelets directly, probably by contact or close proximity [25]. These results are compatible with studies showing that platelets could be activated by ROS generated by neighboring cells such as RBC, neutrophils [55, 56], fibroblasts, and vascular endothelial and smooth muscle cells [39].
\n
RBC might also affect platelets indirectly by a variety of mechanisms: (I) Release of iron-containing oxidants into the plasma [46, 57, 58], as mentioned above. (II) Release of ROS, e.g., superoxide anions, causing oxidation of low-density lipoprotein [59], which, in turn, might activate platelets [60]. (III) Exposure or shedding of phosphatidylserine moieties, which act as a procoagulant that amplifies the generation of thrombin and thus initiates platelet activation [61]. Thalassemic RBC have been shown to carry and shed higher than normal levels of external phosphatidylserine [35].
\n
Other important function of the RBC-AOC is to scavenge and detoxify NO, an important vasodilating agent. released from the vascular endothelial cells [32] and by inflamed tissues [62].
\n
The role of RBC as redox modulators can be compromised under pathological conditions: when their number decrease (anemia) and when their AOC is defective, both of which may co-exist in many diseases. Anemia may elevate oxidative stress by reducing the oxygen availability (hypoxia) to tissue cells and by reducing the AOC of the RBC.
\n
Various therapeutic modalities may be used to correct anemia:
Iron supplementation in the case of deficiency.
Administration of erythropoiesis-stimulating agents such as erythropoietin (EPO) in cases of reduced erythropoiesis. This includes patients with chronic kidney disease where there is insufficient EPO production due to renal dysfunction, patients with malignancies during the course of chemotherapy, and patients with myelodysplastic syndrome. In most of these cases, the treatment comprises both EPO and iron supplementation.
Blood transfusion is used in the event of acute, severe, hemorrhage, or in chronic hemolysis. An example of the latter is β-thalassemia major where patients are transfused with packed RBC every 3 weeks for their entire life.
\n
Both transfusions and EPO have been used pre- and post-major operative procedures that are associated with severe blood loss.
\n
All these therapeutic procedures, on one hand, increase the RBC mass and thereby, supposedly, its AOC. On the other hand, iron supplementation and transfusions might increase the iron load leading to oxidative stress in cells, including RBC, thus compromising their AOC. For example, multi-transfused thalassemic patients, with less severe anemia but higher iron overload, have lower levels of oxidative stress (ROS and lipid hydroperoxides) than un-transfused patients, with more severe anemia but lower iron overload [63]. In cardiovascular diseases, although there is ample clinical evidence for the worsening effect of anemia, RBC transfusions or EPO administration were not always effective [64, 65, 66]. As for EPO, it has been demonstrated to have an antioxidative effect on various cells, including RBC [67], and thereby might increase their AOC. The net effect of anemia and iron overload on oxidative stress warrants a careful study in transfused and non-transfused patients and favors continuous monitoring of the status of iron and oxidative stress during these treatments. This complex relationship is graphically summarized in Figure 2.
\n
Figure 2.
The relationship among anemia, its treatment and RBC antioxidative capacity on oxidative stress. Upward red arrows indicate an increase; the downward blue arrows indicate a decrease.
\n
Some therapeutic protocols are used to reduce the RBC mass (hematocrit). Bloodletting (phlebotomy) is used in cases of polycythemia (erythrocytosis), either primary (polycythemia vera), familiar, or secondary [68], as well as hereditary hemochromatosis—an inheritable disease characterized by iron overload [69]. The benefit of this treatment with respect to decreasing the iron load should be weighed against its potential reducing effect of the RBC-AOC.
\n
\n
\n
6. RBC as redox bioindicators
\n
The oxidative state of RBC depends on intra-RBC factors such as enzymopahtology (e.g., G6PD deficiency), Hb instability (thalassemia and sickle cell disease), membrane pathology (hereditary spherocytosis), glucose metabolism [diabetes [27]], or extra-RBC factors such as in inflammation. Their oxidative state, in turn, may affect their AOC. It was suggested that RBC could be used as bioindicators of prognostic value in clinical practice [19]. They may provide a real-time monitoring of their own conditions as well as those in other parts of the body. This is potentially relevant to RBC-linked and unlinked pathologic conditions associated with oxidative stress.
\n
\n
\n
6.1 Measurement of the redox status in RBC
\n
Measurement of redox parameters in cells and in body fluids, such as the blood plasma, can be accomplished by various methods [3]. These measurements, however, are not a common practice in the clinic mainly because the methodologies are inadequate for the routine clinical laboratory. We have measured redox parameters [54, 70], including the labile iron pool [71], in RBC by flow cytometry, a common methodology in the clinical setting. Various fluorescent probes have been used. For example, ROS were measured by 2′7′-dichlorodihydrofluorescindiacetate, [72]. Following free diffusion into cells, this nonfluorescent compound is esterified and gets trapped intracellularly as 2′7′-dichlorodihydrofluorescein. ROS, mainly peroxides, oxidize it to the fluorescent derivative 2′7′-dichlorodihydrofluorescein that its cellular fluorescence is proportional to ROS generation [72].
\n
Several points should be considered using this method: (I) Since ROS are short-lived, analyses should be performed on fresh samples. (II) The probes used are not specific to a particular ROS—a limitation that does not limit the assessment of general oxidative stress. (III) The intracellular probe content depends on the experimental settings: the concentration of probe added to the composition of the medium and the incubation conditions, such as the temperature. However, it also depends on the cellular uptake of the probe and its esterification, which depends on the different properties of cells (e.g., activated vs. inactivated, pathological vs. normal). To overcome these caveats, we have modified the protocol: Cells were pulsed with the probe, washed, and then re-incubated in probe-free medium. The kinetics of ROS generation was determined by measuring the cellular fluorescence at different times.
\n
The method was validated by determining the effect on RBC fluorescence of the ROS-generating agent peroxide, the catalase inhibitor sodium azide, and the ROS scavenger N-acetyl cysteine. When normal RBC were compared with RBC from β-thalassemia patients, both the basal fluorescence and its kinetics were higher in the latter, confirming that thalassemic RBC were under oxidative stress.
\n
\n
\n
7. Conclusions
\n
The redox state is crucial for physiological functioning of cells, but excess reactive oxygen and nitrogen species causes oxidative stress, which is associated with many diseases, including hemolytic anemia. These anemias are characterized by accelerated destruction (hemolysis) of mature RBC and their precursors that is not balanced by compensatory overproduction. Although oxidative stress is not the primary etiology of most of these anemias, it mediates many of their symptoms. The main function of RBC is oxygen transport, for which they have evolved efficient nonenzymatic and enzymatic antioxidative systems for protection against oxidizing substances to which they are exposed. These systems serve mainly the RBC requirements, but may influence other neighboring cells as well, making the RBC antioxidative protective agents of the cellular and intracellular milieus throughout the body. Their vast number, mobility, occurrence throughout the body and renewability make them good candidates for this function. A decrease in their number (anemia) or function may exacerbate the symptoms of many diseases, including hemolytic anemias, by failing to neutralize oxidative stress. However, correcting anemia, e.g., by repeated RBC transfusions or iron supplementation, may increase the iron load, which, in turn, causes oxidative stress. This situation suggests that the status of both iron and redox should be monitored during treatment, using RBC as bioindicators and using flow cytometry multiparameter analysis.
\n
\n
Conflict of interest
The authors have no conflict of interests.
\n',keywords:"red blood cells, hemolytic anemia, thalassemia, oxidative stress, flow cytometry",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65673.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65673.xml",downloadPdfUrl:"/chapter/pdf-download/65673",previewPdfUrl:"/chapter/pdf-preview/65673",totalDownloads:1088,totalViews:0,totalCrossrefCites:2,dateSubmitted:"October 15th 2018",dateReviewed:"January 17th 2019",datePrePublished:"March 1st 2019",datePublished:"October 23rd 2019",dateFinished:"February 14th 2019",readingETA:"0",abstract:"The oxidative status of cells, representing the balance between prooxidants and antioxidants, is involved in their normal physiological functioning, such as signal transduction, proliferation, and differentiation. When the prooxidant activity overrides the antioxidative capacity oxidative stress occurs. Chronic oxidative stress causes cytotoxicity and organ failure. As such, it is believed to play a role in various pathologies, including the hemolytic anemias. In this review, we suggest that red blood cells (RBC), in addition to their primary role as oxygen carriers, function as redox modulators. In the RBC, various systems afford it with antioxidative capacity that, in addition to balancing its own redox state, can provide antioxidative protection to the cellular and intracellular milieus throughout the body. Their vast number, mobility, occurrence throughout the body, and renewability make them good candidates for this function. A decrease in their number (anemia) or function due to oxidative stress may exacerbate the symptoms of many diseases by failing to neutralize oxidative stress. However, correcting anemia, e.g., by repeated RBC transfusions or iron supplementation, may increase the iron load, which, in turn, causes oxidative stress. This situation suggests that the status of both iron and redox should be monitored during treatment, using RBC as bioindicators.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65673",risUrl:"/chapter/ris/65673",signatures:"Eitan Fibach and Mutaz Dana",book:{id:"7181",type:"book",title:"Erythrocyte",subtitle:null,fullTitle:"Erythrocyte",slug:"erythrocyte",publishedDate:"October 23rd 2019",bookSignature:"Anil Tombak",coverURL:"https://cdn.intechopen.com/books/images_new/7181.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78984-210-4",printIsbn:"978-1-78984-209-8",pdfIsbn:"978-1-78984-693-5",isAvailableForWebshopOrdering:!0,editors:[{id:"202814",title:"Associate Prof.",name:"Anil",middleName:null,surname:"Tombak",slug:"anil-tombak",fullName:"Anil Tombak"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"83134",title:"Prof.",name:"Eitan",middleName:null,surname:"Fibach",fullName:"Eitan Fibach",slug:"eitan-fibach",email:"Fibach@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Hadassah Medical Center",institutionURL:null,country:{name:"Israel"}}},{id:"280928",title:"Dr.",name:"Mutaz",middleName:null,surname:"Dana",fullName:"Mutaz Dana",slug:"mutaz-dana",email:"mutazmt@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Oxidative stress and its involvement in pathology",level:"1"},{id:"sec_3",title:"3. Hemolytic anemia",level:"1"},{id:"sec_4",title:"4. RBC as redox modulators",level:"1"},{id:"sec_4_2",title:"4.1 Proofs of the concept",level:"2"},{id:"sec_5_2",title:"4.2 RBC as oxidants",level:"2"},{id:"sec_6_2",title:"4.3 Probable mechanisms involved in redox protection of RBC",level:"2"},{id:"sec_8",title:"5. Pathological significance of RBC as redox modulators",level:"1"},{id:"sec_9",title:"6. RBC as redox bioindicators",level:"1"},{id:"sec_10",title:"6.1 Measurement of the redox status in RBC",level:"1"},{id:"sec_11",title:"7. Conclusions",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Halliwell B, Gutteridge J. Free Radicals in Biology and Medicine. 3rd ed. Midsomer Norton, Avon, England: Oxford University Press; 1999\n'},{id:"B2",body:'Rifkind JM, Nagababu E, Ramasamy S, Ravi LB. 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Department of Hematology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
Department of Hematology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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A Systematic Review of Microdialysis Studies",slug:"potential-muscle-biomarkers-of-chronic-myalgia-in-humans-a-systematic-review-of-microdialysis-studie",totalDownloads:1928,totalCrossrefCites:8,totalDimensionsCites:16,abstract:null,book:{id:"1959",slug:"biomarker",title:"Biomarker",fullTitle:"Biomarker"},signatures:"Björn Gerdle and Britt Larsson",authors:[{id:"119711",title:"Prof.",name:"Bjorn",middleName:null,surname:"Gerdle",slug:"bjorn-gerdle",fullName:"Bjorn Gerdle"},{id:"138423",title:"Prof.",name:"Britt",middleName:null,surname:"Larsson",slug:"britt-larsson",fullName:"Britt Larsson"}]},{id:"36394",doi:"10.5772/36750",title:"8-Nitroguanine, a Potential Biomarker to Evaluate the Risk of Inflammation-Related Carcinogenesis",slug:"8-nitroguanine-a-potential-biomarker-to-evaluate-the-risk-of-inflammation-related-carcinogenesis",totalDownloads:2242,totalCrossrefCites:2,totalDimensionsCites:8,abstract:null,book:{id:"1959",slug:"biomarker",title:"Biomarker",fullTitle:"Biomarker"},signatures:"Ning Ma, Mariko Murata, Shiho Ohnishi, Raynoo Thanan, Yusuke Hiraku and Shosuke Kawanishi",authors:[{id:"71918",title:"Dr.",name:"Yusuke",middleName:null,surname:"Hiraku",slug:"yusuke-hiraku",fullName:"Yusuke Hiraku"},{id:"109629",title:"Prof.",name:"Ning",middleName:null,surname:"Ma",slug:"ning-ma",fullName:"Ning Ma"},{id:"120432",title:"Dr.",name:"Shiho",middleName:null,surname:"Ohnishi",slug:"shiho-ohnishi",fullName:"Shiho Ohnishi"},{id:"120433",title:"Prof.",name:"Mariko",middleName:null,surname:"Murata",slug:"mariko-murata",fullName:"Mariko Murata"},{id:"120434",title:"Prof.",name:"Shosuke",middleName:null,surname:"Kawanishi",slug:"shosuke-kawanishi",fullName:"Shosuke Kawanishi"},{id:"121961",title:"Dr.",name:"Raynoo",middleName:null,surname:"Thanan",slug:"raynoo-thanan",fullName:"Raynoo Thanan"}]},{id:"36386",doi:"10.5772/38754",title:"Epigenetics in Cancer: The Myelodysplastic Syndrome as a Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers",slug:"epigenetics-in-cancer-the-myelodysplastic-syndrome-as-a-model-to-study-epigenetic-alterations-as-dia",totalDownloads:2463,totalCrossrefCites:0,totalDimensionsCites:4,abstract:null,book:{id:"1959",slug:"biomarker",title:"Biomarker",fullTitle:"Biomarker"},signatures:"Teresa de Souza Fernandez, André Mencalha and Cecília de Souza Fernandez",authors:[{id:"119189",title:"Dr.",name:"Teresa",middleName:null,surname:"De Souza Fernandez",slug:"teresa-de-souza-fernandez",fullName:"Teresa De Souza Fernandez"},{id:"119870",title:"Dr.",name:"André",middleName:null,surname:"Mencalha",slug:"andre-mencalha",fullName:"André Mencalha"},{id:"119871",title:"Prof.",name:"Cecilia",middleName:null,surname:"De Souza Fernandez",slug:"cecilia-de-souza-fernandez",fullName:"Cecilia De Souza Fernandez"}]},{id:"66416",doi:"10.5772/intechopen.84722",title:"Salivary Diagnostics",slug:"salivary-diagnostics-1",totalDownloads:1028,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Saliva is one of the most ideal diagnostic tools. It is inexpensive, noninvasive, and easy to use. Other advantages like ease of collection and minimal patient discomfort make it more acceptable to the patient as well as the clinician. The most challenging aspect in salivary diagnostics is to identify the biomarker that is linked to a disease. Researches are also ongoing to develop a device that can have reliable and valid clinical applications. This chapter briefly discusses the background and current scope of salivary diagnostics, technologies for the discovery of biomarkers along with a summary of salivary sample collection, and processing methods.",book:{id:"7905",slug:"saliva-and-salivary-diagnostics",title:"Saliva and Salivary Diagnostics",fullTitle:"Saliva and Salivary Diagnostics"},signatures:"Varsha Pathiyil and Rahul Udayasankar",authors:[{id:"281226",title:"Dr.",name:"Varsha",middleName:null,surname:"Pathiyil",slug:"varsha-pathiyil",fullName:"Varsha Pathiyil"},{id:"290603",title:"Dr.",name:"Rahul",middleName:null,surname:"Udayasankar",slug:"rahul-udayasankar",fullName:"Rahul Udayasankar"}]},{id:"36392",doi:"10.5772/36793",title:"Biomarkers and Therapeutic Drug Monitoring in Psychiatry",slug:"biomarkers-and-therapeutic-drug-monitoring-in-psychiatry",totalDownloads:1947,totalCrossrefCites:1,totalDimensionsCites:4,abstract:null,book:{id:"1959",slug:"biomarker",title:"Biomarker",fullTitle:"Biomarker"},signatures:"R. Lozano, R. Marin, A. Pascual, MJ. Santacruz, A. Lozano and F. Sebastian",authors:[{id:"109838",title:"Dr.",name:"Roberto",middleName:null,surname:"Lozano Ortiz",slug:"roberto-lozano-ortiz",fullName:"Roberto Lozano Ortiz"},{id:"115991",title:"Dr.",name:"Reyes",middleName:null,surname:"Marin",slug:"reyes-marin",fullName:"Reyes Marin"},{id:"115992",title:"Dr.",name:"Asuncion",middleName:null,surname:"Pascual",slug:"asuncion-pascual",fullName:"Asuncion Pascual"},{id:"115993",title:"Ms.",name:"Francisca",middleName:null,surname:"Sebastian",slug:"francisca-sebastian",fullName:"Francisca Sebastian"},{id:"115994",title:"Ms.",name:"Maria Jesus",middleName:null,surname:"Santacruz",slug:"maria-jesus-santacruz",fullName:"Maria Jesus Santacruz"}]}],mostDownloadedChaptersLast30Days:[{id:"72837",title:"The Na/K-ATPase Signaling Regulates Natriuresis in Renal Proximal Tubule",slug:"the-na-k-atpase-signaling-regulates-natriuresis-in-renal-proximal-tubule",totalDownloads:516,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"For decades, the Na/K-ATPase has been proposed and recognized as one of the targets for the regulation of renal salt handling. While direct inhibition of the Na/K-ATPase ion transport activity and sodium reabsorption was the focus, the underlying mechanism is not well understood since decreases in basolateral Na/K-ATPase activity alone do not appear sufficient to decrease net sodium reabsorption across the renal tubular epithelium. The newly appreciated signaling function of Na/K-ATPase, which can be regulated by Na/K-ATPase ligands (cardiotonic steroids (CTS)) and reactive oxygen species (ROS), has been widely confirmed and provides a mechanistic framework for natriuresis regulation in renal proximal tubule (RPT). The focus of this review aims to understand, in renal proximal tubule, how the activation of Na/K-ATPase signaling function, either by CTS or ROS, stimulates a coordinated reduction of cell surface Na/K-ATPase and sodium/hydrogen exchanger isoform 3 (NHE3) that leads to ultimately decreases in net transcellular sodium transport/reabsorption.",book:{id:"10119",slug:"biomarkers-and-bioanalysis-overview",title:"Biomarkers and Bioanalysis Overview",fullTitle:"Biomarkers and Bioanalysis Overview"},signatures:"Jiang Liu, Yanling Yan and Joseph I. Shapiro",authors:[{id:"69199",title:"Dr.",name:"Joseph",middleName:"Isaac",surname:"Shapiro",slug:"joseph-shapiro",fullName:"Joseph Shapiro"},{id:"313470",title:"Associate Prof.",name:"Jiang",middleName:null,surname:"Liu",slug:"jiang-liu",fullName:"Jiang Liu"},{id:"314323",title:"Dr.",name:"Yanling",middleName:null,surname:"Yan",slug:"yanling-yan",fullName:"Yanling Yan"}]},{id:"66233",title:"Functions of Saliva",slug:"functions-of-saliva",totalDownloads:2e3,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Saliva is produced and secreted by salivary glands. The basic secretary units of salivary glands are clusters of acini cells. It is fluid that contains water, electrolytes, mucus, and enzymes, all of which flow out of the acinus into collecting ducts, certainly one of the most important components and an integral component to oral health. The protective role and benefits including buffering, remineralization in the healthy oral mucosa, immune defense, digestion, lubrication, diagnostic purpose, and proteome analysis are fulfilled by saliva. It aids in maintaining mucosal integrity and indigestion through salivary enzymes. The functions of saliva in maintaining oral health and the main factors that cause alterations in salivary secretion and the importance of saliva in caries development and bacterial plaque formation are discussed, and also its role and functions and organic and inorganic constituents in saliva are discussed. This is of great importance in ruminants, which have non-secretory forestomachs. Diseases of the salivary glands and ducts are not uncommon in animals and man, and excessive salivation is a symptom of almost any lesions in the oral cavity.",book:{id:"7905",slug:"saliva-and-salivary-diagnostics",title:"Saliva and Salivary Diagnostics",fullTitle:"Saliva and Salivary Diagnostics"},signatures:"Narendra Maddu",authors:[{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu"}]},{id:"67237",title:"Advantages of Salivary DNA in Human Identification",slug:"advantages-of-salivary-dna-in-human-identification",totalDownloads:785,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Since two and a half decades, in human identification, the short tandem repeat (STR) markers represent the “gold standard.” Besides them, haploid markers such as X-STR and Y-STR are also used to complement the autosomal markers. In human identification, DNA from body fluids, especially saliva, represents an important tool. The aim of this chapter is to present the importance of analyzing X-STR markers in a relatedness case between a sister and her presumptive brother, a carbonized victim using body fluids for their DNA identification. Our laboratory had to establish the relatedness between a woman and her presumptive brother (PB), who was the victim of a car accident explosion. In this case, as reference sample we used saliva collected on swabs from the woman and blood sample from the deceased victim. For the DNA extraction, DNA IQ Casework (Promega, USA) was used. DNA quantification was done with PowerQuant System kit (Promega, USA). Furthermore, the DNA samples were amplified with Investigator 24plex QS (Qiagen, Germany) for the STR markers and Investigator Argus 12-X QS kit (Qiagen, Germany) for the X-STR markers. The amplified DNA products were separated by capillary electrophoresis on a 3500 Genetic Analyzer. In this case, full genetic profiles were obtained for the woman and her presumptive brother on both STR and X-STR markers. Thus, we could confirm a full sibling relationship between them. Since the introduction of DNA in human identification, it represents a useful tool in establishing sibling relationship from different biological samples.",book:{id:"7905",slug:"saliva-and-salivary-diagnostics",title:"Saliva and Salivary Diagnostics",fullTitle:"Saliva and Salivary Diagnostics"},signatures:"Raluca Dumache, Veronica Ciocan, Camelia Muresan, Ramona Parvanescu and Alexandra Enache",authors:[{id:"179199",title:"Dr.",name:"Raluca",middleName:null,surname:"Dumache",slug:"raluca-dumache",fullName:"Raluca Dumache"},{id:"181860",title:"Prof.",name:"Alexandra",middleName:null,surname:"Enache",slug:"alexandra-enache",fullName:"Alexandra Enache"},{id:"195502",title:"Dr.",name:"Veronica",middleName:null,surname:"Ciocan",slug:"veronica-ciocan",fullName:"Veronica Ciocan"},{id:"298285",title:"Dr.",name:"Camelia",middleName:null,surname:"Muresan",slug:"camelia-muresan",fullName:"Camelia Muresan"},{id:"298644",title:"Dr.",name:"Ramona",middleName:null,surname:"Parvanescu",slug:"ramona-parvanescu",fullName:"Ramona Parvanescu"}]},{id:"67299",title:"Salivary Diagnostics in Oral Diseases",slug:"salivary-diagnostics-in-oral-diseases",totalDownloads:1123,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Common oral diseases like dental caries, periodontal diseases and oral cancer have major impact on quality of life. For prevention, treatment and prognosis, it is essential to measure the disease objectively and accurately in a quantitative manner. Quantification of biochemical or molecular specific products of cancers in serum or localized body juices can be one of the current methods of measuring oral diseases objectively. Salivary diagnostics has influenced several researchers and has been verified as an important tool in the diagnosis of many systemic conditions and prognosis of the disease. Developments in the field of molecular biology, salivary genomics and proteomics have directed to the detection of novel molecular markers for oral disease diagnosis, therapeutics and prognosis.",book:{id:"7905",slug:"saliva-and-salivary-diagnostics",title:"Saliva and Salivary Diagnostics",fullTitle:"Saliva and Salivary Diagnostics"},signatures:"Manohar Bhat and Devikripa Bhat",authors:[{id:"280750",title:"Dr.",name:"Manohara",middleName:null,surname:"Bhat",slug:"manohara-bhat",fullName:"Manohara Bhat"},{id:"296530",title:"Dr.",name:"Devikripa",middleName:null,surname:"Bhat",slug:"devikripa-bhat",fullName:"Devikripa Bhat"}]},{id:"80105",title:"Diagnosis of Amyloidosis: From History to Current Tools",slug:"diagnosis-of-amyloidosis-from-history-to-current-tools",totalDownloads:91,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The term amyloid encompasses a large variety of misfolded proteins with varying amino acids unified by the antiparallel beta-pleated sheet configuration and characteristic Congo red staining. The etiology of these proteins is equally varied, ranging from neoplastic plasma cell disorder, hereditary causes to inflammatory disorders. The protean clinical manifestation makes a high index of clinical suspicion the first crucial step in the diagnosis. A battery of investigations needs to be carried out for a complete diagnosis of amyloidosis and its underlying etiology. Biopsy with Congo red staining constitutes the most important modality for confirmation of amyloid. For further testing, varying modalities with increasing complexity, such as immunohistochemistry, electron microscopy, and mass spectrometry, need to be employed. We discuss, in the course of the current chapter, this fascinating protein from a clinical diagnosis perspective. The requisite investigations are also discussed in detail.",book:{id:"9046",slug:"amyloidosis-history-and-perspectives",title:"Amyloidosis",fullTitle:"Amyloidosis - History and Perspectives"},signatures:"Richa Juneja, Prasad Dange and Rahul Arora",authors:[{id:"437940",title:"Dr.",name:"Richa",middleName:null,surname:"Juneja",slug:"richa-juneja",fullName:"Richa Juneja"},{id:"437941",title:"Dr.",name:"Prasad",middleName:null,surname:"Dange",slug:"prasad-dange",fullName:"Prasad Dange"},{id:"443471",title:"Dr.",name:"Rahul",middleName:null,surname:"Arora",slug:"rahul-arora",fullName:"Rahul Arora"}]}],onlineFirstChaptersFilter:{topicId:"1005",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. 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Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. She holds a Ph.D. from the University of Oulu, Finland.',institutionString:"Swedish Association for Distance Education, Sweden",institution:null},editorTwo:null,editorThree:null},{id:"94",title:"Climate Change and Environmental Sustainability",coverUrl:"https://cdn.intechopen.com/series_topics/covers/94.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"95",title:"Urban Planning and Environmental Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/95.jpg",isOpenForSubmission:!0,annualVolume:11979,editor:{id:"181079",title:"Dr.",name:"Christoph",middleName:null,surname:"Lüthi",slug:"christoph-luthi",fullName:"Christoph Lüthi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHSqQAO/Profile_Picture_2022-04-12T15:51:33.png",biography:"Dr. Christoph Lüthi is an urban infrastructure planner with over 25 years of experience in planning and design of urban infrastructure in middle and low-income countries. He holds a Master’s Degree in Urban Development Planning from the University College of London (UCL), and a Ph.D. in Urban Planning & Engineering from TU Berlin. He has conducted applied research on urban planning and infrastructure issues in over 20 countries in Africa and Asia. In 2005 he joined Eawag-Sandec as Leader of the Strategic Environmental Sanitation Planning Group. Since 2015 he heads the research department Sanitation, Water and Solid Waste for Development (Sandec) at the Swiss Federal Institute of Aquatic Research and Technology (Eawag).",institutionString:"Swiss Federal Institute of Aquatic Science and Technology, Switzerland",institution:null},editorTwo:{id:"290571",title:"Dr.",name:"Rui Alexandre",middleName:null,surname:"Castanho",slug:"rui-alexandre-castanho",fullName:"Rui Alexandre Castanho",profilePictureURL:"https://mts.intechopen.com/storage/users/290571/images/system/290571.jpg",biography:"Rui Alexandre Castanho has a master\\'s degree in Planning, Audit, and Control in Urban Green Spaces and an international Ph.D. in Sustainable Planning in Borderlands. Currently, he is a professor at WSB University, Poland, and a visiting professor at the University of Johannesburg, South Africa. Dr. Castanho is a post-doc researcher on the GREAT Project, University of Azores, Ponta Delgada, Portugal. He collaborates with the Environmental Resources Analysis Research Group (ARAM), University of Extremadura (UEx), Spain; VALORIZA - Research Center for the Enhancement of Endogenous Resources, Polytechnic Institute of Portalegre (IPP), Portugal; Centre for Tourism Research, Development and Innovation (CITUR), Madeira, Portugal; and AQUAGEO Research Group, University of Campinas (UNICAMP), Brazil.",institutionString:"University of Johannesburg, South Africa and WSB University, Poland",institution:{name:"University of Johannesburg",institutionURL:null,country:{name:"South Africa"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"10843",title:"Persistent Organic Pollutants (POPs)",subtitle:"Monitoring, Impact and Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10843.jpg",slug:"persistent-organic-pollutants-pops-monitoring-impact-and-treatment",publishedDate:"April 13th 2022",editedByType:"Edited by",bookSignature:"Mohamed Nageeb Rashed",hash:"f5b1589f0a990b6114fef2dadc735dd9",volumeInSeries:1,fullTitle:"Persistent Organic Pollutants (POPs) - Monitoring, Impact and Treatment",editors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",biography:"Prof. Mohamed Nageeb Rashed is Professor of Analytical and Environmental Chemistry and former vice-dean for environmental affairs, Faculty of Science, Aswan University, Egypt. He received his Ph.D. in Environmental Analytical Chemistry from Assiut University, Egypt, in 1989. His research interest is in analytical and environmental chemistry with special emphasis on: (1) monitoring and assessing biological trace elements and toxic metals in human blood, urine, water, crops, vegetables, and medicinal plants; (2) relationships between environmental heavy metals and human diseases; (3) uses of biological indicators for monitoring water pollution; (4) environmental chemistry of lakes, rivers, and well water; (5) water and wastewater treatment by adsorption and photocatalysis techniques; (6) soil and water pollution monitoring, control, and treatment; and (7) advanced oxidation treatment. Prof. Rashed has supervised several MSc and Ph.D. theses in the field of analytical and environmental chemistry. He served as an examiner for several Ph.D. theses in analytical chemistry in India, Kazakhstan, and Botswana. He has published about ninety scientific papers in peer-reviewed international journals and several papers in national and international conferences. He participated as an invited speaker at thirty international conferences. Prof. Rashed is the editor-in-chief and an editorial board member for several international journals in the fields of chemistry and environment. He is a member of several national and international societies. He received the Egyptian State Award for Environmental Research in 2001 and the Aswan University Merit Award for Basic Science in 2020. 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He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"18",type:"subseries",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",slug:"arli-aditya-parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",slug:"cesar-lopez-camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",slug:"shymaa-enany",fullName:"Shymaa Enany",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRqB9QAK/Profile_Picture_1626163237970",institutionString:null,institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]},onlineFirstChapters:{paginationCount:3,paginationItems:[{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"81188",title:"Structure- and Design-Based Difficulties in Recombinant Protein Purification in Bacterial Expression",doi:"10.5772/intechopen.103958",signatures:"Kubra Acikalin Coskun, Nazlıcan Yurekli, Elif Cansu Abay, Merve Tutar, Mervenur Al and Yusuf Tutar",slug:"structure-and-design-based-difficulties-in-recombinant-protein-purification-in-bacterial-expression",totalDownloads:24,totalCrossrefCites:0,totalDimensionsCites:0,authors:[{name:"Yusuf",surname:"Tutar"},{name:"Nazlican",surname:"Yurekli"},{name:"Merve",surname:"Tutar"},{name:"Mervenur",surname:"Al"},{name:"Elif Cansu",surname:"Abay"},{name:"Kubra",surname:"Acikalin Coskun"}],book:{title:"Protein Detection",coverURL:"https://cdn.intechopen.com/books/images_new/10839.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"79353",title:"Protein Detection in Clinical Diagnosis and Management of Prevalent Neurodegenerative Diseases and Metabolic Disorders",doi:"10.5772/intechopen.101051",signatures:"Ohanube A.K. 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