Classification system of solid forms as described by Wunderlich [51].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"447",leadTitle:null,fullTitle:"Electric Vehicles - Modelling and Simulations",title:"Electric Vehicles",subtitle:"Modelling and Simulations",reviewType:"peer-reviewed",abstract:"In this book, modeling and simulation of electric vehicles and their components have been emphasized chapter by chapter with valuable contribution of many researchers who work on both technical and regulatory sides of the field. 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His work in the Joint Research Center focused on fuels for internal combustion engines, exhaust emission measurement techniques for zero emission vehicles, portable emission measurement systems, and small engines. Dr. Soylu has also worked as independent expert for European Commission in the field of Energy and Transport to evaluate and review Framework Programme (6 & 7th) projects on behalf of the Commission. \nDr. Soylu is currently an Associate Professor of Sakarya University. 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Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52896",title:"X‐Ray Scattering Techniques Applied in the Development of Drug Delivery Systems",doi:"10.5772/65326",slug:"x-ray-scattering-techniques-applied-in-the-development-of-drug-delivery-systems",body:'\nThe term nanocarriers have been used to describe colloidal systems (emulsions, nanospheres, nanoparticles, nanocapsules, liposomes, and micelles) and other compounds such as natural, synthetic, organic, or inorganic materials (ceramic, bioglasses, organometallic compounds, carbon or peptide nanotubes etc.) with dimensions smaller than 500 nm for use as biomaterials, depots, implants, biosensors, vaccines, and biomarkers, in chromatography separation, diagnosis or imaging, and drug delivery systems (DDS) for bioactive compounds such as peptides, proteins, oligonucleotides, nucleic acids, etc., as shown in Figure 1. Those carrier systems can be formulated into various preparations including suspensions, emulsions, capsules, tablets, gels, creams, and ointments for parenteral, oral, or topical use [1].
\nExamples of several drug delivery systems [
The development of new biomaterials, drug delivery systems (DDS), and modified release pharmaceutical formulations have allowed the modulation of physicochemical and biopharmaceutical properties of the several molecules, enhancing their therapeutic effects and promoting their clinical use. The different drug carriers described in the literature presented results specifically for molecules with limited aqueous or lipid solubility, low bioavailability, low stability, and high local or systemic toxicity [21].
\nThe aim is the encapsulation of the bioactive molecule on a specific carrier destined to deliver it at a controlled rate over a prolonged period. The advantages of some DDS, such as nanoparticles, are their high circulation‐residence time and drug bioavailability with enhanced therapeutic efficiency.
\nDespite several studies that report the physicochemical and biological applications of these nanocarriers, few studies have presented a relationship between their applications and structural aspects. In this chapter, our aim is to describe the basic concepts about X‐ray scattering and its application for structural analysis of drug delivery systems.
\nThis chapter explains the basic concepts of X‐ray scattering and its applications in drug delivery systems. The basic equations for converting information obtained during the measurements in structural parameters of the object are also presented. We shall restrict ourselves to coherent and elastic small‐angle X‐ray scattering (SAXS), which is used in structural studies of soft condensed matter and in the X‐ray diffraction (XRD) technique.
\n\nAmong drug delivery systems (DDS), carriers such as liposomes, micelles, hydrogels, and several kinds of hybrid organic‐inorganic nanoparticles [22] can be found. For an effective or stable carrier, the colloidal size, which goes approximately from 1 nm to 1 µm, is an important criterion to select the delivery system that can permeate tissues, circulate with body fluids, or interact with cell membranes. Therefore, the structure is directly correlated with each function and the structural characterization of colloidal systems is in the range of the electron microscopy and X‐ray scattering. In this study, we are going to discuss about small angle X‐ray scattering (SAXS).
\nUnlike many other characterization techniques, the success of the SAXS study will highly depend on the prior knowledge available about the system. It means that one has to study thoroughly the sample preparation history, particle morphology, size distribution, aging stability, etc., before proposing SAXS method. The size distribution in the range of some hundreds of nm can be characterized by dynamic light scattering (DLS) [23] and the results can give a hint about agglomeration of the colloidal system that can favor polydispersity, which causes trouble in the resolution of the scattering signal in some cases. Mapping the aging stability is a crucial task in colloidal studies in order to have a fair referential for comparing a series of samples. Aging of colloidal systems can promote agglomeration or crystallization or even degradation and for each case, there will be a different scattering pattern. Morphology, studied using electron microscopy, prior to SAXS measurements, promotes an easier startup on the SAXS modeling and simulation. Fragile organic colloidal systems are better visualized through cryo‐TEM (transmission electron microscopy) or cryofracture microscopy [24]. It is also import to know about the surface electric charges of the particles, through Zeta potential measurements [25], prior to SAXS measurements in order to facilitate the understanding of the interaction among all the sample constituents, which helps to build the most likely model structure to simulate the scattering intensity.
\nThe SAXS technique is a nondestructive method and the experiment of scattering is relatively simple and fast. All the hard work will be charged on the treatment and analysis of the acquired data. Measurements taken for few days in a synchrotron lab will be enough for one whole year of analyzing data. Thus, the more you know about the system prior to the measurements, the more precise will be the experiment and the earlier you will be compensated by the information that can be determined through SAXS study.
\nThere are several good references for studying basic SAXS theory; the most popular is the book of Glatter and Kratky [26]. For amphiphilic systems, it is worth to check the article, also from Glatter, published in 1991 [27]; the work from Kratky on biological macromolecules, including some aspects from neutron scattering [28]; and more recent studies from our collaborators Trevisan et al. [29], showing the SAXS analysis for an example of modified liposomes after shearing preparation process, published in 2011; and the article of Oliveira et al. showing an efficient method to model and simulate SAXS intensity from unilamellar and multilamellar liposomes [30].
\nThe SAXS technique comes from the fact that X‐rays can interact with the electrons of the materials. When X‐rays strike any matter, part of the energy is absorbed or transmitted. However, the part of the energy that is interesting for this technique is the one that scatters elastically (conserving the original frequency) depending on the structure of the material. The word “scattering” is already explaining everything about the method: instead of passing through the material, some photons are deviated (scattered) after the interaction with the electrons. The angle between the original direction of the photons and the deviation is called the scattering angle. The structure dimensions of the colloids are in the very size limits of the SAXS technique. The bigger the scattering objects, the smaller will be the scattering angle; this is the reason for calling this technique “small angle” scattering in contrast with the “wide angle” scattering used to study atomic distances.
\nThe aim of the method is to study the scattering angle, or the scattering vector
After X‐rays strike the sample, the amplitude
where
which one can recognize as the Fourier transformation of the electronic density. The inverse Fourier transformation would yield the electronic density of the material, which is the very subject of the study. But the SAXS experiment provides only the intensity of the scattered wave, which is the square modulus of the amplitude of the wave:\n
Extracting the electronic density of the material from the intensity
On calculating the square modulus of the wave amplitude of Eq. (3), it could be understood that the expression of the intensity will be dependent not only on the electronic density of one point of the structure, but there will be a crossing term indicating that the intensity is the sum over the pair distance distribution function (PDDF) of the system, which expresses a contrast of the electronic density. This aspect is better explained with some examples of colloidal systems that naturally have this contrast of electronic density, for example, the contrast of electrons in proteins and the solution in which they are embedded; or liposomes and the buffer where they are dispersed; or even the contrast between the hydrogels and the pores that they form.
\nAs the interaction with electrons is the origin of the phenomenon, the more electrons the materials have, the higher will be the intensity of the SAXS signal. Organic molecules have low electronic density compared to inorganic materials, so the signal is weak and the experiment need high brilliance sources like synchrotron facilities or lab equipment with enhanced optics for the best performance.
\nThe routine of the experiment is as follows:
\nData acquirement: a sample is kept in front of the X-ray source and the scattering intensity at all angles is collected by a detector. Several facilities are prepared with special sample holders, environment conditions,
Data treatment: the scattering curve is recovered after data treatment which removes the background scattering caused by possible air gaps, windows, slits, or other parts of the instrumentation. Vacuum chambers are strategically placed to remove air gaps and light materials as beryllium, mica, and polymer films are used as windows to minimize spurious scattering.
\n\nModeling: from the results of complementary techniques the parameters such as particle size, interaction among compounds, crystallization, polydispersity, etc., will help to build a model for the scattering object. For example, one can take a vesicle as a core of water surrounded by lipid bilayers and this model is known as core‐shell structure. The size of the core and shell, as well as the shape of objects interacting with this core‐shell phase or the particles that can exist dissolved or crystallized in water, will all be a part of the model. There are several known models to start the approach of the scattering object, for instance, hard or hollow spheres, cylinders or other shapes, and also combined models for polydispersed systems. The scattering of these objects are called form factor scattering in contrast with structure factor, which is related to the periodicity of the shapes that can exist in some systems, for example, in multilayered liposomes.
\n(a) Laboratory SAXS equipment or Synchrotron SAXS beamline can be used to characterize drug delivery systems. (b) Sample holder pictures; (c) some results from poloxamer systems used as drug delivery systems obtained using the SAXS technique [
Simulation: after having a model one can calculate the scattering intensity of the model, which is easier if done by computing programs. There are several software tools on the market for SAXS analysis that offer ready‐to‐use form factors like the ones that we commented before: hard spheres, core‐shell, etc. Some software tools even offer possibilities to build your own form factor, considering more complex models.
\nFitting: the final step is to compare the simulated scattering intensity with the experimental data. If they fit together, this is the end of the process and one can assume that the chosen model is a reasonable structure supported by all experimental results, not only SAXS, but everything else that helped to build the model. If the simulation does not fit the experimental data, one can make adjustments on the model, make another simulation and compare again until it fits as good as they want.
\nIn the study of Brzustowicz and Brunger [32], they used a model of hard spheres to fit the dispersion of stearoyloleoyl phosphatidylserine (SOPS) micelles in buffer. This study used a monodisperse micelle sample with the main purpose to propose a different approach for analyzing lipid bilayer SAXS data. The graph of Figure 3 of that paper shows a perfect fitting between calculated and experimental data. The results were good to determine the size of the inner core of the liposome and the electronic density profile across the membrane.
\n\nA successful SAXS analysis was reported in the work of some collaborators Gasperini et al. [33] after Balbino et al. [34]. In both cases, a biopolymer was inserted in liposome dispersions, hyaluronic acid (HA), and DNA, respectively. The results indicate that there are similarities at low concentration of incorporation of polymer inside the liposome dispersion. The negatively charged polymers bonded together neighbor unilamellar cationic liposomes like an electrostatic plastic glue. At higher concentrations of polymer, one can observe distinct behavior for these two biopolymers: DNA succeeded to disrupt the lipid membrane promoting the organization of multilamellar liposomes; and HA was able to coat individual unilamellar liposomes stabilizing the dispersion.
\n\nThe SAXS analysis of these two studies, together with the results of the complementary techniques, was able to reveal all these details. For this, the liposome preparation was carefully controlled to have minimum polydispersity and the systems were studied strictly under the aging stability period. Several methods were used as complementary techniques such as DLS, zeta potential, TEM, cryo‐TEM, and chromatography to help build the structure model to calculate the simulated scattering to be compared to the SAXS experimental data. Reasoning aspects were considered to minimize fitting parameters to increase the reliability of the results.
\n\nFor other nanocarriers, such as thermosensitive poloxamer (or Pluronics® ‐PL)‐based micelles and hydrogels (see Figure 3), SAXS technique have presented important contributions for understanding the structural changes after the incorporation of drugs/carriers or the formation of systems composed of PL with different hydrophilic‐lipophilic balance (HLB).
\n\nSAXS studies have reported the formation of wormlike micelles for PL‐P84 [35]; the gelation mechanisms and micelle packing under hexagonal and body‐centered cubic phases for PL‐P85 and PL‐F88, respectively. However, for the PL‐F88/PL‐P85 mixture, the destabilization of the hexagonal phase after PL‐F88 addition [36], a PL with higher HLB (28) compared to PL‐P85 (16) was observed [37]. Other authors also reported SAXS analysis for PL‐based binary hydrogels (PL concentrations ranging from 20 to 30% m/v) with different HLB values, such as PL‐F127/PL‐F68 [38] and PL‐F127/PL‐L81 [39], being observed in the formation of a hexagonal phase at physiological temperature and their purpose as sumatriptan and ropivacaine delivery systems for application by infiltrative routes. However, for fluid systems (with PL concentrations lower than 18% m/v) the binary micelles composed of PL‐F127/PL‐L81 presented a lamellar phase structural organization, even after the incorporation of the drug chlorpromazine [40].
\nExample of successful SAXS analysis of a drug delivery system based on poloxamers (a) poloxamer without drug; (b) poloxamer with sumatriptane (SMT).
In fact, the drug incorporation of PL‐based systems, studied by SAXS, has been highlighted in the literature. In a recent work, Avachat and Parpani [41] described the formulation of liquid crystal nanoparticles for efavirenz oral delivery. The study showed the formation of cubossomes after the incorporation of PL‐F127 and phytantriol, a cosmetic ingredient. Chen et al. [42] studied the acetaminophen and bifonazole crystallization mechanism within polyethylene glycol (PEG), polypropylene glycol (PPG), and PL‐F127 matrices, observing an improvement of crystallization rate for both drugs.
\nAnother innovative approach relates to the combination of different carrier systems (natural and synthetic, for example) that perform different functions, usually synergistic, in the same pharmaceutical formulation. These new carriers, hybrid systems, can provide (in combination) levels of structural organization and different biopharmaceutical properties of the individual carriers, being used as a strategy to overcome limitations in relation to the physicochemical properties (such as aqueous solubility), pharmacokinetic (control local absorption and/or uptake to the bloodstream), pharmacodynamic (increased drug duration of action) or toxicological properties (improvement in biocompatibility, reduced local and systemic toxicity) [43, 44]. In this sense, the interactions and the structural patterns formed between PL and cyclodextrins, inorganic nanoparticles, and natural or synthetic polymers have been described in the literature.
\nSAXS studies revealed a face‐centered cubic phase for PL‐F127 hydrogels (30 wt%) after interaction with PEG 6000 or PEG 35000 and polyvinylpirrolidone [45]. On the other hand, the PL supramolecular structure was destabilized after incorporation of Fe3O4 nanoparticles into PL‐F108 hydrogels, showing that the thermogelation is due to the clustering of nanoparticles into a fractal network [46]. In a different manner, a cubic symmetry was observed by SAXS characterization of the systems composed of ordered mesoporous silica nanoparticles in PL‐F127 hydrogels [47].
\nFor other nanocarriers, such as cyclodextrins (CD), different structural arrangements have been described, being also related to the delivery capability of those systems. Simões et al. [48] reported the development of a syringeable hydrogel composed of PL‐F127 and α‐CD for the delivery of vancomycin. In others reports, the incorporation of α‐CD, studied by SAXS, showed a significant change on gelation behavior of PL‐F68 and PL‐F127 due to the formation of polypseudorotaxane (interaction of the hydrophobic PL unimers with the hydrophobic cavity of CDs, stabilized by noncovalent bonds, van der Waals forces, and interactions between the hydroxyl groups of adjacent CDs and hydrophilic polyethylene glycol polymer unimers) supramolecular complexes, in a similar manner observed in the interaction between β‐CD and PL‐F108 [49, 50].
\nOne of the biggest challenges of the pharmaceutical science is to understand how the drugs interact with the cells in the body. This study is directly linked to physical and chemical properties of the drugs and the drug delivery systems. Therefore, it is important and necessary to use appropriate techniques for characterization, suitable for the development and improvement of the efficacy of the drugs.
\nFor this reason, X‐ray diffraction techniques stands out amongst several characterization techniques to distinguish the solid forms, like salt, polymorphs, solvates and cocrystal, and amorphous forms. X‐ray diffraction provides information about the long ordering crystalline samples and also short ordering in vitreous or amorphous materials. This technique helps to relate the X‐ray diffraction patterns with the structural ordering or disordering in materials science. It is worth to note that there is a clear difference between the crystalline materials, and amorphous and vitreous materials when observed via X‐ray diffractometer. In the X‐ray diffraction pattern for crystalline materials, several sharp peaks can be observed. On the other hand, for vitreous or amorphous materials the diffraction pattern display typically three or less halos (large peaks).
\nIn 1999, Wunderlich [51] proposed a classification system based on the structural ordering and molecular packing present in the organic forms using three ordering parameters: translation, orientation, and conformation, as summarized in Table 1.
\nSolid form | \nTranslation | \nConformation | \nOrientation | \n
---|---|---|---|
Crystal | \nLong order | \nLong order | \nLong order | \n
Condis Crystal | \nLong order | \nShort order | \nLong order | \n
Plastic Crystal | \nLong order | \nShort order | \nShort order | \n
Liquid Crystal | \nShort order | \nShort order | \nLong order | \n
Vitreous or amorphous | \nShort order | \nShort order | \nShort order | \n
Classification system of solid forms as described by Wunderlich [51].
Solid‐form crystals with a long ordering structure can be indexed characterized using X‐ray powder diffraction technique (XRPD) due to its unique combination of order parameters. Although the solid forms of amorphous and vitreous materials do not exhibit any long ordering structure, they can be identified and characterized by their local molecular (short) ordering.
\nSome applications of X‐ray diffraction techniques used to analyze the properties of the solid state of the drugs are: (1) characterizing the ordering in the active pharmacological ingredient (API); (2) identifying the existence forms in the API; (3) determining the solid form of API in the final drug product; (4) determining the physical and chemical stabilities; (5) identifying the components existing in the drug product; (6) detecting impurities or contaminants in the drug product; (7) monitoring changes in the sold form of the drug due to the fabrication; and (8) analyzing quantitatively and qualitatively the final drug product.
\nBased on the sensitivity of the technique to the ordering of structure, with appropriate data obtained from XRPD, it is possible to determine the structure of the solid forms and also the packing of the molecules in the solid. This information contributes significantly in the understanding of the chemical content in the solid state of the drug. Moreover, it is also important from the regulatory perspective.
\nThe X‐ray diffraction technique measures the X‐ray photons after the collision with the electronic cloud of the sample that changes the photon trajectory, though keeping the same phase and energy of the incoming photon. This is the key concept of the coherent elastic scattering process.
\nIn organic samples, there are some specific facts that must be considered:\n
The application of a mathematical simplification known as first Born approximation is important and useful in the explanation of the X‐ray diffraction process.
As expected, the interaction of the solid forms in the organic samples with incoming X‐ray beam is weak and the amplitude of the multiple radiation scattering is almost negligible when compared to the simple radiation scattering.
In the presence of crystal defects, grain boundary or disordering systems, the multiple radiation scattering become even less significant.
Based on these considerations and their limits, we can model the process of diffraction as a Fourier transform of the electronic density inside the sample.
\nWhile each atom is considered a specific source of scattering process, the molecules can also be reduced to specific sources of scattering, considering that the distribution of the electronic density of a collective set of atoms is the sum of electronic density distribution attributed to centralized atoms individually.
\n\nAlthough the atoms in a molecule are not necessary the same as the free atoms, they are frequently considered as being free atoms. In this way, the ordering of the specific centers of scattering in the real space produces a group of diffraction events in the reciprocal space that corresponds to the intensity of the peaks.
\nA
As the Fourier transform can be applied in any molecular translational ordering that exists inside a solid form, the diffracted peak positions can be expressed in terms of
In order to cause a constructive interference of the scattered waves, it is necessary that the Bragg\'s law be obeyed. The Bragg\'s law relates the X‐ray scattering angle
Representation of a simple periodic array of an organic molecule with a single orientation and conformation. The molecules are periodic, separated by a constant spacing
where λ is wavelength of the incident radiation;
Schematic representaion of the Bragg\'s law for the X‐ray diffraction.
The samples analyzed by the X‐ray diffraction technique can be in the powder form or solid with plane surfaces.
\nAnalyzing the diffractogram of a polycrystalline sample, we verify that the peaks related to different set of planes show different intensities. If we build a diffractogram using just geometric aspects (Bragg\'s law), we will expect that all the peaks display the same intensity since all of them are subjected to constructive interference.
\n\nHowever, there are several physical aspects that influence the intensity of the peaks in a diffractogram, such as:\n
Atomic scattering factor (this value indicates how an atom can scatter to a certain angle in a certain wavelength).
Structure factor (quotient of amplitudes of scattered waves by all the atoms in a unit cell and the amplitude of the scattered wave by on electron).
Multiplicity factor (there are planes that, for having the same interplanar distance, scatter to the same peak. This is the case, for instance, of 100, 010, and 001 planes in a cubic cell. Adding also the planes, qith −1 instead of 1, we have in total six planes contributing to the same peak, implying in a factor of multiplicity 6).
In order to get the expression for the intensity, we need three more correction factors: (a) Lorentz factor, (b) polarization factor, and (c) temperature factor. The first two are related to the geometric corrections that affect the diffracted intensity. Finally, the last one is related to temperature process that can cause shift in the position of the peaks, decreasing the intensity of the peaks and increasing the background.
\nA more complete explanation of the expression for the intensity and the factor that affects the intensity can be found in the reference of this chapter [52–57].
\nThe optics and the instrumentation used in the X‐ray diffraction technique are directly related to the type of the X‐ray source. However, we can define three generic elements: X‐ray source, sample (including here the sample holder and sample environment, such as furnaces and cryostat), and detector.
\nAn optimized experiment has as premise the following three conditions:\n
Suitable X-ray source with efficient beam conditioning.
A sample properly prepared, an optimized sample holder with low background and minimum influence in the measurement, and an appropriated sample environment that allows a stabilization of the sample in certain conditions as for example, temperature.
Optimized detection systems (with or without optics to reduce background and to focus the scattered beam in order to improve the signal to noise ratio).
The diffractograms show the diffracted intensities as a function of experimental parameter 2
For materials with long ordering structure (crystalline materials) the diffractograms show sharp peaks, which the shape and the width depend on the instrument geometry where the data were collected. In Figure 6, we display an example of a diffractogram of a drug delivery system, β‐cyclodextrin. The measurements were performed in a conventional diffractometer with Cu radiation, and, it was possible to perform a Rietveld refinement to obtain the final structure (as shown in the insert of Figure 6).
\n\nThe range of the measurement for crystalline materials depends on the aim of the study. For example, when we study big molecules (for instance, biological samples), it is beneficial to measure at low angles, allowed by the geometry of the instrument (approximately 0.5° can be reached in a typical laboratory configuration in modern instruments or less than 0.5° using synchrotron sources).
\nDiffractogram of crystalline β‐cyclodextrin measured in a conventional diffractometer using Cu radiation. Also, Rietveld refinement was performed in order to obtain the crystal structure.
The time for collecting the data varies according to the application, for example, to study polymorphism in drugs. Good diffraction patterns of the crystalline material, using conventional X‐ray instruments can be obtained in the range of 2–10 min per step. In configurations that use high efficiency X‐ray sources (synchrotron) to samples mounted in a planar configuration, the collected time can be less than 1 min. The X‐ray diffraction technique that is typically nondestructive (if the flux of X‐ray is too high, we can observe the radiation damage effect that can affect the sample), needs 2–20 mg of sample, depending on the configuration geometry of the instrument and the application.
\nThe quality of the sample and its correct preparation in order to perform the XRPD experiment influences significantly in the characterization or identification of the crystalline material. We can cite two factors related to the preparation of the sample that can affect the results:\n
Orientation of the crystallites: ideal sample has a big number of random oriented crystallites.
Statistics of particles orientation: the reproducibility of an X‐ray pattern depends on the statistic of the particles orientation when the preferred orientation limits the degree in which the pattern represents the structure.
For these reasons, one must evaluate the statistics of the particle orientation and the degree of the preferred orientation before starting the identification and analysis.
\nThe effect of the preferred orientation of the crystallites in a sample can be observed as the increase in the intensity on some of the peaks and the decrease in the intensity on others. The variation of the intensity is proportional to the degree of preferred orientation. In some cases, the sample holder geometries of the diffractometer can also generate different set of relative intensities.
\nUsing samples that show a relatively small number of crystallites results in a diffractogram with poor statistics. If the small population of the big crystallites does not represent all the possible orientations, the relative intensities will not be reproducible.
\nThe effect of the preferred orientation on the particle orientation can be minimized by spinning the sample holder.
\nAmorphous materials (disorder, vitreous or amorphous materials) have characteristic diffractograms with large halos and do not show sharp peaks in the XRPD patterns. Figure 7(c) and (d) displays examples of a typical diffractogram of an amorphous material.
\n(a) Diffractogram of bupivacaine (BPV); (b) a physical mixture of BPV and HP‐β‐cyclodextrin; (c) complex of BPV and HP‐β‐cyclodextrin and (d) diffractogram of HP‐β‐cyclodextrin. Observe the amorphous diffractogram of the drug delivery systems, HP‐β‐cyclodextrin and the complex (drug delivery with drug).
However, using suitable computational methods it is possible to extract structural information from this X‐ray diffraction patterns. In this case, it is necessary a large angular range, typically from 1 to 100° in 2
In order to obtain a good diffractogram through the X‐ray diffraction technique for amorphous samples, usually one needs 5–100 mg of the samples, depending on the geometry of the instrument.
\nXRPD patterns, for crystalline materials or for amorphous materials, contain artifacts from the instrument, for example, background functions from the instrument, fingerprints from the sample holder, incoherent scattering (Compton), polarization and Lorenz effects, and air scattering. A relatively small pattern generated from the samples means that these artifacts represent a portion bigger of the overall diffracted intensity. Therefore, computational methods used to analyze amorphous materials are more sensitive to experimental artifacts.
\nX‐ray diffraction instrument used typically in conventional laboratories consists in three parts: (1) X‐ray source; (2) sample holder, and (3) detector system.
\nThere are several X‐ray sources that it can be possible to use in a conventional laboratory, but the most common is the copper source (Cu). Slits and optics are used to focus the X‐ray incident beam in the sample and also, the X‐ray diffracted waves scattered from the sample into the X‐ray detector. In order to minimize artifacts from the sample (mentioned before), usually, the sample holder is spinning. The X‐ray detectors can be punctual, linear or area. The detector area has the advantage of being fast in the data acquisition and also makes it possible to evaluate the statistics of the particle orientation and preferred orientation of the samples, through the analysis of the Debye rings in the detector.
\nSynchrotron sources can be used to measure special systems in order to collect high quality data.
\nDiffractometers can be operated typically in reflection (Bragg‐Brentano) or transmission (Debye‐Scherrer). In the reflection setup, the incident beam is reflected from the surface of the sample and the scattered beam is focused into the detector.
\nThe X‐ray penetrates several layers below the surface in organic samples. This means that the average diffracted surface is located below the surface of the sample. This penetration effect can yield to an error of a displacement of the peak positions in the diffraction pattern of the tenth of a degree
\nErrors caused by the displacement of the peaks happen due to the difficulty in the preparation of the sample in the sample holder (Figure 8(b)). The surface of the sample must be leveled with the surface of the flat sample holder (where the instrument is focused). Although computational methods can be used to correct the position of the peaks, the proper preparation of the sample is the only solution to solve this problem.
\n(a) Laboratory XRPD equipment or Synchrotron XRPD beamline can be used to characterize drug delivery systems and drugs; (b) preparation of samples; (c) some results from a biological material, L‐methionine, measured at XRPD synchrotron beamline. Also observed the Rietveld refinement and the possible structure of the sample.
Usually measurement at low angles (below 2.5° in 2
The authors acknowledge the financial support received by CNPq/Brazil and FAPESP (# grant 14/14457-5).
\nThe commonest variant of Chiari malformations, the one that has been labeled “type I,” including some recently derived variants (type 0, type 1.5), is unique among the central nervous system abnormalities by its capacity to elicit just as much apprehension within the community of patients, as bewilderment among the clinicians. Its ominous relationship with sudden death, as well as its resemblance with the tonsillar herniation seen in terminal stages of brain tumors, intracranial hemorrhage, and other space-occupying lesions, would very well serve to explain many of these feelings. Nevertheless, their deeper reason seems rather to be the apparent mystery that clouds its pathogenesis, hindering many attempts at agreement among the authors involved in its investigation.
Notwithstanding, an attentive eye can discover interesting pathogenetic clues issued from recent research that one only has to pin up at the right spots on an older scaffold initiated long ago by some intuitive theories that started to explore into these matters even from the discovery of the hindbrain malformation: while Hans Chiari favored hydrocephalus as the cause of tonsillar descent, Julius Arnold proposed the concept that cord tethering at the level of the associated myelomeningocele determines a caudal traction along the spinal cord that ends in the tonsillar descent of Chiari malformation type II [1].
This is why every effort to unveil the origin and the mechanisms of formation of Chiari malformation type I should be greatly welcomed. It is very likely that the same can be extrapolated to the less common Chiari malformation type II, which could be just a more severe form of the same deformity, caused by more intense but qualitatively similar pathogenetic alterations. The unifying theory that follows is merely the result of attentive, scrupulous efforts to acknowledge valuable data in the middle of puzzling research results and connect them orderly in a logical explanation of the mechanisms likely to be involved in the production of Chiari malformation type I.
The concept of caudal traction as we use it through the following lines should not be understood merely from a physical point of view, as a purely mechanical force, as it refers to a biological system with certain viscoelastic properties and an intrinsic capacity to develop a reaction to any force acting upon it. The development of the human body is a continuous interplay of genetic, molecular, biochemical, and mechanical changes that result in a more or less dynamic structure and function. Absolutely all human beings, as well as other vertebrate species, are subjected to this phenomenon of caudal traction, which is a necessary part of the development of the spinal cord and brainstem, as they grow by lengthening, distinctly from the forebrain and cerebellum, which do it by expansion. In fact, the notion of caudal traction points to a group of deformities of the nervous system and its surrounding tissues, identifiable on diagnostic images and likely to result from this longitudinal growth of its caudal segments during development; they may be discovered at various stages during this process or even later, during adulthood, which is by no means a cease of it, but merely a continuation, as an involution—apparently a reversed process, but in fact an ongoing, caudal traction at a deep structural level of the involved neural organs. After all, the definition and understanding of this dynamic concept will certainly improve in parallel with the abilities of the diagnostic tools that we shall be able to use in these patients.
After an initial presentation of this new pathogenetic theory, we will follow with a second part where we shall bring into view some conditions quite likely to be produced by means of a mechanism of caudal traction and which are frequently associated with Chiari malformation type I. The third part of this chapter will deal with the clinical arguments of our demonstration, presenting a range of suggestive, but often neglected proofs of this pathogenesis, which we meet during the diagnosis and treatment of these patients.
It is very likely that the events that eventually lead to Chiari malformations take place at a very early stage during embryogenesis; a plausible idea if one takes as an example the defects of neural tube closure, related in some way to our problem, as we know well enough that during their evolution, some of them can cause a Chiari malformation type II—and the future will probably show that the relationship between these conditions is not limited to this (and caudal traction could be the link). If some parallel, very early, processes, related but not identical to neurulation abnormalities, would finally result in a Chiari malformation type I, it means that actually all purported etiopathogenetic mechanisms of this condition are in fact late secondary features that simply result from the abnormal development of the cranio-cervical junction. Most importantly, both the small volume of the posterior fossa and the disturbances of cerebrospinal fluid circulation across the foramen magnum would be such
This concept of very early pathogenesis of Chiari malformation type I has also another important consequence in the way we should try to understand it: most, if not all of the morphological and mechanical changes involved in its generation take place in the diminute body of a human embryo, then fetus, and then child (probably of a comparatively decreasing magnitude throughout these stages), even though the diagnosis will eventually be secured only at an adult age. This invalidates many recent research results and actual misconceptions based on mature or adult human anatomy and physiology.
Perhaps Chiari malformation type I is the best example of the meaning of Lewis Wolpert’s famous phrase “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life” [2], as indeed, the events that finally lead to its development seem to originate during gastrulation (third week postfertilization), that is, at a much earlier stage of embrionary development than that stated by all theories invoked nowadays.
Thus, the primordium of the central nervous system divides along its freshly defined anterior-posterior axis into four regions, corresponding to the future forebrain, midbrain, hindbrain, and spinal cord [3], well in advance of any significant differences in shape or length among them. Interestingly, while the first two limits are represented by discrete junctional areas that function as organizing centers for nearby neural territories—the so-called anterior neural ridge between the forebrain and midbrain and the isthmic organizer between the midbrain and anterior hindbrain [4]—there is no specific anatomical hint as to the precise location of the posterior hindbrain-spinal cord transition [3]; moreover, its final position depends on quite sophisticated but also delicate mechanisms involving a negative feedback loop between retinoic acid signaling, Cdx4 transcription factor, and the Cyp26 enzyme involved in the degradation of retinoic acid [3, 5]. Despite its importance for all future development of the nervous system, this hindbrain-spinal cord transition is exposed to be moved cranially or caudally by various alterations in these complex, interconnected signaling pathways [3, 5]. For example, experimental loss of Cdx4 function in zebrafish led to caudal displacement of the transition as far as that corresponding to two somites inside the spinal cord territory. As a consequence, the hindbrain-spinal cord transition along the developing neural tube will be matched to a different mesodermal counterpart, belonging to the first pairs of somites, either occipital or cervical. In this way, it becomes easy to figure out how an alteration of the Cdx4 gene or an equivalent disturbance of retinoic acid signaling could displace the transition caudally and place the junction between the developing brainstem and the spinal cord at the level of the future atlas, while the cerebellum might be expected to expand until the same area well below the occipital foramen. In fact, maternal administration of exogenous retinoic acid has been used to produce Chiari malformations in an experimental model in hamsters [6].
By and large, the tonsillar descent seen in Chiari malformation type I would thus be the result of delicate molecular abnormalities that occur early in a critical area of the future body plan, representing the precise border separating the head, with a neural-driven expansile growth in three directions, from the spine, with a somatic-driven tensile growth in one predominant direction (Figure 1). This is why its developmental importance and pathological associations and consequences are so complex and puzzling in their diversity, far outweighing the apparent trivial significance that it still has in the eyes of many clinicians.
The interplay of molecular and growth influences that grant a special importance to the cranio-cervical junction.
Of course, it is difficult to apply such an ultra-early pathogenesis involving molecular and genetic signaling pathways to what we actually think and know about Chiari malformation type I, but here we have again a point where an analogy with Chiari malformation type II is quite welcome. Since Julius Arnold’s days, it was already supposed that a myelomeningocele would “tether” the growing child’s spinal cord and thus determine a progressive caudal traction on the cerebellum and the tonsillar descent through the occipital foramen. The concept of “tethering” involves both a pathological lesion that fixes the spinal cord to the vertebral column at some point and an uncompensated load, either in the form of continuous growth, repetitive forward flexion movements, or a fracture-dislocation with sudden cord traction. In fact, there is also a third, mandatory component, the lack of an adequate adaptive reaction of the body, which may be due to the overwhelming intensity, suddenness, or persistence of the pull. Now, all these features can yet be expressed in another way if we view tethering more generally, as a relative shortness of the spinal cord, underlying both Chiari malformation types I and II, with the mention that in the former, there is absolutely nothing of spinal cord tethering.
Therefore, patients with Chiari malformation type I would tend to have relatively shorter spinal cords because the neural territory assigned to the formation of the future spinal cord is reduced with respect to the nearby somitic mesoderm, a disproportion that will result in a continuous spinal cord tension during growth, as the neural tissue will always be “one step behind” its mesodermal counterpart (Figure 1).
Interestingly, similar arguments in favor of these pathogenetic mechanisms have come from the other side of the problem, that is, from attempts to explain a supposedly defective development of the mesodermal tissue composing the prospective vertebral column, resulting in idiopathic scoliosis: the so-called “Roth-Porter theory” invokes exactly the same “asynchronism” between the spinal cord and spine during growth [7, 8, 9], reflected in the tridimensional deformity of idiopathic scoliosis in a much more visible manner [10] than in the case of Chiari malformation type I, but we shall develop more of these aspects later.
Just as a collateral observation, here we should mention that retinoic acid was also suspected as a pathogenetic factor in adolescent idiopathic scoliosis [11].
By the way, given its role of mechanical support, the development of osseous tissue has always been regarded as being associated to the creation and maintenance of tensile or compressive forces in the neighboring tissues. Thus, the development of the cranial vault by intramembranous ossification seems to proceed by means of tensile forces created in the sutures by the growth of the underlying brain [12]. Just in the same way, it should not be surprising that the growing vertebral column could exert a barely perceptible but relentless, tensile force that by some yet unknown mechanism stimulates the growth of the contained spinal cord accordingly. Well, this would be exactly the Achilles’ heel in individuals with Chiari malformation type I, as they are exposed more than normal people to a deficiency of the homeostatic mechanisms that maintain coupled the growth of the two structures. In selected cases, this uncoupling can occur also in the absence of a tonsillar descent or with a minimal one, so that its pathological consequences do not require the 5 mm of descent that most authors use to define Chiari malformations.
Without pretending to be exhaustive, Chiari malformation type I is associated with a few pathological conditions that could be explained by similar mechanisms involving genetic and molecular abnormalities followed by an axial traction throughout the spinal cord and the brainstem. But before all, in order to have a crystal clear vision of these associations, we have to rule out any tonsillar descent that is obviously secondary to compressive forces from above, as in benign intracranial hypertension, hydrocephalus of any etiology, craniosynostosis, or Paget disease of the bone and other conditions with calvarial thickening, as these are not real instances of Chiari malformation [1] and only compound the problem unnecessarily: one should better consider them as merely secondary tonsillar descents in specific clinical contexts that require only the treatment of the primary pathology and nothing more, just as is always done in the posterior fossa tumors, the deadliest cause of downward displacement of the cerebellar tonsils, where nobody disputes the foremost therapeutic objective. Nevertheless, if really and honestly open-minded, one has to acknowledge that perhaps every tonsillar descent is secondary to a pathological process, even though in most cases its nature is still unknown. But in the actual state of knowledge, we should better consider as “Chiari malformation type I” only the apparently
Malformations of the occipito-cervical junction, representing a diverse and complex group of pathological conditions and related deformities, are often multiple in the same patient and many times occur in conjunction with Chiari malformation type I—with as many as 38–40% of hindbrain herniations in cases of atlas assimilation combined with Klippel-Feil syndrome [13]. In these patients, the abnormal fusions involving the occiput, atlas, and other cervical vertebrae would most probably be generated by defects in the functions of Hox and Pax-1 genes at different levels in the occipital and cervical somites [14] at a more delayed stage than those mentioned above. A possible explanation could be that the genetic and molecular alterations are more severe and thus extend their effects over segmentation and resegmentation of the somites and specification of the sclerotomes, not only affecting the hindbrain-spinal cord boundary as we have mentioned. A second possibility might be that the anomalous establishment of this boundary creates the conditions for a defective feedback from the neural counterpart to the mesoderm, disturbing these molecular pathways and secondarily the formation of cervical vertebrae. And we could add to these qualitative alterations the obvious quantitative one: if too much mesodermal tissue has been wrongly assigned to build the prospective spine, it goes without saying that the amount of tissue left for building the skull will be insufficient (Figure 1). The consequences of this relative lack of occipito-cervical mesodermal tissue will be distinct from those of the lack of spinal cord progenitor tissue, as the prospective growth of this segment of somitic mesoderm will be governed by the underlying hindbrain which, as far as we know, is very strictly divided in rhombomeres with distinct features, as opposed to the monotony of the spinal cord organization in these early stages. Their feedback over their corresponding (and quantitatively defective) mesodermal counterpart will put quite stressful limits on the availability of compensatory mechanisms and thus determine an abnormal formation of the osseous and ligamentous elements of the occipito-cervical junction.
The same could happen also at more cranial levels, corresponding to the first occipital rhombomeres, where the same disproportion between the neural tissue contained within and the nearby mesoderm that receives its developmental induction would produce the deformities of basilar impression, platybasia, brainstem kinking, and retroflexed odontoid, found in 7.7% of our patients with Chiari malformation type I (Royo-Salvador et al., unpublished data). All these osseous anomalies could probably be explained by the interplay of discrete but persistent compressive and tensile forces developed among occipito-vertebral mesodermal segments during their development, secondarily to the mentioned genetic and molecular defects, recording somehow to the tenets of the Hueter-Volkmann law as applied to the spine [15].
At the same time, the disproportion between the contained, apparently hypertrophic hindbrain and the corresponding scarcely available mesodermal tissue will create the conditions for what Roth described in 1986 with such a brilliant intuition as “cranio-cervical growth collision” [16]: the impaction of the developing hindbrain against the growing vertebral column, which surpasses and deforms the insufficient occipito-cervical junction mesodermal primordium (the former from the inside, the latter from below (Figure 1)), accentuating the tonsillar descent, enlarging the occipital foramen, and leaving too little room for the formation of the occipital bone. It is amazing how the actual general opinion is able to conceive only this last developmental step [1, 17], but yes, finally, there is a para-axial mesodermal insufficiency associated with the Chiari malformations, but it is an associated phenomenon, somehow delayed and of secondary importance.
Among cranio-cervical junction malformations, a special mention deserves odontoid retroflexion, as it is a bony deformity that although it is less known and more imprecisely defined, it was found to be more marked and more common in children and adults with Chiari malformation type I than in normal controls [18, 19]. Moreover, in children with Chiari malformation type I, a study found it was correlated with the presence of syringomyelia and with a lower position of the
Since long ago, observations were published on the frequent association between Chiari malformation type I and idiopathic scoliosis [20], even though no coherent explanation of this fact has ever been provided. As a specific point, we have to insist that the presence of syringomyelia is not really necessary, as many have thought so far. Among our patients, Chiari malformation type I was associated with idiopathic scoliosis in 78.8% of cases, out of which only 52.1% also had idiopathic syringomyelia (Royo-Salvador et al., unpublished data). Instead, a common pathogenesis, based on an abnormal caudal traction, seems more likely to be involved: in fact, as we mentioned before, the concept of “neuro-vertebral growth asynchrony” was coined in the realm of idiopathic scoliosis and constitutes the mainstay of the Roth-Porter pathogenetic theory [7, 8, 9], which uses various mechanical experimental models to demonstrate that an uncoupling of the growth velocity between the spine and spinal cord makes the latter to lag behind, putting tension on the posterior elements which will grow at a slower pace (here we come once again in close contact to the Hueter-Volkmann law), so that the anterior elements will grow too much and the vertebral bodies, “tethered” posteriorly, will start to rotate around an axis represented by the spinal cord itself and will deviate to one side as they grow restrained in this way, thus creating the scoliotic curve [21]. It is not difficult to imagine how a similar mechanism of caudal traction would produce both a Chiari malformation type I and an idiopathic scoliosis if this intrinsic “tether” acted continuously over the vertebral column and spinal cord throughout their development and associated longitudinal growth, a fact especially conceivable if, following the mentioned alterations in the definition of the hindbrain-spinal cord boundary, there is a relative excess of mesenchymal tissue composing the sclerotomes of the future thoracic spine, even though it would be much later that this unbalanced tissue distribution would become manifested, during the growth spurt of the adolescence.
Last but not the least, among enlightening pathological associations of Chiari malformation type I is the tethered cord syndrome, maybe the most interesting of all, the most difficult to explain, and nevertheless, the most important, as it forms a bridge between Chiari malformation types I and II. In fact, this association should be better regarded as a separate third category of Chiari malformations, taking into account the different mechanism of relative spinal cord “shortening”: if in Chiari malformation type I this originated in a caudal displacement of the hindbrain-spinal cord boundary and in Chiari malformation type II, in the traction exerted by a caudal myelomeningocele on the growing spinal cord, here there is an abnormal
Now of course, if one accepts that the pathogenesis of Chiari malformations includes a common pathway of relative shortening of the spinal cord with respect to the vertebral column, of various etiologies that can be grouped into these three large groups, an important question comes about: why not any patient with this relative spinal cord shortening has a tonsillar descent? Well, the answer is quite simple, because, as we have already pointed out, there is another decisive factor that will eventually determine the occurrence or not of a Chiari malformation: the adequacy of the neural tissue reaction to the tensile forces developed as a consequence of the growth asynchrony. In other words, the tonsils will descend only if this homeostatic mechanism doesn’t function properly for one reason or another; moreover, any degree of tonsillar descent and of brainstem and fourth ventricle distortion should be possible in every one of the three main etiopathogenetic groups mentioned, so it should be time that we stop associating Chiari malformation type II only to myelomeningocele and instead, consider, for example, three degrees of tonsillar descent, perhaps labeled as Chiari malformation types 1, 1.5, and 2 (even four if a Chiari malformation type 0 were added) and defined with clear-cut morphological criteria, including measures of brainstem elongation and fourth ventricle distortion [22].
Magnetic resonance imaging, if scrutinized really carefully, can provide much more information than just detect Chiari malformation type I. Early on, we mentioned the special meaning that a retroflexed odontoid can get as a proof of caudal traction applied on the occipito-cervical junction (Figure 2).
The causative vector of a retroflexed odontoid is likely parallel to the caudal traction (arrow).
In many Chiari malformation type I patients, we can ascertain a descent not only of the cerebellar tonsils but seemingly of the whole cerebellum, as there is a readily identifiable difference of width of subarachnoid spaces above and behind the cerebellum, a feature that others have labeled “obliteration of retrocerebellar cerebrospinal fluid spaces” [17] following a different interpretation; of course, if a diminished posterior fossa volume were the cause of the tonsillar descent, there would be no free subarachnoid space visible underneath the tentorium as we see in many patients (Figure 3).
Increased subarachnoid spaces between the tentorium and the cerebellum reflect the global displacement of the latter towards the
But maybe the most spectacular image testimony of the mechanisms mentioned above is the feature that we called “tense spinal cord,” which has also been described in relation to idiopathic scoliosis [9] but that we could identify in many patients with Chiari malformation type I with or without scoliosis: in sagittal cuts, the spinal cord does not follow closely to the curves of the spinal canal, but instead, it takes the shortest route within the canal and is thus more or less straightened, in some cases even stuck on the concave side of the lordotic or kyphotic curve of the spinal canal (Figure 4a), corresponding in axial cuts to an eccentric position of the spinal cord in the canal, closer to the concave side (Figure 4b).
Tense spinal cord in a sagittal cut (a) and an axial one (b). The spinal cord travels closer to the concavity of the curves and occupies an eccentric downward position in axial images (arrows).
We interpret in a similar way another associated image feature, denominated “lateralized spinal cord,” visible in coronal or axial cuts (Figure 5) and that can be understood as a marker of tension through the spinal cord if one keeps in mind Porter’s experimental model [9], this time conditioned by the presence of at least a minimal degree of scoliosis. All this is even easier to figure out by neurosurgeons, because here the spine recalls the principle of functioning of the Leyla retractor system introduced by Gazi Yasargil and so often used to hold brain spatulas. In other words, a central cable in a hollow curved construct will deviate towards the concavity if subjected to axial tension, and in the vertebral column, this can happen either in the sagittal plane, in the coronal plane, or in both.
Lateralized spinal cord deviated towards the left inside the spinal canal.
As an expected consequence of an incomplete understanding of the etiopathogenesis of Chiari malformation type I, its surgical treatment seems the unhappy heir of a mysterious real estate, haunted by dreadful ghosts such as sleep apnea and sudden death. If in some cases it is indeed elementary caution and justified to do no treatment at all, as the tonsillar descent is merely an asymptomatic deformity discovered incidentally, in many other instances, the patients are left to struggle with their own despair as the obvious symptoms and signs they present are not recognized as such by the neurosurgeons in charge. And the reverse is also true: when an active treatment is chosen, it consists usually of suboccipital craniectomy, C1 laminectomy, and duraplasty, which is equivalent to performing an en bloc resection with healthy borders followed by radiotherapy and chemotherapy for a tumor of unknown behavior (not to mention the tonsillar resection added at times). Well, some minimalizing technical advances have been proposed, like leaving the dura mater or the atlas intact, but their problem rests in not getting to the heart of the matter—so, they might lack the desired efficacy. Recent efforts complicating more this subject have tried to define instances of cranio-cervical or atlantoaxial instability that supposedly would require complicated and risky procedures applied without firstly securing more confidently a diagnosis of genuine instability—one that is perfectly plausible in selected cases of traumatic spine injury.
Many of the delusions and mishaps issued from the actual therapeutic strategy applied to Chiari malformation type I could be avoided if, taking into account patiently all the facts presented above, one should switch his or her vision from the actual obsession to perform a
The most logical initial step for interfering with this pathogenesis, considering caudal traction as a final common pathway of multiple etiologies, would be to interrupt this unique route of producing damage to the brain, spinal cord, and spine itself. Technically, this is straightforward if done at the caudal end of the tense spinal cord instead of a frontal attack upon the delicate, impacted cranio-cervical junction. This should consist of a
Of course, the actual surgical approach of suboccipital craniectomy
Interestingly, against all odds, some subtle developments occurred in recent years in the surgical treatment of Chiari malformation type I, proving that more and more clinicians are starting to accept that maybe suboccipital craniectomy is not the only surgical solution to this condition. For this reason, we can present here three “surgical” testimonies in favor of the theory of caudal traction, as follows:
In fact, it is suboccipital craniectomy itself that opened these new perspectives when in the hands of some fearless teams [23, 24]; it started to be used for treating patients with syringomyelia without tonsillar descent, with encouraging results, but they did not realize their meaning not even when they discovered that in these children, there were image features suggesting a caudal elongation of the brainstem with displacement of the obex and increased diameter of the
Another ingenious team discovered that if they performed idiopathic scoliosis correction by a technique of posterior vertebral column resection with spine shortening and instrumentation after applying compressive forces, the cerebrospinal fluid flow at the level of the
Yet the most important testimony came from the hands of a group which operated 318 patients presenting both tethered cord syndromes defined according to very exigent criteria and Chiari malformation type I or low-lying cerebellar tonsils of 0–4 mm descent (that we consider as being also Chiari malformation type I, together with more and more authors [1]), but the technique used was not suboccipital craniectomy, but sectioning of the
Preoperative (a) and postoperative (b, at 30 months) magnetic resonance images of a 56-year-old male patient with Chiari malformation type 0, operated of filum terminale sectioning; the improvement of his idiopathic syringomyelia, visible also in a previous control (not shown), is now quite obvious, pointing to caudal traction as a possible mechanism.
Preoperative (A–F) and postoperative (G–L, at 3 months) photographs, radiographs, and magnetic resonance images of a 17-year-old male patient with Chiari malformation type I, idiopathic syringomyelia, and severe scoliosis, operated of spinal resection and instrumentation, with marked improvement of his syringomyelia (with permission from Wang et al. [
Preoperative (a) and postoperative (b, at 7 years) magnetic resonance images of a 49-year-old female patient with Chiari malformation type I, operated of
In the actual state of knowledge, it is imperative to recognize that the development of the hindbrain and the spinal cord is a complex process regulated by genetic, molecular, mechanical, endocrine, and nervous homeostatic mechanisms that compensate one for another—within certain limits—in case of imbalances and disturbances. Nevertheless, it is exactly this complexity, coupled with the elevated functional requirements that the cranio-cervical junction has to meet, that makes their union so sensitive to various pathogenetic factors and determines malformations among which the one known as Chiari malformation type I is the most common. According to all the arguments presented in this chapter, the final common pathway of these etiopathogenetic aggressions seems to be caudal traction, a complex biological phenomenon that by no means should be reduced to a simple mechanical force of axial pull. There is still much left to discover about the physiologic mechanisms that govern the coupling between the growth of the vertebral column and that of the spinal cord during somatic development, where maybe future research will define the roles played by the pineal gland, the subcommissural organ, and the
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\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Article but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Article as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world. The Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Article and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Article.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Article as a consequence of IntechOpen's changes to the Article arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Article, the Corresponding Author agrees to credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen, when they are distributing or re publishing the Article.
\\n\\n3.2 When submitting the Article, the Corresponding Author agrees to:
\\n\\n• Comply with all instructions and guidelines provided by IntechOpen;
\\n\\n• Produce the Article with all due skill, care and diligence, and in accordance with good scientific practice;
\\n\\n• Submit all the corrections in due time as defined during the publishing process schedule.
\\n\\nThe Corresponding Author will be held responsible for the payment of the Article Processing Charge.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Article worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Article does not and will not breach any applicable law or the rights of any third party and, specifically, that the Article contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Article is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Article has not been formally published in any other peer-reviewed journal or in a Journal or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication
\\n\\nAgreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Article to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Article was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Article on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Article attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Article and has the right to contact the Corresponding Author and any Co-Author until the Article is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Article,
\\n\\nIntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n"}]'},components:[{type:"htmlEditorComponent",content:"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Journal Article:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Article who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author. Co-Author: All other Authors of the Article besides the Corresponding Author. IntechOpen: IntechOpen Ltd., the Publisher of the Journal.
\n\nJournal: The publication as a collection of Articles compiled by IntechOpen .
\n\nArticle: The original literary work created by Corresponding Author and any Co Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Article, including the right to deposit the Article in open access digital repositories.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Article under a Creative Commons 4.0 International Licence).
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Article but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Article as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world. The Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Article and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Article.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Article as a consequence of IntechOpen's changes to the Article arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Article, the Corresponding Author agrees to credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen, when they are distributing or re publishing the Article.
\n\n3.2 When submitting the Article, the Corresponding Author agrees to:
\n\n• Comply with all instructions and guidelines provided by IntechOpen;
\n\n• Produce the Article with all due skill, care and diligence, and in accordance with good scientific practice;
\n\n• Submit all the corrections in due time as defined during the publishing process schedule.
\n\nThe Corresponding Author will be held responsible for the payment of the Article Processing Charge.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Article worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Article does not and will not breach any applicable law or the rights of any third party and, specifically, that the Article contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Article is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Article has not been formally published in any other peer-reviewed journal or in a Journal or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication
\n\nAgreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Article to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Article was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Article on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Article attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Article and has the right to contact the Corresponding Author and any Co-Author until the Article is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Article,
\n\nIntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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Development of Safer and More Effective Technologies"},signatures:"Nabil El-Wakeil, Nawal Gaafar, Ahmed Sallam and Christa Volkmar",authors:[{id:"80199",title:"Prof.",name:"Christa",middleName:null,surname:"Volkmar",slug:"christa-volkmar",fullName:"Christa Volkmar"},{id:"82718",title:"Dr.",name:"Nabil",middleName:null,surname:"El-Wakeil",slug:"nabil-el-wakeil",fullName:"Nabil El-Wakeil"},{id:"83353",title:"Dr.",name:"Ahmed",middleName:"Ahmed",surname:"Sallam",slug:"ahmed-sallam",fullName:"Ahmed Sallam"},{id:"83363",title:"Dr.",name:"Nawal",middleName:null,surname:"Gaafar",slug:"nawal-gaafar",fullName:"Nawal Gaafar"}]},{id:"42228",doi:"10.5772/54742",title:"Physiological Dysfunction in Fish After Insecticides Exposure",slug:"physiological-dysfunction-in-fish-after-insecticides-exposure",totalDownloads:3876,totalCrossrefCites:14,totalDimensionsCites:46,abstract:null,book:{id:"3055",slug:"insecticides-development-of-safer-and-more-effective-technologies",title:"Insecticides",fullTitle:"Insecticides - Development of Safer and More Effective Technologies"},signatures:"Mahdi Banaee",authors:[{id:"83012",title:"Dr.",name:"Mahdi",middleName:null,surname:"Banaee",slug:"mahdi-banaee",fullName:"Mahdi Banaee"}]},{id:"25668",doi:"10.5772/27852",title:"Ecosmart Biorational Insecticides: Alternative Insect Control Strategies",slug:"ecosmart-biorational-insecticides-alternative-insect-control-strategies",totalDownloads:6694,totalCrossrefCites:5,totalDimensionsCites:44,abstract:null,book:{id:"2036",slug:"insecticides-advances-in-integrated-pest-management",title:"Insecticides",fullTitle:"Insecticides - Advances in Integrated Pest Management"},signatures:"Hanem Fathy Khater",authors:[{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater"}]}],mostDownloadedChaptersLast30Days:[{id:"52383",title:"Assessment of Maize (Zea mays) as Feed Resource for Poultry",slug:"assessment-of-maize-zea-mays-as-feed-resource-for-poultry",totalDownloads:4801,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Maize, also known as corn (Zea mays L), has been recognised worldwide as a major energy feed ingredient in the diets of poultry. Its major nutritional limitation has been the low protein content and poor protein quality, which necessitates the use of expensive high‐protein supplements or synthetic amino acids such as lysine in diets containing large proportion of maize. Therefore, extensive research has been conducted by maize breeders on the world maize germplasms collection with the aim of improving its nutritive value, particularly protein quality for monogastric animals. This chapter assesses the genetic upgrading of the nutritional quality of maize protein that culminated in the development of a new class of maize known as “Quality Protein Maize (QPM)”. Various studies on the nutritionally improved maize for poultry as well as future challenges confronting maize utilisation in poultry production are highlighted.",book:{id:"5315",slug:"poultry-science",title:"Poultry Science",fullTitle:"Poultry Science"},signatures:"Herbert K. Dei",authors:[{id:"28844",title:"Prof.",name:"Herbert Kwabla",middleName:"Kwabla",surname:"Dei",slug:"herbert-kwabla-dei",fullName:"Herbert Kwabla Dei"}]},{id:"61570",title:"Adenoviruses and Their Diversity in Poultry",slug:"adenoviruses-and-their-diversity-in-poultry",totalDownloads:1717,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"An investigation into the aetiology of fowl adenovirus strains and their distribution worldwide in populations of poultry flocks industry has been conducted. Pathogenic role of the viruses is not always clear. They can cause latent infection or several diseases and are the reason of economic losses in poultry flock industry. Ubiquity of adenovirus strains was commonly described, and stand-alone pathogenicity for a long time has been disputed. A globally emerging trend of adenoviruses and adenovirus-associated diseases has been increasing from year to year in all over the world. Mainly, type FAdV-4 is responsible for hydropericardium hepatitis syndrome (HP), type FAdV-1 for gizzard erosion and ulceration (GEU), and types FAdV-2, 8a, 8b, and 11 seem to be responsible for inclusion body hepatitis (IBH). Defining the spreading of the avian adenovirus strains in different types of fowl profile production, recognising their property and determining their types and molecular characterisation are very important from the epidemiological point of view and are considered as excellent basis for vaccine development and gene therapy implementation. This chapter provides a comprehensive review of FAdVs, including their epidemiology, pathogenesis, diagnostic, detection, and molecular characterisation. This comprehensive review is needed to better understand the latest progress in study of the viruses and prospects regarding disease control and implementation of gene therapy.",book:{id:"6623",slug:"application-of-genetics-and-genomics-in-poultry-science",title:"Application of Genetics and Genomics in Poultry Science",fullTitle:"Application of Genetics and Genomics in Poultry Science"},signatures:"Jowita Samanta Niczyporuk",authors:[{id:"212649",title:"Dr.",name:"Jowita Samanta",middleName:null,surname:"Niczyporuk",slug:"jowita-samanta-niczyporuk",fullName:"Jowita Samanta Niczyporuk"}]},{id:"65864",title:"Poultry Housing and Management",slug:"poultry-housing-and-management",totalDownloads:3121,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Majority of the people in the poorest regions of the tropics rely on poultry production as their major source of protein supply. However, poultry production is hindered by the harsh environmental conditions in this regions therefore, reducing the daily supply of protein. It is believed that understanding heat stress in birds by paying detail attention to the sources of heat generation in a poultry house can help manage the heat stress situation in this region. This text reviews the internal climatic conditions of the poultry houses, how the birds respond to them, and their implications for heat management in poultry production. Thus, it provides pertinent information for guidance on parameters for open poultry houses architectural design that ensures optimum climatic conditions that will alleviate heat stress problem in poultry production in hot and humid climate.",book:{id:"8470",slug:"poultry-an-advanced-learning",title:"Poultry",fullTitle:"Poultry - An Advanced Learning"},signatures:"Ayodeji Oloyo and Adedamola Ojerinde",authors:[{id:"273409",title:"Mr.",name:"Ayodeji",middleName:null,surname:"Oloyo",slug:"ayodeji-oloyo",fullName:"Ayodeji Oloyo"},{id:"274920",title:"MSc.",name:"Adedamola",middleName:null,surname:"Ojerinde",slug:"adedamola-ojerinde",fullName:"Adedamola Ojerinde"}]},{id:"61583",title:"Domestication and Welfare in Farmed Fish",slug:"domestication-and-welfare-in-farmed-fish",totalDownloads:1657,totalCrossrefCites:4,totalDimensionsCites:16,abstract:"The domestication of fish species is still in its early stages when compared to terrestrial animals. The effects of domestication on welfare of farmed fishes are complex to study because fish differ from livestock in genetics, physiology and behaviour, and experience different sensory worlds. Consequently, empathy with fish and understanding of their needs becomes more problematic than with land animals. Additionally, the acknowledgement and study of mental dimensions of fish existence is very recent. We discuss that higher levels of domestication in fish do not necessarily correspond to better welfare because (1) artificial selection by the aquaculture industry is mostly focused on production-related traits such as growth, and this selection process may have unknown negative effects on welfare-related traits; (2) the number of fish species presently farmed (circa 300) is 10-fold higher than land animals, rendering the establishment of standard welfare guidelines extremely complicated; (3) the current paradigm of the Five Freedoms guiding welfare is out-dated and was designed for livestock; and (4) there are still severe knowledge gaps in the biology of farmed fishes, especially in welfare-related traits. The implementation of humane farming systems should integrate industry, science and ethics in an open dialogue in order to produce relevant results.",book:{id:"6053",slug:"animal-domestication",title:"Animal Domestication",fullTitle:"Animal Domestication"},signatures:"João L. Saraiva, Maria F. Castanheira, Pablo Arechavala-López, Jenny Volstorf and Billo Heinzpeter Studer",authors:null},{id:"53276",title:"Mycotoxins in Poultry",slug:"mycotoxins-in-poultry",totalDownloads:3686,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Mycotoxins, the toxic secondary metabolites of fungi, particularly produced by many species of Aspergillus, Fusarium and Penicillium, have affected animal and human health for over thousand years, whereas little has been discovered so far about these complex substances in poultry, which are generally very sensitive. Even though it varies by species and sex, some common effects are reduced feed intake, weight gain, feed efficiency, growth performance, immunity and hatchability along with increased mortality, organ damages (mainly kidney and liver), carcinogenicity, teratogenicity and decreased egg production. Besides their adverse health effects and the decrease in production rate, concerns over their importance in public health is still under debate. Decontamination approaches to reduce mycotoxins in feed are technologically diverse and based on chemical, biological and physical strategies. Chemical remediation strategies involve the conversion of mycotoxins via chemical reactions. Biological strategies involve various substances such as plant ingredients, enzymes and microorganisms. Physical processes include sorting, milling, dehulling, cleaning, heating, irradiation or combinational approaches. New strategies for the prevention and treatment of mycotoxicosis, including beneficial microorganisms/products, along with alternative treatments, including plant extracts/essential oils, are current hot topics in the poultry industry.",book:{id:"5315",slug:"poultry-science",title:"Poultry Science",fullTitle:"Poultry Science"},signatures:"Ayhan Filazi, Begum Yurdakok-Dikmen, Ozgur Kuzukiran and Ufuk\nTansel Sireli",authors:[{id:"152542",title:"Dr.",name:"Ayhan",middleName:null,surname:"Filazi",slug:"ayhan-filazi",fullName:"Ayhan Filazi"}]}],onlineFirstChaptersFilter:{topicId:"31",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:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. 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Researcher",institution:{name:"Harran University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9081",title:"Equine Science",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9081.jpg",slug:"equine-science",publishedDate:"September 23rd 2020",editedByType:"Edited by",bookSignature:"Catrin Rutland and Albert Rizvanov",hash:"ac415ef2f5450fa80fdb9cf6cf32cd2d",volumeInSeries:5,fullTitle:"Equine Science",editors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8460",title:"Reproductive Biology and Technology in 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2019",editedByType:"Edited by",bookSignature:"Catrin Sian Rutland and Valentina Kubale",hash:"75cdacb570e0e6d15a5f6e69640d87c9",volumeInSeries:2,fullTitle:"Veterinary Anatomy and Physiology",editors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7233",title:"New Insights into Theriogenology",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7233.jpg",slug:"new-insights-into-theriogenology",publishedDate:"December 5th 2018",editedByType:"Edited by",bookSignature:"Rita Payan-Carreira",hash:"74f4147e3fb214dd050e5edd3aaf53bc",volumeInSeries:1,fullTitle:"New Insights into Theriogenology",editors:[{id:"38652",title:"Dr.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Animal Nutrition",value:20,count:2},{group:"subseries",caption:"Animal Reproductive Biology and Technology",value:28,count:3},{group:"subseries",caption:"Animal Science",value:19,count:5}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:3},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:1},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:302,paginationItems:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/198499/images/system/198499.jpeg",biography:"Dr. Daniel Glossman-Mitnik is currently a Titular Researcher at the Centro de Investigación en Materiales Avanzados (CIMAV), Chihuahua, Mexico, as well as a National Researcher of Level III at the Consejo Nacional de Ciencia y Tecnología, Mexico. His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. 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