\r\n\tThe book on Ventricular Tachycardia is expected to assist clinicians to navigate within the forest of new information on cardiac arrhythmias and especially ventricular tachycardia. The advances made in cardiac mapping brought new and substantial information on the effect of antiarrhythmic drugs, catheter ablation and ICDs. Clinicians deserve relevant information on the proven therapies and those more scrupulous should find out about the newest experimental and promising therapies.
\r\n\r\n\tThe authors are expected to cover the Anatomy of the left and right ventricles, the Mechanisms of ventricular tachycardia: Reentry, Automaticity and Triggered activity, and the general evaluation of patients with VT: ECG, Holter EKG, stress test, echocardiography and MRI. The book should also include information on invasive methods of arrhythmia testing: coronarography and electrophysiological testing.
\r\n\r\n\tFurthermore, the book will deal with treatment and prevention of VT: antiarrhythmic drugs like betablockers, amiodarone, sotalol and class IC, implantable defibrillators and catheter ablation. The editor would appreciate if authors also decided to cover special topics such asVT as a side effect of chemotherapy and Brugada Syndrome.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f968d9a2e5d4e8d6c0a6339c5d18b7f6",bookSignature:"Dr. Gabriel Cismaru",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8675.jpg",keywords:"Ventricular Tachycardia, ECG, Holter, Stress Test, Echocardiography, Amiodarone, Sotalol, Lidocaine, Propafenone, Catheter, Mapping",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 16th 2018",dateEndSecondStepPublish:"November 6th 2018",dateEndThirdStepPublish:"January 5th 2019",dateEndFourthStepPublish:"March 26th 2019",dateEndFifthStepPublish:"May 25th 2019",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"4 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"191888",title:"Dr.",name:"Gabriel",middleName:null,surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru",profilePictureURL:"https://mts.intechopen.com/storage/users/191888/images/system/191888.jpeg",biography:"Dr. Cismaru Gabriel is an Assistant Professor at the University of Medicine and Pharmacy Cluj-Napoca, certified in Cardiology. He earned his MD degree from the same university in 2005 and received his Ph.D. in medicine in 2016. After completing his certification in cardiology, Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, Nancy, France. In 2011, he started working at the Electrophysiology Laboratory of the Rehabilitation Hospital, Cluj-Napoca. He is a well-versed operator and performs pacemaker, CRT, and ICD implantations both in children and adults. He is also trained for catheter ablation of both supraventricular and ventricular arrhythmias. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5970",title:"Bedside Procedures",subtitle:null,isOpenForSubmission:!1,hash:"ba56d3036ac823a7155f40e4a02c030d",slug:"bedside-procedures",bookSignature:"Gabriel Cismaru",coverURL:"https://cdn.intechopen.com/books/images_new/5970.jpg",editedByType:"Edited by",editors:[{id:"191888",title:"Dr.",name:"Gabriel",surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9064",title:"Epidemiology and Treatment of Atrial Fibrillation",subtitle:null,isOpenForSubmission:!1,hash:"1cd6bf2b3181eb82446347fbe478a2bc",slug:"epidemiology-and-treatment-of-atrial-fibrillation",bookSignature:"Gabriel Cismaru and Keith Andrew Chan",coverURL:"https://cdn.intechopen.com/books/images_new/9064.jpg",editedByType:"Edited by",editors:[{id:"191888",title:"Dr.",name:"Gabriel",surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"358",title:"Advances in Electrocardiograms",subtitle:"Methods and Analysis",isOpenForSubmission:!1,hash:"a61fed85204779463e6e483483601fdf",slug:"advances-in-electrocardiograms-methods-and-analysis",bookSignature:"Richard M. 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Millis",coverURL:"https://cdn.intechopen.com/books/images_new/1291.jpg",editedByType:"Edited by",editors:[{id:"45295",title:"PhD.",name:"Richard",surname:"Millis",slug:"richard-millis",fullName:"Richard Millis"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"312",title:"New Aspects of Ventricular Assist Devices",subtitle:null,isOpenForSubmission:!1,hash:"1e87f2ee94ce52fb291dfcaaeb0dd147",slug:"new-aspects-of-ventricular-assist-devices",bookSignature:"Guillermo Reyes",coverURL:"https://cdn.intechopen.com/books/images_new/312.jpg",editedByType:"Edited by",editors:[{id:"21175",title:"Dr.",name:"Guillermo",surname:"Reyes",slug:"guillermo-reyes",fullName:"Guillermo Reyes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"129",title:"Ventricular Assist Devices",subtitle:null,isOpenForSubmission:!1,hash:"2b6b9dbd504cdf6ed9c20a742e3f2a9d",slug:"ventricular-assist-devices",bookSignature:"Jeffrey Shuhaiber",coverURL:"https://cdn.intechopen.com/books/images_new/129.jpg",editedByType:"Edited by",editors:[{id:"22152",title:"Dr.",name:"Jeffrey",surname:"Shuhaiber",slug:"jeffrey-shuhaiber",fullName:"Jeffrey Shuhaiber"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"290",title:"Cardiac Pacemakers",subtitle:"Biological Aspects, Clinical Applications and Possible Complications",isOpenForSubmission:!1,hash:"d336ffc14d9ab1745072534d4448305f",slug:"cardiac-pacemakers-biological-aspects-clinical-applications-and-possible-complications",bookSignature:"Mart Min",coverURL:"https://cdn.intechopen.com/books/images_new/290.jpg",editedByType:"Edited by",editors:[{id:"62780",title:"Prof.",name:"Mart",surname:"Min",slug:"mart-min",fullName:"Mart Min"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"51876",title:"Nanotoxicology: A Review",doi:"10.5772/64754",slug:"nanotoxicology-a-review",body:'\nNanotoxicology is regarded as the assessment of the toxicological properties of nanoparticles (NPs) with the intention of determining whether (and to what extent) they may pose an environmental or societal threat. Nanotechnology has advanced exponentially over the past decade, with nanoscale materials being exploited in several applications and in several disciplines (including industry, science, pharmacy, medicine, electronics, and communication products). Vance et al. [1] reported a 30-fold increase in nano-based products between 2011 and 2015 (Figure 1) and an estimated global market of over $1 trillion in 2015 [2]. Metal NPs (specifically, carbon and silver NPs) represent the largest and fastest growing group of NPs (Figure 2). Hence, human and environmental exposure is already occurring and is predicted to increase dramatically. This growth in nanotechnology has not advanced without concerns regarding their potential adverse environmental impacts. Several reviews have reported on the toxicity of various NPs [3, 4]. However, much is still unknown.
\nNanomaterial growth trend 2010–2015 [
Composition of nanomaterials (adapted from Vance et al. [
Nanomaterials (NMs) are generally defined as a substance having particles with at least one dimension of 1–100 nm in length. Their novel physical and chemical characteristics have made them useful in several applications; however, these very properties can be potentially toxic. Once introduce into aquatic ecosystems, the fate and toxicity of NPs and its uptake by aquatic organisms depend on several factors. Both the properties of NP (such as size, shape, and coatings) and water chemistry (such as dissolved organic carbon, ionic strength, pH, temperature) will largely influence the extent to which NPs will either remain in suspension, partition to dissolved organic carbon in the water column, form aggregates, or adsorb to suspended particles. In aquatic organisms, the accumulation of NPs is dependent on both the uptake and the elimination of the NP out of the organism. These processes also regulate the bioaccumulation (and bioavailability) of NPs. The availability of appropriate methodologies is needed to address key issues in nanotoxicology and to gain a better understanding of nanoparticle toxicity mechanisms (including oxidative stress, cytotoxicity, genotoxicity, and inflammatory responses). Exposure to NMs is largely through ingestion and adsorption to surface epithelia such as the gills.
\nAquatic ecosystems are progressively coming under pressure due to the presence of emerging anthropogenic contaminants, including NMs, posing health hazards to inhabitant organisms. In recent years, increasing data demonstrated that NPs could induce toxicity and genotoxicity under a variety of exposure scenarios. An accepted mechanism by which NPs may induce cytotoxicity is considered to be through the induction of reactive oxygen species (ROS) which can induce oxidative stress which in turn may lead to cytotoxicity, DNA damage, and other effects.
\nAlthough research on the environmental impacts of NMs has grown dramatically over the past decade, studies investigating the environmental fate, transport, and toxicity of a variety of nanomaterials are still lacking. This chapter will review the available research pertaining specifically to NMs in the aquatic environment (in plants, aquatic invertebrates, and fish) and their use in biomarkers studies.
\nThe behavior of NPs in various environmental matrices is complex and involves several processes. Properties of NMs are unique and different from conventional materials. Properties such as (1) particle size, (2) surface area and charge, (3) shape/structure, (4) solubility, and (5) surface coatings are known to affect NP toxicity.
\nSmall owing to their small size, NMs have unique physical and chemical characteristics such as magnetic, optical, thermal, mechanical, electrical properties which make them suitable in several applications including in medicine, electronics, and energy production, and in several consumer products. However, these very properties have the potential to affect humans and the environment adversely. NPs can easily penetrate cell membranes and other biological barriers into living organisms causing cell damage. Studies reporting increased toxicity of NPs when compared to their larger bulk particles have led to a generally assumed hypothesis that NPs are more potent in causing damage. Lankvel et al. [5] reported the significance of particle size of AgNPs, reporting size-specific tissue distribution and size-specific toxicity. Scown et al. [6] reported the lowest aggregation potential for the smallest AgNPs (i.e., 10 nm vs. 35 and 600–1600 nm) and was most highly concentrated in the gills and liver. Gaiser et al. [7] studied the acute and chronic toxicities of nano- and bulk Ag and CeO2. Reported mortality rates for Ag and AgNP were as follows: micro-Ag at 0.1 mg/L was 13% and at 1 mg/L was 80%, while for AgNP at 0.1 mg/L was 57% and at 1 mg/L was 100%.
\nAlthough NPs size can be the most distinguishing characteristic when compared to conventional particles, shape and morphology also represent important factors when considering NP toxicity. Morphology (particles, spheres, rods, cubes, truncated triangles, wires, films, and coatings) affects NP kinetics and their transport in the environment. NP shape is also of importance as triangular nanoplates was reported to have greater inhibition of
When NPs are discarded, they can enter the aquatic environment as aggregates and soluble ions, which can be highly toxic to aquatic organisms. Aggregation and dissolution are key processes governing NP behavior and toxicity in the aquatic environment. These processes are largely driven by size and surface properties of NMs, as well as by the stability of natural colloids (such as dissolved organic matter). Colloidal stability is affected by several factors including the type environmental conditions such pH, temperature, and ionic strength. Romer et al. [10], investigating the stability of AgNPs, reported rapid aggregation in media with high ionic strength. Similarly, Walters et al. [11] reported higher toxicity due to the formation of smaller aggregates at elevated temperatures. These and other studies reported changes in organism exposure levels and consequent toxicity due to levels of aggregation [12]. Dissolution of NPs is also a significant process determining NPs effects in the aquatic environment. Most NPs do not dissolve in solution, but form colloid dispersions which will either remain dispersed or aggregate. As such, interactions with other colloid materials will affect the rate at which particles aggregate in an aqueous environment.
\nIn the natural environment, NPs are not present in isolation. As such, it is important to consider the presence of other environmental stressors. For example, Walters et al. [13] reported that higher temperatures resulted in higher toxicity due to the formation of smaller aggregates at elevated temperatures and that AgNP dissolution and sedimentation contributed to a higher availability and toxicity of AgNP (and Ag+) to
Surface charge is a major factor in determining the particle dispersion characteristics and also will influence the adsorption of ions and biomolecules [15]. Baalousha [16] reported disaggregation of FeO NPs due to enhanced surface charge. Similarly, El Badawy et al. [17] reported surface charge-dependent toxicity of AgNPs. In addition, surface coating is indirectly related to aggregation and dissolution, as it is reported to increase the surface charge.
\nThese unique physical and chemical properties of NPs raise concern as the conventional assumptions of chemical reactivity and behavior may not necessarily apply with regard to NPs.
\nNanomaterial behavior and toxicity are influenced by their physical and chemical properties. As such, characterization of NMs is essential in order to understand how their physical and chemical properties correlate with chemical, ecological, or biological responses. Full characterization of NPs includes determining the bulk (shape, size, phase, electronic structure, and crystallinity) and surface (surface area, arrangement of surface atoms, surface electronic structure, surface composition, and functionality) properties of the NM. In addition, environmental factors (such as temperature, pH, ionic strength, salinity, organic matter) may also affect NP behavior and toxicity.
\nStandardized tests established by the Organization for Economic Co-operation and Development (OECD) summarized some of the analytical methods commonly used in the characterization of NMs (OECD ENV/JM/MONO (2016)2. The morphology of NMs is frequently characterized using scanning electron microscopy (SEM) or transmission electron microscopy (TEM). Energy-dispersive X-ray (EDX) spectrometry coupled to SEM is a common method to characterize elemental analysis of NMs. Particle size in aqueous phase may also be determined indirectly by dynamic light scattering (DLS) which measures the Brownian movement of the NPs, or by electrophoretic light scattering spectroscopy (ELS) which uses oscillating electric field. X-ray powder diffraction (XRD) is employed to measure particle size in the dry state and which applies the Scherrer method. Murdock et al. [18] investigated the use of DLS to characterize NM dispersion.
\nBrunauer-Emmet-Teller (BET) is used to measure surface area. Zeta potential measures surface charge in particles in the aqueous phase and is a fundamental parameters known to affect stability. Atomic force microscopy (AFM) and scanning tunneling microscopy (STM) allow three-dimensional imaging of nanometer scale surfaces and the measurement of forces between surfaces at the pico newton scale. UV-vis and Fourier transform infrared spectroscopy (FTIR) are spectroscopic techniques used in the characterization of fullerenes in solution [19, 20]. Surface enhanced Raman spectroscopy (SERS) is a surface-sensitive technique that enhances Raman scattering by nanostructures allowing the detection of single molecules. Chemical characterization techniques include Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), and Energy-dispersive X-ray spectroscopy (EDS) used to investigate the elemental composition of NMs.
\nDue to the surge in nanotechnology, there have been significant increases in the number of various NPs released into the aquatic environment. Figure 3 provides a summary of the possible routes in a typical aquatic environment to nanoparticles, potential interactions, and the possible clearance routes. Aquatic ecosystems are susceptible to environmental contamination since they are at the receiving end of contaminants, particularly from runoff sources. Identified sources of NPs in the aquatic environment include production facilities, production processes, wastewater treatment plants, and accidents during the transport. In addition, aquatic ecosystems are known to sequester and transport contaminants, including NMs. Baun et al. showed that NPs may adhere to algae which may then be consumed by filter-feeders and transfer to higher trophic levels. In the aquatic environment, NPs may aggregate thus reducing the NPs available for direct uptake in the aqueous phase by aquatic organisms. However, aggregated NPs may settle into sediment thereby posing a threat to benthic organisms. In the aquatic environment, NMs are generally associated with sediments [21]. Sediments and soil represent porous environmental matrices which typically have large specific surface areas.
\nPossible pathways of nanoparticles in the aquatic environment.
Uptake of nanoparticles into the aquatic biota is a major concern. Nanomaterials are able to cross biological barriers, gaining entering due to their small size. In aquatic organisms, the major routes of entry are via ingestion or direct passage across the gill and other external surface epithelia. In invertebrates, the cellular immune system, gut epithelium, and hepatopancreas are likely to be targeted [22]. Recent studies with Mozambique tilapia (
Endocytosis (<100 nm) and phagocytosis (100–100,000 nm) represent the two processes by which NPs might be absorbed into eukaryotic cells. At the cellular level, internalizations of NPs occur via endocytosis. Iron oxide NP internalization via endocytosis has been reported by Auffan et al. [26].
\nNPs released into the environment are affected by environmental factors such as pH, temperature, and presence of organic matter. The pH affects NP surface charge and consequently also aggregation. This has been reported by Gilbert et al. [27] who reported a pH-driven aggregation and disaggregation with larger aggregate radius at higher pH. Furthermore, Adams and Kramer [28] reported increased mobility under increased acidi-fication. Temperature is also known to affect aggregation. Walters et al. [11] reported that formation of smaller aggregates at higher temperatures suggests higher toxicity. Liu and Hurt [14] reported higher dissolution rates of AgNPs with increased temperature. NPs can be immobilized as a result of sorption or binding to particles such as organic matter. These effects have been reported. For example, Chen and Elimelech [29] reported that, in the presence of humic acid, the adsorbed humic acid on the fullerene NPs led to steric repulsion, stabilization of the NP suspension, and reduced aggregation.
\nMany studies have attempted to elucidate the mechanisms of NP toxicity and distinguish between their bulk counterparts. Nanomaterials differ from their bulk counterparts in several ways, including high surface/volume ratio. Other factors such as dissolution, size, shape, aggregation state, surface coatings, and solution chemistry also influence the toxicity of NPs.
\nThe toxicity of various NMs AgNP [5–7, 30–32]), CuO NP [19, 33], TiO2 NP [34], and Ni NP [23] has been studied in various aquatic species, such as
The assessment of NP toxicity has largely been assessed
Oxidative stress is referred to as an imbalance between the production of reactive oxygen species (ROS) and the cells’ ability to reduce ROS, which may be as a result an increased ROS production, a decrease in the cell’s defense mechanisms, or a combination of both [40]. An overproduction of ROS may induce oxidative stress, resulting in cells failing to maintain normal physiological redox-regulated functions further resulting in oxidative modification of proteins to generate protein radicals [41], initiation of lipid peroxidation [42], DNA strand breaks and modification to nucleic acids [43], modulation of gene expression [44], thereby leading to cell death and genotoxic effects [45]. To minimize the effects of ROS-oxidative damage to cellular components, biological systems have developed a complex antioxidant system, comprised of both enzymatic and non-enzymatic defense mechanisms. Figure 4 summarizes the redox cycle including ROS generation by NPs and the antioxidant defense system.
\nROS production and defense mechanisms (adapted from Unfired et al. [
The antioxidant defense system has evolved to provide a balance between the production and removal of ROS. These are catalyzed by a number of different enzymes including Phase I and Phase II enzymes. Phase I enzymes, such as cytochrome P450, initiate the detoxification process by introducing a polar moiety which renders a lipophilic contaminant more hydrophilic. Activity of Phase I enzymes typically leads to an increase in ROS production. Phase II enzymes are involved in conjugating metabolized xenobiotics to endogenous molecules. Phase III involves further modification and excretion.
\nThe potential role of oxidative stress as a mechanism of toxicity of AgNPs was evaluated by several authors. Walters et al. [13] studied oxidative stress, viz. antioxidant enzyme activity following a 7-day exposure to AgNPs (100 nm) at 10 and 100 μg/mL. The levels of ROS and oxidative stress were concentration-dependant, with an x-fold increase compared to control levels. Federici et al. [47] measured ROS generation following 14 days of exposure to TiO2 NPs (average particle size = 21 nm at 0.1, 0.5, or 1.0 mg/mL). The level of ROS (i.e., thiobarbituric acid-reactive substances (TBARS)) in the gills, intestine, and brain of the rainbow trout (
The potential ecotoxicity of NPs has currently provoked public and scientific dialogues due to debates around the risks and benefits of these materials. As such, studies on the ecotoxicological fate and effects of NMs have increased in recent years. There has been extensive research investigating the toxicity of NPs to aquatic organisms with several recent reviews reporting on ecotoxicology of NPs [3, 4]. Data on the biological effects of NPs indicate that NPs can be toxic to bacteria, algae, invertebrates, fish, and mammals. Nonetheless, nano-ecotoxicology studies remain poorly and unevenly distributed as most research undertaken has largely been restricted to a narrow range of test species. Most of the current ecotoxicological data pertaining to NMs have been done on
Nanoparticles are able to penetrate the semipermeable membranes of some aquatic organisms, thereby forming aggregates around the exoskeleton of aquatic organisms [52]. Uptake of various NPs by aquatic organisms crustacean
Nanoparticle internalization in some aquatic organisms.
Uptake of NPs generally occurs across the gills and other epithelial surfaces [6]. Scown et al. [6] reported size-dependant uptake of AgNPs (10–35 nm) and associated oxidative stress in the gills of
Studies showing enhanced ecotoxicity of NPs when compared to their bulk counterparts have led to the assumption that NPs generally represent a more potent threat. Once such study investigated the toxicity of various NPs with bulk counterparts [57], the authors reported significantly differences in toxicity (24-h LC50) between Al2O3 NPs (82 mg/L) and bulk Al2O3 (153 mg/L) and between TiO2 NPs (80 mg/L) and bulk TiO2(136 mg/L).
\nStudies reporting on reproduction and developmental end points are common. Wu et al. [58] recently showed that AgNPs induced a variety of morphological malformations such as edema, spinal abnormalities, fin fold abnormalities, heart malformations, and eye defects in Japanese medaka (
An important issue relating to the toxicity of NPs in biological media is the ability to cause damage to the genetic material, particularly since NPs have the capacity to cross cell membranes. In the section below, evidence of NP-induced genotoxicity is reviewed. DNA is a significant cellular component highly susceptible to oxidative damage. As such, there has been increasing interest in the analysis of the potential nanoparticle genotoxicity to aquatic organisms.
\nGenotoxic assessments of various NPs have largely been reported on in
As with NP toxicity, NPs are also known to have more adverse genotoxic effects than their bulk counterparts. For example, Park and Choi [32] studied the genotoxicity of AgNPs on the freshwater crustacean
As such, there is a general consensus that smaller sized NPs produce higher reactivity and thus higher genotoxicity [62, 63]. However, particle size is not the only factor that determines particle (geno-)toxicity. Nanoparticle surface coating has also been reported to promote genotoxicity. Surface coating modifies the particle surface, and therefore, they may also alter the particle’s genotoxicity. For instance, Hong et al. [64] reported positively charged coatings of iron oxide NPs which consequently resulted in increased DNA strand breaks, while the impact of genotoxicity of negatively charged coatings was insignificant. Similarly, Lui et al. [65] reported various genotoxic responses of iron oxide NPs depending on the type of coating. polyethylene glycol (PEG) coating exhibited mutagenic activity, while solid electrolyte interphase (SEI) exhibited no genotoxicity.
\nAs with ecotoxicological effects, genotoxicity effects of coated NPs have also been investigated. Ahamed et al. [66] reported that coated AgNPs resulted in more upregulation of these proteins, suggesting that coated Ag NPs causes greater genotoxicity than uncoated AgNP. In similar study, AshaRani et al. [35] investigated the genotoxicity of coated silver NPs vs. uncoated silver NPs in the zebrafish embryos (
The use of NMs in consumer products and their potential environmental and human health risks is of increasing concern. As nanotechnologies and products increase, nanoproducts entering the aquatic ecosystems and other water sources too will increase, thereby increasing the potential threat to aquatic organisms. This chapter provides a review of nanotoxicology—an emerging multidisciplinary field of science—with special focus on the effects of metal-NMs on aquatic invertebrates. NMs, depending on the size, shape, elemental materials, and the surface functional groups, induce oxidative stress thus leading to (nano)toxicity and genotoxicity. The risks associated with NMs (i.e., its fate, behavior, and toxicity in the environment) are largely unknown and difficult to predict. As the ultimate sink for conventional contaminants, the aquatic ecosystem is therefore predisposed to the potential effects of NPs.
\nAlthough our knowledge on the toxicity of various NMs in the aquatic environment has increased over the past few years, there is still a lack of knowledge regarding exposure concentrations, bioaccumulation in tissues, as well as environmental factors which could potentially affect its toxicity or bioaccumulation. Exposure to NPs is inevitable since NPs become more widely used, but there remains much more to be understood regarding their safety.
\nAlthough current toxicity testing protocols is generally applicable to identify deleterious effects associated with NPs, the mechanisms of action that govern toxicity of NMs are the subject of ongoing research. Research into new analytical methods is also required to address the special properties of NMs. The outcomes will thus enable researchers to predict the toxicological effects of AgNPs with the intent of guiding its development, application, and regulation. This will be important when considering measures for exposure control and environmental remediation of AgNPs.
\nThis research was supported by the Council for Scientific and Industrial Research (CSIR).
\nBrain malignancies are difficult to treat due to the blood–brain barrier (BBB), a layer of endothelial cells that separates the circulation from the brain and protects the central nervous system from pathogens and toxic materials [1, 2]. Although brain tumor cells cultured
IF7 is a linear 7-mer peptide with the sequence IFLLWQR [14]. This peptide is considered a carbohydrate mimetic, as it was identified in studies of cancer cell surface carbohydrates [15, 16]. Epithelial cancer cells express complex carbohydrate antigens, and some serve as ligands for carbohydrate binding proteins known as selectins. We hypothesized that interaction between selectin and selectin ligand functions in carbohydrate-dependent tumor cells colonization to the lung [17], in a manner similar to that seen in selectin-dependent hematogenous liver metastasis [18, 19].
Our goal, however, was challenging, as chemical synthesis of oligosaccharides as elaborate as the selectin ligand involved tedious, time-consuming and therefore expensive steps. To overcome this problem, we used phage display technology to identify carbohydrate mimetic peptides that might function as an E-selectin ligand. However, initially when we used E-selectin as the target, we did not obtain a phage clone. We then took a different approach and screened peptides for ability to bind anti-carbohydrate antibodies that recognize E-selectin ligands or related carbohydrates. Using this approach, we succeeded in identifying a linear 7-mer peptide from a phage display library. Since carbohydrate antigen specificity is determined by 3–4 carbohydrate residues of 600–800 Da, we assumed that a 7-mer peptide of 770 Da would mimic a carbohydrate antigen. The phage library screening yielded a series of peptides with the consensus sequence IXLLXXR [15] (Figure 1).
E-selectin binding of linear 7-mer peptide sequences. Phage clones were selected by mouse monoclonal anti-Lewis A antibody (clone 7LE). Each cloned phage was added to microtiter plate wells coated with E-selectin-IgG chimeric protein. Phage binding to E-selectin was tested in the presence or absence of 1 mM CaCl2. The best binder, IELLQAR, was designated I-peptide.
Among those peptides, the strongest binder to E-selectin was IELLQAR, which we designated I-peptide. Chemically synthesized I-peptide inhibited hematogenous colonization of the tumor cells to the lung in mouse [15]. However, in E/P-selectin doubly-deficient mice, tumor cells expressing selectin ligand carbohydrate colonized the lung, and that colonization was inhibited by I-peptide [20]. These results indicated that I-peptide receptor is not an E- or P-selectin and raised the question of what receptor I-peptide bound to in lung vasculature?
To identify the I-peptide receptor, we injected mice intravenously with a biotinylation reagent plus I-peptide-displaying phage or controls. We then isolated lung tissue and immunoprecipitated lysates with rabbit anti-phage antibody or control IgG. When we resolved immunoprecipitates on SDS-PAGE, we detected two
Detection of I-peptide receptor(s) on the surface of lung endothelial cells by
Full-length Anxa1 is 37 kDa; therefore, we considered the 20 kDa band seen in Figure 2 to be a fragment of the full-length protein. By the time we identified Anxa1 fragments, Oh
Next, to visualize tumor targeting by chemically synthesized IF7 peptide, we used intravital microscopy, in which tumor was implanted in a dorsal skinfold chamber [23] visualized tumor vasculature targeting of IF7 under fluorescence microscopy. Green fluorescent Alexa 488-labeled IF7 was injected intravenously and green fluorescent signals were recorded over time by video [14]. Fluorescence appeared in the tumor within 30 sec of injection and increased over time (Figure 5). Analysis of tumor tissue sections taken 15 minutes after A488-IF7 injection indicated fluorescent signals as a punctate staining pattern over endothelial cells (Figure 6, upper). By 40 min, green fluorescence had moved to the stroma (Figure 6, lower), suggesting that IF7 passed through endothelial cells and penetrated the tumor stroma where cancer cells reside. The punctate appearance of Alexa 488 staining suggests that IF7-bound to Anxa1 is internalized by endothelial cells, possibly in vesicles. Anxa1 on the tumor vasculature surface reportedly localizes in caveolae and, when bound by anti-Anxa1 antibody, the complex is internalized into vesicles transported to the basal surface via transcytosis [24]. Accordingly, we concluded that IF7 bound to Anxa1 on the tumor vasculature was transported from the luminal surface to the basal membrane via transcytosis through endothelial cells and likely released to the tumor stroma. Therefore, we asked whether IF7-conjugated chemotherapeutics could cross the BBB to deliver a cytotoxic drug to brain stroma.
Intravital microscopy of Alexa 488-conjugated IF7 peptide. Mouse lung carcinoma LL/2 tumors were inoculated in the skin of nude mice of a dorsal skin-fold chamber [
Fluorescence micrograms of subcutaneous B16 tumor sections from mice intravenously-injected with A488-IF7. Tissue sections taken at 15 (upper) and 40 (lower) min after A488-IF7 injection were stained by anti-CD34 antibody plus red fluorescence-conjugated secondary antibody to mark endothelial cells. Note that at 15 min, green IF7 signals are seen as punctate signals over endothelial cells, whereas at 40 min IF7 signals are in the stroma and seen as diffuse green fluorescence.
To test this possibility we injected A488-IF7 through the tail vein into brain tumor-bearing mice and then prepared sections of mouse brain tissue 20 minutes later. Fluorescence microscopy analysis revealed bright fluorescence in tumor tissue [25]. At higher magnification A488-IF7 fluorescent signals were evident in cytoplasm and/or nuclei of cancer cells. Micrographs of representative organs from the same mouse showed no significant fluorescent signals in normal organs. Brain tumors and representative organs from an animal injected with A488-C(RR) peptide control showed background fluorescence. These results strongly suggest that intravenously-injected IF7 crosses the BBB to target and penetrate brain tumor vasculature and reach cancer cells [25].
Several lines of evidence suggest that IF7 binds to human and mouse Anxa1 at the N-terminal domain. First, an IF7 peptide-displaying phage clone failed to bind full-length recombinant ANXA protein when the N-terminus was blocked by a His6-tag, whereas IF7 bound to full-length ANXA1 that was C-terminally tagged with His6 [14]. Second, IF7 bound to full-length ANXA1 but not to an N-terminal deletion delta 27 mutant [14]. Third, when IF7 peptide-displaying phage was injected intravenously into a tumor-bearing mouse, phage targeted the tumor vasculature, but that binding was blocked in comparable mice injected with an antibody raised against the ANXA1 N-terminal domain (Figure 4) [14]. Finally,
The molecular weight of full-length Anxa1 is 37 kDa, but Western blotting of endothelial plasma membranes and caveolae isolated from tumors detected a 34 kDa band [24]. Proteomics analysis of this 34 kDa protein suggested that it may lack the N-terminal domain. To determine whether the Anxa1 N-terminal domain is on the tumor vasculature surface, we generated a mouse monoclonal antibody specific to the human ANXA1 N-terminal domain (or MC16 peptide). Immunohistochemical analysis of various clinical specimens with anti-MC16 antibody revealed positive signals located at endothelial cells lining malignant tumor tissues in specimens from prostate, breast, lung, liver, ovarian and brain cancers [25], indicating that the ANXA1 N-terminus is present on endothelial cells in many human malignancies. Immunostaining alone did not reveal whether the antigen was on the cell surface or in the cytoplasm.
We confirmed that the MC16 domain was present on the luminal side of the plasma membrane by
Both we and others have reported that IF7-conjugated drugs show efficient anti-tumor activity in mouse models of tumors other than brain tumors. Examples include IF7-conjugated geldanamycin (GA) against prostate, lung, and breast cancers as well as melanoma [21], IF7-SN38 against colon cancer [21], IF7-taxol against breast cancer [26] and IF7-conjugated10B with boron neutron capture therapy against bladder carcinoma [27]. Below we focus on our studies of the effect of IF7-SN38 on mouse brain tumor models.
To target brain tumors, we chose to conjugate IF7 to SN-38, the active component of irinotecan (CPT-11), which is used clinically to treat brain cancer [28, 29]. To compare IF7-SN38 dosages we employed a dual-tumor model, in which a single mouse receives luciferase gene-transfected cancer cells in brain and under the skin (Figure 7). Growth of tumors in both regions was quantitatively monitored using an IVIS imager to detect photon numbers produced by luciferase. Once tumors were formed in the brain and under the skin, the dual tumor model mice were injected intravenously with IF7-SN38 and tumor growth in both locations was assessed
Analysis of whether IF7-SN38 overcomes the blood–brain barrier using a dual tumor mouse model. (upper) schematic showing that single mice established to harbor both brain and subcutaneous tumors are injected with IF7-conjugated drug through the tail vein. If the drug cannot overcome the BBB, only subcutaneous tumors are eradicated; if drug overcomes the BBB, growth of both is suppressed. (lower) graphs show that daily injection of IF7-SN38 (7.0 μmoles/kg) suppressed both brain (left) and subcutaneous (right) tumor growth. Moreover, CPT-11, the SN-38 pro-drug, suppressed growth of subcutaneous tumors at high dosage (50 μmoles/kg) [
For the dual tumor model experiments (Figure 7), we had dissolved IF7-SN38 in Cremophore EL, a non-ionic detergent used clinically to administer taxol, prior to injection. However, there are concerns about potential inflammatory effects of this detergent [30, 31]. Thus, we conducted experiments in which we dissolved IF7-SN38 in 10% Solutol HS15, a non-ionic surfactant with low toxicity. The therapeutic effect of IF7-SN38 in 10% Solutol HS15 improved significantly relative to administration with Cremophore EL (Figure 8A): B16 brain tumors began shrinking during the first week of daily injections at dosages as low as 2.5 μmoles/kg, continued shrinking during the second week without drug injection, and then completely disappeared. Mice survived for more than 3 months after cessation of drug treatment without showing signs of B16-Luc cell growth in brain or other parts of their body, suggesting complete remission and potential involvement of host immune systems.
IF7-SN38 treatment promotes complete remission of B16 brain tumors and a host immune response against tumor cells. (A) Effect of IF7-SN38 on B16-Luc brain tumors in isogeneic C57BL/6 mice. Drug dosage was 2.5 μmoles/kg each for IF7-SN38 and control C(RR)-SN38 diluted with 10% Solutol HS15 in water and administered daily for 7 days. Note that brain tumors continued shrinking after cessation of IF7-SN38 administration in C56BL/6 mice. (B) Growth of two syngeneic cancer lines in naïve and brain-tumor-recovered mice 4 days after subcutaneous injection of LL/2-Luc and B16-Luc cells. (C) Immunohistochemistry with anti-CD8 antibody of B16-Luc cells at subcutaneous injection sites, 20 hours after B16-Luc cell injection.
Relevant to potential immunogenicity, when we injected cells of either one of two isogenic lines, B16-Luc or LL/2-Luc, subcutaneously into naïve C57BL/6 mice, both lines produced tumors at injected site. By contrast, when either of these lines were injected into mice that had recovered from brain B16-Luc tumors, LL/2-Luc tumors grew but B16-Luc tumors did not (Figure 8B). The presence of tumor-infiltrating lymphocytes, especially CD8+ cytotoxic T cells, is correlates with better prognosis of various cancers [32, 33]. Immunohistochemistry of subcutaneous B16-Luc injection site using an anti-CD8 antibody 20 hours after injection of naïve C57BL/6 mice with B16-Luc cells revealed a minimal number of CD8+ T cells at challenged sites. By contrast, we observed significant CD8+ cell infiltration at injection sites of B16-Luc cells in C57BL/6 mice that had recovered from B16-Luc brain tumors following IF7-SN38 treatment (Figure 8C). Thus it is likely that IF7-SN38 therapy leads to complete remission in part by promoting immunological rejection of tumor cells by the host, preventing tumor recurrence elsewhere in the body.
As described, in mouse the Anxa1 N-terminal domain is present on the surface of tumor vasculature as peptide fragments. Nonetheless, such fragments should serve an IF7 receptor, as either the first 15 amino acid residues of ANXA1 or synthetic MC16 peptide is sufficient for IF7 binding [25]. IF7 binds both human and mouse MC16 peptides equally, suggesting that our results with IF7 in mouse tumor models are relevant to humans.
Although IF7-conjugated drugs are effective in various cancer types [14, 26, 27], their effectiveness against brain malignancies may be particularly high as gene expression data indicates
Mode of action of chemotherapeutics directed against brain tumors. General chemotherapeutics do not penetrate brain tumors due to the BBB and thus are administered to patients at high dosage. Some low molecular weight chemotherapeutics such as temozolomide penetrates the brain but requires high dosage, because temozolomide does not target brain tumors. IF7-SN38 targets brain tumors and overcomes the BBB. At low dosage, IF7-SN38 becomes concentrated in tumors, including brain tumors, and exhibits therapeutic activity.
We found the effective dosage of IF7-SN38 in the mouse brain tumor models to be 2.5 μmoles (5.35 mg)/kg (Figure 8), which translates into a human equivalent [36] of 0.43 mg/kg or SN-38 0.079 mg. This dosage is considerably lower than that currently recommended for CPT-11 (the SN-38 pro-drug) administered to cancer patients, namely, 120 ~ 200 mg/m2 or 2.91 ~ 4.85 mg/kg [37, 38]. Anticipated doses of IF7-SN38 in humans are also unlikely to be toxic at pharmacologically active dosage.
Historically, reagents like IF7 emerged with the advent of carbohydrate mimetic peptides [15, 16]. The surprising finding that Anxa1 is an I-peptide receptor led us to identify IF7 [14, 21]. When IF7 was injected intravenously into brain tumor-bearing mice, it targeted tumor vasculature by binding the Anxa1 N-terminal domain and then crossed the vasculature via transcytosis, to overcome the BBB. Due to its highly specific tumor vasculature targeting activity, IF7-SN38 eradicated brain tumors at low dosage, initiating an immune reaction against cancer cells, followed by complete remission of brain tumors [25]. A similar host immune reaction was also found in IF7-conjugated boron neutron capture therapy in a mouse bladder carcinoma model [27].
IF7-SN38 is, however, susceptible to esterases and proteases. To circumvent stability issues, we have developed an ANXA1-binding D-peptide, designated dTIT7 [39]. We have found that GA-dTIT7, in which geldanamycin is conjugated to dTIT7 through an esterase-resistant linker, is orally administrable and suppresses brain tumor growth in the mouse.
Cancer treatments are increasingly expensive due to development of sophisticated diagnostics and therapies. IF7-SN38 can be chemically synthesized cost-effectively and is stable as a dry powder. Furthermore, orally-administrable peptide-conjugated drugs would be advantageous in societies that lack infrastructure required for costly treatment. Further development of peptide-conjugated drugs could reveal additional candidates with clinical applications against intractable cancers.
We thank Dr. Elise Lamar for her editing of the manuscript.
The authors declare no conflict of interest.
Supporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.
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MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. The performance of these filters will be compared exploitation the applied mathematics parameter Peak Signal-to-Noise Ratio (PSNR).",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications",title:"High-Resolution Neuroimaging",fullTitle:"High-Resolution Neuroimaging - Basic Physical Principles and Clinical Applications"},signatures:"Hanafy M. Ali",authors:[{id:"213318",title:"Dr.",name:"Hanafy",middleName:"M.",surname:"Ali",slug:"hanafy-ali",fullName:"Hanafy Ali"}]},{id:"41589",doi:"10.5772/50323",title:"The Role of the Amygdala in Anxiety Disorders",slug:"the-role-of-the-amygdala-in-anxiety-disorders",totalDownloads:9671,totalCrossrefCites:4,totalDimensionsCites:28,abstract:null,book:{id:"2599",slug:"the-amygdala-a-discrete-multitasking-manager",title:"The Amygdala",fullTitle:"The Amygdala - A Discrete Multitasking Manager"},signatures:"Gina L. Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"146553",title:"BSc.",name:"Andrew",middleName:null,surname:"Novick",slug:"andrew-novick",fullName:"Andrew Novick"},{id:"146554",title:"MSc.",name:"Jamie",middleName:null,surname:"Scholl",slug:"jamie-scholl",fullName:"Jamie Scholl"},{id:"146555",title:"Dr.",name:"Michael",middleName:null,surname:"Watt",slug:"michael-watt",fullName:"Michael Watt"}]},{id:"26258",doi:"10.5772/28300",title:"Excitotoxicity and Oxidative Stress in Acute Ischemic Stroke",slug:"excitotoxicity-and-oxidative-stress-in-acute-ischemic-stroke",totalDownloads:7157,totalCrossrefCites:6,totalDimensionsCites:25,abstract:null,book:{id:"931",slug:"acute-ischemic-stroke",title:"Acute Ischemic Stroke",fullTitle:"Acute Ischemic Stroke"},signatures:"Ramón Rama Bretón and Julio César García Rodríguez",authors:[{id:"73430",title:"Prof.",name:"Ramon",middleName:null,surname:"Rama",slug:"ramon-rama",fullName:"Ramon Rama"},{id:"124643",title:"Prof.",name:"Julio Cesar",middleName:null,surname:"García",slug:"julio-cesar-garcia",fullName:"Julio Cesar García"}]},{id:"62072",doi:"10.5772/intechopen.78695",title:"Brain-Computer Interface and Motor Imagery Training: The Role of Visual Feedback and Embodiment",slug:"brain-computer-interface-and-motor-imagery-training-the-role-of-visual-feedback-and-embodiment",totalDownloads:1439,totalCrossrefCites:13,totalDimensionsCites:23,abstract:"Controlling a brain-computer interface (BCI) is a difficult task that requires extensive training. Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:192666,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. Vaccaro",authors:[{id:"91165",title:"Prof.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"63258",title:"Anatomy and Function of the Hypothalamus",slug:"anatomy-and-function-of-the-hypothalamus",totalDownloads:4558,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"The hypothalamus is a small but important area of the brain formed by various nucleus and nervous fibers. Through its neuronal connections, it is involved in many complex functions of the organism such as vegetative system control, homeostasis of the organism, thermoregulation, and also in adjusting the emotional behavior. The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing. It also modulates the endocrine system through its connections with the pituitary gland. Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3478,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3601,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. Wydell",authors:[{id:"87489",title:"Prof.",name:"Taeko",middleName:"N.",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}]},{id:"58597",title:"Testosterone and Erectile Function: A Review of Evidence from Basic Research",slug:"testosterone-and-erectile-function-a-review-of-evidence-from-basic-research",totalDownloads:1331,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81646",title:"Cortical Plasticity under Ketamine: From Synapse to Map",slug:"cortical-plasticity-under-ketamine-from-synapse-to-map",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104787",abstract:"Sensory systems need to process signals in a highly dynamic way to efficiently respond to variations in the animal’s environment. For instance, several studies showed that the visual system is subject to neuroplasticity since the neurons’ firing changes according to stimulus properties. This dynamic information processing might be supported by a network reorganization. Since antidepressants influence neurotransmission, they can be used to explore synaptic plasticity sustaining cortical map reorganization. To this goal, we investigated in the primary visual cortex (V1 of mouse and cat), the impact of ketamine on neuroplasticity through changes in neuronal orientation selectivity and the functional connectivity between V1 cells, using cross correlation analyses. We found that ketamine affects cortical orientation selectivity and alters the functional connectivity within an assembly. These data clearly highlight the role of the antidepressant drugs in inducing or modeling short-term plasticity in V1 which suggests that cortical processing is optimized and adapted to the properties of the stimulus.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Ouelhazi Afef, Rudy Lussiez and Molotchnikoff Stephane"},{id:"81582",title:"The Role of Cognitive Reserve in Executive Functioning and Its Relationship to Cognitive Decline and Dementia",slug:"the-role-of-cognitive-reserve-in-executive-functioning-and-its-relationship-to-cognitive-decline-and",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.104646",abstract:"In this chapter, we explore how cognitive reserve is implicated in coping with the negative consequences of brain pathology and age-related cognitive decline. Individual differences in cognitive performance are based on different brain mechanisms (neural reserve and neural compensation), and reflect, among others, the effect of education, occupational attainment, leisure activities, and social involvement. These cognitive reserve proxies have been extensively associated with efficient executive functioning. We discuss and focus particularly on the compensation mechanisms related to the frontal lobe and its protective role, in maintaining cognitive performance in old age or even mitigating the clinical expression of dementia.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Gabriela Álvares-Pereira, Carolina Maruta and Maria Vânia Silva-Nunes"},{id:"81488",title:"Aggression and Sexual Behavior: Overlapping or Distinct Roles of 5-HT1A and 5-HT1B Receptors",slug:"aggression-and-sexual-behavior-overlapping-or-distinct-roles-of-5-ht1a-and-5-ht1b-receptors",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104872",abstract:"Distinct brain mechanisms for male aggressive and sexual behavior are present in mammalian species, including man. However, recent evidence suggests a strong connection and even overlap in the central nervous system (CNS) circuitry involved in aggressive and sexual behavior. The serotonergic system in the CNS is strongly involved in male aggressive and sexual behavior. In particular, 5-HT1A and 5-HT1B receptors seem to play a critical role in the modulation of these behaviors. The present chapter focuses on the effects of 5-HT1A- and 5-HT1B-receptor ligands in male rodent aggression and sexual behavior. Results indicate that 5-HT1B-heteroreceptors play a critical role in the modulation of male offensive behavior, although a definite role of 5-HT1A-auto- or heteroreceptors cannot be ruled out. 5-HT1A receptors are clearly involved in male sexual behavior, although it has to be yet unraveled whether 5-HT1A-auto- or heteroreceptors are important. Although several key nodes in the complex circuitry of aggression and sexual behavior are known, in particular in the medial hypothalamus, a clear link or connection to these critical structures and the serotonergic key receptors is yet to be determined. This information is urgently needed to detect and develop new selective anti-aggressive (serenic) and pro-sexual drugs for human applications.",book:{id:"10195",title:"Serotonin and the CNS - New Developments in Pharmacology and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg"},signatures:"Berend Olivier and Jocelien D.A. Olivier"},{id:"81093",title:"Prehospital and Emergency Room Airway Management in Traumatic Brain Injury",slug:"prehospital-and-emergency-room-airway-management-in-traumatic-brain-injury",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.104173",abstract:"Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Dominik A. Jakob, Jean-Cyrille Pitteloud and Demetrios Demetriades"},{id:"81011",title:"Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition as a Background for Future Clinical Applications",slug:"amino-acids-as-neurotransmitters-the-balance-between-excitation-and-inhibition-as-a-background-for-f",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.103760",abstract:"For more than 30 years, amino acids have been well-known (and essential) participants in neurotransmission. They act as both neuromediators and metabolites in nervous tissue. Glycine and glutamic acid (glutamate) are prominent examples. These amino acids are agonists of inhibitory and excitatory membrane receptors, respectively. Moreover, they play essential roles in metabolic pathways and energy transformation in neurons and astrocytes. Despite their obvious effects on the brain, their potential role in therapeutic methods remains uncertain in clinical practice. In the current chapter, a comparison of the crosstalk between these two systems, which are responsible for excitation and inhibition in neurons, is presented. The interactions are discussed at the metabolic, receptor, and transport levels. Reaction-diffusion and a convectional flow into the interstitial fluid create a balanced distribution of glycine and glutamate. Indeed, the neurons’ final physiological state is a result of a balance between the excitatory and inhibitory influences. However, changes to the glycine and/or glutamate pools under pathological conditions can alter the state of nervous tissue. Thus, new therapies for various diseases may be developed on the basis of amino acid medication.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Yaroslav R. Nartsissov"},{id:"80821",title:"Neuroimmunology and Neurological Manifestations of COVID-19",slug:"neuroimmunology-and-neurological-manifestations-of-covid-19",totalDownloads:41,totalDimensionsCites:0,doi:"10.5772/intechopen.103026",abstract:"Infection with SARS-CoV-2 is causing coronavirus disease in 2019 (COVID-19). Besides respiratory symptoms due to an attack on the broncho-alveolar system, COVID-19, among others, can be accompanied by neurological symptoms because of the affection of the nervous system. These can be caused by intrusion by SARS-CoV-2 of the central nervous system (CNS) and peripheral nervous system (PNS) and direct infection of local cells. In addition, neurological deterioration mediated by molecular mimicry to virus antigens or bystander activation in the context of immunological anti-virus defense can lead to tissue damage in the CNS and PNS. In addition, cytokine storm caused by SARS-CoV-2 infection in COVID-19 can lead to nervous system related symptoms. Endotheliitis of CNS vessels can lead to vessel occlusion and stroke. COVID-19 can also result in cerebral hemorrhage and sinus thrombosis possibly related to changes in clotting behavior. Vaccination is most important to prevent COVID-19 in the nervous system. There are symptomatic or/and curative therapeutic approaches to combat COVID-19 related nervous system damage that are partly still under study.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Robert Weissert"}],onlineFirstChaptersTotal:17},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"22",title:"Business, Management and Economics",doi:"10.5772/intechopen.100359",issn:"2753-894X",scope:"\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:null},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null,editorialBoard:[{id:"114318",title:"Dr.",name:"David",middleName:null,surname:"Rodeiro",slug:"david-rodeiro",fullName:"David Rodeiro",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2a8QAC/Profile_Picture_2022-04-22T08:29:52.jpg",institutionString:null,institution:{name:"University of Santiago de Compostela",institutionURL:null,country:{name:"Spain"}}},{id:"114073",title:"Prof.",name:"Jörg",middleName:null,surname:"Freiling",slug:"jorg-freiling",fullName:"Jörg Freiling",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2UPQA0/Profile_Picture_1642580983875",institutionString:null,institution:{name:"University of Bremen",institutionURL:null,country:{name:"Germany"}}},{id:"202681",title:"Dr.",name:"Mojca",middleName:null,surname:"Duh",slug:"mojca-duh",fullName:"Mojca Duh",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD2dQAG/Profile_Picture_1644907300283",institutionString:null,institution:{name:"University of Maribor",institutionURL:null,country:{name:"Slovenia"}}},{id:"103802",title:"Ph.D.",name:"Ondrej",middleName:null,surname:"Zizlavsky",slug:"ondrej-zizlavsky",fullName:"Ondrej Zizlavsky",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQJQA0/Profile_Picture_1643100292225",institutionString:null,institution:{name:"Brno University of Technology",institutionURL:null,country:{name:"Czech Republic"}}},{id:"190913",title:"Dr.",name:"Robert M.X.",middleName:null,surname:"Wu",slug:"robert-m.x.-wu",fullName:"Robert M.X. Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/190913/images/system/190913.jpg",institutionString:"Central Queensland University",institution:{name:"Central Queensland University",institutionURL:null,country:{name:"Australia"}}}]},{id:"87",title:"Economics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. He has advised, among others, the United Nations Development Program, Inter-American Development Bank, Organization of American States, Pre-investment Organization of Latin America and the Caribbean, Technical Cooperation of the Suisse Government, and the World Bank. Dr. Ortiz is the author, co-author, or editor of books, book chapters, textbooks, research monographs and technical reports, and refereed journal articles. He is listed in Who’s Who in the World, Who’s Who in America, Who’s Who in Finance and Business, Who’s Who in Business Higher Education, Who’s Who in American Education, and Who’s Who Directory of Economists. Dr. Ortiz has been a Fulbright Scholar and an MSI Leadership Fellow with the W.K. Kellogg Foundation. His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"104262",title:"Dr.",name:"Chee-Heong",middleName:null,surname:"Quah",slug:"chee-heong-quah",fullName:"Chee-Heong Quah",profilePictureURL:"https://mts.intechopen.com/storage/users/104262/images/system/104262.jpg",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},{id:"236659",title:"Prof.",name:"Monica Violeta",middleName:null,surname:"Achim",slug:"monica-violeta-achim",fullName:"Monica Violeta Achim",profilePictureURL:"https://mts.intechopen.com/storage/users/236659/images/system/236659.jpg",institutionString:null,institution:{name:"Babeș-Bolyai University",institutionURL:null,country:{name:"Romania"}}},{id:"202039",title:"Dr.",name:"Nahanga",middleName:null,surname:"Verter",slug:"nahanga-verter",fullName:"Nahanga Verter",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCwtQAG/Profile_Picture_1643101901237",institutionString:null,institution:{name:"Mendel University Brno",institutionURL:null,country:{name:"Czech Republic"}}},{id:"107745",title:"Emeritus Prof.",name:"Panagiotis E.",middleName:null,surname:"Petrakis",slug:"panagiotis-e.-petrakis",fullName:"Panagiotis E. 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