*3.2.1 Advantages of microwaves in solid-state conditions*

Microwave energy can be defined as non-ionizing electromagnetic radiation with frequencies between 300 MHz and 300 GHz [48]. Similar to the effects of sonochemistry in liquid-state conditions, microwaves can be beneficial to solid-state synthesis procedures to increase the interaction between the powders of raw materials. Unlike traditional calcination techniques, the heating direction is from the inside to the outside of the heated sample in microwave conditions. This situation could assist both to increase reaction yield in solid-state conditions and to decrease the byproduct formation. The temperature increase is supplied with the microwave effects. The reaction costs can be reduced effectively with the optimization of reaction

*Magnesium Borates: The Relationship between the Characteristics, Properties, and Novel… DOI: http://dx.doi.org/10.5772/intechopen.104487*

conditions. In the reaction procedure, microwave power level and microwave treatment time are notable operating parameters. However, the relationship between the microwave parameters and supplied temperature increase has not been comprehensively studied. In that case, more detailed experimental setups should be designed for the determination of the reaction mechanisms.

Very few studies indicated the possible use of microwave energy in magnesium borate synthesis. Kipcak et al. [49, 50], proved the beneficial effects of microwave to decrease the reaction time in magnesium borate synthesis in comparison with traditional calcination techniques [49, 50].

## **3.3 Hybrid synthesis**

Hybrid synthesis procedure can be defined as the combination of liquid and solidstate conditions. The experimental procedure generally begins in hydrothermal conditions and continues with a solid-state step. Pechini, combustion, and sol-gel synthesis techniques can be assumed as examples of hybrid synthesis [51]. The steps of the hybrid procedure could be more complex than the traditional techniques; however, high purity and homogeneous morphology can be obtained. To strengthen the properties of magnesium borates, hybrid methods should be supported with novel technologies.

Gonzalez et al. [27], synthesized the Tm and Ag-doped MgB4O7 with the reaction of Mg(NO3)2 and H3BO3 in urea medium, at the calcination temperature range of 750– 950°C by using the combustion method [27]. Zhang et al. [37]; preferred the capping agent of N, N, dimethylformamide nitrate to fabricate the hierarchic porous particles of magnesium borates. The liquid-state reaction occurred at 150°C for 12 hours whereas the solid-state reaction continued at 600°C for 12 hours [37]. Chen et al. [44], fabricated the mesoporous structure of Mg2B2O7 in microsphere morphology by adding the SDS to the reaction medium of Mg(NO3)2 and borax. The two-step process began with the 80°C for 2 hours and continued with 500°C for 4 hours [44]. Wang et al. [52], prepared the fibers of magnesium borates with a two-step reaction. The mixture of MgCl2 and borax is reacted at 80°C for 12 hours and then sintered at 800°C for 6 hours [52]. In the hybrid synthesis of Zhu et al., the high purity of Mg2B2O5 was synthesized with the reaction of MgCl2, H3BO3, and NaOH [53].

The comparison of the obtained morphological features of hybrid and traditional procedures can be seen in **Figure 8**. The uniform particle formation was obtained in

### **Figure 8.**

*The comparison of the obtained particle morphologies (a) hybrid [44], and (b) traditional [6] synthesis.*

### **Table 3.**

*Comparison of traditional and advanced synthesis techniques.*

the hybrid synthesis of Chen et al. [44] whereas the heterogeneous morphology can be seen in the traditional hydrothermal synthesis of Derun et al. [6].


**Author details**

Cherian Paul1 \* and Ramasamy Sellamuthu2

1 Department of Mechanical Engineering, SAINTGITS College of Engineering, Kottayam, Kerala, India

2 Department of Mechanical Engineering, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Coimbatore, Tamilnadu, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**93**

*Development of Functionally Gradient Cu-Sn-Ni Alloy Using GTA Heat Source*

[10] Zhang SZ, Jiang B, Ding WJ. Wear of Cu-15Ni-8Sn spinodal alloy. Wear.

[11] Zhang SZ, Jiang B, Ding WJ. Dry sliding wear of Cu-15Ni-8Sn alloy. Tribology International.

2009;**264**(3-4):199-203

2010;**43**(1-2):64-68

*DOI: http://dx.doi.org/10.5772/intechopen.86315*

[1] Benkisser G, Horn G, Semjonov S, Kaps R. Surface layer hardening of heterogeneous multialloy aluminium bronzes by laser beam melting. Metall.

investigation on the effect of process parameters on microstructure, hardness and wear properties of surface modified Cu-Sn bronze alloy. Applied Mechanics and Materials. 2014;**592-594**:58-62

[3] Gadag SP, Galun R, Weisheit A, Mordike BL. Laser alloying of copper and its alloys. In: Laser Processing: Surface Treatment and Film Deposition.

[4] Yilbas BS, Matthews A, Leyland A, Karatas A, Akhtar SS, Abdul Aleem BJ. Laser surface modification treatment of aluminium bronze with B4C. Applied Surface Science. 2012;**263**:804-809

[5] Yilbas BS, Akhtar SS, Karatas C. Laser notriding of the surface of phosphor bronze. International Journal of Advanced Manufacturing Technology. 2013;**65**:1553-1565

[6] Kac S, Kusinski J. Structure and properties of the bronze laser alloyed with titanium. Applied Surface Science.

[7] Viswanadham CS, Goswami GL, Galun R, Mordike BL. Laser melt injection of TiC particles into aluminium bronze. Laser in engineering. 2006;**16**:207-213

[8] Majumdar JD, Manna I. Laser processing of materials. Sadhana.

[9] Singh JB, Cai W, Bellon P. Dry sliding of Cu-15 wt%Ni-8 wt%Sn bronze: Wear behaviour and microstructures. Wear.

2003;**28**(3&4):495-562

2007;**263**:830-841

2007;**253**:7895-7898

Vol. 307. 1996. pp. 359-377

**References**

1992;**46**(4):324-328

[2] Paul C, Sellamuthu R. An

*Development of Functionally Gradient Cu-Sn-Ni Alloy Using GTA Heat Source DOI: http://dx.doi.org/10.5772/intechopen.86315*


Preface

Noise and vibration are two interrelated terms in the field of engineering. Vibration is caused by unbalanced inertial forces and moments, whereas noise is the result of such vibrations. Such phenomena have always been a matter of concern for both researchers and practicing engineers. The lower level of vibration can ensure less tear and wear, less tolerance, and longer fatigue life of the machine or structure. This book presents the established fundamentals in the area of passive, semi-active, and active vibration control, and explores the new and emerging technologies and techniques. There has been a considerable amount of effort devoted to the development and realization of methodologies for the control of sound and vibration, and this book covers the latest theoretical, algorithmic, and practical applications, including:

*Chapter 1:* A hysteresis nonlinear model is established for a giant magnetostrictive actuator to fully describe the actuator dynamic characteristics.

*Chapter 2:* The dynamic modeling and simulation of proportional–integral– derivative controls for rail car systems are investigated.

*Chapter 3:* Effective low-frequency noise insulation active damping approaches are illustrated to improve a structure's noise insulation performance.

*Chapter 4:* The dynamic behavior of aero-elastic vibrations in the presence of nonlinear stiffness such as free-play mechanisms and softening or hardening stiffness is investigated.

*Chapter 5:* Background information on the assistance of ultrasonic vibration in the hot glass embossing process is provided.

*Chapter 6:* The generation mechanism of the self-sustained tone is clarified experimentally and numerically, and the methods for suppressing a self-sustained tone using baffle plates and perforated plates are investigated.

*Chapter 7:* The relationship between energy of vibration and noise signals measured in the magnetic resonance imaging scanning area and its vicinity are mapped to minimize these negative impacts.

*Chapter 8:* Empirical results quantifying various signals from heartbeat to material vibration are investigated.

It is my hope that this book, which integrates the modeling and design aspects of various noise and vibration control techniques, will serve as a comprehensive guide and reference for practicing engineers and educators, and, more importantly, is a welcome-mat for recent graduates entering the vibration control engineering profession.

> **Dr. Ehsan Noroozinejad Farsangi** Assistant Professor, Department of Earthquake Engineering, Graduate University of Advanced Technology, Kerman, Iran

Chapter 1

Abstract

control, active control

1. Introduction

agency [5, 6].

1

Active Control

Nonlinear Giant Magnetostrictive

Actuator and Its Application in

Lihua Yang, Haipeng Zhang, Hailong Jiang, Shuyong Liu,

Haiping Wu, Haifeng Li and Ehsan Noroozinejad Farsangi

The giant magnetostrictive actuator has great use in vibration control, but the linear model cannot fully describe its dynamic characteristics. In this chapter, based on the domain wall theory and piezomagnetic theory, a hysteresis nonlinear model is established to fully describe the actuator dynamic characteristics. In combination with the regularisation method, a sliding mode controller has been designed, and the giant magnetostrictive actuator is also studied in the application of active control. Experimental results show that the hysteresis nonlinear model proposed in the chapter can fully describe the actuator's dynamic characteristics in a wider frequency band and the active control also has a much better isolation effect than the passive vibration; it can significantly attenuate the external incentives.

Keywords: giant magnetostrictive actuator, hysteresis nonlinearity, sliding mode

Passive vibration isolation has been widely used as an effective isolation method; it can significantly reduce the vibration transmission between mechanical equipment and the base, while the isolation effect is limited in the micro-vibration and low frequencies. Therefore, the active control has been a focus of research at home and abroad [1–4]. With the development of smart materials, intelligent actuators manufactured by those materials including the magneto-rheological actuator, shape memory alloy actuator, giant magnetostrictive actuator (GMA), and others. These actuators have played a huge role in promoting the active control as the executing

With the advantages of high-positioning accuracy, fast response, and wide frequency band, among others, the GMA has a wide variety of applications in fields including vibration control and precision positioning [7–10]. Many scholars have studied the linear modelling method of GMA, which is only suitable for describing low-frequency dynamic characteristics [11, 12]. However, the hysteresis nonlinear model based on the domain walls theory can more clearly reveal the coupling relationship among the magnetization process, the stress magnetic machine effect, and stretching amount, and it can more fully describe the GMA's dynamic characteristics on a wide frequency band [13], which is suitable for the active control


**1. Introduction**

*Staphylococcus aureus* is a Gram-positive bacterium that lives in symbiosis with humans, it is an opportunistic and potentially lethal pathogen [1, 2] of great clinical importance due to the different virulence, invasiveness and resistance factors that it may possess [3]. In humans, it colonizes various tissues, forming part of the normal microbiota [3, 4], although it is also one of the principal cause of community-associated and nosocomial-associated infections; is one of the main causes of bacteremia and infective endocarditis, as well as skin, soft tissue and pleuropulmonary infections and contamination of medical devices [4]. Invasive disease is associated with a mortality rate of ≥20% [2]. Uncontrolled use of antibiotics, particularly their inappropriate and excessive use, has favored the emergence and maintenance of strains of *S. aureus* resistant to multiple antibiotics such as penicillin (penicillin-resistant *S. aureus*, PRSA), methicillin (methicillin-resistant *S. aureus*, MRSA) [5, 6] or vancomycin, strains with high rates of morbidity and mortality in many countries of the world [5]. The most studied primary reservoir site for *S. aureus* in humans is the nose, predominantly found in the anterior nasal vestibule [7]. Approximately 30% or more of the world population is colonized with *S. aureus* on the skin, mucous membranes, or in the nose [4, 5] (**Figure 1**).

#### **Figure 1.**

S. aureus *can cause a wide range of diseases by spreading to various tissues, among the survival mechanisms being the formation of biofilms regulated by several genes such as the accessory regulatory gene* agr *and by intracellular infection mechanisms (Modified from Sasegbon and Hamdy. [49]).*

The mechanisms of colonization and persistence of *S. aureus* in the human nose have been extensively studied, however, it must be recognized that the clinical relevance of *S. aureus* carriers in the pharynx has not been sufficiently investigated [8]. This omission seems to be justified, if the nose is considered as the primary site of colonization of *S. aureus*, from there, other regions of the body are colonized by manual propagation [9]. However, in the adult population *S. aureus* can be commonly found in other parts of the body such as the armpits (8%), chest / abdomen (15%), perineum (22%), intestine (17–31%), vagina (5%) [10].

*S. aureus* carriers have been found in the pharynx and have been reported with high variability in different populations from 4 to 64% [11], some studies mention a higher rate of carriers in the pharynx than in the nose when samples are taken in parallel [10, 12, 13].

Colonization of *S. aureus* in the nose and pharynx is a multifactorial process that involves genetic aspects of the host, virulence factors of the pathogen, and possible interactions between the microbiota of the host [14], although in principle it is thinks that colonization of the pharynx is secondary to colonization of the nose, it is likely that both processes are independent [15].

#### **2. Human determinants**

The human determinants that allow bacterial colonization can be changes at the molecular level that alter the adhesiveness, recognition and eradication properties. Epidemiological studies present little information related to molecular studies [10].

The anterior nostrils are one of the main reservoir niches of *S. aureus*, however, the colonization of the nose begins from a cutaneous site, where the bacterium plays

#### *Factors of Nasopharynx that Favor the Colonization and Persistence of* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.95843*

a role of commensal microbiota and, through contact with contaminated hands, spreads to the nose and other parts of the body [16].

Colonization of the nose begins a few days after birth [17]. Between 40 and 50% of newborns become carriers during the first eight weeks of life but decreases to 21% in the sixth month [18]. In another research, 80% of identical strains were found among mother–child pairs, and in 90% of newborns, *S. aureus* came from the maternal nose [16].

Days after birth, the hands are the main source of transmission of *S. aureus* from contaminated surfaces to the nose. Reagan et al. [19] demonstrated by means of a randomized, double-blind and placebo-controlled trial, the link between the passage from the hand to the nose of *S. aureus*, in addition they demonstrated that nasal decolonization with mupirocin decreased the carriage in the hands and nose [16].

Research in people living in the same household has found that they tend to carry genetically similar nasal strains, suggesting their horizontal transmission. Furthermore, it has been shown that the carriage of MRSA strains in various parts of the body increases the risk of nasal colonization by MRSA [16].

#### **2.1 Overview of the nostrils**

The nasal passage filters 95% of the particles with a diameter greater than 15 μm from the inspired air. The nose is extremely important in protecting the distal airways from the influence of gases, aerosols, and pathogens [20].

The anterior part of the nasal cavity (*vestibulum nasi*) is formed with stratified squamous epithelium, non-ciliated keratinized (60% of the strains of *S. aureus* originating from the nose are isolated in this part). It has also been shown that *S. aureus* can colonize and persist in ciliated nasal epithelial cells in the inner part of the nasal cavity (internal nostrils) with pseudostratified columnar ciliated epithelium [9, 14].

The epidermis and dermis are the two main layers that line the *vestibulum nasi.* The dermis is a connective tissue that contains both epidermal and lymphatic structures, and vascular ducts, nerves, nerve endings, collagen, and elastic fibers, as well as a wide variety of specialized immune cells [7].

The epidermis is made up of the basal, spiny, granular, lucid and corneal striatum [7]. These five main strata are characterized by cells in different stages of differentiation, during which the anterior nasal epithelial cells change their appearance to keratinized squamous anucleated cells called corneocytes, these cells form the stratum corneum (also called cornified layer) being the most external, they are also surrounded by a protein structure containing loricrin and involucrin (**Figure 2**) [7, 14]. The upper layers of the keratinized epithelium are constantly being replaced, which could contribute to the elimination of the attached bacteria, however, this does not happen [14].

#### *2.1.1 Loricrin*

Epithelial tissues are the main appendages that protect the internal organs of the body from environmental stress, chemical damage, and microbial infections. The stratified epithelia seen on the skin and oral mucosa are one of the most resistant and protective epithelia, as it resists severe physical and chemical forces and do so by producing a hardened structure: the cornified cell envelope (CE). Loricrin is an important component of keratins. These keratins are structural proteins and constitute approximately 85% of a fully differentiated keratinocyte (**Figure 3**) [21, 22].

#### **Figure 2.**

*Nasal colonization sites of* S. aureus*. 1.* Vestibulum nasi *or nasal cavity, is the ecological niche of* S. aureus *in humans.* S. aureus *Has a large amount of adhesins such as ClfB (light blue line), IcaA (strong blue line), Spa (orange line), SdrC (green dots), FnBPA (pink triangle), which can bind to various proteins of the nasal epithelial cells such as keratin and loricrin (red line), involucrin (purple line), unknown receptors (black triangle), fibronectin (gray rectangle). 2. The inner part of the nasal cavity can also be colonized by* S. aureus *and survive for a long time, at this site it binds by multiple load interactions by the teichoic acids of the bacterial wall (WTA) with the SREC-1 nasal cell receptor. (modified from Sakr et al. [16]).*

#### **Figure 3.**

*Location of loricrin, involucrin, keratin and other macromolecules in mature corneocytes (modified from Ishitsuka and Roop. [21]).*

Loricrin is an insoluble polypeptide with a molecular weight of 26 kDa. It has a conserved epitope and is a major cornified envelope protein seen in the cytoskeleton of the stratified parakeratinized epithelium. Being a late differentiating protein, it is introduced into the cornified envelope structure due to its cross-linking and binding property. It improves the function of the corneocyte protective barrier in differentiated keratinocytes [21].

Loricrin occupies an important part (70%) of the cornified epidermal envelope. Its concentration is reduced to approximately 30–50% in certain areas such as the palate and esophagus, while it is not expressed in many internal epithelia such as the oral mucosa. In *in vivo* studies in mammalian tissues, loricrin has a very high expression in all stratified epithelia, and is expressed even more in moist tissues of

#### *Factors of Nasopharynx that Favor the Colonization and Persistence of* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.95843*

newborns such as the epidermis, foreskin, epidermal sweat ducts, in addition to the oral and anal mucosa and the esophagus [21, 22].

In vitro analysis and studies in animal models have revealed that the main colonization target ligand of *S. aureus* is loricrin, binding with clumpling factor B (ClfB) in squamous epithelial cells [23].

#### *2.1.2 Involucrin*

Involucrin is a soluble cytosolic protein that is the precursor of the cornified envelope, its main function is to donate a glutamyl or glutamine in the crosslinking reaction catalyzed by the enzyme transglutaminase and it disappears from the soluble phase after the activation of calcium-dependent transglutaminase. 20% of its structure is glutamate and 25% glutamine. An important biochemical characteristic of involucrin is that it contains a central domain composed of 39 tandem repeats of 10 amino acids each segment, this repetitive structure is conserved in the involucrins of all higher primates, only varying the number of repeats [24]. In the cornified structure, involucrin is adjacent to the cell membrane, when the cell membrane is replaced, involucrin is the main substrate to which lipids esterify, primarily ceramides, are covalently attached to form the outer surface of the cornified envelope (**Figure 3**) [25].

The iron-regulated surface determining protein (IsdA) promotes the adhesion of *S. aureus* to squamous cells that cooperate in binding to the cornified cell envelope with the host proteins loricrin, involucrin, and cytokeratin [26].

#### *2.1.3 Cytokeratine 10 (K10)*

In the epidermis, keratinocytes travel from the basal cell layer to the postmitotic spinous suprabasal cells, and during the process, there is a significant change in the expression of basal cell keratins (K5, K14, and K15) to suprabasal epidermal keratins first to type II K1 keratin and later to type I K10 keratin. The keratin filaments are structurally composed of the K1 / K10 pair and form dense bundles, characteristic of suprabasal epidermal keratinocytes, and this gives the cells and the entire epidermis mechanical integrity (**Figure 3**). However, there are more functionalities, as K10 has been shown to specifically inhibit the proliferation and progression of the keratinocyte cell cycle and the decrease in K10 leads to an increase in keratinocyte renewal [27, 28].

It has been shown that cytokeratin 10 is a receptor for ClfB of *S. aureus*, which facilitates the nasal colonization of this and other bacteria [29].

#### **2.2 Interactions with the nasal cavity**

Another ecological niche of *S. aureus* in addition to the *vestibulum nasi* is the internal part of the nasal cavity (**Figure 2**). The teichoic acids of the bacterial wall (WTA) are a principal factor for the colonization process. A study reported in an animal model that mutated strains deficient in the *tagO* and *tarK* genes that participate in WTA biosynthesis did not adhere to or colonize the nose cells of cotton rats compared to control bacteria [14].

Baur et al. [30] re-studied the adhesion to nasal cells of WTA and reported the expression of the SREC-1 receptor (from the family of Scavenger receptors type F) in the nose of cotton rats and in epithelial cell lines of the human internal nasal cavity. In addition, they found that SREC-1 interacts with WTA and verified it in cotton rats infected with a previous treatment with anti-SREC-1 antibodies, significantly decreasing colonization after 8 hours and 6 days after inoculation compared to the control group.

#### *2.2.1 SREC-1 receptor*

The key role that WTA plays in the early colonization stages of *S. aureus* has been demonstrated, however, until recently the ligand with which it binds to initiate adhesion and colonization with the host was found.

The Scavenger receptor superfamily can bind and endocyte many ligands, which causes the elimination of both exogenous and unnecessary endogenous molecules [31]. It is important to mention that the affinity for the ligands is shared by several Scavenger receptors, regardless of whether their classes (A-J) have little or no biochemical homology [31, 32].

The Scavenger 1 class F receptor (SREC-1, SCARF1 or SR-F1), is the most expressed by endothelial cells (of the Scavenger family). It is a type I transmembrane protein that weighs 86 kDa, contains some epidermal growth factors (EGF) with similarity to the extracellular region, a small transmembrane domain, and a long cytoplasmic tail rich in proline and serine [33].

The size of the cytoplasmic domains could have a role in intracellular signaling, however, this function has not been found. SREC-1 is an evolutionarily highly conserved receptor, particularly in the extracellular domain, and shows significant homology with the *Caenorhabditis elegans* Scavenger receptor CED-1, important in homeostasis and innate immunity of *C. elegans* [34].

SREC-1 was obtained from human umbilical vein endothelial cells (HUVEC), but its expression has been reported in multiple cells, including epithelial cells [30], sinusoidal endothelial cells [33, 35], dendritic cells, B-1 cells. [36] and macrophages [35, 36]. It is important to mention that almost all studies focused on the functionality of this receptor have used transfected cell lines, designed to express the receptor extracellularly in vitro, and some studies have used cells that naturally express the SREC-1 receptor in vivo [33]. Furthermore, the first reports of the expression of this receptor showed high transcriptional expression in multiple human tissues such as spleen, lung, heart, liver, and kidney and it has been corroborated in murine tissues [33, 36]. However, more studies are needed to investigate its expression and cellular distribution at the protein quantity in these tissues. So far, there is only one study that has fully characterized the cellular distribution and expression of the SREC-1 receptor in healthy and chronically ill human liver [35]; therefore, much remains to be studied to understand the activity of this receptor in human cells and tissues [33].

#### **2.3 Individual host factors favoring nasal colonization of** *S. aureus*

Some studies have found that *S. aureus* nasal carriers are more common in people infected with the Human Immunodeficiency Virus (HIV) [37] and obese patients [38], compared to healthy individuals. Nowak et al. [39] published the positive correlation between percentage of body mass and susceptibility to colonization by *S. aureus* in healthy male individuals. This high prevalence was also reported in diabetic dialyzed patients, compared with non-diabetic patients [16]. Other diseases such as granulomatosis with rheumatoid arthritis, skin and soft tissue infections [40], atopic dermatitis, and recurrent furunculosis have been associated with an increased carrier rate [16].

Contrary to what was reported by Nowak et al. [39], Liu et al. [41] found similar percentages of carriers in women and men, however, men had a higher density of bacteria. To date, it has not been confirmed that hospital workers are at increased risk of being nasal carriers of *S. aureus* compared to the rest of the population [42, 43]. The association between nasal carriers of *S. aureus* and

#### *Factors of Nasopharynx that Favor the Colonization and Persistence of* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.95843*

smoking is controversial, Olsen et al. [44], reported that healthy active smokers are protected from becoming carriers of *S. aureus*, due to the possible antibacterial activity of tobacco. However, another experimental inoculation study showed that smokers are colonized more frequently than non-smokers and that quitting smoking improves clearance of *S. aureus* nasal [45]. Other host pathologies, such as hormonal contraception [46], have also been extensively studied, and the presence of hemoglobin in nasal secretions has been reported as an additional predisposing factor [16].

Regarding host genetics, no significant heritability data has been detected for nasal colonization of *S. aureus* in twins and family studies [47, 48]. However, some polymorphisms have been found in genes involved in inflammatory processes and have been associated with the carriage of *S. aureus* in the nose, for example, the phenotype of the histocompatibility antigen HLA-DR3 could be a predisposition [16].

The host cell presents modified carbohydrates and secretes surface proteins, such as blood group antigens, which are involved in bacterial adhesion and colonization. An investigation found that people with blood group O have a 6.5 times higher risk of being carriers of *S. aureus* in the pharynx, compared to people with blood group A [9].

#### **2.4 Overview of the pharynx**

The pharynx is a muscular chamber that serves the respiratory and digestive systems to receive air for the nasal cavity and food and water for the oral cavity [49]. The oropharynx consists of five layers: mucosa, submucosa, pharyngobasilar fascia, constrictor muscle, and oropharyngeal fascia [50]. The pharynx has stratified non-ciliated epithelium that secretes mucus with mucin. Specifically, the posterior wall of the oropharynx (and the soft palate) is lined by a nonkeratinized stratified squamous epithelium, supported by an underlying lamina propria and a muscular layer. In the palatal and lingual tonsil regions, there are nodules of lymphoid tissue located below the epithelium, each tonsil is in a fixed position, in other regions there are membrane-associated lymphoid tissue [MALT], found throughout the body. The structural support is mainly provided by reticular fibers composed of type III collagen. These fibers condense and combine with elastin fibers to form septa that dissect the tonsillar parenchyma [50]. *S. aureus* can bind to multiple ligands of the pharynx such as collagen, fibronectin, fibrinogen through adhesin proteins such as Cna, FnBa, FnBb, among others (**Figure 4**) [16].

The oropharynx links the mouth, nasopharynx, lower respiratory tract, and gastrointestinal tract and is always exposed to a large number of microorganisms, both exogenous and endogenous. The set of species to be studied is wide, since there are very diverse bacterial communities in both adults and the elderly. The pharynx is also a niche for pathogenic bacteria that can cause localized (pharyngitis) or disseminated disease (primarily lung disease or systemic if spread) [51].

#### *2.4.1 Importance of the study of* S. aureus *in the pharynx*

The pharynx has recently been identified as a potential colonization site for *S. aureus*, this colonization can occur in the presence or absence of nasal colonization [52]. Being a carrier of *S. aureus* in the pharynx has potentially important implications in decolonization strategies for populations at high risk of infection, it is unlikely that topical drugs aimed at eradicating nasal colonization affect transport in the throat, therefore which could be an important focus in future infections if *S. aureus* persists in the pharynx [53].

#### **Figure 4.**

*Colonization of* S. aureus *in the human pharynx.* S. aureus *Competes directly with bacteria that predominantly colonize the pharynx; it is known that bacteria such as* Streptococcus pneumoniae*,*  Streptococcus mutans*,* Streptococcus mitis*, among others, inhibit the growth of* S. aureus*. Regarding the colonization mechanism, so far only the same ones as in the nose have been studied, for example, their binding to fibrinogen, fibronectin, collagen, among other proteins expressed in both anatomical sites, however, they have not been analyzed in depth its specific interactions with the pharynx.*

Most of the *S. aureus* detections, in particular MRSA, are only made from nasal swabs, since the pharyngeal swab is not considered a standard, Mertz et al. [54] mention that some drawbacks of pharyngeal exudate is causing discomfort to the patient and that it increases the cost to the health care system without significantly greater sensitivity. However, as mentioned above, pharyngeal colonization may be more common than nose colonization than has been published.

The rate of nasal carriers of MRSA in hospital patients has been found to be 5.9 to 15.6%, however, the rate of pharyngeal MRSA carriers is between 10 and 23.1%, which represents a greater number of carriers in the pharynx [55].

Cirkovic et al. [56] conducted a study of carriers and genetic diversity of MRSA in 195 hospitalized patients and 105 workers of a University Hospital in Serbia and reported a rate of 32.2% of exclusive MRSA carriers in the nose and another 32.2% of exclusive carriers of the pharynx, in addition of 35.5% of MRSA carriers in both sites, so the exclusion of pharyngeal exudates would result in a significant error in a substantial part of this work, since around a third are MRSA carriers exclusive to the pharynx [12, 13].

#### *2.4.2 Interaction of* S. aureus *with the microbiota*

Pathogenic bacteria can coexist with their host in two ways, as harmless microbiota microorganisms or as invading pathogens that enter healthy tissues after overcoming innate defense mechanisms or if the immune system is compromised [57]. Despite microbiology studies regarding infection mechanisms, ecological studies of pathogenic microorganisms present in the human microbiota are still lacking [58].

In vitro and in vivo studies that simulate colonization by *S. aureus*, as well as analysis of microbiomes and metagenomes reveal that the nose presents an intermediate level of bacterial diversity compared to the human oral cavity and intestine, but they present greater diversity than the vagina, which has less diversity. A percentage of the human population carries several bacterial species in the nose, such as *Finegoldia magna*, *Dolosigranulum pigrum* and *Salmonella* spp., are negatively correlated with colonization by *S. aureus* [41, 59]. It is not known how the nasal microbiota can prevent *S. aureus* colonization. Understanding this mechanism can help to understand why about 30% of the human population is persistently colonized by *S. aureus*, another 30% is highly resistant to nasal colonization by *S. aureus*, and the remainder are considered intermittent carriers [58].

*Factors of Nasopharynx that Favor the Colonization and Persistence of* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.95843*

#### *2.4.3 Nasal microbiota*

The nasal cavity of humans harbors a diverse bacterial community that is in principle stable at the gender level [41, 59, 60], but may vary between individuals and with season [61] In the same way, other places in the human body that are exposed to the environment are the skin and the oropharynx [61–63]. The dynamics of the nasal microbiota have not yet been analyzed. The analysis of the nasal microbiota is performed by amplification and sequencing of the 16S rRNA gene, that in many cases it is not possible to distinguish between species, therefore should implement shotgun metagenome sequencing techniques [58].

Many species of nasal bacteria are anaerobic [64], indicating that part of the nasal epithelium is barely exposed to air in the nasal cavity. Many species cannot be cultivated in vitro, they require special growth conditions [58].

Bacteria in the nose belong mainly to three phyla (Actinobacteria, Firmicutes, and Proteobacteria) and 80% humans or more are colonized with *Corynebacterium* spp., *Propionibacterium* spp., and *Staphylococcus* spp. [62, 65, 66]. Other genera are found less frequently [41].

Based on the abundance of characteristic species in the human nose, seven types of community status (CST) have been defined. (CST), each of which represents a nasal bacterial community dominated by *S. aureus* (CST1), Enterobacteriaceae (*Escherichia* spp., *Proteus* spp., *Klebsiella* spp. and others; CST2), *S. epidermidis* (CST3), *Propionibacterium* spp. (CST4), *Corynebacterium* spp. (CST5), *Moraxella* spp. (CST6) or *Dolosigranulum* spp. (CST7) [41]. *S. aureus* was found in several CSTs, although much less frequently than in CST1 [58].

During the first years of life, the microbiota of the respiratory tract develops [67, 68]. The oral microbiota is similar to that of the skin, but is less similar to that of the oral cavity. So the nose could be an intermediate step between these two niches [62]. The microbiota of the sebaceous and moist areas of the skin is more similar to that of the nose than to the dry areas of the skin [61]. *Streptococcus spp.* is abundant in the oral cavity, but it is found in low numbers in the nose [69]. Species of Coagulase-negative *Staphylococcus* (SCN), such as *Staphylococcus capitis*, *Staphylococcus warneri*, *Staphylococcus hominis*, and *Staphylococcus lugdunensis*, are prevalent on the skin, but they are only found in the nasal cavity of some people, with the exception of *S. epidermidis*, which colonizes both the nose and the skin of most people [58].

#### *<IP_ADDRESS> Factors influencing composition of the nasal microbiota*

Bacterial communities in the nose undergo seasonal variations, mainly during the change from winter to spring [70]. The environment plays an important role in the composition of the nasal microbiota as factors such as humidity, temperature, dust or pollen influence [41, 70]. Furthermore, smoking has been shown to prevent nasal colonization by *S. aureus* [44], although it is still under discussion [45]. Some studies have shown that the gender and genetic composition of the host have a moderate influence on the colonization of *S. aureus*, however the type of nasal microbiota seems to be an important factor for the colonization of this bacterium [41, 48]. Furthermore, nasal colonization by *S. aureus* hardly varies between humans of different ethnic and geographic origins [70]. The various regions of the nose, from the anterior vestibule to the sphenoethmoidal recess in the posterior nasal cavity, are lined with mucus, thus differing in the composition of the microbiota between individuals [60].

Metagenomic studies have shown the importance of the role of bacteriophages in the dynamics of the microbiota of the skin and intestine [71]. In the human nose the abundance and diversity of bacteriophages have not yet been analyzed, they can alter the nasal microbiota. Bacteriophages are one of the main mechanisms for horizontal transfer of virulence and antibiotic resistance genes between staphylococci and other bacteria, which can contribute to the appearance of new strains [72].

#### *<IP_ADDRESS> Competition for nutrients*

Unlike the gastrointestinal microbiota, bacteria in the nasal cavity do not interact with food in the diet and can only acquire nutrients that are excreted by cells, so nasal secretions contain few nutrients [73] and are has hypothesized that bacteria in the nasal microbiota compete for scarce nutrients. Nasal secretions contain NaCl in physiological concentrations (~ 150 mM) and low levels of potassium, magnesium, and phosphate. Carbohydrates, amino acids, and other nutrients are found in nasal secretions in much lower amounts than those found in plasma [58]. There is a synthetic nasal medium (SNM), containing nutrients in the same amounts as in nasal fluid, allowing *S. aureus* to develop, but most SCNs cannot grow under these conditions or grow very slowly [73]. This would indicate that most of the SCNs present in the nose are only transitory and are not a permanent colonization site for these bacteria. Many of the genes involved in the nutrient absorption systems and anabolic metabolic pathways in *S. aureus* are highly expressed in NMS or in the nose [73]. *S. aureus* is successful when it competes with other nasal microorganisms as it depends on its ability to grow in low amounts of nutrients. Nasal bacteria do not always compete with other bacteria for nutrients, in certain cases they can also cooperate with others to obtain specific nutrients, such as *S. aureus* and *Corynebacterium accolens* that seem to have a mutualistic relationship [60].

The main carbohydrate in nasal fluids is glucose and it is found in low concentrations (between 35 μM and 1 mM, with an average value of ~370 μM) [73] which depends on the nutritional status of the person. The colonized by *S. aureus* is higher in diabetic people, perhaps due to high concentrations of nasal glucose. Sialic acids, which line the membrane of eukaryotic cells, can be an important source of energy for bacteria in the nasal cavity [58]. Many bacteria can metabolize sialic acids how *S. aureus* and some SCNs including *S. intermedius, S. lugdunensis*, and *S. saprophyticus*, but not *S. epidermidis*, can absorb and use sialic acid [74].

*S. aureus* is the only one of the staphylococci that can degrade the main phosphatidylcholine group that is released from eukaryotic cells, extracellular glycerophosphocholine (GroPC)*. S. aureus* can grow with GroPC as the sole carbon source so it can survive in limited nutrient conditions [58].

Nasal fluids contain several of the 20 amino acids necessary for protein biosynthesis in concentrations between 10 μM and 250 μM; however, several such as methionine, tyrosine, aspartate, asparagine, glutamine, and isoleucine are found in very low concentrations [73] so they need to be synthesized by nasal bacteria. This was verified since a mutant of *S. aureus* that presents a deficiency in the synthesis of methionine was isolated and this affected its growth in the cotton rat nasal colonization model [14, 73]. In certain sites of the nose, the concentrations of amino acids and peptides may be higher, *S. aureus* and other nasal bacteria secrete proteases that can degrade host proteins, which are found in high concentrations in nasal fluids, such as albumin, lactoferrin, mucins, cytokeratin 10, and hemoglobin [75]. *S. aureus* produces approximately ten extracellular proteases, which makes it different from most other nasal bacteria that do not produce extracellular proteases or produce only a few [76].

Nasal discharge, in addition to being low in nutrients, is also poor in essential metal ions such as zinc, manganese, iron, and other host proteins such as calprotectin and lactoferrin, which sequester these ions from the nasal cavity to prevent

#### *Factors of Nasopharynx that Favor the Colonization and Persistence of* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.95843*

bacterial growth [75]. Because of this, the microbiota needs specific mechanisms to compete with the host's defense, known as "nutritional immunity" [58].

When the growth of nasal bacteria slows due to a lack of nutrients, some bacteria produce antimicrobial substances to inhibit competing bacteria, these antimicrobial substances are normally ribosomally synthesized and post-translationally modified peptides (RiPP) or nonribosomal peptide-synthetase (NRPS) enzymes. Bacteria that produce these molecules are protected from specific immunity. Antimicrobial RiPPs (called bacteriocins) sometimes have a limited range of activity and are produced against specific groups of nasal bacteria. Most bacteriocins in nasal bacteria show changes such as thiazole heterocycles, lanthionine bridges (lantibiotics), and oxazole (microkines) or pyridine rings (thiopeptides) [77]. There are not many reports of bacteriocins in bacterial species isolated from the human nose [78].

Nasal strains of *Staphylococcus* spp. were studied for antimicrobial substances and found to be produced with a high frequency (86%) and a wide diversity of activities against groups of nasal bacteria. Due to this, bacteriocins can play a very important role in the formation of the nasal microbiota. Most members of Firmicutes and Proteobacteria are unaffected by the inhibitory activities of staphylococci, except *Dolosigranulum pigrum* and *Moraxella catarrhalis*. However, some bacteria of the phylum Actinobacteria, such as *Corynebacterium pseudodiphtheriticum* and *Micrococcus luteus*, were inhibited by staphylococcal bacteriocins [79]. These susceptible bacteria may be the main competitors of nasal staphylococci [58]. Most of the staphylococcal genes used in bacteriocin biosynthesis are found in mobile genetic elements forming part of plasmids or on the bacterial chromosome, which undergo extensive genetic rearrangements and horizontal gene transfer [79].

Bacteriocins have a wide variation in amino acid sequence, which can cause changes in the spectrum of activity [80, 81]. Due to this, the evolutionary process could have increased and changed the type of nasal bacteria, causing changes in the composition of the microbiota. This is the case with thousands of genes that produce secondary metabolites, many of which are potential antimicrobial substances. In investigations of the human metagenome of different surfaces of the human body, it was found that antimicrobial peptides can play an important role in the maintenance of the human microbiota [81]. In an investigation of nasal strains, *S. epidermidis* strains were found to be the main antimicrobial-producing bacteria, while *S. aureus* rarely produces these substances. The production of various antimicrobials is favored by stressful conditions during colonization, such as iron limitation or the presence of hydrogen peroxide (H2O2), indicating that many antimicrobials are tightly regulated [79].

Most staphylococcal bacteriocins are inactive for *S. aureus*. But, *S. lugdunensis* can synthesize an antimicrobial compound called lugdunin that inhibits and kills *S. aureus*. Lugdunin is encoded by the bacterial genome and is the first identified antimicrobial NRP produced by a human commensal bacterium, and represents a new class of cyclic peptide antibiotics containing thiazolidine. The lugdunin production operon is present in almost all nasal strains of *S. lugdunensis*, allowing this bacterium to compete with and kill *S. aureus*. People colonized by *S. lugdunensis* have a six times lower risk of being carriers of *S. aureus* than people who are not colonized [82]. Similarly, SCNs that produce certain bacteriocins can prevent *S. aureus* from colonizing the skin in patients with atopic dermatitis [83]. These results show the importance of the production of antimicrobial compounds by commensal bacteria that can prevent colonization by pathogenic bacteria such as *S. aureus* [58]. Another enzyme called lysostafin that is produced by *Staphylococcus simulans* could degrade the cell wall of multiple species of staphylococci, including *S. aureus*, by hydrolyzing the pentaglycine bonds that bind peptidoglycan [84].

Other bacteria in the nose use indirect methods to inhibit the growth of competing bacteria, such as *S. pneumoniae*, which is found mainly in the throat and rarely in the nose, but colonization by *S. pneumoniae* prevents colonization of the nose by *S. aureus* [58]. Possibly, this inhibition may be due to the release of hydrogen peroxide, a metabolite produced by *S. pneumoniae* that produces the generation of free radicals that damage DNA, and which also activates the prophages contained in the genome of *S. aureus* strains, which that causes the lysis of bacteria [85]. Also, *S. pneumoniae* can interfere with *S. aureus* in other ways, such as by inducing cross-reactive antibodies that prevent *S. aureus* colonization [86]. Viridans group streptococci (*S. mitis*, *S. sanguis*, *S. oralis*, *S. mutans*, and *S. sobrinus*) have also been found to prevent MRSA colonization of the pharynx in newborns, due to bacteriocin activity of peroxidase type [87].


*Article* **High-Precision Monitoring of Volume Change of Commercial Lithium-Ion Batteries by Using Strain Gauges**

**Lisa K. Willenberg 1,2, Philipp Dechent 1,2, Georg Fuchs 1,2, Dirk Uwe Sauer 1,2,3,\* and Egbert Figgemeier 2,4,\***

Received: 17 December 2019; Accepted: 9 January 2020; Published: 11 January 2020

**Abstract:** This paper proposes a testing method that allows the monitoring of the development of volume expansion of lithium-ion batteries. The overall goal is to demonstrate the impact of the volume expansion on battery ageing. The following findings are achieved: First, the characteristic curve shape of the diameter change depended on the state-of-charge and the load direction of the battery. The characteristic curve shape consisted of three areas. Second, the characteristic curve shape of the diameter change changed over ageing. Whereas the state-of-charge dependent geometric alterations were of a reversible nature. An irreversible effect over the lifetime of the cell was observed. Third, an s-shaped course of the diameter change indicated two different ageing effects that led to the diameter change variation. Both reversible and irreversible expansion increased with ageing. Fourth, a direct correlation between the diameter change and the capacity loss of this particular lithium-ion battery was observed. Fifth, computer tomography (CT) measurements showed deformation of the jelly roll and post-mortem analysis showed the formation of a covering layer and the increase in the thickness of the anode. Sixth, reproducibility and temperature stability of the strain gauges were shown. Overall, this paper provides the basis for a stable and reproducible method for volume expansion analysis applied and established by the investigation of a state-of-the-art lithium-ion battery cell. This enables the study of volume expansion and its impact on capacity and cell death.

**Keywords:** lithium-ion batteries; ageing; mechanical fatigue; volume change; measurement technique; silicon anode


**3.** *RELN***-Related Human Neurological Conditions and Their Mouse Counterparts**

Several human neurological conditions have a direct or indirect link with *RELN* and its encoded protein, as well as with the components of the RELN signaling pathway (Figure 1 and Table 1). We will briefly describe these conditions below, aiming to put in the better perspective those features that may be useful for well understanding the translational relevance of the *Reeler* mouse.

**Figure 1.** Summary of the most relevant human pathologies modeled in the *Reeler* mouse. The monogenic conditions provoked by the *RELN* gene, i.e., ADLTE and LIS2, are in red, those related to genes encoding for the proteins of the Reln intracellular cascade or only tentatively linked to RELN are indicated in blue. Autism and schizophrenia, which have a complex multifactorial etiology, are in black with an interrogative mark to underline the still tentative association of the two disorders with *RELN*.

Note that only LIS2 and autosomal-dominant lateral temporal epilepsy (ADLTE) have a demonstrated link with *RELN*. *RELN* may be relevant for *LIS1*.

#### *3.1. Neurological Conditions Caused by RELN Mutations*

Several diseases are based on mutations of *RELN* or of genes encoding for proteins associated with the RELN signaling pathways. Among these, lissencephaly 2 (LIS2) and autosomal-dominant lateral temporal epilepsy (ADLTE) are of relevance to the present discussion as they have a clear genetic link with *RELN*.

#### 3.1.1.  Broadly speaking, the structural phenotype in lissencephalies ranges from a thickened cortex and complete absence of sulci (agyria) to a thickened cortex with a few, shallow sulci (pachygyria) [23]. The main feature of classic lissencephaly, formerly referred to as type I lissencephaly but today named lissencephaly 1 (LIS1), is a marked thickening of the cerebral cortex with a posterior to anterior grade of severity. An anomalous neuronal migration in the interval between the ninth to the thirteenth week of pregnancy causes LIS1, resulting in an assortment of agyria, mixed agyria/pachygyria, and pachygyria. An abnormally thick and ill ordered cortex with four highly disorganized layers, diffuse neuronal heterotopia, enlarged cerebral ventricles of anomalous shape, and, often, hypoplasia of the corpus callosum are typical of LIS1 [24]. The basal ganglia are normal, except that the anterior limb of the internal capsule is usually not noticeable, and, most often, the cerebellum is normal as well.

Lissencephalies are now classified based on brain imaging results and molecular investigation [25], as they have been associated with mutations in several genes such as *LIS1* (*PAFAH1B1*; MIM#601545), *DCX* (Doublecortin; MIM#300121), *ARX* (Aristaless-related homeobox gene; MIM#300382), *RELN* (Reelin; MIM#600514), *VLDLR* (MIM#224050) and *TUBA1A* (αtubulin 1a) [26]. Some rare forms of lissencephaly (LCH) are associated with a disproportionately small cerebellum.

#### Lissencephaly 2

#### a) Humans

Lissencephaly 2 (LIS2) also referred to lissencephaly syndrome, Norman–Roberts type or Norman–Roberts syndrome (OMIM #257320) is associated with *LIS1* but displays several specific clinical features. In 2000, Hong and colleagues were the first to describe an autosomal recessive form of lissencephaly that, at MRI, also exhibited severe alterations of the cerebellum, hippocampus, and brainstem. More specifically, these alterations consisted of a thickening of the cerebral cortex with a simplified convolutional pattern that was particularly evident in the frontal and temporal lobes, whereas the parietal and occipital lobes were almost normal. The hippocampus was unfolded and flattened, lacking definable upper and lower blades. The corpus callosum was thin and the lateral ventricles enlarged. The cerebellum was clearly smaller than in the normal brain, hypoplastic, and devoid of folia. Authors also showed that the responsible gene mapped to chromosome 7q22 and that the condition was associated with two independent mutations in *RELN*, resulting in low or undetectable amounts of RELN after Western blots analysis of the patients' serum [9]. Two other unrelated groups of patients, later, presented the same type of LIS2 [27]. They were children that, at MRI, displayed a 5–10 mm thick cerebral cortex, a malformed hippocampus and a very hypoplastic cerebellum, almost completely devoid of folia. As LIS2 is a rare disease, there are very limited histopathological data on the condition. To our knowledge, the only post-mortem description of a male fetus with Norman–Roberts syndrome reported the occurrence of a four-layered cerebral cortex (Figure 2A,B), a well-developed cerebellum with organized folia, and heterotopia of the dentate nucleus [28].

**Figure 2.** Structural alterations in human, LIS2, and homozygous *Reeler* mouse (**A**–**D**)**;** modifications of the neocortex architecture in human LIS2 (**B**); and *Reeler* mutation (**D**); compared to healthy controls (**A**,**C**). After MRI imaging, the human LIS2 cortex is thicker than normal, whereas there are apparently no thickness changes in mouse. Note that in both species the pathological neocortex only consists of four layers, with an upside-down layer disposition mainly affecting the pyramidal neurons that are also irregularly oriented compared to their usual positioning in normal individuals/mice. Pyramidal neurons are in different color and sizes according to their position in cortical layers. Stellate spiny cells of layer 4 are orange. Inhibitory interneurons are black with a red nucleus. Cajal-Retzius cells of layer 1 are red.

(**E**–**H**): Structural alterations in the *Reeler* mouse cerebellum; (**E**) sagittal sections of the P15 cerebellum in a normal *reln*+/+ mouse; and (**F**) a *Reeler reln*−/− mouse: the *Reeler* cerebellum is much smaller and devoid of folia, with a smooth surface. (**G**) Misalignment of the Purkinje neurons in the P60 cerebellum of the *Reeler* mouse. After calbindin 28 kDa immunostaining, the Purkinje neurons are well aligned in a monolayer below the molecular layer in *reln*+/+ mice. They, instead, form a large internal cellular mass within the white matter in *reln*−/− mutants (**H**). Abbreviations: DAPI = 4- ,6-Diamidine-2- -phenylindole; GL = granular layer of the cerebellar cortex; ICM = internal cellular mass; ML = molecular layer of the cerebellar cortex; P = postnatal day.

#### b) *Reeler* Homozygous Mice

Alterations in *Reeler* homozygous recessive mice fully recapitulate those in human LIS2 (Figure 1). Due to obvious technical and practical reasons, the amount of MRI data in mouse is by far less abundant than in patients, whereas mice have provided extensive histopathological information. The first MRI description of the neuroanatomical phenotypes in homozygous (and heterozygous) mice using morphometry and texture analysis, led to conclude that the structural features of the *Reeler* brain most closely copied the MRI phenotype of LIS2 patients [29]. Indeed, the *reln*−/− mice had a smaller brain, but larger lateral ventricles compared to wild-type littermates. Sharp differences existed in the olfactory bulbs, dorsomedial frontal and parietal cortex, certain districts of the temporal and occipital lobes, and the ventral hippocampus where gadolinium-based active staining demonstrated a general disorganization with differences in the thickness of individual hippocampal layers. The cerebellum also resulted profoundly affected by the mutation and appeared strongly hypoplastic. A subsequent study, based on the use of manganese-enhanced MRI (MEMRI) to better detect the cortical laminar architecture, compared the MEMRI signal intensity in the cerebral cortex of normal and mutant mice. The authors of this survey observed that signal was low in cortical layer 1, increased in layer 2, decreased in layer 3 until mid-layer 4, and increased again, peaking in layer 5, before decreasing through layer 6. In *Reeler* there were, instead, no appreciable changes in signal intensity, an observation consistent with the absence of cortical lamination after histological examination [30]. A more recent and very elegant study has employed diffusion tractography imaging (DTI) to perform an in vivo origin-to-ending reconstruction of the mouse somatosensory thalamo-cortical connections and demonstrated an extensive remodeling in *Reeler* mutants because of the highly disorganized cortical lamination [31].

In keeping with the results of imaging studies, at gross anatomical examination the *reln*−/− mouse brain was atrophic, as total volume in mutants decreased of about 19% when compared to normal mice [29]. Such a reduction was particularly evident in the cerebellum (Figure 2E,F) that also displayed a very limited degree of foliation. Therefore, also the gross anatomy of the *Reeler* brain closely resembled that of the LIS2 human brain.

In general, it seems that the histological anomalies in mutants depended on an abnormal migration of neurons, rather than an alteration in cell fate determination or axonal guidance. Among these anomalies, the most distinguishing ones are that the cerebral and cerebellar cortices lose their layered structure, in accordance with the MEMRI observations [30]; numerous neuronal nuclei disappeared or, at least, became hardly recognizable in several brain regions; and neurons often displayed an ectopic position. Table 2 summarizes the most important structural anomalies of the *reln*−/− CNS without taking into consideration the histological alterations in the cerebral cortex, hippocampus and cerebellum, as we will analytically discuss the phenotype of these brain areas in the following sections. Detailed descriptions of the morphological phenotype of the *Reeler* mouse CNS can be found e.g., in [29,32].

**Table 2.** Main histopathological changes in the homozygous *Reeler* mouse.

The Table does not list the histopathological observations on cerebral cortex, hippocampus, and cerebellum.

Very early observations demonstrated the occurrence of dendritic anomalies in cortical and hippocampal neurons of *Reeler* mice [48,49]. The discovery of *Reln* confirmed the dendritic pathology, as not only Reln but also the molecules of its signaling pathway resulted to be necessary for the correct maturation and differentiation of the dendritic branches and spines in hippocampal and neocortical pyramidal neurons [50,51].

Due to the complexity of the phenomena involved in dendritic maturation, one can argue that dendritic anomalies represented a consequence of the deep cytoarchitectonic derangement occurring in *Reeler* mice rather than a primary effect of the lack of Reln, but observations on heterozygous mice were not supportive of this interpretation [52,53]. Interestingly, the block of the Reln signaling by means of specific antibodies resulted in an increased complexity of branching in the apical dendrites of layer 2/3 cortical pyramidal neurons, whereas their basal arborizations remained unaffected [54].

There are many important issues related to the structure and role of the dendritic tree of neocortical and hippocampal pyramidal neurons that make the *Reeler* mouse an important tool for the study of (forebrain) neurodevelopment. Inputs to layer 5 neurons are processed by separate compartments, with the basal dendrites receiving bottom-up information and the apical dendrite being the recipient of a feedback input from higher cortical areas, see e.g., [55]. This framework is, however, even more complex because apical dendrites span most cortical layers before reaching layer 1, where the apical tuft is located [56]. Today we know well that the type and distribution of ion channels at the neurolemma ultimately determine the electrophysiological properties of a neuron.

Essential to the function of the long apical dendrite of the pyramidal neurons is the progressively increasing density of hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, proceeding from proximal to distal segments [57]. Such a gradient critically contributes to the functional distinction between dendritic compartments. Although Reln signaling specifies this gradient [58], 17β-estradiol, which stimulates Reln expression, promoted the enrichment of HCN1 in the distal dendritic compartment of CA1 neurons without the intervention of Reln [59]. The evidence that Reln was involved in the trafficking and targeting of ion channels in cortical and hippocampal neurons suggested that their intrinsic electrophysiological properties could indeed be different in the *Reeler* mouse. However, an early study by Bliss and Chung [60] demonstrated that, despite the layering derangement, the basic synaptic organization of the hippocampus was largely unchanged in mutants.

More recently, Silva et al. [61] carried out an accurate survey dealing with the intrinsic electrophysiological properties of cortical neurons in *Reeler* mice. These authors showed that the firing pattern and synaptic responses of the pyramidal neurons were normal, but with an inverted radial distribution. Notably, these authors concluded that, although mispositioned, neurons maintained the membrane properties appropriate to their function.

The apparent discrepancy between the data demonstrating the role of Reln in the modulation of ion channels and the relative lack of anomalies in the intrinsic properties of cortical neurons in mutant mice might have several explanations. Other factors, such as neuronal activity [62] could be more effective than Reln for the modulation of membrane channel targeting. Furthermore, the complex machinery of the long apical dendrite is required when layer 5 neurons settle appropriately but might be useless for the same neurons displaced to more superficial cortical layers. Finally, future investigations based on refined electrophysiological techniques, such as direct dendritic recordings, will help to establish if indeed the cortical neurons in *Reeler* mice display subtler changes of their firing/intrinsic properties that those so far ascertained.

Reln signaling is also able to modulate key molecules of the cascade leading to synaptic plasticity, such as the NMDA receptors [63,64]. Therefore, several studies concentrated on the changes of synaptic plasticity in *Reeler* mutants. Ishida et al. [65] reported that the induction of long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus, claiming that the malpositioning of some neuronal populations could account for such an alteration. On the other hand, both the overexpression of Reln in transgenic mice [66] and Reln supplementation strongly increased LTP [67]. Later, a defective LTP was observed in the hippocampus of *vldr*-deficient mice, but slice perfusion with Reln was able to enhance LTP in CA1 [68].

Most cortical neurons are spiny, glutamatergic pyramidal cells, whose migratory path during prenatal development follows an inside-out radial pattern from the ventricular zone to the final position [69]. Reln signaling is essential for the localization of pyramidal neurons to appropriate cortical layers, as reviewed in [70]. Consequently, the lack of Reln caused a disruption of the layered cortical organization, including abnormal positioning [71,72], as well as an increased percentage of inverted pyramidal cells [73,74] (Figure 2C,D).

Inhibitory GABAergic interneurons represent a minority population within the neocortex. Yet, their morphological, neurochemical and functional diversity likely plays a key role for the cortical function, see e.g., [75]. Unlike pyramidal neurons, interneurons originate in the ganglionic eminence of the ventral telencephalon and follow a tangential migratory path to the cortex [69]. While the malpositioning of the pyramidal neurons in *Reeler* mice is evident, it is not clear if the Reln signaling cascade also affects the migration of the interneurons. An answer to this latter issue came from observations on *Reeler* mutants crossed with mice expressing the green fluorescent protein (GFP) in inhibitory neurons. Thus, the results of these observations confirmed that also the cortical interneurons displayed an abnormal laminar position and morphology [76]. However, we still do not know whether interneurons' ectopy directly depends from Reln signaling or is rather the consequence of the malpositioning of principal pyramidal projection neurons. The debate on this issue is still open, as contradictory views exist in the literature. Namely, while some observations [77,78] argue against a direct role of Reln,

Hammond et al. [79] showed that only early-generated cortical interneurons were misplaced as a consequence of the ectopy of the pyramidal neurons, whereas the correct layering of late-generated interneurons seemed to be directly modulated by Reln signaling.

Other basic neurodevelopmental features, such as cortical [80] and cerebellar neurogenesis, seem to be as well regulated by the glycoprotein. Consequently, the minicolumnar organization of the cerebral neocortex appeared to be deeply affected by Reln deficiency [81] and some physiological counterparts of cortical connectivity, such as trans-synaptic signal propagation, were also impaired [82]. However, the outcome of Reln deficiency on the microcircuitry sustaining the cortical machinery is controversial and, surprisingly, the deep architectonic disorganization that follows the lack of the protein occurs in the absence of dramatic functional anomalies. Both early and more recent studies point out that the absence of Reln did not prevent the development of functionally appropriate cortical connections and maps [31,83–86]. In addition, when studied at the fine-scale electron microscopic level, the basic synaptic organization of misplaced cortical neurons was unchanged [87]. Therefore, although the laminar organization is thought to be critical for cortical computation [88,89], evidences obtained in *Reeler* mice led Guy and Staiger [90] to challenge the importance of cortical lamination, affirming that "future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location".

Macroscopically, the cerebellum of the *Reeler* mouse is smaller than that of age-matched littermates (Figure 2E,F); it is club-shaped with the main axis transverse to the mid plan of the body, and has an almost completely smooth surface, with just a few superficial grooves [91]. The architecture of the *Reeler* cerebellum is profoundly different from the normal pattern, firstly because of the impairment in the complicated series of migrations made by neurons to reach their destination in the mature organ. Trajectories of migrating neurons follow two opposite directions from the surface to the depth of the cerebellum and the other way around, depending from the species, the type(s) of neurons and the developmental stages (for details see e.g., [92]). Eventually, disturbances in the migration of the cerebellar neurons make that *Reeler* mice display a cerebellum that retains several features of immaturity.

The area of the cerebellar cortex in mutants was analyzed quantitatively during postnatal (P0–P25) development and resulted to be reduced compared to age-matched controls [93]. Reduction in the extension of the cortex was particularly evident in the molecular layer and the (internal) granular layer. Physiologically, as the cerebellum matured, the molecular layer became more and more populated by the parallel fibers, but, at P25, its increase in size was about one third in the mutants compared to *reln*+/+ mice [93]. Post-migratory granule cells, which are born in the temporary subpial external granular layer, progressively populate the (internal) granular layer during normal cerebellar development. This process was disturbed in *Reeler*, to the extent that, from P0 to P10, the granular layer of *reln*+/+ mice increased about five-folds in size, but only 2.6-fold in *reln*−/−, where it was significantly reduced in size to 0.62-fold that of normal mice after P10 [93]. In a different way from the cortex, the medullary body was larger in the mutants than in wild-type mice. Its progressively increasing area mainly reflected the ongoing myelination of the axons of the Purkinje neurons that abandon the cortex moving across the white matter to reach the cerebellar nuclei, as well as the expansion of the incoming afferent and departing efferent fiber systems. The mass of the medullary body augmented in relation to postnatal age irrespectively of the lack of Reln (*reln*−/− 2.59, *reln*+/+ 1.93-fold), but, at P25, *Reeler* mice had a larger medullary body than normal mice (1.88-fold) [93]. In brief, *Reeler* mice had a reduced cerebellar cortex but a bigger medullary body than their *reln*+/+ littermates. The cerebellar hypoplasia was thus a consequence of a reduction in cortical magnitude and cellularity and the latter, in turn, resulted to be associated to measurable differences in the degree of cell proliferation and apoptosis, as well as imbalances in the timing of postnatal cortical maturation [93]. The same study led to conclude that density of proliferating cells was the most significant predictive factor to determine the cortical cellularity in *Reeler* [93]. Therefore, beside the well-defined consequences onto neuronal migration, the lack of Reln also caused a calculable deficit in neuronal expansion. Ultrastructurally, the cerebellar

neurons underwent several different forms of programmed cell death during postnatal development and the deficit of Reln affected the kind and grade of neuronal death [94].

Perhaps the most striking histological feature in mutants is the lack of alignment of the Purkinje neurons to form a discrete intermediate layer in the cerebellar cortex (Figure 2G,H). Thus, in *Reeler*, only about 5% of the Purkinje neurons were in a normal position, 10% were still inside the cortex but in the granular layer, and the remaining 85% formed an internal cellular mass intermixed with the white matter [95–97]. Ultrastructurally, in *Reeler* there was a reduction in the density of the contacts between the Purkinje neurons and the parallel and climbing fibers, from P5 onward [98]. Functionally, both the normally placed Purkinje neurons and those ectopically dislocated in the granular layer displayed a 0–1 response to stimulation, indicating that, as in normal mice, they received a synaptic contact by a single climbing fiber. The Purkinje neurons in the internal cellular mass, instead, showed intensity-graded responses to electrical stimulation, as several climbing fibers provided them with a convergent input [95], likely as a failure of physiological pruning to occur [99]. Neurochemically, there were no obvious variations between normal mice and the mutants in the temporal expression of some widely diffused neuronal and glial markers (NeuN, vimentin, calbindin, GFAP, Smi32, GAD67) during postnatal development [93], but the Bergmann glia was misplaced in *Reeler* [100].

To conclude, the histological and electrophysiological observations in *Reeler* mutants suggest that similar structural and functional alterations may also occur in LIS2 patients, particularly in relation to the postnatal growth retardation, severe intellectual disability, and spasticity observed in affected subjects (see also https://www.orpha.net/).

#### Lissencephaly 3

*TUBA1A* mutations [101,102] cause lissencephaly 3 (LIS3), another human condition that has a mouse counterpart. TUBA1A chiefly occurs in cortical, hippocampal, cerebellar and brainstem post-mitotic neurons, with expression falling soon after birth but persisting through adulthood [103]. The mouse phenotype consists, among others, in a failure of the cerebellar Purkinje neurons to migrate, so that, similarly to *Reeler*, they remain entrapped into the medullary body, where they form a series of streaks intermingled with the neurons of the cerebellar nuclei [104]. Several other mutations of *TUBA1A* exist in humans. They give rise to a predominant phenotype of LCH, which also shows irregularities of the corpus callosum and the basal ganglia/internal capsule [105].

## 3.1.2. Autosomal-Dominant Lateral Temporal Epilepsy and the Heterozygous *Reeler* Mouse

ADLTE, also referred to as autosomal dominant epilepsy with auditory features, partial epilepsy with auditory aura or partial epilepsy with auditory features, is a genetic epileptic syndrome, clinically showing typical focal seizures in response to specific sounds. ADLTE is genetically heterogeneous, and mutations in the leucine-rich, glioma inactivated 1 gene (*LGI1*) account for fewer than 50% of affected families. Very recent observations demonstrated that heterozygous *RELN* mutations give rise to a classic ADLTE syndrome, clinically identical to that associated with mutations of *LGI1*. Seven different heterozygous missense mutations in *RELN* were, in fact, described in some unrelated families of Italian ancestry with familial temporal lobe epilepsy-7 (ETL7–OMIM #616436) [106]. Incidence was 17.5% over the total number of families studied that were specifically suffering by lateral temporal lobe epilepsy [106]. By three-dimensional modeling, the same authors anticipated that the outcomes of these mutations would be protein structural defects and misfolding. Some of the affected individuals displayed a reduction up to 50% of their serum levels of the 310 kDa RELN isoform in comparison to healthy subjects and thus, very likely, the mutations also resulted in a loss of function. In a subsequent study on the same patients, 1.5 T MRI scans were not useful in detecting structural anomalies of the brain [107]. Similarly, in a very recent study on an 18-year old ADLTE patient, 3T MRI brain scans could not provide relevant information on indistinct grey-white matter connections, voxel-based morphometry, and cortical thickness [108]. However, analysis of functional connectivity with high-density electroencephalography (HdEEG) revealed greater local synchrony in

the left temporal (middle temporal gyrus), left frontal (supplementary motor area, superior frontal gyrus), and left parietal (gyrus angularis, gyrus supramarginalis) regions of the cerebral cortex and the cingulate cortex (middle cingulate gyrus) as compared to normal subjects [108].

As the discovery of RELN mutations in ADLTE is a quite recent finding, there are, at present, no observations on heterozygous *Reeler* mice focused to ascertain possible similarities with the human phenotype. Like ADLTE patients, *reln*+/− mice display a 50% reduction of Reln in their serum. Therefore, it would be interesting to investigate whether sound-triggered epileptic manifestations also occur in these animals. A very recent study has demonstrated that optogenetic stimulation of the parvalbumin (PV) immunoreactive GABAergic neurons of the mouse basal forebrain can modulate the cortical topography of auditory steady-state responses [109]. As the regional distribution of these neurons displayed relevant differences in *reln*+/− mice compared to wild-type animals [110,111], any phenotypic alteration may be of interest to shed additional light onto human ADLTE. Finally, a very latest report has provided proof of concept that HdEEG can be used to record electrical activity from the mouse brain in a model of juvenile myoclonic epilepsy [112]. Therefore, one can envisage applying such an approach to analyze the brain electrical pattern in *reln*+/− mice aiming to collect data for translational comparison with ADLTE.

#### *3.2. Human Conditions Caused by Mutations of Genes of the Reln Intracellular Pathway and Their Mouse Correlates*

In general, the brain phenotype of the human monogenetic conditions that are consequent to mutations of the genes coding for the proteins of the RELN intracellular signaling pathway is similar to that of the *reln*−/− mouse brain, except that, in certain cases, differently from *Reeler*, the human cerebellum is normal at MRI and gross anatomical observation (Figure 1). We will briefly describe these conditions below.


*Experiences of Socio-Environmental Organizations and Movements in the Framework… DOI: http://dx.doi.org/10.5772/intechopen.106282*

and conditions, among others. Only one way of contributing to learning or one way of teaching. Based on the results of the research reviewed the priority is training in reflection, exchange of experiences, organization reflection, exchange of experiences, organization, administration, coordination, dynamism, capacity for promotion, innovation, planning, execution, and transformation of environmental situations in specific contexts in specific contexts; broadening and complexifying the profile of the environmental leader.


**5. The discounting of grass to single purposes and uses**

**4.1. Ethnobotany, traditional use and the search for resilient grasses**

94 Grasses - Benefits, Diversities and Functional Roles

'next' food, nutraceutical, medicine or biotechnology product.

of species [86].

adaptation and resilience [92].

The search for plants that have been traditionally used for food, technology and particularly medicine to replace ineffective modern creations has triggered a considerable amount of ethnobotanical field research across the planet. A plethora of research has been published, very recently, and I cite just a few here to provide some scope on the richness of information available for study [72–84]. Make no mistake that some of the studies cited are motivated by economics and profiteering, as the planet is scoured for 'new' plant materials that can become the

The drive to find better-yielding drought or flood-resistant cereals will tread heavily on the territory and cultures of Indigenous peoples. We must avoid the past mistakes of colonial resource exploitation, extraction and expropriation, or as Vandana Shiva says, 'biopiracy' [85]. Biopiracy is commonly seen as misappropriation or theft of plant genetic material—in part, or in whole. However, others speculate whether in the rush to find the 'next new', the motivation could be based on mutual aid and, with prior informed consent, results in knowledge transfer that helps bilateral economic development and conservation

Prior informed consent requires the honouring of several UN international conventions. The *Convention on Biodiversity* [87], the *Universal Declaration on Cultural Diversity* [88], and most importantly, the *United Nations Declaration on the Rights of Indigenous Peoples* [89], which set forth global obligations to respect biodiversity and cultural diversity while protecting Indigenous rights to lands and intellectual property. If an outcome of plant exploration is the

With the consent of residents, a study of home gardens in Iberia found TEK and agricultural knowledge to have blended with modern knowledge, resulting in greater social resilience to change [90]. This is attributed to personal changes acquired through learning new knowledge, practices and beliefs. An important point to note is that TEK is not static, but rather grows in response to new knowledge [91]. Rural to urban migration in China has had a negative impact on the environment as modern agriculture supplanted TEK, though through an experimental ecological education programme, the TEK of more ecological agricultural practices was successfully transferred back to the participating agricultural community [91]. Acceptance of TEK and Indigenous low-carbon living is advocated as being the key to climate change

Climate change is an evidence-based wicked problem that may be incrementally and cumulatively solvable if we accept that we are all in it together, and admit that ingenuity may come from outside science. This requires solid doses of knowledge intersectionality, and humility, which requires recognizing and responding to ignorance in decision-making [93]. A final point to note is, '*that a specific unit of knowledge is lost or kept by a society is not as important as whether the society retains the ability to generate, transform, transmit, and apply knowledge'*, which ultimately strengthens socio-ecological resilience [94, p. 646]. Good advice indeed as I con-

tinue this exploration of the changing role of Poaceae in this age of climate change.

documentation of TEK, Indigenous peoples reserve their right to share, or not.

In the 'Western' world particularly, and anywhere else that was exposed to European colonization, 'grass' is a generic term used to describe lawn, turf, sod and pasture. Where did these words originate, what do they really mean and why have they been essentially reduced to single purposes and uses? For the definitions and etymology of the 15 grass-related words shown in **Table 2**, I turned to the *Oxford English Dictionary* (OED) online [95].

plants). If only grass is growing in a slice of land, the words to use are sward [100] or sod [101]. Pasture [102] and grass are related to providing food and space for livestock to graze, while fodder [103] and forage [104] refer to swathes [105] of grass cut from meadows, dried and stored for winter feeding of livestock. A meadow [106] is a land permanently covered with grass (and other herbage [107] or forbs [108]) that is protected from grazing most of the year in order to harvest hay [109] to be used as winter fodder. Cereal only entered the lexicon in

Beyond Turf and Lawn: Poaceae in This Age of Climate Change

http://dx.doi.org/10.5772/intechopen.69736

97

While turf has retracted in meaning, the term lawn has expanded from its earliest connotation in the 1300s to describe an open space between treed woods that may have been used for pasturing livestock. By 1674 CE, the OED [98] indicates a change in definition to '*a stretch of untilled ground; an extent of grass-covered land'* and a hundred years later, lawn again grew to mean, '*a portion of a garden or pleasure-ground, covered with grass, which is kept closely mown'*. In his monumental *Gardener's Dictionary* [111], Philip Miller, the chief gardener at the Chelsea Physic Garden from 1722 to 1770, expanded on the meaning of lawn, which he described as

*a great Plain in a Park, or a spacious Plain adjoining to a noble Seat. As to the Dimensions of it, it should be as large as the Ground will permit; but never less, if possible, than thirty or forty Acres. As to the Situation of a Lawn, it will be best in the Front of the House, and to lie open to the neighbouring*

This larger meaning, which Miller expands upon for several pages, certainly coincides with the period-defining works of the English landscape architects Capability Brown (c.1715–1783) and Humphry Repton (1752–1818), who were employed by wealthy landowners to modernize old Medieval gardens and agricultural land into what the designers called 'landscape parks', which would front many country mansions and stately homes throughout Britain, and

Miller's suggestion that the lawn be located at the front of the house was essentially a visual cue to all who passed by to take notice that the landowner was so rich that they did not need the space for pasturing livestock. Landowners with lawns could afford to do nothing with it except look at it, sit on it and take walks on it, while their livestock was pastured somewhere else on the estate. In another display of landowner wealth, labourers were employed to maintain the large acreages of lawn by hand-scything the grass, with some assistance from pasturing sheep to maintain bucolic aesthetics. Fortuitously, the Industrial Revolution overlapped (c1760–1840), and the 1830 invention of the reel lawn mower pulled by horses, along with subsequent refinements throughout the nineteenth century, gave rise to a push mower that

Alongside the Industrial Revolution, the many mechanized inventions allowed an agricultural revolution to occur, shifting surplus labourers from farms into city factories, where they

1818, as the term for edible grains harvested from various grass species [110].

**6. The meaning of lawn**

*Country and not pent up with Trees.*

be admired and then copied elsewhere.

could be used by anyone to maintain a lawn.

follows:

**Table 2.** Words related to grass, extracted from the Oxford English Dictionary online [95].

Old English was spoken between the fifth and twelfth centuries in areas of what is now England and Southern Scotland, and it is from this period that several words related to grass made their appearance. Turf [96] and grass [97] are derived from Old English and make their way into our vocabulary around the same time. However, according to the OED they have never been combined into a single word viz., 'turf-grass' or 'turfgrass', which is commonly encountered in the industry. The second meaning of turf is related to its use in *seisin*, a c1300 feudal term for the conveyance of ownership, which required a witness to observe the physical and literal transfer of a small piece of ground from one person to another. From this meaning, it is easy to see how we talk about personal space in terms of 'my turf', or 'turf wars'.

While today, turf growers and managers would have you believe that turf is just grass or another word for lawn [98], it is clear from the definition that turf has always meant a slice cut from the surface of the land [99], including soil, grass and herbage (other low-growing plants). If only grass is growing in a slice of land, the words to use are sward [100] or sod [101]. Pasture [102] and grass are related to providing food and space for livestock to graze, while fodder [103] and forage [104] refer to swathes [105] of grass cut from meadows, dried and stored for winter feeding of livestock. A meadow [106] is a land permanently covered with grass (and other herbage [107] or forbs [108]) that is protected from grazing most of the year in order to harvest hay [109] to be used as winter fodder. Cereal only entered the lexicon in 1818, as the term for edible grains harvested from various grass species [110].


**Author details**

Mehdi Chihi\*, Ulrich Sure and Ramazan Jabbarli Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany

\*Address all correspondence to: mehdi.chihi@uk-essen,de

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**181**

*Demographic, Clinical, and Radiographic Characteristics of Cerebral Aneurysms in Tuberous…*

of tuberous sclerosis. British Journal of

[10] Davidson S. Tuberous sclerosis with fusiform aneurysms of both internal carotid arteries manifested by unilateral visual loss and papilledema. Bulletin of the Los Angeles Neurological Societies.

[11] Chihi M, Gembruch O, Oppong MD, Chen B, Dinger TF, Barthel L, et al. Intracranial aneurysms in patients with tuberous sclerosis complex: A systematic

Korf B, et al. Tuberous sclerosis complex

[13] Yi J, Galgano M, Tovar-Spinoza Z, Deshaies E. Coil embolization of an intracranial aneurysm in an infant with tuberous sclerosis complex: A case report and literature review. Surgical Neurology International.

[14] Investigators UJ. The natural course of unruptured cerebral aneurysms in a Japanese cohort. New England Journal of Medicine. 2012;**366**:2474-2482

[15] dos Santos MLT, Spotti AR, dos Santos RMT, Borges MA, Ferrari AF, Colli BO, et al. Giant intracranial aneurysms: Morphology and clinical presentation. Neurosurgical Review.

[16] Beez T, Steiger H-J, Hänggi D. Evolution of management of intracranial aneurysms in children: A systematic review of the modern literature. Journal of Child Neurology.

review. Journal of Neurosurgery: Pediatrics. 2019;**24**:174-183

[12] Krueger DA, Northrup H, Roberds S, Smith K, Sampson J,

surveillance and management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurology. 2013;**49**:255-265

Urology. 1974;**46**:583-583

1974;**39**:128-132

2012;**3**:129-129

2013;**36**:117-122

2016;**31**:773-783

*DOI: http://dx.doi.org/10.5772/intechopen.93802*

Korf B, et al. Tuberous sclerosis complex

[2] Green AJ, Johnson PH, Yates JR. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Human Molecular Genetics.

[3] Green AJ, Smith M, Yates JR. Loss of heterozygosity on chromosome 16p13. 3 in hamartomas from tuberous sclerosis patients. Nature Genetics. 1994;**6**:193

[4] Hyman MH, Whittemore VH. National Institutes of Health consensus conference: Tuberous sclerosis complex. Archives of Neurology. 2000;**57**:662-665

[5] Gomez MR. Criteria for Diagnosis. Tuberous Sclerosis. 2nd ed. New York:

Raven Press; 1988. pp. 9-19

Sciences. 1991;**615**:125-127

[7] Nurmonen HJ, Huttunen T, Huttunen J, Kurki MI, Helin K, Koivisto T, et al. Polycystic kidney disease among 4,436 intracranial aneurysm patients from a defined population. Neurology. 2017;**89**(18):1852-1859. DOI: 10.1212/

WNL.<PHONE_NUMBER>004597

[8] Beltramello A, Puppini G, Bricolo A, Andreis IAB, El-Dalati G, Longa L, et al. Does the tuberous sclerosis complex include intracranial aneurysms? Pediatric Radiology. 1999;**29**:206-211

[9] Snowdon J. Cerebral aneurysm, renal cysts and hamartomas in a case

[6] Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Annals of the New York Academy of

[1] Northrup H, Krueger DA, Roberds S, Smith K, Sampson J,

diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurology. 2013;**49**:243-254

1994;**3**:1833-1834

**References**

*Demographic, Clinical, and Radiographic Characteristics of Cerebral Aneurysms in Tuberous… DOI: http://dx.doi.org/10.5772/intechopen.93802*