**4.2 Extension to the use of other spacers**

As previously said, this second method of electropolymerization allows to avoid the synthesis of the monomeric substituted porphyrin (ZnOEP(bpy)+ for example). Thus, this new way of electropolymerization more conveniently allows the use of the commercial free base porphyrin (H2OEP) or metalloporphyrins (MOEP) with different central metals (M = CoII, MgII, NiII, RuII(CO)…) (Giraudeau et al., 2010). For all of them, an electropolymerization process has been observed, even when porphyrins with oxidable central metal (CoOEP and NiOEP) have been used. Consequently, further applications could be envisaged. For example, polymer with CoOEP could be promising for dioxygen reduction, cobalt porphyrins being known to catalyze this reaction (Chen et al., 2010; Collman et al., 1980).

Moreover, it is also possible to modulate easily the nature of the bridging spacers between the porphyrin macrocycles. Indeed, instead of using free bpy, this process of electropolymerization can be extended to other spacers by varying the nature of the nucleophile, since each compound having two pendant pyridyl groups can be used as spacer. The spacers can be selected for their specific chemical and structural properties: rigid or not; long or short; electron conducting or not; electroreducible or not; with conjugated π bonds (aromatic/alkene/alkyne chains) or successive σ bonds (alkyl chains)… For instance, electropolymerization has been successfully carried out with different nucleophilic compounds (named Py-R-Py) as 1,2-bis(4-pyridyl)ethane (bpe), trans-1,2-bis(4 pyridyl)ethylene (tbpe), but also with reducible spacers as 4,4'-azopyridine (azpy) and 3,6 bis(4-pyridyl)-*s*-tetrazine (tzpy) (Fig. 9) (Giraudeau et al., 2010; Schaming et al., 2011b).

Fig. 9. Several Lewis bases (Py-R-Py) used as spacers: 1,2-bis(4-pyridyl)ethane (bpe), trans-1,2-bis(4-pyridyl)ethylene (tbpe), 4,4'-azopyridine (azpy) and 3,6-bis(4-pyridyl)-*s*-tetrazine (tzpy).


**1.1 Salt lakes and the classification of hydrochemistry**

Salt lakes are widely distributed in the world, and some famous salt lake resources are shown in Tables 1 and 2. In China, salt lakes are mainly located in the area of the Qinghai-Xizang (Tibet) Plateau, and the Autonomous Regions of Xinjiang and Inner Mongolia (M.P. Zheng et al., 1989). The composition of salt lake brines can be summarized to the complex salt-water multicomponent system (Li - Na – K – Ca - Mg - H - Cl – SO4 – B4O7 – OH- HCO3 – CO3 - H2O).

According to the chemical type of salt lake brines, it can be divided into five types, i.e. chloride type, sulphate type, carbonate type, nitrite type, and borate type among those salt lake resources in the world (Gao et al., 2007).

Chloride type: the component of brines in Death Sea, Mideast and Caerhan Salt Lake in China belongs to the system of chloride type (Na – K – Mg - Cl - H2O), and the main precipitation of salts are halite (NaCl), sylvite (KCl), carnallite (KCl•MgCl2•7H2O), and bischofite (MgCl2•6H2O).

Sulphate type: this kind of salt lake resources is similar with the sea water system (Na – K – Mg – Cl – SO4 – H2O), and it can be divided into two kinds of hypotypes i.e. sodium sulphate and magnesium sulphate. As to sodium sulphate hypotype, the Great Salt Lake in America, the gulf of Kara-Bogaz-Golin Urkmenistan, and Da-Xiao Qaidan in China belong to this hypotype with the main deposit of glauberite (Na2SO4•CaSO4), glauber salt (Na2SO4·10H2O), halite, galserite (Na2SO4•3K2SO4), schonenite (K2SO4•MgSO4•6H2O), and so on. As to magnesium sulphate hypotype, there are Yunchen Salt Lake in Shanxi Provine and Chaka Salt Lakes in Qinghai Province, China, especially Salt Lakes of the Qaidam Basin in Qinghai Province are a sub-type of magnesium sulphate brines famous for their

Stable and Metastable Phase Equilibria in the Salt-Water Systems 401

Caerhan and Caida, China 10 million tons Kata Baca, Argentina Sever million tons

America 6.34 million tons Chile 4.3 million tons Canada 6.6 million tons Greenbusbse, Australian 6 million tons Table 2. Statistical distribution of the lithium reserves in the world (Song, 2000; Zhao, 2003)

It is essential to study the stable and metastable phase equilibria in multi-component systems at different temperatures for its application in the fields of chemical, chemical engineering such as dissolution, crystallization, distillation, extraction and separation.

The research method for the stable phase equilibria of salt-water system is isothermal dissolution method. It is worthy of pointing out that the status of the stable phase equilibrium of salt-water system is the in a sealed condition under stirring sufficiently, and the speed of dissolution and crystallization of equilibrium solid phase is completely equal with the marker of no change for the liquid phase composition. As to the thermodynamic stable equilibrium studies aiming at sea water system (Na – K – Mg – Cl – SO4 – H2O), J.H. Vant'hollf (1912) was in the earliest to report the stable phase diagram at 293.15 K with

In order to accelerate the exploiting of Qaidam Basin, China, a number of the stable phase equilibria of salt-water systems were published at recent decades (Li et al., 2006; Song, 1998,

However, the phenomena of super-saturation of brines containing magnesium sulfate, borate is often found both in natural salt lakes and solar ponds around the world. Especially for salt lake brine and seawater systems, the natural evaporation is in a autogenetic process with the exchange of energy and substances in the open-ended system , and it is controlled by the radiant supply of solar energy with temperature difference, relative humidity, and air current, etc. In other word, it is impossible to reach the thermodynamic stable equilibrium,

For the thermodynamic non-equilibrium phase diagram of the sea water system as called "solar phase diagram" in the first, N.S. Kurnakov (1938) was in the first to report the experimental diagrams based on the natural brine evaporation, and further called

Country and section Lithium storage capacity,

Uyuni, Bolivia More than 19 million tons Silver and Searles, US More than 10 million tons

(Li2O)

Type of lithium resources

Salt lakes

Type of crystalline rocks

**1.2 Phase equilibria of salt-water systems**

isothermal dissolution method.

2000; Song & Du, 1986; Song & Yao, 2001, 2003).

**1.2.2 The metastable phase equilibria of salt-water systems**

and it is in the status of thermodynamic non-equilibrium.

**1.2.1 The stable phase equilibria of salt-water systems**

abundance of lithium, potassium, magnesium and boron resources (Zheng et al., 1989). The main precipitation of salts are halite, glauber salt, blodite (Na2SO4•MgSO4•7H2O), and epsom salt (MgSO4•7H2O).

Carbonate type: this type belongs to the system (Na – K – Cl – CO3 - SO4 – H2O), and Atacama Salt Lake in Chile and Zabuye Salt Lake in Tibet are the famous carbonate type of salt lake. The main precipitated minerals are thermonatrite (Na2CO3•10H2O), baking soda (NaHCO3), natron (Na2CO3•10H2O), glauber salt, and halite.

Nitrite type: the brine composition of this type salt lake can be summarized as the system (Na – K – Mg - Cl – NO3 - SO4 – H2O). The type salt lake main locates in the salt lake area in the northern of Chile among the salt lake group of Andes in the South-America, semi and dry salts in Luobubo and Wuzunbulake Lakes in Xinjiang, the northern of China. There are natratime saltier (NaNO3), niter (KNO3), darapskite (NaNO3•Na2SO4·H2O), POTASSIUMdarapskite (KNO3•K2SO4•H2O), humberstonite (NaNO3•Na2SO4•2MgSO4•6H2O).

Borate type: it can be divided into carbonate-borate hypotype and sulphate-borate hypotype. Searles Salt Lake in America, Banguo Lake and Zabuye Salt Lakes in Tibet, China belong to the former, and the brines mostly belong to the system (Na - K - Cl - B4O7 - CO3 - HCO3 - SO4 - H2O). In order to prove the industrial development of Searles Lake brines, Teeple (1929) published a monograph after a series of salt-water equilibrium data on Searles lake brine containing carbonate and borate systems. The latter includes Dong-xi-tai Lake, Da-xiao-chaidan Lake and Yiliping Lake in Qinghai Province, Zhachangchaka Lake in Tibet, China. In those lake area, the natural borate minerals of raphite (NaO•CaO•3B2O3•16H2O), pinnoite (MgO•B2O3•3H2O), chloropinnoite (2MgO•2B2O3•MgCl2•14H2O), inderite (2MgO•3B2O3•15H2O), hungchanoite (MgO•2B2O3•9H2O), mcallisterite (MgO•3B2O3•7.5H2O), kurnakovite (2MgO•3B2O3•15H2O) and hydroborate were precipitated (Zheng et al., 1988; Gao et al., 2007). In addition, the concentration of lithium ion exists in the surface brine of salt lakes.

Table 1. Basic data of salt lakes and their salt reserves in the world. unit, /t (Song, 2000)

abundance of lithium, potassium, magnesium and boron resources (Zheng et al., 1989). The main precipitation of salts are halite, glauber salt, blodite (Na2SO4•MgSO4•7H2O), and

Carbonate type: this type belongs to the system (Na – K – Cl – CO3 - SO4 – H2O), and Atacama Salt Lake in Chile and Zabuye Salt Lake in Tibet are the famous carbonate type of salt lake. The main precipitated minerals are thermonatrite (Na2CO3•10H2O), baking soda

Nitrite type: the brine composition of this type salt lake can be summarized as the system (Na – K – Mg - Cl – NO3 - SO4 – H2O). The type salt lake main locates in the salt lake area in the northern of Chile among the salt lake group of Andes in the South-America, semi and dry salts in Luobubo and Wuzunbulake Lakes in Xinjiang, the northern of China. There are natratime saltier (NaNO3), niter (KNO3), darapskite (NaNO3•Na2SO4·H2O), POTASSIUM-

Borate type: it can be divided into carbonate-borate hypotype and sulphate-borate hypotype. Searles Salt Lake in America, Banguo Lake and Zabuye Salt Lakes in Tibet, China belong to the former, and the brines mostly belong to the system (Na - K - Cl - B4O7 - CO3 - HCO3 - SO4 - H2O). In order to prove the industrial development of Searles Lake brines, Teeple (1929) published a monograph after a series of salt-water equilibrium data on Searles lake brine containing carbonate and borate systems. The latter includes Dong-xi-tai Lake, Da-xiao-chaidan Lake and Yiliping Lake in Qinghai Province, Zhachangchaka Lake in Tibet, China. In those lake area, the natural borate minerals of raphite (NaO•CaO•3B2O3•16H2O), pinnoite (MgO•B2O3•3H2O), chloropinnoite (2MgO•2B2O3•MgCl2•14H2O), inderite (2MgO•3B2O3•15H2O), hungchanoite (MgO•2B2O3•9H2O), mcallisterite (MgO•3B2O3•7.5H2O), kurnakovite (2MgO•3B2O3•15H2O) and hydroborate were precipitated (Zheng et al., 1988; Gao et al., 2007). In addition, the concentration of lithium

darapskite (KNO3•K2SO4•H2O), humberstonite (NaNO3•Na2SO4•2MgSO4•6H2O).

Searles lake,

Intragranular

Table 1. Basic data of salt lakes and their salt reserves in the world. unit, /t (Song, 2000)

2300 1400

brine

1.1×108 — 1.2×108 — 2.8×106 — — — 1.6×107 —

Intragranular

Atacama, Chile Caerhan, China Zabuye,

Intragranular

2900 5882

brine

3×108 4.3×1010 2.7×109 — — — — 3.4×105 5.5×106 —

Tibet

2677 120 ~3

6.6×107 2×108 5.7×108 — — — — — 1.8×106 —

US

512 1000

brine

2.8×106 — — — 2.7×106 — — — 3×107 7.5×104

(NaHCO3), natron (Na2CO3•10H2O), glauber salt, and halite.

ion exists in the surface brine of salt lakes.

lake, US

1280 3600 ~5

1×108 3.2×109 1.2×109 1.7×107 3.2×106 — — — 1.9×106 —

Salt lakes Death Sea Great

2×109 1.2×1010 2.2×1010 — 1.7×107 6×109 1×108 1×109 — —

Altitude, /m Area, /km2 Dept, m

KCl NaCl MgCl2 MgSO4 LiCl CaCl2 CaSO4 MgBr2 B2O3 WO3

epsom salt (MgSO4•7H2O).

Table 2. Statistical distribution of the lithium reserves in the world (Song, 2000; Zhao, 2003)


*Article* **On the Dressed Photon Constant and Its Implication for a Novel Perspective on Cosmology**

**Hirofumi Sakuma \* and Izumi Ojima**

> Research Origin for Dressed Photon, 3-13-19 Moriya-cho, Kanagawa-ku, Yokohama 221-0022, Japan<EMAIL_ADDRESS>
**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** As an important follow-up report on the latest study of the first author (H.S.) on an off-shell quantum field causing a dressed photon and dark energy, we further discuss a couple of intriguing subjects based on the new notion of simultaneous conformal symmetry breaking. One is the dressed photon constant. If we use it, in addition to ¯ *h* and *c*, as the third component of natural units, it is defined as the geometric mean of the smallest and the largest lengths: Planck length and that relating to the cosmological constant. Interestingly, this length (≈50 nanometers) seems to give a rough measure of the Heisenberg cut for electromagnetic phenomena. The other is a new perspective on cosmology that combines two original notions, i.e., twin universes and conformal cyclic cosmology, proposed, respectively, by Petit and Penrose, into one novel picture where universes expand selfsimilarly. We show the possibility that twin universes having a dual structure of (matter with (dark energy and matter)) vs. corresponding anti-entities, separated by an event horizon embedded in the geometric structure of de Sitter space, undergo endless cyclic processes of birth and death, as in the case of the pair creation and annihilation of elementary particles through the intervention of a conformal light field.

**Keywords:** dressed photon; dressed photon constant; natural units; Heisenberg cut; de Sitter space; dark energy; dark matter; cosmological constant; twin universes; conformal cyclic cosmology


**6. Antioxidant enzymes**

The enzymatic and non-enzymatic mechanisms are available for scavenging of reactive oxygen species (ROS) in plants. The biochemical adaptive function of osmoprotectants to scavenge these harmful ROS by-products of hyperosmotic and ionic stresses causes membrane dysfunction and cell death ultimately. These active oxygen species are superoxide (O2 −), hydrogen peroxide (H2 O2 ), hydroxyl radical (√OH), and singlet oxygen (1O2 ) which is produced through oxidation phenomenon. Many plants have the ability to eliminate superoxide with the help of superoxide dismutase (SOD), which catalyzes the superoxide into H2 O2 and O2 . Thylakoid membrane has potential enzyme ascorbate peroxidase (APX) to eliminate hydrogen peroxide to save cell membrane from severe damage.

### **6.1. Superoxide dismutase**

SOD concentrations typically increase with the degree of stress conditions as the compartmentalization of different forms of SOD throughout the plant makes them counteract stress very effectively. There are three classes of SOD metallic coenzymes that exist in plants that act to control increased levels of oxidative stress. SOD's role as a free radical scavenger is established, and those genotypes have higher levels indicating a higher level of stress tolerance in wheat. The availability of different forms of SOD in plants show a maximum stress tolerance in affected crops, giving protection to the plant. The trends observed in the present research might be due to the reasons discussed earlier.


**2.4 Statistical analysis**

Measurements are expressed as means ± standard deviations (SD) for three replicate determinations. Multivariate analysis was performed using SPSS 17.0 for Windows (SPSS Inc., Chicago, USA). As a typical data reduction and visualisation technique, principal component analysis (PCA) was used.


**EMBRYO CLEAVAGE**

Edited by **Bin Wu**

#### **Embryo Cleavage**

http://dx.doi.org/10.5772/65555 Edited by Bin Wu

#### **Contributors**

Meng Ju Lee, Juan Carlos Fierro-González, Anna Leida, Aisha Khan, Gabor Laszlo Kovacs, Gergely Montsko, Zita Zrinyi, Akos Varnagy, Jozsef Bodis, Pinar Tulay, Nasim Tabibnejad, Bin Wu

#### **© The Editor(s) and the Author(s) 2017**

The moral rights of the and the author(s) have been asserted.

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#### **Notice**

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.

First published in Croatia, 2017 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

Legal deposit, Croatia: National and University Library in Zagreb

Additional hard and PDF copies can be obtained from<EMAIL_ADDRESS>
Embryo Cleavage Edited by Bin Wu p. cm. Print ISBN 978-953-51-3511-1 Online ISBN 978-953-51-3512-8 eBook (PDF) ISBN 978-953-51-4675-9


**Anaerobic digestion process in similar conditions**

\* Some of the results may vary from the literature review as they were originally expressed in different units from the ones used in this manuscript. that is, NmL per gram of volatile soled degraded (unit used in other manuscript), instead of gram of volatile solid content in the residue (unit used in this manuscript).


**7. Revision endoscopic dacryocystorhinostomy**

The principles are similar to those of primary DCR. As far as the bone along the lateral nasal wall has already been removed, endoscopic revision DCR is much easier than the primary procedure. The important point in revision DCR is the size of the lacrimal sac.

If the sac is normal in size, the rate of success is high (89%)11, 12. If there is scarring and cicatrizaion of the sac, the success rate is lower because only a small amount of lacrimal mucosa can be marsupialized.

In severe stenosis and scarring of the lacrimal sac, the agger nasi mucosa can be used as a free graft to create functional mucosa surrounding the common canaliculus-sac junction.


Kejian Wang

76 Viscoelasticity – From Theory to Biological Applications

Cambridge University Press)

Physics. Singapore: World Scientific. Pp.241-330.

30 134-144

[22] Erdelyi A (ed.) 1955 *Table of Integral Transforms* Vol . I (New York: McGraw Hill)

[25] Sneddon I. N 1972 *The Use of Integral Transform ,*( New York: McGraw-Hill )

[27] Kolsky H 1963 *Stress Waves in Solids*(New York: Dover Publications) p106

[23] Schneider W R and Wyss W 1989 Fractional diffusion and wave equations. *J. Math Phys*.

[24] McLachlan N W 1963 *Complex Variable Theory and Transform Calculus* 2nd ed (Cambridge:

[26] Douglas J. F (2000)Polymer Science Applications of Path-Integration,Integral Equations, and Fractional Calculus. In: Hilfer R, editor.Applications of Fractional calculus in

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/50137


*1.3. ABC Multidrug Transporters in Fungal Kingdoms*

Invasive fungal diseases account for ~1.5 million deaths per year worldwide [220,221]. The increasing numbers of immunosuppressed people, including the elderly, transplant recipients, cancer and HIV/AIDS patients will most likely increase future cases of infections by opportunistic pathogens like *Candida* species (spp.) [222]. Candida spp. are commensal colonizers and part of the microflora present on mucosal and epithelial barriers such as the gastrointestinal and urogenital tracts. *Candida* spp. are a major part of the physiological mycobiome species [223], along with several thousand bacterial species constituting tissuespecific microbiomes [224–229]. Several *Candida* spp. can cause life-threatening invasive systemic disease in severely immunocompromised individuals [230]. The small number of chemical entities in antifungal drugs have been very problematic in the past, especially after prolonged use or after extensive prophylaxis, as was the case for pronounced azole resistance in HIV patients. Hence, the propensity to develop MDR is lower when larger drug arsenals against different targets are available [231]. For example, *C. auris* is a newly emerging pan-resistant fungal pathogen first reported from an ear infection in Japan in 2009 [232]. Within a decade, *C. auris* appeared in more than 40 countries around the globe, causing hospital outbreaks of invasive candidemia [233–240]. Importantly, *C. auris* is also causing severe superinfections with viruses, as seen in a recent co-infection of COVID-19 patients in a Mexican hospital ICU, leading to a dramatic overall mortality of 83%. In fact, intrinsic MDR in other *Candida* spp. such as *C. glabrata* and *C. kruzei* have also been increasing over the last decade [230,241,242]. Importantly, among other mechanisms, such as drug target gene mutations [243,244], efflux-based MDR/PDR has been recognized as a major cause of fungal anti-infective drug resistance [219,235,244–247].

Fungal ABC proteins are also quite diverse and are implicated in many biological functions, contributing to pivotal cellular processes, including cellular detoxification and stress adaptation [214,248,249]. Owing to space constraints, we will limit our discussion to paradigm fungal PDR family members implicated in drug resistance phenomena, but refer the reader to numerous recent reviews discussing fungal ABC proteins at large [249,250]. Fungal ABC proteins of the PDR subfamily are the closest eukaryotic orthologues of human ABCG family exporters [245,251]. For instance, *C. albicans* and *C. glabrata* harbor 27 and 18 ABC proteins in total, respectively [250]. Interestingly, *Cryptococcus neoformans* and *Aspergillus fumigatus* harbor even larger numbers, with 54 and 49 ABC transporters, respectively [252,253]. While we are not discussing transporters which are not linked to MDR phenomena, we still provide a comprehensive list of all known ABC transporters in non-pathogenic yeasts (Table 1) and their phylogenetic relationships (Figure 1A). MRP-like yeast ABC transporters including Yor1, Ycf1, Ybt1, Vmr1 and Bpt1 mediate vacuolar detoxification and heavy metal resistance [214]. Of note, Ycf1, which also has a rudimentary R-domain motif as present in human CFTR [50], was the first yeast homologue of mammalian MRP [254], while pathogenic fungi such as *C. albicans* harbor only Yor1 and Mlt1 (Table 2).

**Figure 1.** Phylogeny and structural organization of ABC transporters in mammals and yeast. (**A**) The phylogenetic tree shows the evolutionary relationships of ABC transporter subfamilies in yeast and mammals. Some 29 ABC transporters were subjected to amino acid sequence alignments. Branch length was analyzed using MEGA-X, and represents the evolutionary distance in the units of the number of amino acid substitutions per site. Names are given in the UniProt code, protein name and organism, respectively. The analysis reveals two major exporters subfamilies referred to as type I and II. Type I was sub-classified into ABCB/MDR (blue) and ABCC/MRP (green) subgroups. The type II family represents ABCG/PDR subgroups with the fungal (red) and mammalian transporters (orange). Ca: *Candida albicans*, Cg: *Candida glabrata*, Caur: *Candida auris*, Cd: *Candida dubliniensis*, Ct: *Candida tropicalis*, Cn: *Cryptococcus neoformans*, Sc: *Saccharomyces cerevisiae*, Sp: *Schizosaccharomyces pombe*. (**B**) Predicted membrane topologies of three MDR ABC exporter families. The transporters hold several diagnostic hallmark domains, including two NBDs (NBD1: light green; NBD2: green), two TMD regions usually with 6 putative membrane-spanning helices each (TMD1: light yellow; TMD2: bright orange), elbow helix (pink), re-entry helix (blue) and TMD0 (purple), respectively.

The fungal PDR (ABCG) or pleiotropic drug resistance family is the largest subfamily of ABC transporters of the type II exporter class [251]. PDR transporters are the closest structural orthologues of all mammalian ABCG subfamily transporters (Figure 1A),

sharing the same topological orientation and domain arrangements with mammalian ABCG5/ABCG8 [255] and ABCG2 [256–259] (Supplementary Figure S1). PDR transporters in fungal pathogens implicated in clinical antifungal resistance in *C. albicans* include Cdr1, Cdr2, Cdr3, Cdr6 and Cdr11, in *C. glabrata* (Cdr1, Pdh1, Snq2 and Aus1) [260], in *C. auris* (Cdr1), in *C. tropicalis* (Cdr1), in *C. dubliniensis* (Cdr1 and Cdr2) and in *Cryptococcus neoformans* (Afr1) (Table 2). All are highly conserved in non-pathogenic yeasts (Table 1). Their overexpression in pathogens causes hallmark MDR phenotypes seen for mammalian or bacterial ABC transporters [111,141,217,218,235,261–264].

Diversity of fungal PDR transporters and evolutionary relationships to mammalian ABC transporters. Most ABC proteins from non-pathogenic baker's yeasts (Table 1) are also found in various numbers and functions in pathogenic fungi (Table 2). A phylogenetic tree analysis suggests two major groups, referred to as exporter type I and type II [4,248,265,266], contain three MDR, MRP and PDR subfamilies (Figure 1A). While type I exporters (MDR/ABCB and MRP/ABCC) hold a TMD1–NBD1–TMD2–NBD2 configuration, all PDR/ABCG type II exporters adopt a "reverse" architecture, such as NBD1– TMD1–NBD2–TMD2 (Figure 1B). By contrast with the mammalian ABCG subfamily, all fungal PDR proteins are full-size transporters (Figure 1B).

**Table 2.** ABC efflux transporters mediating MDR in pathogenic fungi.

\* All transporters located in the plasma membrane, except for Atm1 and Mlt1, residing in the mitochondrial and vacuolar membrane, respectively. GS: glutathione, PC: phosphatidylcholine, PE: phosphatidylethanolamine, PS: phosphatidylserine.


**2. Pathophysiology of congenital AS**

The mechanism underlying the increase in severity of AS in children is similar to that seen in adults. The orifice size can decrease because of increased thickness and rigidity of the valve leaflets, independent of the morphological anomalies of the aortic valve, although native abnormal morphological features have greater impact on the progression of stenosis in children than in adults. The mechanisms underlying the exacerbation of stenosis also need to be determined. Valvular fibrosis, lipid accumulation, [4,5] inflammatory changes, [6] and acquired fibrotic fusion of commissures, which increase cusp thickness/stiffness, [5,7] could also be associated with the development of valvular stenosis, even in childhood AS. Metabolic syndrome is an emerging issue even in children and may be associated with these exacerbating mechanisms, [8] resulting in calcification, which reduces the possibility of valvular plastic surgery. In addition, bicuspid aortic valves possibly develop aortic calcification earlier than tricuspid aortic valves. [9,10] In this section, we will discuss the hemodynamic aspects of aortic stenosis in fetuses, neonates, and children.

#### **2.1. AS with signs and symptoms that develop during the fetal or neonatal period**

**Figure 1.** A schema of hypoplastic left heart syndrome (A) and that of critical aortic stenosis (B).

particular group of patients in the following section.

*2.2.1. Monitoring methods for AS*

**2.2. AS with signs and/or symptoms that develop during late infancy and school age**

When the severity of AS is mild such that the LV can cope with the increased afterload, patients present with clinical symptoms during late infancy or school age. Although their LV exhibits hypertrophy, AS may be mild enough in patients such that they will be asymptomatic. There are also a group of patients who had no signs and symptoms other than heart murmur. In general, the aortic valves of this group of patients can supply the systemic blood flow during the neona‐ tal period. This is verified by the fact that the ductus flow during the neonatal period shows leftto-right shunting. The timing of the onset of AS symptoms in this group is dependent on the severity of stenosis that is associated with the LV's capability to exert its adaptive mechanism to increased afterload. Of note, unlike adult onset AS, the severity of AS in children is also influ‐ enced by somatic growth, which induces a relative increase in the blood flow through the aortic valve and thereby causes augmentation of LV afterload. In addition, it was reported that an in‐ creased pressure gradient across the aortic valve is related to earlier progression of stenosis and a higher frequency of complicating aortic regurgitation. [15, 16] Therefore, the pathophysiology of AS in this age group may be dependent on preload change due to aortic regurgitation as well as the increasing afterload. In the clinical setting, it is important to follow-up with these patients periodically to detect such changes and to determine the appropriate timing and method of treatment. Therefore, we will discuss methods for monitoring the dynamic changes in AS in this

Congenital Aortic Stenosis in Children http://dx.doi.org/10.5772/54806 519

Clinical symptom evaluation, physical examination, electrocardiogram (ECG), and echocar‐ diography are essential sources for obtaining comprehensive information for appropriate

The fundamental underlying pathophysiology of AS involves an increase in afterload to the left ventricle (LV). The mechanism by which the LV copes with this increase in afterload is an increase of myocardial mass (hypertrophy) to generate a higher force to confront the increased afterload. If the aortic valve stenosis is too severe to allow the LV to become adaptive, LV contractility is depressed and the LV becomes markedly dilated. In this critical condition, the fetal circulation can maintain, to some extent, the systemic output using the right ventricle (RV), because there are interatrial communication (foramen ovale) and ductus arteriosus in the fetal ciculation. The ascending aortic flow and sometimes even the coronary arterial flow rely on retrograde blood flow from the ductus arteriosus. However, an LV exposed to massive afterload with relatively reduced coronary blood flow supply is at high risk of progressive ventricular failure, and is associated with an increased risk of sudden cardiac death. If the patient can survive this condition for a certain period, a marked increase in LV end-diastolic pressure (EDP) hinders the blood flow from the left atrium entering into the LV, leading to a gradual reduction of LV cavity volume. This process is postulated as one mechanism of evolving hypoplastic left heart syndrome (HLHS). Degeneration of the endocardium may accompany this process, representing a condition known as endocardial fibroelastosis. [11]

In other cases, an increase in LV afterload may allow the LV to exert its adaptive mechanism of hypertrophy, which also inhibits LV inflow due to increased LV stiffness and resultant EDP rise. [12] This is another form of evolving HLHS physiology (Figure 1A).

Of course, the above pathophysiological mechanisms should be understood as a continuum, [13, 14] and some patients may be born with a markedly dilated LV and depressed contractility, known as critical AS (Figure 1B). Such patients suffer from severe circulatory failure and pulmonary congestion, which is often life threatening and requires emergency intervention, either by catheters or surgery, as discussed below.

**Figure 1.** A schema of hypoplastic left heart syndrome (A) and that of critical aortic stenosis (B).

#### **2.2. AS with signs and/or symptoms that develop during late infancy and school age**

When the severity of AS is mild such that the LV can cope with the increased afterload, patients present with clinical symptoms during late infancy or school age. Although their LV exhibits hypertrophy, AS may be mild enough in patients such that they will be asymptomatic. There are also a group of patients who had no signs and symptoms other than heart murmur. In general, the aortic valves of this group of patients can supply the systemic blood flow during the neona‐ tal period. This is verified by the fact that the ductus flow during the neonatal period shows leftto-right shunting. The timing of the onset of AS symptoms in this group is dependent on the severity of stenosis that is associated with the LV's capability to exert its adaptive mechanism to increased afterload. Of note, unlike adult onset AS, the severity of AS in children is also influ‐ enced by somatic growth, which induces a relative increase in the blood flow through the aortic valve and thereby causes augmentation of LV afterload. In addition, it was reported that an in‐ creased pressure gradient across the aortic valve is related to earlier progression of stenosis and a higher frequency of complicating aortic regurgitation. [15, 16] Therefore, the pathophysiology of AS in this age group may be dependent on preload change due to aortic regurgitation as well as the increasing afterload. In the clinical setting, it is important to follow-up with these patients periodically to detect such changes and to determine the appropriate timing and method of treatment. Therefore, we will discuss methods for monitoring the dynamic changes in AS in this particular group of patients in the following section.

#### *2.2.1. Monitoring methods for AS*

**2. Pathophysiology of congenital AS**

518 Calcific Aortic Valve Disease

stenosis in fetuses, neonates, and children.

The mechanism underlying the increase in severity of AS in children is similar to that seen in adults. The orifice size can decrease because of increased thickness and rigidity of the valve leaflets, independent of the morphological anomalies of the aortic valve, although native abnormal morphological features have greater impact on the progression of stenosis in children than in adults. The mechanisms underlying the exacerbation of stenosis also need to be determined. Valvular fibrosis, lipid accumulation, [4,5] inflammatory changes, [6] and acquired fibrotic fusion of commissures, which increase cusp thickness/stiffness, [5,7] could also be associated with the development of valvular stenosis, even in childhood AS. Metabolic syndrome is an emerging issue even in children and may be associated with these exacerbating mechanisms, [8] resulting in calcification, which reduces the possibility of valvular plastic surgery. In addition, bicuspid aortic valves possibly develop aortic calcification earlier than tricuspid aortic valves. [9,10] In this section, we will discuss the hemodynamic aspects of aortic

**2.1. AS with signs and symptoms that develop during the fetal or neonatal period**

The fundamental underlying pathophysiology of AS involves an increase in afterload to the left ventricle (LV). The mechanism by which the LV copes with this increase in afterload is an increase of myocardial mass (hypertrophy) to generate a higher force to confront the increased afterload. If the aortic valve stenosis is too severe to allow the LV to become adaptive, LV contractility is depressed and the LV becomes markedly dilated. In this critical condition, the fetal circulation can maintain, to some extent, the systemic output using the right ventricle (RV), because there are interatrial communication (foramen ovale) and ductus arteriosus in the fetal ciculation. The ascending aortic flow and sometimes even the coronary arterial flow rely on retrograde blood flow from the ductus arteriosus. However, an LV exposed to massive afterload with relatively reduced coronary blood flow supply is at high risk of progressive ventricular failure, and is associated with an increased risk of sudden cardiac death. If the patient can survive this condition for a certain period, a marked increase in LV end-diastolic pressure (EDP) hinders the blood flow from the left atrium entering into the LV, leading to a gradual reduction of LV cavity volume. This process is postulated as one mechanism of evolving hypoplastic left heart syndrome (HLHS). Degeneration of the endocardium may accompany this process, representing a condition known as endocardial fibroelastosis. [11]

In other cases, an increase in LV afterload may allow the LV to exert its adaptive mechanism of hypertrophy, which also inhibits LV inflow due to increased LV stiffness and resultant EDP

Of course, the above pathophysiological mechanisms should be understood as a continuum, [13, 14] and some patients may be born with a markedly dilated LV and depressed contractility, known as critical AS (Figure 1B). Such patients suffer from severe circulatory failure and pulmonary congestion, which is often life threatening and requires emergency intervention,

rise. [12] This is another form of evolving HLHS physiology (Figure 1A).

either by catheters or surgery, as discussed below.

Clinical symptom evaluation, physical examination, electrocardiogram (ECG), and echocar‐ diography are essential sources for obtaining comprehensive information for appropriate management of AS in this patient group. If fainting, convulsion, or resuscitated cardiac arrest are observed, relieving AS is indicated for preventing further adverse events. [17, 18] Although angina and syncope are reported to be observed only in <10% of patients whose peak-to-peak pressure gradient is greater than 80 mmHg, chest pain is an important clinical sign indicating the need for intervention, as adverse events are likely to occur within a few years after the complaint of initial chest pain.

Exercise testing may provide more accurate information about the risk of cardiac events than other examinations. Lewis et al. demonstrated the usefulness of exercise testing to identify sub‐ clinical ischemia in patients with severe AS. [26] Thus, exercise testing and Holter ECG may

Congenital Aortic Stenosis in Children http://dx.doi.org/10.5772/54806 521

Echocardiography is a direct method for evaluating the anatomical features and severity of AS. Valvular anatomy can be assessed for leaflet number, balance, thickening, or doming. The an‐ nulus diameter is also important, particularly when intervention is indicated. M-mode study in short-axis view provides information regarding LV pressure calculated by Glanz's equation: LV systolic pressure=225\*LVPWs/LVIDs, where LVPWs and LVIDs represent LV systolic pos‐ terior wall thickness and LV systolic diameter, respectively. [20] This equation is clinically use‐ ful, because the peak-to-peak pressure gradient can be evaluated when coupled with the arterial pressure measurement. The LV dimension and wall thickness values provide informa‐ tion regarding the risk of cardiac events and ischemia. In addition, combining an echocardiog‐ raphy study with exercise testing may be useful for predicting a higher risk of cardiac events, even in asymptomatic patients. [21] Velocity measurement by spectral pulse wave and continu‐ ous wave Doppler reflects the severity of AS if cardiac function is not impaired. The pressure gradient calculated by applying the Bernoulli equation in the outflow tract is one of the guides for determining the need for intervention, although it has some limitations. [22, 23] Spectral pulse wave Doppler could also be a powerful tool for confirming the localization of obstruction

The indication for the catheter examination is limited, but this modality provides accurate information regarding coronary arteries and severity of AS. Because the LV outflow tract is truncated, the severity of AS tends to be over-estimated by velocity-derived pressure gradient. In contrast, a precise PIPG as well as a peak-to-peak gradient can be evaluated by the catheter examination (Figure 3). The aortic valve area is also calculated by Gorlin's method. [24]

**Figure 3.** Simultaneous measurements of ascending aortic pressure and left ventricular pressure by the catheter examina‐ tion. Both instantaneous and peak to peak pressure gradient can be clearly monitored. A; normal, B; aortic stenosis

play a key role in clinician decision making for the management of AS patients.

and estimating the valvular area.

ECG examinations are informative if ST-segment changes are observed. Usually, severe AS shows a 0–90°QRS-axis with high voltages in the left precordial leads. However, it is important to note that the above ECG findings of LV hypertrophy do not necessarily reflect the severity of the stenosis. Wagner et al. reported that one-third of AS patients with peak-to-peak pressure gradients greater than 80 mmHg do not exhibit the above LV hypertrophic findings on ECG. [17] In contrast, the ST strain pattern in the left precordial leads is thought to be more specific to LV hypertrophy and reflects the severity of AS (Figure 2).

**Figure 2.** Electrocardiogram of severe aortic stenosis. This is an electrocardiogram (ECG) of a patient with severe aortic stenosis with an estimated pressure gradient of 140mmHg. Surprisingly, ECG shows no prominent finding of left ven‐ tricular hypertrophy other than changes in ST-T segment.

Holter ECG is also useful for predicting sudden deaths, even in asymptomatic AS patients. Wolfe et al. reported that multiform ventricular premature contraction, couplet, and ventric‐ ular tachycardia are serious arrhythmias that are associated with sudden cardiac death. [19]

Exercise testing may provide more accurate information about the risk of cardiac events than other examinations. Lewis et al. demonstrated the usefulness of exercise testing to identify sub‐ clinical ischemia in patients with severe AS. [26] Thus, exercise testing and Holter ECG may play a key role in clinician decision making for the management of AS patients.

management of AS in this patient group. If fainting, convulsion, or resuscitated cardiac arrest are observed, relieving AS is indicated for preventing further adverse events. [17, 18] Although angina and syncope are reported to be observed only in <10% of patients whose peak-to-peak pressure gradient is greater than 80 mmHg, chest pain is an important clinical sign indicating the need for intervention, as adverse events are likely to occur within a few years after the

ECG examinations are informative if ST-segment changes are observed. Usually, severe AS shows a 0–90°QRS-axis with high voltages in the left precordial leads. However, it is important to note that the above ECG findings of LV hypertrophy do not necessarily reflect the severity of the stenosis. Wagner et al. reported that one-third of AS patients with peak-to-peak pressure gradients greater than 80 mmHg do not exhibit the above LV hypertrophic findings on ECG. [17] In contrast, the ST strain pattern in the left precordial leads is thought to be more specific

**Figure 2.** Electrocardiogram of severe aortic stenosis. This is an electrocardiogram (ECG) of a patient with severe aortic stenosis with an estimated pressure gradient of 140mmHg. Surprisingly, ECG shows no prominent finding of left ven‐

Holter ECG is also useful for predicting sudden deaths, even in asymptomatic AS patients. Wolfe et al. reported that multiform ventricular premature contraction, couplet, and ventric‐ ular tachycardia are serious arrhythmias that are associated with sudden cardiac death. [19]

complaint of initial chest pain.

520 Calcific Aortic Valve Disease

to LV hypertrophy and reflects the severity of AS (Figure 2).

tricular hypertrophy other than changes in ST-T segment.

Echocardiography is a direct method for evaluating the anatomical features and severity of AS. Valvular anatomy can be assessed for leaflet number, balance, thickening, or doming. The an‐ nulus diameter is also important, particularly when intervention is indicated. M-mode study in short-axis view provides information regarding LV pressure calculated by Glanz's equation: LV systolic pressure=225\*LVPWs/LVIDs, where LVPWs and LVIDs represent LV systolic pos‐ terior wall thickness and LV systolic diameter, respectively. [20] This equation is clinically use‐ ful, because the peak-to-peak pressure gradient can be evaluated when coupled with the arterial pressure measurement. The LV dimension and wall thickness values provide informa‐ tion regarding the risk of cardiac events and ischemia. In addition, combining an echocardiog‐ raphy study with exercise testing may be useful for predicting a higher risk of cardiac events, even in asymptomatic patients. [21] Velocity measurement by spectral pulse wave and continu‐ ous wave Doppler reflects the severity of AS if cardiac function is not impaired. The pressure gradient calculated by applying the Bernoulli equation in the outflow tract is one of the guides for determining the need for intervention, although it has some limitations. [22, 23] Spectral pulse wave Doppler could also be a powerful tool for confirming the localization of obstruction and estimating the valvular area.

The indication for the catheter examination is limited, but this modality provides accurate information regarding coronary arteries and severity of AS. Because the LV outflow tract is truncated, the severity of AS tends to be over-estimated by velocity-derived pressure gradient. In contrast, a precise PIPG as well as a peak-to-peak gradient can be evaluated by the catheter examination (Figure 3). The aortic valve area is also calculated by Gorlin's method. [24]

**Figure 3.** Simultaneous measurements of ascending aortic pressure and left ventricular pressure by the catheter examina‐ tion. Both instantaneous and peak to peak pressure gradient can be clearly monitored. A; normal, B; aortic stenosis

### **3. Treatment of AS**

#### **3.1. Fetal and neonatal AS**

If the patients have an established HLHS circulation with an underdeveloped LV, all the treatment options are directed to the future completion of the Fontan circulation, a final goal for patients with single ventricular circulation. However, if the LV size and components are to be sufficient to generate systemic output when the excessive afterload due to AS is relieved, interventions for the aortic valve per se are indicated, including either catheters or surgery. [25] The most attractive merit of catheter intervention (percutaneous transluminal aortic valvuloplasty [PTAV]) is that it is less invasive. In this procedure, cardiopulmonary bypass, which is a prerequisite for surgical procedures, can be avoided. PTAV is known to accelerate annular growth even in small sized aortic valve [26] if mitral valve stenosis is not complicated [27] .In performing PTAV, the carotid artery is generally used for blood access because lower body hypoperfusion makes it difficult to achieve access from the femoral artery and has a high risk of arterial obstruction with a prolonged sheath insertion, and because the curvature of aortic arch makes it difficult to manipulate the catheter and successfully pass it through the tiny aortic orifice (Figure 4). Therefore, central nervous system damage can be a potential adverse event associated with PTAV. More importantly, PTAV is a procedure used to enlarge the aortic orifice area by tearing the weak portions of the valve, not necessarily in the anatom‐ ically proper portion (commissures). Therefore, PTAV cannot be applied to valves with preexisting aortic regurgitation because the procedure generally worsens this condition, which could be fatal. It was reported that 15% of 113 patients younger than 60 days old who had undergone PTAV developed significant aortic regurgitation. [26] Surgical interventions in this patient group include aortic valve plasty (AVP) and aortic valve replacement (AVR) with the autologous pulmonary artery valve (Ross procedure). The advantage of open AVP is that surgeons can perform the procedure on the basis of a detailed examination of the valve anatomy, which may reduce the risk of aortic regurgitation. Bhabra et al. [28] reported that if the aortic valve is tricuspid, the rate of freedom from reintervention after open AVP was 92% and that of AVR was 100% at a 10-year follow-up. These rates for bicuspid valves were only 33% and 57%, respectively. This report emphasizes the importance of valve morphology as a determinant of outcome following AVP. The other surgical option is the Ross procedure, which is particularly useful when sub/suprastenosis coexists with valvular stenosis (Ross-Konno procedure). The survival rate for the Ross procedure was 77% and rate of freedom from reintervention was 50%, comparable to the results of the Norwood procedure. [29-31] To apply the Ross procedure, autologous graft (pulmonary valve) function is important. Concha et al. reported that the rate of freedom from autograft failure at a 5-year follow-up was 95%, demonstrating a low incidence of autograft failure. [32] However, future pulmonary insuffi‐ ciency remains as a matter of concern in long-term follow-ups.

output, then the systemic circulation should rely on the RV. In such a case, the Fontan proce‐ dure becomes a goal of treatment. Multicenter studies have elucidated that the outcome of biventricular repair with a small LV is much worse than that of the Fontan procedure [13, 14], although the survival rate of Fontan completion for patients with a small LV or severely

Congenital Aortic Stenosis in Children http://dx.doi.org/10.5772/54806 523

reduced LV function is only approximately 50-70%, even in the recent reports. [33-35]

**Figure 4.** Percutaneous transluminal aortic valvuloplasty performed for a patient with critical aortic stenosis

remain to be solved.

Based on the pathophysiology of evolving HLHS as previously discussed and the poor survival rate of HLHS patients, fetal intervention has been attempted, aimed at relieving AS at earlier stages before the LV cavity is reduced. For the first time, Maxwell et al. reported their experi‐ ence of intrauterine balloon dilatation of the fetal aortic valve in 1991. [36] Thereafter, a case series of 12 fetuses that underwent balloon valvuloplasty in the third trimester were reported, with no improvement was observed in their LV growth. [37] Tworetzky et al. also reported the results of fetal intervention for 24 AS patients (ranging from 21 to 29 weeks of gestation) who were thought to have a high probability of developing HLHS. [38] Technical success was achieved in 14 patients, but only 3 patients were able to undergo two-ventricular repair. Therefore, fetal intervention should be regarded as experimental at present, as many issues

We often encounter intermediate cases between established HLHS with underdeveloped LV and potentially normal-sized LV under excessive afterload. In such situations, accurate diag‐ nosis about whether the LV has the potential to generate systemic output after relieving af‐ terload is of primary importance. If the LV is judged to be incapable of generating systemic output, then the systemic circulation should rely on the RV. In such a case, the Fontan proce‐ dure becomes a goal of treatment. Multicenter studies have elucidated that the outcome of biventricular repair with a small LV is much worse than that of the Fontan procedure [13, 14], although the survival rate of Fontan completion for patients with a small LV or severely reduced LV function is only approximately 50-70%, even in the recent reports. [33-35]

**3. Treatment of AS**

522 Calcific Aortic Valve Disease

**3.1. Fetal and neonatal AS**

If the patients have an established HLHS circulation with an underdeveloped LV, all the treatment options are directed to the future completion of the Fontan circulation, a final goal for patients with single ventricular circulation. However, if the LV size and components are to be sufficient to generate systemic output when the excessive afterload due to AS is relieved, interventions for the aortic valve per se are indicated, including either catheters or surgery. [25] The most attractive merit of catheter intervention (percutaneous transluminal aortic valvuloplasty [PTAV]) is that it is less invasive. In this procedure, cardiopulmonary bypass, which is a prerequisite for surgical procedures, can be avoided. PTAV is known to accelerate annular growth even in small sized aortic valve [26] if mitral valve stenosis is not complicated [27] .In performing PTAV, the carotid artery is generally used for blood access because lower body hypoperfusion makes it difficult to achieve access from the femoral artery and has a high risk of arterial obstruction with a prolonged sheath insertion, and because the curvature of aortic arch makes it difficult to manipulate the catheter and successfully pass it through the tiny aortic orifice (Figure 4). Therefore, central nervous system damage can be a potential adverse event associated with PTAV. More importantly, PTAV is a procedure used to enlarge the aortic orifice area by tearing the weak portions of the valve, not necessarily in the anatom‐ ically proper portion (commissures). Therefore, PTAV cannot be applied to valves with preexisting aortic regurgitation because the procedure generally worsens this condition, which could be fatal. It was reported that 15% of 113 patients younger than 60 days old who had undergone PTAV developed significant aortic regurgitation. [26] Surgical interventions in this patient group include aortic valve plasty (AVP) and aortic valve replacement (AVR) with the autologous pulmonary artery valve (Ross procedure). The advantage of open AVP is that surgeons can perform the procedure on the basis of a detailed examination of the valve anatomy, which may reduce the risk of aortic regurgitation. Bhabra et al. [28] reported that if the aortic valve is tricuspid, the rate of freedom from reintervention after open AVP was 92% and that of AVR was 100% at a 10-year follow-up. These rates for bicuspid valves were only 33% and 57%, respectively. This report emphasizes the importance of valve morphology as a determinant of outcome following AVP. The other surgical option is the Ross procedure, which is particularly useful when sub/suprastenosis coexists with valvular stenosis (Ross-Konno procedure). The survival rate for the Ross procedure was 77% and rate of freedom from reintervention was 50%, comparable to the results of the Norwood procedure. [29-31] To apply the Ross procedure, autologous graft (pulmonary valve) function is important. Concha et al. reported that the rate of freedom from autograft failure at a 5-year follow-up was 95%, demonstrating a low incidence of autograft failure. [32] However, future pulmonary insuffi‐

ciency remains as a matter of concern in long-term follow-ups.

We often encounter intermediate cases between established HLHS with underdeveloped LV and potentially normal-sized LV under excessive afterload. In such situations, accurate diag‐ nosis about whether the LV has the potential to generate systemic output after relieving af‐ terload is of primary importance. If the LV is judged to be incapable of generating systemic

**Figure 4.** Percutaneous transluminal aortic valvuloplasty performed for a patient with critical aortic stenosis

Based on the pathophysiology of evolving HLHS as previously discussed and the poor survival rate of HLHS patients, fetal intervention has been attempted, aimed at relieving AS at earlier stages before the LV cavity is reduced. For the first time, Maxwell et al. reported their experi‐ ence of intrauterine balloon dilatation of the fetal aortic valve in 1991. [36] Thereafter, a case series of 12 fetuses that underwent balloon valvuloplasty in the third trimester were reported, with no improvement was observed in their LV growth. [37] Tworetzky et al. also reported the results of fetal intervention for 24 AS patients (ranging from 21 to 29 weeks of gestation) who were thought to have a high probability of developing HLHS. [38] Technical success was achieved in 14 patients, but only 3 patients were able to undergo two-ventricular repair. Therefore, fetal intervention should be regarded as experimental at present, as many issues remain to be solved.

#### **3.2. AS with signs and symptoms that develop during late infancy and school age**

The treatment strategy for AS in which signs and/or symptoms develop later in childhood is different from that for neonatal AS. The American College of Cardiology/American Heart Association Guidelines for the management of AS of this group [31] recommended that patients with a peak instantaneous pressure gradient (PIPG) measured by Doppler echocar‐ diography ≥70 mmHg be considered for cardiac catheterization and treatment in asympto‐ matic children and young adults. If the patients desire to participate in competitive sports or become pregnant, a PIPG of 50–70 mmHg is an indication for further evaluation and inter‐ ventions. If patients have symptoms (angina, syncope, or dyspnea on exertion), a PIPG ≥50 mmHg is the indication for treatment. If the PIPG is less than 50 mmHg and a symptom is present, another origin of the symptom should be investigated.

advanced stages in which LV hypertrophy and fibrosis may coexist. The degree of diastolic dysfunction is important for predicting prognosis because it takes years to achieve reverse

Congenital Aortic Stenosis in Children http://dx.doi.org/10.5772/54806 525

In contrast to the relatively uniform geometric and functional LV changes observed in adultonset AS, such changes in children's AS are diverse and somewhat different from those of adults. The difference primarily stems from the diversity of the initial impact of afterload on the LV. Because adult onset of AS is largely due to a bicuspid valve or atherosclerotic change with aging, AS gradually increases LV afterload. This allows the LV to confront the increased afterload by inducing hypertrophic changes. However, the severity of AS that initially imposes afterload on the LV is diverse in children, as previously discussed, thus excessive afterload may not allow the LV to become hypertrophic, resulting in LV dilation and systolic dysfunction as observed in critical AS. With increasing age, the LV geometry and function gradually resembles those of adult AS: a hypertrophic LV with diastolic dysfunction. However, it is rare in children to observe a marked increase in LV diastolic stiffness, even in cases of hypertrophic LV (Figure 5). In addition, it is interesting that LV relaxation appears to be relatively preserved in children with AS and hypertrophic LV. These differences in LV functional responses between children and adults may have a clue to a better management of patients with AS.

**Figure 5.** Examples of left ventricular pressure-volume relationships in a control patient (A) and a patient with aortic stenosis (B). The steep slope of the end-systolic pressure-volume relationship (solid line) and arterial elastance (dashed line) indicate increased ventricular contractility and afterload. Note that the slope of the end-diastolic pressure-vol‐

In adults, AS generally develops slowly, with the progression of valve calcification or leaflet degeneration being independent of the existence of substrates for congenital abnormalities.

ume relationship in aortic stenosis is comparable to that of control.

**5. Conclusions**

remodeling of diastolic function after normalization of afterload. [44]

There are several treatment options for cases in which intervention is indicated, including PTAV, open AVP, the Ross procedure, and AVR. Procedure selection is primarily dependent upon whether the patient's somatic size (aortic annular size) is large enough to use a prosthetic valve, because AVR is considered as the first-line procedure at present. If the prosthetic valve is not available, procedures other than AVR are selected so that patients can live with their own valve until they can use a prosthetic aortic valve. In such situations, the most important concept for treatment is that the procedure should be regarded as a bridge to AVR. Therefore, the aim of any intervention should be to reduce the afterload without any significant aortic regurgitation so that patients can grow uneventfully until AVR can be performed. In this sense, if these patients do not have heart failure but have exertion-induced ischemic signs, restriction of exercise without invasive intervention may be selected to achieve a better outcome. Application of PTAV in this age group is relatively limited because AVP is thought to be better than PTAV in terms of preserving aortic valve function, [39, 40] and because aortic insufficiency caused by valvuloplasty is known to be progressive in nature. [15, 16] However, some patients may still benefit from PTAV to achieve the therapeutic goal in this AS group. The Ross procedure is also not regarded as a definitive repair surgery, because neoaortic regurgitation and pulmonary insufficiency are frequently observed postoperative complications, which require further interventions in the future. [40, 41] Therefore, the Ross procedure indication is limited to patients who cannot grow due to severe aortic insufficiency.

### **4. The hemodynamic effects of AS on ventricular function in children**

In this last section, we briefly comment on the differences in LV geometric and functional changes between adult- and child-onset of AS. The natural history of LV geometric and functional changes in adult-onset AS is characterized by LV concentric hypertrophy in the early stage, followed by diastolic dysfunction, systolic dysfunction with eccentric hypertro‐ phy, and heart failure at the end-stage. [42] Most of the patients who are candidates for surgical intervention are ranked in the state between diastolic and systolic ventricular dysfunction. Delayed relaxation characterizes early-stage ventricular diastolic dysfunction, and thus is observed in almost all AS patients, [43] while increased diastolic stiffness is observed in more advanced stages in which LV hypertrophy and fibrosis may coexist. The degree of diastolic dysfunction is important for predicting prognosis because it takes years to achieve reverse remodeling of diastolic function after normalization of afterload. [44]

In contrast to the relatively uniform geometric and functional LV changes observed in adultonset AS, such changes in children's AS are diverse and somewhat different from those of adults. The difference primarily stems from the diversity of the initial impact of afterload on the LV. Because adult onset of AS is largely due to a bicuspid valve or atherosclerotic change with aging, AS gradually increases LV afterload. This allows the LV to confront the increased afterload by inducing hypertrophic changes. However, the severity of AS that initially imposes afterload on the LV is diverse in children, as previously discussed, thus excessive afterload may not allow the LV to become hypertrophic, resulting in LV dilation and systolic dysfunction as observed in critical AS. With increasing age, the LV geometry and function gradually resembles those of adult AS: a hypertrophic LV with diastolic dysfunction. However, it is rare in children to observe a marked increase in LV diastolic stiffness, even in cases of hypertrophic LV (Figure 5). In addition, it is interesting that LV relaxation appears to be relatively preserved in children with AS and hypertrophic LV. These differences in LV functional responses between children and adults may have a clue to a better management of patients with AS.

**Figure 5.** Examples of left ventricular pressure-volume relationships in a control patient (A) and a patient with aortic stenosis (B). The steep slope of the end-systolic pressure-volume relationship (solid line) and arterial elastance (dashed line) indicate increased ventricular contractility and afterload. Note that the slope of the end-diastolic pressure-vol‐ ume relationship in aortic stenosis is comparable to that of control.

### **5. Conclusions**

**3.2. AS with signs and symptoms that develop during late infancy and school age**

present, another origin of the symptom should be investigated.

524 Calcific Aortic Valve Disease

limited to patients who cannot grow due to severe aortic insufficiency.

**4. The hemodynamic effects of AS on ventricular function in children**

In this last section, we briefly comment on the differences in LV geometric and functional changes between adult- and child-onset of AS. The natural history of LV geometric and functional changes in adult-onset AS is characterized by LV concentric hypertrophy in the early stage, followed by diastolic dysfunction, systolic dysfunction with eccentric hypertro‐ phy, and heart failure at the end-stage. [42] Most of the patients who are candidates for surgical intervention are ranked in the state between diastolic and systolic ventricular dysfunction. Delayed relaxation characterizes early-stage ventricular diastolic dysfunction, and thus is observed in almost all AS patients, [43] while increased diastolic stiffness is observed in more

The treatment strategy for AS in which signs and/or symptoms develop later in childhood is different from that for neonatal AS. The American College of Cardiology/American Heart Association Guidelines for the management of AS of this group [31] recommended that patients with a peak instantaneous pressure gradient (PIPG) measured by Doppler echocar‐ diography ≥70 mmHg be considered for cardiac catheterization and treatment in asympto‐ matic children and young adults. If the patients desire to participate in competitive sports or become pregnant, a PIPG of 50–70 mmHg is an indication for further evaluation and inter‐ ventions. If patients have symptoms (angina, syncope, or dyspnea on exertion), a PIPG ≥50 mmHg is the indication for treatment. If the PIPG is less than 50 mmHg and a symptom is

There are several treatment options for cases in which intervention is indicated, including PTAV, open AVP, the Ross procedure, and AVR. Procedure selection is primarily dependent upon whether the patient's somatic size (aortic annular size) is large enough to use a prosthetic valve, because AVR is considered as the first-line procedure at present. If the prosthetic valve is not available, procedures other than AVR are selected so that patients can live with their own valve until they can use a prosthetic aortic valve. In such situations, the most important concept for treatment is that the procedure should be regarded as a bridge to AVR. Therefore, the aim of any intervention should be to reduce the afterload without any significant aortic regurgitation so that patients can grow uneventfully until AVR can be performed. In this sense, if these patients do not have heart failure but have exertion-induced ischemic signs, restriction of exercise without invasive intervention may be selected to achieve a better outcome. Application of PTAV in this age group is relatively limited because AVP is thought to be better than PTAV in terms of preserving aortic valve function, [39, 40] and because aortic insufficiency caused by valvuloplasty is known to be progressive in nature. [15, 16] However, some patients may still benefit from PTAV to achieve the therapeutic goal in this AS group. The Ross procedure is also not regarded as a definitive repair surgery, because neoaortic regurgitation and pulmonary insufficiency are frequently observed postoperative complications, which require further interventions in the future. [40, 41] Therefore, the Ross procedure indication is

> In adults, AS generally develops slowly, with the progression of valve calcification or leaflet degeneration being independent of the existence of substrates for congenital abnormalities.

This allows the LV to adapt to the increased afterload by becoming concentrically hypertro‐ phied. Therefore, it takes a long time before LV systolic function is severely impaired and critical events occur.45 Because valvular calcification is a commonly observed morphological change and because a prosthetic valve is generally available for adults, aortic valve replace‐ ment is selected as a first-line treatment and plastic surgery is seldom chosen for this popula‐ tion. Thus, the treatment strategy is rather straightforward.

[4] Palta, S, Pai, A. M, & Gill, K. S. Pai RG: New insights into the progression of aortic

Congenital Aortic Stenosis in Children http://dx.doi.org/10.5772/54806 527

[5] Pohle, K, Maffert, R, & Ropers, D. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. *Circulation* (2001).

[6] Olsson, M, Dalsgaard, C. J, Haegerstrand, A, Rosenqvist, M, & Ryden, L. Nilsson J: Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheu‐

[7] Parolari, A, Loardi, C, & Mussoni, L. Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention. *Eur J Cardiothorac Surg* (2009).

[8] Capoulade, R, Clavel, M. A, & Dumesnil, J. G. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. *J Am Coll Cardiol*

[9] Pomerance A: Pathogenesis of aortic stenosis and its relation to age. (1972). *Br Heart J*.

[10] Hope, M. D, Urbania, T. H, Yu, J. P, & Chitsaz, S. Tseng E: Incidental aortic valve calcification on CT scans: significance for bicuspid and tricuspid valve disease.

[11] Mcelhinney, D. B, Vogel, M, & Benson, C. B. Assessment of left ventricular endocardial fibroelastosis in fetuses with aortic stenosis and evolving hypoplastic left heart

[12] Mcelhinney, D. B, Marshall, A. C, & Wilkins-haug, L. E. Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic

[13] Lofland, G. K, Mccrindle, B. W, & Williams, W. G. Critical aortic stenosis in the neonate: a multi-institutional study of management, outcomes, and risk factors. Congenital

[14] Jacobs, J. P, Mavroudis, C, & Jacobs, M. L. Lessons learned from the data analysis of the second harvest ((1998). of the Society of Thoracic Surgeons (STS) Congenital Heart

[15] Eroglu, A. G, Babaoglu, K, & Saltik, L. Echocardiographic follow-up of congenital aortic

[16] Davis, C. K, Cummings, M. W, & Gurka, M. J. Gutgesell HP: Frequency and degree of change of peak transvalvular pressure gradient determined by two Doppler echocar‐ diographic examinations in newborns and children with valvular congenital aortic

[17] Wagner, H. R, Weidman, W. H, & Ellison, R. C. Miettinen OS: Indirect assessment of

stenosis with evolving hypoplastic left heart syndrome. *Circulation* (2009).

Heart Surgeons Society. *J Thorac Cardiovasc Surg* (2001).

Surgery Database. *Eur J Cardiothorac Surg* 2004, 26(1):18-37.

severity in aortic stenosis. *Circulation* (1977). Suppl):I, 20-3.

valvular stenosis. *Pediatr Cardiol* (2006).

stenosis. *Am J Cardiol* (2008).

stenosis: implications for secondary prevention. *Circulation* (2000).

matic stenotic aortic valves. *J Am Coll Cardiol* (1994).

(2012).

*Academic radiology* (2012).

syndrome. *Am J Cardiol* (2010).

In contrast, as discussed in this chapter, a wide range of clinical phenotypes is seen in pediatric AS. Depending on the severity of the native aortic valve abnormality and associated hemo‐ dynamic features, AS could be one of the most severe forms of congenital heart defects in children, leading to a critical condition in neonates or even during fetal life. In the milder form of pediatric AS, no clinical symptoms are seen throughout the patient's life. Therefore, the complexity of the treatment approach depends upon the patient's age, body size, and associ‐ ated cardiac anomalies. In particular, because of the limited availability of prosthetic aortic valves for small children, the native valve morphological features constitute an extremely important determinant of treatment strategy. A detailed assessment of LV function as well as accurate anatomical diagnosis, including analysis of the potential utility of the native aortic valve, is essential for achieving a better outcome for patients. The use of specific medications [46] and prevention of metabolic syndrome from childhood may help improve outcomes.

Accumulation of information regarding the outcomes of underdeveloped valves, detailed mechanisms underlying disease progression, surgical outcomes, and improvements in surgical techniques should lead to considerably improved outcomes in the pediatric population.


*Edited by Teodora Emilia Coldea*

Given the rapid growth of engineering fields, namely the food industry with novel food process technologies, novel ingredients, advanced enzyme production and applications, and other complementary technologies, this book will disclose the latest trends in food engineering. This text is a compilation of selected research articles and reviews covering current efforts in research in and application of emerging technologies in the food industry. The chapters in this book are divided into three broad sections. Section 1 deals with introductory information about enzyme application, preserving treatments (such as thermal treatment, active packaging concepts) in a sustainable, cost-effective manner, inclusion in food processing of wild edible plants as a part of cultural and generic heritage, and the upscaling of extraction techniques to increase the bioavailability of bioactive compounds. Section 2 provides data concerning the food industry's emerging technologies. Section 3 reveals the latest trends in food fortification. Overall, this book serves as an inspiring source for both scientific and industrial actors or anyone involved in any aspect related to the food industry.

ISBN 978-1-83881-975-0

Food Engineering

Published in London, UK © 2019 IntechOpen © noblige / iStock


2. Problem statement

minTAC ¼ AF � ∑

96 Heat Exchangers– Design, Experiment and Simulation

minTAC ¼ 1

þ∑ iϵH ∑ jϵC ∑ kϵK

þ ∑ pϵP

> þ∑ iϵH ∑ jϵC ∑ kϵK

same interval of the superstructure at different periods of operations.

iϵH ∑ jϵC ∑ kϵK

DOPp NOP ∑ jϵC

NOP þ 1 ∑

(

CFzi,j, k þ ∑

i,j, k þ ∑ jϵC

CUHqj,hu,p þ ∑

i,j, k þ ∑ jϵC

ACi,j, kAAEi,j

pϵP ∑ iϵH

ACi,j, kAAEi,j

where AF is the annualisation factor, CF is the fixed charge for heat exchangers, AC is the area costs for heat exchangers, AE is the area cost exponent for heat exchangers, CUH and CUC are the costs of hot and cold utilities, respectively, DOP is the duration of period p, NOP is the number of periods/operating conditions, Ai,j,k is the area of heat exchanger for hot and coldprocess stream pairs i,j in interval k. Aj,hu and Ai,cu are the area of heat exchangers exchanging heat between hot utility and cold-process streams and cold utility and hot-process streams, respectively. H,C,HU,CU are the set of hot streams, cold streams, hot utilities and cold utilities, respectively. It should be known that the area Ai,j,k is the representative heat exchange area which, as explained previously, are used by the same pair of streams exchanging heat in the

Eqs. (1) and (2) are the objective functions used in determining the TAC for the first-step initial candidate multi-period network that is later tested for flexibility using various kinds of approaches in some of the existing methods [5, 9–14]. It can be seen that the utility cost calculation component of these equations will result in allotting equal contributions, in terms of utility usage durations, for each of the periods of operations present in the first-step candidate multi-period network. This implies that the candidate multi-period network that is designed at the initial step, and later tested for flexibility, may be limited based on the fact that it is designed with the assumption that these initial candidate critical points have equal-period durations. Since TAC is being solved for at the first step, the objective functions in Eqs. (1) and (2) will aim to simultaneously minimise both utility consumption and investment costs. The investment cost is influenced by the size of heat-exchanger areas and the number of units. Allowing this limitation at the first step of the flexible network synthesis process means that the flexibility analysis step needs to be sophisticated so as to compensate for this limitation. This is because some candidate networks that lie in the uncertain process parameter range that are tested in the flexibility step may be disqualified from being included in the flexible network feasible space due to the fact that Eqs. (1) and (2) were used as the objective functions for

iϵH ∑ CU

CFzi, cu þ ∑

ACj, huAAEj,hu

DOPp NOP ∑ iϵH

pϵP ∑ jϵC

ACj, huAAEj,hu

pϵP

" #

" #

CUCqi, cu, p þ ∑

jϵC ∑ HU

j,hu þ ∑ iϵH

CFzj, hu

CUCqi, cu,p

CUHqj, hu, p

j,hu þ ∑ iϵH

ACi, cuAAEi, cu i, cu

> ACi, cuAAEi, cu i, cu

)

(1)

(2)

Given a set of hot-process streams and a set of cold-process streams, which have to be cooled and heated, respectively. Given also are the supply and target temperatures and the flow rates of these streams. Hot and cold utilities are also available. The task is to synthesise a flexible heatexchanger network which is optimally operable (i.e. featuring a minimum TAC network) for any unforeseen process-operating parameter point lying within an uncertain operating range.


**2. Waste management hierarchy**

The waste management hierarchy designates the best solutions for managing waste according to what is most suitable for environment [10] and is presented in **Figure 1**.

### **2.1 Prevention**

Priority is given to preventing waste and this entails using less material, waste reduction at source, or retaining products for long [10]. Prevention of waste is advantageous from any waste management strategy such as energy recovery, recycle,

**Figure 1.** *Illustration of the waste hierarchy [10].*

*Evaluating Waste-to-Energy Technologies as a Waste Management Solution for Uganda DOI: http://dx.doi.org/10.5772/intechopen.101904*

and landfill because the production of material that becomes waste as well as its treatment is circumvented. The definition of waste prevention includes avoidance of waste creating products, waste reduction at source, increasing the life cycle of a product, and reuse [11]. According to the World Bank Report, the fastest way to manage and decrease waste is to minimise economic activity because when countries urbanise, their economic wealth grows along with standards of living, disposable incomes, and consumption of goods and services which leads to an increase waste generated [12]. Another suggested solution is moving from a linear to circular economy that is by curtailing resource extraction and material inputs, and improving efficiency through developmental designs, recollection, and recycling [8].

#### **2.2 Reuse and recycle**

Under these stages, the waste producer is required to check, clean, repair, and reuse the material or shift the use of the material to another function. Useless waste is converted into useful materials, and hazardous waste is turned in harmless material hence improving utilisation [10, 11]. Resource recycling promotes economic, social, and environmental benefits because the country saves on natural resources, decreases energy consumption, promotes employment while decreasing waste and pollution. Useless waste is converting into useful materials, and hazardous waste is turned in harmless material hence improving utilisation [11]. An increase in recyclable material in the composition of waste requires reuse and recycle management, while an increase in organic waste or other unrecyclable material would require other management techniques [13].

#### **2.3 Recovery**

Recovery can be through energy recovery techniques and/or using waste for either agricultural purposes or backfilling [10]. Section 3 provides more insight on energy recovery techniques. It involves recovering usefulness from the waste through energy recovery techniques such as anaerobic digestion, fermentation, incineration, gasification and pyrolysis to produce energy (fuel, heat and power), and using waste for backfilling [10]. The recovery of biogas and heat energy from landfills and incineration plants, respectively, will reduce waste generation and help in the appropriate reutilization of resources. Resource utilisation of livestock and manure, agricultural waste, domestic sewage sludge, and other organic SWs during aerobic composting and anaerobic digestion and then recycling the organic substances and nutrients, etc. are some of the efficient ways to realise SW resources and materials recovery systems [11].

#### **2.4 Disposal**

Depending on a country's policies, waste is disposed of through grinding, milling, open dumping, landfilling, and compaction or burned in an incinerator without energy recovery. The waste can also be disposed of in other countries only when it has a market in those specific countries [8, 10, 11].

High income countries mostly dispose through landfilling and thermal treatments while middle- and low-countries mostly dispose by open dumping and poorly managed landfilling. However, the middle-income countries operate with managed dumping processes [12].


**3.10 P10 presentation phase**

During P10 phase, 1-n presentations will be held. This can also be considered as a proof of concept (**Table 12**).

• Travel expenses

• Approval conditions

**3.13 P13 decision phase**

*3.13.1 Other activities*

*Activities in the decision phase.*

**4. Conclusion**

**5. Future work**

**63**

model for the selection of CRM systems.

• Service-Level-Agreements (SLA)

*Qualitative Analysis of Different CRM Evaluation Models*

*DOI: http://dx.doi.org/10.5772/intechopen.89776*

In the decision phase, all decisions are collected, and a management summary is given. Final tests provide information and form the final basis for a definite decision

**Activities Nomination in phase** P **A B CD** Final testing 1, 2 2 1.5000 1.5000 0.1250 2 Make decision 3, 4, 5, 6, 8 8 5.5000 5.2500 1.0000 3 Summarize criteria 1 2 1.0000 1.0000 0.0000 1

Possible reference customers (clients) of the final vendor are identified, contacted, and visited. During reference visits, the implementation project, the industry experience of the consultants, and the ongoing support will be discussed. The final contract negotiations are carried out. In the final phase, the most suitable

The study is interesting since viewpoints from a literature perspective as well as from a business side have been considered. The results of the qualitative content analysis (**Figure 2**) offer the possibility of the individual design of a procedure

The selection model can be changed or adjusted if necessary. This applies to the

In the qualitative analysis of CRM evaluation models, 13 phases including specific activities were identified. Based on this literature review, it is planned to conduct expert interviews. On the basis of these expert interviews, a new CRM evaluation model will be defined an afterwards tested via a quantitative analysis to

analyzed phases as well as to the respective activities within the phases.

system and the vendor or implementation partner are selected.

• Liability

• Warranty

• Delay

• etc.

(**Table 15**).

**Table 15.**

#### **Table 12.**

*Activities in the presentation phase.*

#### *3.10.1 Other activities*

An agenda must be created for vendor presentations. The vendor presentations should be moderated. A documentation (e.g., minutes) of each vendor presentation is created. Each vendor presentation is rated by a defined Team via defined questionnaire. For the vendor presentations, data for the prototype is provided. The activities for the vendor presentations are also valid for the proof of concept.

#### **3.11 P11 shortlist phase**

#### *3.11.1 Other activities*

A shortlist of CRM systems and CRM providers (vendors and implementation partners) must be created (**Table 13**). All CRM systems and CRM providers from the reduced longlist are collected in the list. Based on previous defined detailed criteria, the CRM systems and CRM providers are evaluated and reduced to a shortlist.

**Table 13.**

*Activities in the shortlist phase.*

#### **3.12 P12 negotiation and contract phase**

The focus in this phase is to design the contracts (project contract, software contract, maintenance contract) and conduct contract negotiations (**Table 14**).

**Table 14.**

*Activities in the project initialization phase.*

#### *3.12.1 Other activities*

The negotiation strategy is defined, and the following important contract elements are identified:

*Qualitative Analysis of Different CRM Evaluation Models DOI: http://dx.doi.org/10.5772/intechopen.89776*

**3.10 P10 presentation phase**

*Customer Relationship Management and IT*

proof of concept (**Table 12**).

*3.10.1 Other activities*

*Activities in the presentation phase.*

**Table 12.**

**3.11 P11 shortlist phase**

*Activities in the shortlist phase.*

**3.12 P12 negotiation and contract phase**

• Costs for licenses, consulting, development

*3.11.1 Other activities*

**Table 13.**

**Table 14.**

**62**

*3.12.1 Other activities*

*Activities in the project initialization phase.*

elements are identified:

• Terms of payment

During P10 phase, 1-n presentations will be held. This can also be considered as a

**Activities Nomination in phase** P **ABCD** Perform presentations 3, 4, 7 8 4.2500 8 0.6824 1 Proof of concept 4 2 4.0000 2 0.7143 2

An agenda must be created for vendor presentations. The vendor presentations should be moderated. A documentation (e.g., minutes) of each vendor presentation

A shortlist of CRM systems and CRM providers (vendors and implementation partners) must be created (**Table 13**). All CRM systems and CRM providers from the reduced longlist are collected in the list. Based on previous defined detailed criteria, the CRM systems and CRM providers are evaluated and reduced to a shortlist.

**Activities Nomination in phase** P **A B CD** Create shortlist 3, 4, 5 4 4.0000 4.0000 0.7667 1

The focus in this phase is to design the contracts (project contract, software contract, maintenance contract) and conduct contract negotiations (**Table 14**).

**Activities Nomination in phase** P **A B CD** Carry out negotiations 3, 7 2 5.0000 5.0000 0.9286 1

The negotiation strategy is defined, and the following important contract

is created. Each vendor presentation is rated by a defined Team via defined questionnaire. For the vendor presentations, data for the prototype is provided. The activities for the vendor presentations are also valid for the proof of concept.

#### **3.13 P13 decision phase**

In the decision phase, all decisions are collected, and a management summary is given. Final tests provide information and form the final basis for a definite decision (**Table 15**).

#### **Table 15.**

*Activities in the decision phase.*

#### *3.13.1 Other activities*

Possible reference customers (clients) of the final vendor are identified, contacted, and visited. During reference visits, the implementation project, the industry experience of the consultants, and the ongoing support will be discussed. The final contract negotiations are carried out. In the final phase, the most suitable system and the vendor or implementation partner are selected.

#### **4. Conclusion**

The study is interesting since viewpoints from a literature perspective as well as from a business side have been considered. The results of the qualitative content analysis (**Figure 2**) offer the possibility of the individual design of a procedure model for the selection of CRM systems.

The selection model can be changed or adjusted if necessary. This applies to the analyzed phases as well as to the respective activities within the phases.

#### **5. Future work**

In the qualitative analysis of CRM evaluation models, 13 phases including specific activities were identified. Based on this literature review, it is planned to conduct expert interviews. On the basis of these expert interviews, a new CRM evaluation model will be defined an afterwards tested via a quantitative analysis to confirm the results. Based on this new model, it is planned to develop guidelines how the model can be used.

**Model name Number**

*DOI: http://dx.doi.org/10.5772/intechopen.89776*

*Qualitative Analysis of Different CRM Evaluation Models*

Auswahl und Einführung von CRM-Systemen [24]

*Overview of the evaluation models.*

[25]

**Table 16.**

**Table 17.**

**65**

*Normalization formula.*

Evaluationsprozess für CRM-Systeme

**phases**

CRM-Projekt [26] 2 Selection Phases White paper Vorgehensweie im Überblick [27] 5 Selection Phases Presentation slides

**# of phases Split # of phases Split # of phases Split # of phases Split** 1 0.0000 1 0.0000 1 0.0000 1 0.0000 2 1.0000 2 0.5000 2 0.3333 2 0.2500

**# of phases Split # of phases Split # of phases Split # of phases Split** 0.0000 1 0.0000 1 0.0000 1 0.0000 0.2000 2 0.1667 2 0.1429 2 0.1250 0.4000 3 0.3333 3 0.2857 3 0.2500 0.6000 4 0.5000 4 0.4286 4 0.3750 0.8000 5 0.6667 5 0.5714 5 0.5000 1.0000 6 0.8333 6 0.7143 6 0.6250

**Model type Procedure Document type**

6 Selection Road map Study

3 1.0000 3 0.6667 3 0.5000

7 1.0000 7 0.8571 7 0.7500

4 1.0000 4 0.7500

8 1.0000 8 0.8750

5 1.0000

9 1.0000

3 Evaluation Phases Bachelor thesis

**Figure 2.**

*Thirteen-stage selection model.*


**Acknowledgement**

Studies of probiotics' immune modulating effects on the rotavirus vaccine in gnotobiotic pigs were supported by a grant (R01AT004789) from the National Center of Complementary and Alternative Medicine (NCCAM), National Institutes of Health, Bethesda, MD.


Contents

**Chapter 9 191** Optimal Control of Fuzzy Systems with Application to Rigid Body Attitude Control *by Yonmook Park*

Preface

This book is a collection of reviewed and relevant research chapters, concerning the developments within the Aerospace Engineering field of study. The book includes scholarly contributions by various authors, edited by an expert in the engineering field. Each contribution is a separate chapter but each is directly related to the

The book includes nine chapters dealing with the following topics: Green

The target audience comprises scholars and specialists in the field.

Comparable Alternatives of Hydrazines-Based Monopropellant and Bipropellant Rocket Systems, High Strain Rate Characterization of Thermoplastic Fiber-Reinforced Composites under Compressive Loading, Matrix Converter for More Electric Aircraft, Turbine Engine Lubricant and Additive Degradation Mechanisms, The Evolution of the Composite Fuselage: A Manufacturing Perspective, Robotic Autonomous Spacecraft Missions: Cassini Mission-To-Saturn Example, Advanced Nonlinear Modeling of Gas Turbine Dynamics, Effect of Microstructure on Microhardness and Electrochemical Behavior in Hypereutectic Al-Fe Alloy

Processed by Laser Surface Remelting, and Optimal Control of Fuzzy Systems with

**IntechOpen**

book's topic and objectives.

Application to Rigid Body Attitude Control.


**5. Conclusions**

The experimental training program based on the principles of CrossFit training had a positive effect on the physical fitness of the kickboxers in terms of strength, flexibility, agility, and speed indices in the experimental group. The experimental training program based on the principles of CrossFit training had a positive effect on special physical fitness. There were significant correlations in the parameters of special and general fitness, i.e., Cooper test vs. total of punches and kicks, shuttle run vs. hip-turning speed, and tapping vs. punching speed after the experimental training program.