**1. Introduction**

We all are exposed through air, food, drinks and skin contacts to harmful compounds throughout the period of our lifetime, including, a variety of pharmaceuticals and food-de‐ rived carcinogen metabolite (e.g. N-acetoxy-PhIP), [52], plant toxins (such as *glycoalkaloids* in nightshades1 , *cyanogenic glucosides* 2 , or *pyrrolizidine alkaloids* in some herbs and herbal teas), xenobiotics3 producing during early human pregnancy, fungal and bacterial toxins such as aflatoxins4 ; and cyanotoxin5 ; as well as free radicals and hydroperoxides. Many of these compounds are lipophilic and the organism can get rid of them only through metabolism.

Biotransformation has been conveniently categorized into three distinct phases, which act in a tightly integrated manner. Phases I and II enzymes catalyze the conversion of a lipophilic, non-polar xenobiotic into a more water-soluble and therefore less toxic metabolite, which can then be more easily excreted from the body. Phase I biotransformation seems to be en‐ zymes that catalyzes oxidation, reduction or hydrolyze reactions, it usually converts sub‐ strates to more polar forms by introducing or unmasking a functional group (e.g., —OH, — NH2, or —SH). Phase I consist primarily of microsomal enzymes, which are found abun‐ dantly in the liver, gastrointestinal tract, lung and kidney, consisting of families and subfa‐ milies of enzymes that are classified based on their amino acid sequence identities or similarities. [84]. Many of the enzymes like monooxygenases are found in the endoplasmic

5 - A toxin producing by cyanobacteria of which microcystin-LR is predominant

© 2013 Ziglari and Allameh; licensee InTech. This is an open access article 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. © 2013 Ziglari and Allameh; licensee InTech. This is a paper 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.

1 - Plants like potatoes, tomatoes, peppers, egg plant, tobacco, some spices.

2*- Like bitter almond, cassava root, sorghum root, lima bean, fruit seed, etc.*

3 - Chemical compounds foreign to the human organism without nutritional value

4 - A group of mycotoxins of which aflatoxin B1 is the most potent hepatocarcinogen

reticulum membrane, but others such as the dehydrogenases for example alcohol dehydro‐ genases and peroxidases located in the cytoplasm, while still others such as monoamine oxi‐ dase are localized in mitochondria. Monooxygenases are also known as mixed function oxidases because in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule: one oxygen atom appearing in the product and the other in a molecule of water. The reaction scope of monooxygenases includes heteroatom oxidation, aromatic and aliphatic hydroxylation, epoxidation, and Baeyer-Villiger oxidation. There are two ma‐ jor types of microsomal monooxygenase, both of which require NADPH as an external re‐ ductant: the cytochrome P450 (CYP) system and flavin-containing monooxygenases. The mechanism of CYP is a complex cascade of individual steps involving the interaction of pro‐ tein redox partners and consumption of reducing equivalents, usually in the form of NADPH. The iron heme containing enzyme, CYP, consists of two enzymes: NADPH–cyto‐ chrome P450 reductase and CYP. It is involved in the oxidative metabolism of many endog‐ enous substances such as steroids and bile acids, as well as the detoxication of a wide variety of xenobiotics. It can oxidize AFB1 to several products. Only one of these, the 8,9 exo-epoxide, appears to be mutagenic and the others are detoxification products. P4503A4, which can both activate and detoxicate AFB1, is found in the liver and the small intestine. [33], [52]. Flavincontaining monooxygenases catalyze an NADPH- and an oxygen-requiring oxidation of substances (primarily xenobiotics) bearing functional groups containing nitro‐ gen, sulfur, or phosphorus. The properties of the CYPs electron transport systems have also been reported [77].

phase III of detoxification system to be called antiporter activity. Antiporter activity is an important factor in the first pass metabolism of pharmaceuticals and other xenobiotics. The antiporter is an energy-dependent efflux pump, which pumps xenobiotics out of a cell, thereby decreasing the intracellular concentration of xenobiotics. In eukaryotic organisms, they are actively excreted or compartmentalized in the vacuole by ATP-dependent GS-X pumps [42], [27]. Indeed, as the glutathionylated moiety is hydrophilic, the conjugate cannot usually simply re-diffuse back into the cell [77]. Antiporter activity in the intestine appears to be co-regulated with intestinal phase I CYP3A4 enzyme. This observation suggests the antiporter may support and promote detoxification. Possibly, its function of pumping nonmetabolized xenobiotics out of the cell and back into the intestinal lumen, may allow more opportunities for phase I activity to metabolize the xenobiotic before it is taken into circula‐ tion. Although, most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous com‐ pounds, however, the first contact the body with the majority of xenobiotics take places in the gastrointestinal tract. Intestinal mucosa possesses enzyme systems capable of various types of biotransformation of xenobiotics [52]. Among the detoxification pathways, gluta‐ thione conjugation pathway is the prominent route of AFB1 inactivation in liver of mamma‐ lians. Depending on the availability of cellular GSH and the activation of glutathione S-

The Significance of Glutathione Conjugation in Aflatoxin Metabolism

http://dx.doi.org/10.5772/52096

269

Glutathione is a ubiquitous thiol-containing isotripeptide (γ-glu-cys-gly, FW 307.3), consist‐ ing of glycine, glutamic acid and cysteine molecules which was first discovered by Sir Fre‐ drick Gowland Hopkins in 1920s, synthesized de novo in mammalian cells (Figure 1). This water soluble antioxidant compound is an unusual peptide in that the peptide bond be‐ tween the glutamate residue and the cysteine residue is formed with the γ-carboxylate group of the former rather than the α-carboxylate group. Today along with β-carotene, as‐ corbic acid (vitamin C), α-tocopherol (vitamin E) and flavonoids *etc*., GSH6 is commonly re‐ ferred to as an antioxidant [17], which neutralizes free radicals due to the high electrondonating capacity of its sulfydryl (-SH) group, [13], and prevents damage to important cellular components, implicates in the cellular defense against xenobiotics. Glutathione sta‐ tus is a highly sensitive indicator of cell functionality and viability. Its levels in human tis‐ sues normally range from 0.1 to 10 mM, being most focused in liver (up to 10 mM) and in the spleen, kidney, lens, erythrocytes and leukocytes and its emptying be joined to a variety of diseases. Under normal conditions, glutathione is predominantly present in its reduced

other cellular thiol in a reduced state. Finally, GSH tends to a substrate or cofactor in some of

pair with their high reduction potential participates in maintaining

transferase subclasses, detoxification of AFB1 is facilitated [24].

form, with only a small proportion present in its fully oxidized state [20].

**2. Glutathione**

Moreover, the GSH/GSSG7

6 - Glutathione, reduced form 7 - Glutathione, oxidized state

In detoxification pathway, a series of enzyme-catalyzed processes with broad specificities convert the toxic substances into less toxic metabolites by chemical reactions within the body. Although biotransformation reactions take place within cytoplasm and mitochondria but they mostly happen within endoplasmic reticulum (E.R). Cell types also differ in their biotransforming potential for example cells located near the major points of xenobiotic entry into the body such as liver, lung, and intestine possess greater concentrations of biotrans‐ forming enzymes than others [52].

Phase II conjugation reactions which generally act follow phase I activation consists of reac‐ tions in which metabolites containing appropriate functional groups are conjugated with substances such as glucuronate, glutamate, sulfate, reduced glutathione or uridine diphos‐ phate (UDP)-glucuronic acid to finally discharge them through urine or bile. In general, con‐ jugation dramatically improves solubility, which then promotes rapid excretion. Among the several types of conjugation reactions which are present in the body, including glucuronida‐ tion, sulfation, and glutathione and amino acid conjugation, glutathione which is catalyzed by glutathione S-transferases, is the major phase II reaction in many species [52]. With the exception of acetylation, methylation and fatty acid conjugation, the strategy of phase II bio‐ transformation is to convert a xenobiotic to a more hydrophilic form via the attachment of a chemical moiety which is ionizable at physiological pH. This metabolic transformation also results in reduced affinity of the compound for its cellular target. [67], [23].

In animals, elimination of the soluble compounds from cells and excretion of biotrans‐ formed molecules from the body referred to as phase III. It has been suggested that the phase III of detoxification system to be called antiporter activity. Antiporter activity is an important factor in the first pass metabolism of pharmaceuticals and other xenobiotics. The antiporter is an energy-dependent efflux pump, which pumps xenobiotics out of a cell, thereby decreasing the intracellular concentration of xenobiotics. In eukaryotic organisms, they are actively excreted or compartmentalized in the vacuole by ATP-dependent GS-X pumps [42], [27]. Indeed, as the glutathionylated moiety is hydrophilic, the conjugate cannot usually simply re-diffuse back into the cell [77]. Antiporter activity in the intestine appears to be co-regulated with intestinal phase I CYP3A4 enzyme. This observation suggests the antiporter may support and promote detoxification. Possibly, its function of pumping nonmetabolized xenobiotics out of the cell and back into the intestinal lumen, may allow more opportunities for phase I activity to metabolize the xenobiotic before it is taken into circula‐ tion. Although, most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous com‐ pounds, however, the first contact the body with the majority of xenobiotics take places in the gastrointestinal tract. Intestinal mucosa possesses enzyme systems capable of various types of biotransformation of xenobiotics [52]. Among the detoxification pathways, gluta‐ thione conjugation pathway is the prominent route of AFB1 inactivation in liver of mamma‐ lians. Depending on the availability of cellular GSH and the activation of glutathione Stransferase subclasses, detoxification of AFB1 is facilitated [24].


**8.2 Solar electrical conversion application**

	- a. Solar water pumping.
	- b. Hydrogen Fuel.

There are some other types of solar electric power systems based on different technologies. Some of which are in practice and some are under development. Some of them are:

The first four are the major ones while the fifth one, under development, is a latest technology in solar energy conversion. It is related to thin film, and will be discussed latter in the chapter.


**3.3. Energy system overview**

An overview of the energy system being planned for this project is shown in **Figure 5**. The system composition follows the plans that were developed during the design of the master plan. The capacity of the solar panels was changed to approximately 75 kW to address actual conditions.


3.Sequence alignment using BLAST

4.Physico-chemical parameters including secondary structure, charge, size, hydrophobicity and amphiphilic character as these yielded an appreciable accuracy using machine learning technique. The values of physico-chemical properties were retrieved from AA index database (Kawashima and Kanehisa 2000)

The three-dimensional model of the peptides was fabricated by Chimera 1.8.1 software.

ToxinPred tool was run with default parameters to calculate toxicity prediction of the determined peptides. All 25 peptides were non-toxic [30].

#### **Figure 1.**

*Structures of EBVO proteins obtained from PDB; (A) GP; (B) L, (C) NP, (D) VP24, (E) VP30, (F) VP35, (G) VP40.*

*Docking-Based Screening of Cell-Penetrating Peptides with Antiviral Features and Ebola Virus… DOI: http://dx.doi.org/10.5772/intechopen.97222*


**2.2 Thermal stress analysis**

skips past the 30°C (86°F) mark in the middle of the month and rises to 33°C (91°F)

This work aims to assess thermal stress based on the various measurable thermal stress parameters (wet bulb temperature, air speed, radiation temperature, black

This is an exhaustive cross-sectional study carried out during the two months of August and September 2015, in a Tunisian steel company specialized in the manufacture of springs for heavy vehicles and located in the industrial zone of Teboulba-Moknine of the governorate of Monastir, Tunisia. This company counted 120 workers. A list of names and contact details of all workers was provided by the Human Resources Management Department. Included patients were those who had a job tenure exceeding one year and belonged to production workshops. Exclusion criteria consisted of a participation refusal and a disability or cognitive impairment

The survey was preceded by an individual interview with each eligible worker in order to explain the objectives of the work, its practical progress, guarantee anonymity and obtain informed consent. During the survey, data collection focused on general characteristics, as well as thermal stress measurements. Data analysis was subsequently carried out by the same investigator, using statistical and computer

1.General characteristics related to age, weight, height, Body Mass Index

2.Measurement of the thermal environment carried out in the workstation of each worker and in the external environment (rest area during recovery breaks). These recordings were preceded by open observation days to estimate the actual duration of the activity set at five hours. Open observation also enabled a contact with the operators and the collection of their opinions concerning the time and extent of the temperature peak. The thermal stress mainly concerns the morning and afternoon shiftwork and extended from 7 am to 7 pm. Thus, measurements were made every 15 minutes at the workstations. The values obtained were means of all measurements

performed. These measurements were carried out in accordance with the ISO

workstation at a height of 1.5 m, far from the employees and sheltering the sensor against radiation (sun, oven, etc.). It is a calibrated device with a low response time, a stabilization time of a few seconds enabling punctual measurement of air temperature and relative humidity.

• a vane anemometer (YK-80AP Vane Anemometer) for measuring air speed. The measurement was discontinuous and the axis of rotation was

7726 standard "*Ergonomics of the thermal environment - Instruments for*

• a thermo-hygrometer (TA5 Thermal Anemometers) placed at the

*measuring physical quantities*" [4] using:

placed in the direction of the air flow.

in July and August.

*Occupational Wellbeing*

globe temperature...).

**2. Materials and methods**

precluding participation.

programs.

**68**

**2.1 Data collection**

(BMI)...

This evaluation was conducted by the program "Ergonomics of work in heat - Calculation of PMV indices - PPD, WBGT and P.H.S." developed by Prof. Malchaire [5] and based on the various physical parameters of the thermal environment (air temperature, black globe temperature, relative humidity, speed of air) as well as on:

	- Predicted Mean Vote (PMV) at work and during recovery. This PMV index predicts the average vote value of a large group of people on the following seven-point thermal sensation scale: + 3 very hot; + 2 hot; + 1 slightly hot; 0 neither hot nor cold; �1 slightly cold; �2 cold; �3 very cold [1]
	- Predicted Percentage of Dissatisfied (PPD) in the workplace and during recovery. This PPD index is defined as the percentage of people who, placed in identical conditions, consider themselves cold/very cold or hot/very hot. These are the people who would have cast a vote outside the interval (�1, 1) on the sensation scale [1]. To obtain a thermal comfort situation, it is recommended that the PPD be less than 10%, which corresponds to a PMV between �0.5 and + 0.5 [1].
	- Thermal sensation in work situation and during recovery: This index is calculated from the PMV and PPD indices and In accordance with ISO 7730 "Ergonomics of the thermal environments - Analytical determination and interpretation of thermal comfort by calculating the PMV and PPD indices and by local thermal comfort criteria" [8].
	- The natural humid temperature (Thn) in work situation and during recovery.
	- The Wet Bulb Globe Temperature (WBGT) in the workplace and during recovery. The WBGT corresponds to a weighting between the radiation temperature and the natural wet bulb temperature.

$$\begin{aligned} \text{WBGT} &= \text{0.7 then} + \text{0.3 tg without solar R} \\ &= \text{0.7 then} + \text{0.2 tg} + \text{0.1 ta with solar R} \end{aligned} \tag{1}$$

◦ The WBGT limits in work situation and during recovery

The working hours - rest limits (K): This duration is calculated in accordance with ISO 7243 "Hot environments - Estimation of the thermal stress of man at work, based on the WBGT index (wet bulb and black globe temperature)" [9] and according to the following equation:

$$\text{K} = \frac{\text{32} - \text{WBGT}}{\text{32} - \text{WBGT}\_{\text{lim}}} \tag{2}$$

humidity, and air speed) as well as on the equivalent metabolism M and the Iclo clothing insulation index evaluated in accordance with the ISO 9920 standard "Ergonomics of the thermal environment - Determination of thermal insulation and

Men 80

*Ergonomic Evaluation of Thermal Stress in a Tunisian Steel Industry*

*DOI: http://dx.doi.org/10.5772/intechopen.98697*

Mean age (extremes) 37,9 9,25 years (from 21 to 54 years)

Mean job tenure (extremes) 12,5 11,4 years (from1 to 35 years).

62 (77,5%) 18 (12,5%)

61 (76,25%) 10 (12,5%) 27 (33,75%) 24 (30%)

26,9 3,6 kg/m2 (17,8 à 38,7 kg/m2) 19 (23.75%) 49 (61,25%) 12(15%).

1.*Thermal environment*: The mean air temperature inside the workshops was 29.66 2.57°C with a mean air speed of 0.58 0.82 m/s, a mean relative humidity of 59, 56 10.98 and a mean global temperature of 34.15 2.87°C

2.*Thermal stress evalation*: Based on the evaluation of the equivalent metabolism and the characteristics of the thermal environment, the thermal stress to which

the workers of the different production workshops were exposed, was evaluated by the indices of Predicted Mean Vote (PMV) and Predicted

• Mean PMV of 3.2 0.47 with extremes ranging from 1.5 to 4.7.

• The Thermal sensation was rated "very hot" on 98.75% of all working

• The mean WBGT limit 28.4 0.81°C. Based on previous estimates, and in accordance with ISO 7243 "Hot environments - Estimation of the thermal stress of humans at work, based on the WBGT index (wet bulb and black globe temperature)" [9], the mean cut-off working time was evaluated at

Percentage of Dissatisfied (PPD) as follows (**Table 3**):

• The mean WBGT was 27.5 2.62°C

• Mean PPD 97.3 3.7% with extremes of 50 to 100%.

resistance to evaporation of a clothing" [7].

(**Table 2**).

**Characteristics**

Groups: n(%) • **Men > 45 years:** • **Men < 45 years:**

Depending children: • 0 **child** • 1 **to** 3 **children** • ≥3 **children**

Mean BMI (extremes)

Married

• **Normal** • **Overweight** • **Obesity**

**Table 1.** *Study population.*

Thereby:

days.

**71**

48 13.19 min.

	- a. C1: Comfort category: neither discomfort nor health risk;
	- b. C2: Discomfort category: discomfort that can be very significant, but without health risk;
	- c. C3: Category of long-term constraint: discomfort and risk of dehydration after several hours of exposure;
	- d. C4: Short-term stress category: health risk after 30 to 120 minutes of exposure;
	- e. C5: Immediate Constraint Category: health risk even for very short exposure (less than 30 minutes)

#### **3. Results**

#### **3.1 Study population**

The survey was carried out exhaustively among the operators of the production workshops of the steel company, and included a total of 80 male workers. The mean age was 37.9 � 9.25 years and the mean professional tenure was 12.5 � 11.4 years (**Table 1**).

#### **3.2 Evaluation of thermal stress**

This stress was evaluated based on the different physical parameters of the thermal environment (air temperature, temperature of the black globe, relative *Ergonomic Evaluation of Thermal Stress in a Tunisian Steel Industry DOI: http://dx.doi.org/10.5772/intechopen.98697*

The working hours - rest limits (K): This duration is calculated in accordance with ISO 7243 "Hot environments - Estimation of the thermal stress of man at work, based on the WBGT index (wet bulb and black globe temperature)" [9]

(2)

K ¼ 32 � WBGT 32 � WBGTlim

and according to the following equation:

*Occupational Wellbeing*

◦ Sweat flow in a work situation and during recovery.

◦ Total water loss in the workplace and during recovery

◦ The core temperature reached after 8 hours of work

◦ The time interval to reach a core temperature of 38°C.

◦ The time interval to achieve excessive water loss

but without health risk;

exposure (less than 30 minutes)

predicted heat strain" [10]:

of exposure;

**3. Results**

(**Table 1**).

**70**

**3.1 Study population**

**3.2 Evaluation of thermal stress**

◦ The time interval indicated for drinking 200 cc of water at 10°C

◦ The climatic condition categories in the work situation and during recovery:

a. C1: Comfort category: neither discomfort nor health risk;

b. C2: Discomfort category: discomfort that can be very significant,

d. C4: Short-term stress category: health risk after 30 to 120 minutes

e. C5: Immediate Constraint Category: health risk even for very short

c. C3: Category of long-term constraint: discomfort and risk of

The survey was carried out exhaustively among the operators of the production workshops of the steel company, and included a total of 80 male workers. The mean age was 37.9 � 9.25 years and the mean professional tenure was 12.5 � 11.4 years

This stress was evaluated based on the different physical parameters of the thermal environment (air temperature, temperature of the black globe, relative

Identified in five levels in accordance with ISO 7933 "Analytical determination and interpretation of heat stress using calculation of the

dehydration after several hours of exposure;

humidity, and air speed) as well as on the equivalent metabolism M and the Iclo clothing insulation index evaluated in accordance with the ISO 9920 standard "Ergonomics of the thermal environment - Determination of thermal insulation and resistance to evaporation of a clothing" [7].

	- Mean PMV of 3.2 0.47 with extremes ranging from 1.5 to 4.7.
	- Mean PPD 97.3 3.7% with extremes of 50 to 100%.


*Edited by Amit Agrawal*

Brain tumors comprise a spectrum of histological patterns. Their presentation and management depend on their location, size, and grade of lesions. This book is a collection of high-quality research work from global experts on brain tumors, including meningiomas, and their treatment.

ISBN 978-1-83969-803-3

Brain Tumors

Published in London, UK © 2022 IntechOpen © Marwani22 / iStock


**1. Introduction**

The economic growth that Spain was experiencing after the mid-1990s abruptly ended in 2008 because of the global economic and financial crises. These exacerbated deindustrialization and globalization processes and favored inequality, which has grown in recent decades in both Spain and the majority of other capitalist countries [1]. In fact, this recession was partly caused by global financial markets that intended to maximize short-term benefits by investing in a secondary accumulation market linked to urban space production. These massive financial transactions targeted housing markets and produced a real estate bubble that, when it burst, triggered an economic recession in Spain, with the public and private debt crisis being another component. This observed urban basis of the economic crisis explains why the most negative effects were concentrated in large cities, reflecting the vulnerability of urban spaces [2].

This economic recession also affected international migration, Spain's main driver of population and urban growth, at the beginning of the 21st century. The previous highly positive migratory growth became negative [3], return flows slightly increased, and the number of young Spaniards moving to other European countries also rose. In addition, the economic crisis had an impact on residential mobility by reducing suburbanization flows [4,5] and increasing the attractiveness of urban cores [6,7].

**Citation:** Gil-Alonso, F.; López-Villanueva, C.; Bayona-i-Carrasco, J.; Pujadas, I. Towards an Even More Spatially Diversified City? New Metropolitan Population Trends in the Post-Economic Crisis Period. *Urban Sci.* **2021**, *5*, 41. https://doi.org/ 10.3390/urbansci5020041

Academic Editor: David Plane

Received: 1 March 2021 Accepted: 4 May 2021 Published: 14 May 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The literature on the effects of the economic expansion and crisis on residential flows and urban dynamics extensively covers the Spanish context [4,5,8–10], particularly its two main urban regions, Madrid and Barcelona [11–17]. However, few studies have analyzed the consequences of the post-crisis economic recovery on urban dynamics.

Indeed, in 2014, the country started to show signs of economic recovery [18]. Economic activity and employment levels progressively rose, which had an impact on the real estate market [19]. Simultaneously, residential mobility levels seemed to recover while socio-residential strategies began to diversify [20], subsequently transforming interactions between intra-metropolitan spaces [21].

Thus, together with changes in the economic cycle, Spanish urban areas shifted from unprecedented population growth to stagnation and once again, more recently, to a new population growth phase that abruptly ended due to the impact of the COVID-19 pandemic. Still a scarcely studied period, this brief recovery phase between around 2014 and March 2020, the period studied herein, seems to have its own specificities. Residential mobility flows did not regain their pre-economic crisis characteristics, becoming more unstable, complex, and fragmentary [22]. This means that the direction of movement, migrants' reasons for moving, their socio-economic categories, and their ages all diversified, as did their impacts on Spanish urban cores and rings.

Therefore, our primary hypothesis is that, during the post-crisis period, Spanish urban areas experienced a great diversity of situations regarding the population growth of their cores and rings and that of whole metropolises. In other words, some city cores grew more than their peripheries, while, in other cases, suburbanization prevailed. At the same time, although the metropolitan population as a whole rose (again) in some areas, it continued to decline in others, as in the previous crisis period. Analyzing the population growth in Spanish urban areas while establishing a typology based on the increase and decline in core and peripheral populations, both in the economic crisis and post-crisis phases, is the first aim of this paper.

A secondary objective is to study the population growth and decline in the municipalities of the five largest Spanish metropolises for the same two four-year periods. Whereas the first part of the paper focuses on whether population change was diversifying among Spanish metropolitan areas in the post-crisis period, the second part analyzes whether this population growth heterogeneity increased within them.


Meet the editor

Abdo Abou Jaoudé has been teaching for many years and has a passion for researching and teaching mathematics. He is currently an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé (NDU), Lebanon. He holds a BSc and an MSc in Computer Science from NDU, and three Ph.D.'s in Applied Mathematics, Computer Science, and Applied Statistics and Probability, all from Bircham International University

through a distance learning program. He also holds two PhDs in Mathematics and Prognostics from the Lebanese University, Lebanon, and Aix-Marseille University, France. Dr. Jaoudé's broad research interests are in the field of applied mathematics. He has published twenty-three international journal articles and six contributions to conference proceedings, in addition to seven books on prognostics, applied mathematics, and computer science.

Contents

*by Abdo Abou Jaoudé*

*by Abdo Abou Jaoudé*

Theoretic Particles

for Radiotherapy

Appropriation Algorithm *by Maher Abdelghani*

*by Alison Wells and Chad L. Pope*

*by Tokunbo Ogunfunmi and Manas Deb*

Monte Carlo and Medical Physics

**Preface XI**

**Chapter 1 1**

**Chapter 2 45**

**Chapter 3 117**

**Chapter 4 133**

**Chapter 5 155**

**Chapter 6 177**

**Chapter 7 199**

**Chapter 8 211**

The Paradigm of Complex Probability and Thomas Bayes' Theorem

The Paradigm of Complex Probability and Isaac Newton's Classical

Flooding Fragility Model Development Using Bayesian Regression

Markov Chain Monte Carlo in a Dynamical System of Information

*by Omaima Essaad Belhaj, Hamid Boukhal and El Mahjoub Chakir*

Reliability and Comparison of Some GEANT4-DNA Processes and Models for Proton Transportation: An Ultra-Thin Layer Study *by Gabriela Hoff, Raquel S. Thomaz, Leandro I. Gutierres, Sven Muller,*

Applications of Simulation Codes Based on Monte Carlo Method

Physical Only Modes Identification Using the Stochastic Modal

*by Iury Mergen Knoll, Ana Quevedo and Mirko Salomón Alva Sánchez*

*Viviana Fanti, Elaine E. Streck and Ricardo M. Papaleo*

Mechanics: On the Foundation of Statistical Physics

## Contents

Preface

illustrates the famous Monte Carlo methods and the computer simulation of random experiments in different areas of science. As such, the book will be of interest to all scholars, researchers, and undergraduate and graduate students in mathematics and

*The Monte Carlo Methods - Recent Advances, New Perspectives and Applications*

In applied mathematics, the name Monte Carlo is given to the method of solving problems by means of experiments with random numbers. This name, after the casino at Monaco, was first applied around 1944 to the method of solving deterministic problems by reformulating them in terms of a problem with random elements, which could then be solved by large-scale sampling. But, by extension, the term has come to

The development and proliferation of computers has led to the widespread use of Monte Carlo methods in virtually all branches of science, ranging from nuclear physics (where computer-aided Monte Carlo was first applied) to astrophysics, biology, engineering, medicine, operations research, and the social sciences.

The Monte Carlo method of solving problems by using random numbers in a computer, either by direct simulation of physical or statistical problems or by reformulating deterministic problems in terms of one incorporating randomness, has become one of the most important tools of applied mathematics and computer science. A significant proportion of articles in technical journals in such fields as physics, chemistry, and statistics contain articles reporting results of Monte Carlo simulations or suggestions on how they might be applied. Some journals are devoted almost entirely to Monte Carlo problems in their fields. Studies in the formation of the universe or of stars and their planetary systems use Monte Carlo techniques. Studies in genetics, the biochemistry of DNA, and the random configuration and knotting of biological molecules are studied by Monte Carlo methods. In number theory, Monte Carlo methods play an important role in determining primality or factoring of very large integers far beyond the range of deterministic methods. Several important new statistical techniques such as "bootstrapping" and "jackknifing" are based on Monte

Hence, the role of Monte Carlo methods and simulation in all the sciences has increased in importance during the past several years. These methods play a central role in the rapidly developing subdisciplines of the computational physical sciences, computational life sciences, and other computational sciences. Therefore, the growing power of computers and evolving simulation methodology has led to the recognition of computation as a third approach for advancing the natural sciences, together with theory and traditional experimentation. Knowing that at the kernel

Moreover, the book develops methods for simulating simple or complicated

processes or phenomena. If the computer can be made to imitate an experiment or a process, then by repeating the computer simulation with different data, we can draw

of Monte Carlo simulation is random number generation.

mean any simulation that uses random numbers.

science in general.

Carlo methods.


**Abstract**

Blistering diseases comprise a large group of clinically polymorphic and sometimes devastating diseases. Blistering diseases are evaluated according to the level of the blister, the mechanism of blister formation and the type of inflammation. There are many connections in the normal structure of the skin that hold the cells together. These connections both hold the cells in the epidermis together and ensure that these cells attach to the basement membrane. As a result of damage to these connections by genetic, immune, infectious or physical reasons, intercellular connections are broken and blistering developments due to the accumulation of extracellular fluid in the intercellular spaces. Autoimmune bullous diseases are classified according to the decomposition site of the epidermis. While the pemphigus group is used to classify diseases with intraepidermal separation, the pemphigoid group diseases are used to classify diseases with subepidermal separation. In this section, pemphigoid group diseases, such as bullous pemphigoid, mucous membrane pemphigoid, acquired epidermolysis bullosa, linear IgA bullous dermatosis, and anti-p200 pemphigoid, will be explained with a brief introduction to blistering diseases of the skin.

**Keywords:** blistering diseases, subepidermal bullous disorders, pemphigoid, linear IgA bullous dermatosis, mucous membrane pemphigoid, anti-p200 pemphigoid


**Author details**

Jaroslav Legemza\*, Róbert Findorák, Mária Fröhlichová and Martina Džupková Institute of Metallurgy, Faculty of Materials, Metallurgy and Recycling, Technical University of Košice, Slovakia

\*Address all correspondence to<EMAIL_ADDRESS>
© 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.


*Article* **Age-at-Death Estimation of Fetuses and Infants in Forensic Anthropology: A New "Coupling" Method to Detect Biases Due to Altered Growth Trajectories**

**Mélissa Niel 1,\* , Kathia Chaumoître 1,2 and Pascal Adalian 1**

**Simple Summary:** In forensic anthropology, estimating the age-at-death of young juvenile skeletons is crucial as a direct determinant of legal issues in many countries. Most methods published for this purpose are based on either maturation or growth processes (two essential components of development) and focus on "normal" (i.e., nonpathological) growth. However, when the osseous remains available for study are from an individual that experienced an altered growth process, age estimation may be biased, and accounting for this would be helpful for potentially avoiding inaccuracies in estimation. In this research, we developed a method based on the combined evaluation of both maturation and growth. Maturation is evaluated by the conformation of the *pars basilaris*, a bone at the skull base that provides an indirect estimate of brain maturation, while growth is assessed using femoral biometry. The method was tested on two medical validation samples of normal and pathological individuals. The results show that it was possible to identify "uncoupling" between maturation and growth in 22.8% of the pathological individuals. Highlighting potential uncoupling is therefore an essential step in assessing the confidence of an age estimate, and its presence should lead experts to be cautious in their conclusions in court.

**Abstract:** The coupling between maturation and growth in the age estimation of young individuals with altered growth processes was analyzed in this study, whereby the age was determined using a geometric morphometrics method. A medical sample comprising 223 fetuses and infants was used to establish the method. The *pars basilaris* shapes, quantified by elliptic Fourier analysis, were grouped into consensus stages to characterize the maturation process along increasing age groups. Each *pars basilaris* maturation stage was "coupled" to biometry by defining an associated femur length range. The method was tested on a validation sample of 42 normal individuals and a pathological sample of 114 individuals whose pathologies were medically assessed. Couplings were present in 90.48% of the normal sample and 77.19% of the pathological sample. The method was able to detect "uncoupling" (i.e., possibly altered growth) in more than 22.8% of samples, even if there was no visible traces of pathology on bones in most cases. In conclusion, experts should be warned that living conditions may cause alterations in the development of young individuals in terms of uncoupling, and that the age-at-death estimation based on long bone biometry could be biased. In a forensic context, when age has been estimated in cases where uncoupling is present, experts should be careful to take potential inaccuracies into account when forming their conclusions.

**Keywords:** forensic anthropology; age estimation; femur length; *pars basilaris* shape; inverse Fourier transform; geometric morphometrics

**Citation:** Niel, M.; Chaumoître, K.; Adalian, P. Age-at-Death Estimation of Fetuses and Infants in Forensic Anthropology: A New "Coupling" Method to Detect Biases Due to Altered Growth Trajectories. *Biology* **2022**, *11*, 200. https://doi.org/ 10.3390/biology11020200

Academic Editors: Ann H. Ross and Eugénia Cunha

Received: 23 December 2021 Accepted: 25 January 2022 Published: 27 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Estimating an individual's age-at-death from skeletal remains is one of the major issues in biological and forensic anthropology when assessing a biological profile. In the case of young individual skeletons, age-at-death is crucial to any analysis of biological remains. In forensic anthropology, a fetus's legal personality is dependent on fetal age estimation, with the resulting social, ethical, and economic consequences [1], and the assessment of fetal viability and legislation on abortion and infanticide are also directly dependent on fetal and infant age estimation—hence contributing to the need and importance of developing reliable and accurate methods.

Several fetal and infant age-at-death estimation methods have been established. Most of these are osteometric, radiographic, or ultrasound methods [2–20]. They can be development based, which aim to estimate physiological age based on maturation processes (e.g., skeletal morphology, appearance and maturation of secondary ossification centers, maturation of dental germs), or biometric based, which rely on growth processes (e.g., crown–rump length, cranial and abdominal perimeters, and the maximum length of long bones).

However, the question of living conditions and, therefore, the context in which the development of a young juvenile took place can remain unanswered. Most methods assume that these conditions are "favorable" or "normal", though these can obviously be disturbed by any pathological conditions experienced by the mother or child. In other words, the ontogenetic trajectory—the child's developmental trajectory—is likely to be altered.

It is generally accepted that brain maturation is the best criterion to establish physiological age during early development, regardless of the environmental or socioeconomic conditions, even in cases of fetal or maternal pathologies [21–23]. The brain unfortunately undergoes rapid autolysis after death (within approximately 48 h) and can no longer be studied, but it has an influence on skull base osseous structures [24–31]. Therefore, these structures can be considered to be indirect and taphonomically resistant testaments of brain maturation.

To establish a biometric age, it is accepted that femoral length is the most reliable and accurate estimation indicator [3,7–9,32]. Nevertheless, growth-based age estimation may be biased in cases of growth delay or growth advancement caused by pathological conditions. These conditions are difficult to detect because most pathologies leave little or no trace on fetal and infant bones. Sherwood et al. [32] demonstrated that diseases causing abnormally short femurs (such as trisomy 21 or Turner syndrome) or abnormally long femurs (such as *spina bifida*) can lead to inaccuracies of up to almost four weeks in fetuses when estimating age at death.

Therefore, when only using femoral length without considering possible alterations in developmental conditions, one cannot know whether the age at death will be underestimated, correct, or overestimated with respect to the chronological age (real age).

Our biological hypothesis is that the physiological age (maturation) is more reliable and stable than the biometric age (growth), and that these two "different kinds of ages" are coupled for nonpathological individuals. Accepting this hypothesis, it can be argued that living conditions, whether they are simply "changing" or truly "unfavorable" to development, influence biometric growth more than maturation.

This "coupling" or agreement between maturation and growth processes could be used to assess and control fetal and infant age-at-death estimation, targeting individuals with growth variation due to possible pathological conditions. As a consequence, the demonstration of the "uncoupling" of these two processes would be an indication, or even serve as an alert, that the accuracy of the age-at-death estimation of a young juvenile skeleton must be considered with great caution.

As a direct indicator of skull base maturation and therefore an indirect indicator of brain (and thus general) maturation, we chose to use the *pars basilaris* of the future occipital bone [33–36]. We quantified its degree of maturation with geometric morphometric analyses from its outline shape. The estimation of biometric age (growth) was based on the maximum diaphyseal length of the femur.

These two bones are both dense and compact [11,37,38], and they are generally found to be in good preservation states considering forensic and archaeological contexts [11,37].

Using computerized tomography (CT) scan imaging of fetuses and infants with nonpathological conditions, the aim of our study was to develop a method based on the expected coupling between maturation and growth to detect possible growth variation.

Once established on a medical imaging sample (learning sample) of nonpathological individuals, the method was applied to a separate validation medical sample of nonpathological individuals and another sample of individuals whose pathologies were fully documented.

If an individual presents the "normal" (i.e., nonpathological) coupling variability established by the learning sample, the hypothesis of an alteration of his ontogenetic trajectory can be proposed. It is then necessary to discuss the potential reason for this alteration (growth delay or advancement in connection or otherwise with an identified pathology). Regardless, this study shows that estimated age must be considered with caution.

#### **2. Materials and Methods**

#### *2.1. Sample*

An anonymized database composed of 1136 individuals aged between 11 weeks in utero and 20 years old was compiled within UMR 7268 ADES (AMU-CNRS-EFS). From this, a medical imaging sample of 379 individuals aged 16 weeks in utero to approximately one and a half years (17.7 months) was derived.

#### 2.1.1. Normal and Pathological Development

The studied population was divided into three samples. A learning sample (A) comprising 223 fetuses and infants with nonpathological conditions (77 girls, 115 boys, and 31 of unknown sex) ranging from 16 fetal weeks to 77 postnatal weeks (mean age: 33.28 fetal weeks; Figure 1) was used to establish the method. A second sample (B) comprising 42 fetuses and infants ranging between 18 fetal weeks and 61 postnatal weeks (mean age: 34.69 fetal weeks; Figure 1) was used as a separate validation sample. Given that the available age classes were not homogeneous for normal individuals, random selection by age classes was conducted to ensure a good representation of age; the selection comprised approximately 85% for the learning sample and 15% for the validation sample.

For our analyses, the ages of fetuses (based on accurate reports of the mother's last normal menstrual period and ultrasound data obtained at 10 weeks of gestation, which is an obligatory examination under French law) and infants were expressed in weeks: from 16 to 38 weeks for fetuses and from 39 to 115 weeks for postnatal individuals. This means that a "45-week-old" individual is actually an individual aged 45 weeks minus 38 weeks (average length of pregnancy), which corresponds to 7 postnatal weeks.

Nonpathological conditions were essential for sample A and B individuals. The conditions considered for mothers were the absence of congenital disease, diabetes, or arterial hypertension. The nonpathological conditions of fetuses (such as the absence of external or visceral malformation, the absence of bone anomaly on a CT scan, the absence of cerebral anomaly on MRI, and normal karyotypes) were established based on multidisciplinary ante mortem and post mortem examinations conducted by medical experts of the prenatal diagnosis center. Concerning infants, CT scans allowed us to verify developmental normality. Examinations were performed in cases of road accidents, sudden or unexpected infant death syndrome, and forensic investigations.

Fetuses and infants with identified pathological conditions were included in a third sample (C) comprising 114 fetuses and infants (61 girls, 47 boys, and 6 of unknown sex) ranging from 16 fetal weeks to 47 postnatal weeks (mean age: 27.24 fetal weeks) (Figure 1C). 2 3

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of the prenatal diagnosis center. Concerning infants, CT scans allowed us to verify developmental normality. Examinations were performed in cases of road accidents, sudden or unexpected infant death syndrome, and forensic investigations. **Figure 2.** Age (in weeks) and sex distribution of the pathological sample (C) comprising 114 individuals. **Figure 1.** Age (in weeks) and sex distribution of the learning sample (**A**) comprising 223 individuals and the validation sample (**B**) comprising 42 individuals. Age (in weeks) and sex distribution of the pathological sample (**C**) comprising 114 individuals.

disciplinary ante mortem and post mortem examinations conducted by medical experts

#### Fetuses and infants with identified pathological conditions were included in a third sample (C) comprising 114 fetuses and infants (61 girls, 47 boys, and 6 of unknown sex) 2.1.2. Pathologies Groups 2.1.2. Pathologies Groups

ranging from 16 fetal weeks to 47 postnatal weeks (mean age: 27.24 fetal weeks) (Figure Depending on the pathological conditions, the following subgroups were established: Depending on the pathological conditions, the following subgroups were established:

Girl

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16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 The same individual could be classified in several types of pathologies, such as a localized anomaly and a cerebral anomaly.

#### *2.2. Data Acquisition*

> **Figure 2.** Age (in weeks) and sex distribution of the pathological sample (C) comprising 114 individuals. 2.1.2. Pathologies Groups Depending on the pathological conditions, the following subgroups were established: The ante mortem and post mortem CT scans of sample A, B, and C individuals were collected from the Picture Archiving and Communication System (PACS) in the hospital of Marseilles (Assistance Publique—Hôpitaux de Marseille, France). Individuals were scanned using a helical CT scanner (Somatom Sensation Cardiac 64; Siemens, Erlangen, Germany). The scanning parameters were as follows: voltage of 100–140 kVp, amperage of 50–180 mAs, 512 × 512 pixels, resolution of 0.25–4.87 pixels per mm, voxel size of approximatively 0.5 × 0.5 × 0.6 or 1 mm3 , and a slice thickness of 0.6–1 mm. These highresolution native slices recorded in the Digital Imaging and Communications in Medicine

(DICOM) format were anonymized before being used in the study, in accordance with the standards of the French National Consultative Ethics Committee for health and life sciences (CCNE) and the Helsinki Declaration of 1975 concerning the privacy and confidentiality of personal data.

#### *2.3. Bone Reconstruction*

Before reconstructing the femur and *pars basilaris* in three dimensions (3D), region of interest (ROI) segmentation on the DICOM slices was performed with the ImageJ®v1.51 software (National Institutes of Health, Bethesda, MD, USA) to separate the bone from adjacent tissues. The threshold value was obtained by calculating a threshold mean value (TMV) [38], which is an average of the half-maximum height (HMH) values [39]. The TMV was used in Avizo Standard Edition (v.7.0.0®, Visualization Sciences Group, SAS, Berlin, Germany) to reconstruct the 3D bone surfaces.

Since there are no significant differences between the right and left femur in young juveniles [3,9,10,40–42] and convention suggests that the left femur is preferred, we only measured the right femur when the left was not available.

#### *2.4. Maturation Criterion: Elliptic Fourier Analysis of the Pars Basilaris*

The complete protocol was described by Niel et al. [43] and was used in this study.

#### 2.4.1. Outline Process

Briefly, we defined a homologous reference plane for all the *pars basilaris* in the inferior (external) view. This was defined thanks to two type II and one type III landmarks [44]. Type II landmarks are the most posterior point of the left and right horns, and a type III landmark is the central point of the anterior surface. All landmarks were digitized on 3D reconstructed surfaces using Avizo Standard Edition® software.

This step allowed us to project all reconstructions in the same 2D plane and with the same orientation. Then, outline shapes were quantified according to 150 equally linearly spaced points digitized along the *pars basilaris* contour with the tpsDig2 v.2.17® digitization program [45]. Finally, the contour data of the *pars basilaris* were normalized using generalized Procrustes analysis (GPA) [46–49] based on four type II and III homologous landmarks [44] called control points [46].

#### 2.4.2. Measurement Error

Repeatability (intra-observer error) and reproducibility tests (inter-observer error) were realized to validate the protocol on 30 randomly selected individuals in sample A. Repeatability was tested by the same observer repeating the protocol twice several weeks apart; for reproducibility, a second observer applied the protocol once.

#### 2.4.3. Harmonics Number

With EFA, one may wonder what the appropriate number of harmonics is, since this number determines the accuracy of the contour reconstruction. The following two paragraphs of text is the explanation as reproduced from Niel et al. pp. 37–38 [43]:

According to the Nyquist theorem [50], the harmonic number must be less than half the number of sampled outline points. Consequently, on the 150 points sampled for EFA, only the first 74 harmonics were retained for analysis. Given that we cannot retain all the Fourier coefficients for our analysis" (74 harmonics × 4 coefficients = 296 coefficients), because the measurement error is expected to increase with harmonic ranks, the percentage of error on harmonic coefficients was calculated using a Procrustes analysis of variance (ANOVA) on the three sessions [51]. This procedure calculated the mean sums of squares for the four coefficients of each harmonic to observe the evolution of error according to the rank of the harmonics (in percentage). Only the first harmonics, showing an acceptable digitization error rate, were retained for further analyses. An error rate under 35% is considered to be reasonable in an outline analysis using EFA [51].

The assessment of the total percentage of measurement error was then performed using a Procrustes ANOVA [51–55] adapted to elliptic Fourier coefficients [51]. The Fourier coefficients of the coupled series are used in the Procrustes ANOVA with the number of harmonics previously defined. The intra- and interindividual variances were directly calculated from the means of the sums of squares and crossed products corresponding to individuals and residual sources of variation [51]. These residuals, representing the variability between the two sessions, correspond to the measurement error [55].


**5.4 Pathogenesis and pathological changes**

### *5.4.1 Research achievements from relevant research institutions*

*T. cruzi* can colonize any nucleated cell. Most of the symptoms in the acute phase of the disease are thought to be caused by damage to host cells by *T. cruzi*. For the

chronic phase-related pathogenesis, there are currently two theories. One theory is that *T. cruzi* persists, leading to chronic inflammation [75], and the other theory is that it is caused by autoimmune damage [76]. Possible mechanisms include antigen cross-reactivity [77], direct cell-mediated cytotoxicity [78], antigenic Submitting changes [79], and cardiac mitochondrial dysfunction [80] etc.

Pathological changes in the acute phase showed mononuclear cell infiltration [81], interstitial edema [82], accumulation of amastigotes in muscle cells of subcutaneous tissue [83], and formation of pseudocysts at the invasion site of Trypanosoma [83]. Myocarditis with cardiac enlargement is usually seen in acute-phase deaths. In patients with sudden death in the chronic phase (mostly due to ventricular arrhythmia or conduction block), the heart size is usually normal or only slightly enlarged. In other patients with chronic Chagas heart disease, cardiac hypertrophy, dilation, and thickening can be seen, especially in the apex of the heart, resulting in apical aneurysm. Mural thrombosis and lung and peripheral organ embolism may be seen in some patients. Microscopic examination showed mononuclear cell infiltration, myocardial fiber hypertrophy, degeneration, necrosis and edema. Microscopic changes in megaesophagus or megacolon are similar to those of the heart.

#### *5.4.2 Research achievements from our institution*

We firstly have shown that cardiac mitochondria-response plays a very important roles in *T. cruzi–*induced cardiomyopathy [80, 84–92], and established the third theory that oxidative stress was involved in cardiac mitochondrial dysfunction [84, 86, 88] and heart dysfunction [80, 93–97]. In detail, we have contributed to the understanding of the mechanism behind the decline of MnSOD and enhancement of SIRT1/PGC1/PARP-1 in correlation with *T. cruzi–*induced consistently oxidative heart damage [90–92, 97]. From this research, we have observed that (1) MnSODtg mice/ MnSOD overexpression in cell lines are beneficial in preserving *T. cruzi–*induced mitochondrial/heart dysfunction [90]; (2) MnSOD−/+ mice were worse of *T. cruzi* infection*–*induced heart dysfunction [91]; and (3) inhibition of PARP-1 would prevent *T. cruzi–*induced heart function [92]. We also have observed *T. cruzi–*induced oxidative stress occurred in adipose tissues by utilizing oxidative markers, which is a novel finding [96, 98]. We have contributed to an understanding of *T. cruzi–*induced oxidative etiopathogenesis [85, 86, 88, 89]. Additionally, we have isolated high quality heart mitochondria to (1) recognize *T. cruzi–*induced oxidative mitochondrial proteins by using combination of BN-PAGE [84] and TOP MALDI MS/MS [88, 95]; (2) ascertain that mitochondrial complex III Qo site was prime source of *T. cruzi–*induced ROS generation [86]; and (3) find that administration of antioxidants improved *T. cruzi–*induced oxidative damage in heart mitochondria and heart tissues [85, 89]. We have conducted a thorough analysis of mitochondrial bioenergetic function as well as the biochemical and molecular factors that are deregulated and contribute to compromised adenosine triphosphate (ATP) production in the myocardium during *T. cruzi* infection. Our team is focused on the discovery and development of novel therapeutics against *T. cruzi*. We found that combination treatment (antioxidants and anti-parasites) is beneficial in arresting the *T. cruzi*–induced inflammatory and oxidative pathology and chronic heart failure in Chagasic rats. We have proven that the *T. cruzi*–induced oxidative alterations in circulation are correlated with heart tissue, suggesting that Chagasic human patients' circulation can replace heart tissue, as issue we are planning to investigate. We also confirmed that this was the case in human

patients with Chagasic cardiomyopathy development and assessed different ways to oxidatively modify mitochondrial respiratory complexes (**Figure 1**) [80, 94].


**7. Online instructional skills**

Tham and Werner (2005) highlight studies that indicate that instructors in an online environment must fulfil many roles or "hats". These hats include:

Senior management in institutions must harness the power of technology to deliver the curriculum to lifelong learners while recognising that the set of instructional skills required are quite different, the cohort of students are different and the role of the institution, instructor and student must adopt to this changing dynamic.


3. Treatment

#### 3.1 Medical treatment

The same fundamental aspects about the antibiotic therapy in IE is applied to the right-sided endocarditis, making emphasis in the early and proper setting of the cultures, the prompt and adequate starting of empirical antimicrobial therapy (if the suspicious of IE is higher), and the administration of a culture-antibiogram sensible antibiotic.

One aspect that changed in the antimicrobial treatment of RSIE in comparison with LSIE is the duration of the therapy when the implicated bacteria is the methicillin-sensible Staphylococcus aureus, due to the 2015 European Society of Cardiology guidelines for the management of infective endocarditis recommending a short treatment of 2 weeks in this scenario. This approach is attributed to the less aggressive evolution of RSIE with these bacteria [5].

The prophylactic treatment in the patient with high suspicion of RSIE should cover Staphylococcus aureus, streptococci, and enterococci and should include penicillinase-resistant penicillins or vancomycin, depending on the local prevalence of methicillin-resistant Staphylococcus aureus (MRSA) [6].

#### 3.2 Surgery treatment

In RSIE, the medical treatment usually resolves the disease; nevertheless, the surgery for right-sided infective endocarditis is recommended in the following situations: (1) right-heart failure due to severe tricuspid valve regurgitation, (2) inability to eliminate bacteremia or organisms resistant to culture-directed antibiotic treatment, within 7 days, and (3) tricuspid valve vegetations >20 mm [1–3, 5].

During the surgery, most of the infected tissue must be removed; if it is possible, we should try to repair the native valve but guarantee the adequate functioning of the valve. When a valve-sparing is impossible, the implantation of a prosthetic valve is necessary, always trying to use the less foreign material to diminish the risk of IE recurrence [14].

Sometimes the endocardial destruction is highly extensive that compromises the valve repairing as well as the valve prosthesis replacement; this scenario is hideous and requires the reconstruction of the annular structure using endocardium patch or other materials.

Another potential complication of IE can be the formation of ventricular septal defect due to the infection's aggressiveness which can show communication between the right ventricle and left ventricle through the membranous septum. This anatomical defect also can be figured out with a pericardium patch [15].

Some surgeons can feel uncomfortable with the idea of setting up a prosthetic valve in tricuspid position due to being afraid of high gradients through the valve and the potential thrombosis of the prosthesis. However, large prostheses (>30 mm) guarantee low transvalvular gradients, and the incidence of thrombosis is small if the patient has an adequate anticoagulation control (biological and mechanic prostheses are anticoagulated). Moreover, bioprosthesis degeneration develops more slowly owing to the low-pressure conditions in the right ventricle [6].

In 1991, Arbulu et al. published a paper showing their experience in tricuspid valvulectomy without replacement, generally indicated for IVDA, to avoid the potential IE recurrence; nevertheless, about 25% of patients cannot tolerate tricuspid regurgitation and require a second operation for tricuspid valve replacement [14, 16].

#### 4. Prognosis

RSIE implies a better prognosis than LSIE; the previous study revealed the mortality of right-sided IE is 12% in-hospital patients and 0–7.3% for surgical patients. However, these percentages increase at least twice in patients with intensive care unit (ICU) admission; actually, this issue will be described forward [3, 9].

Concomitant left-sided IE carries a worse prognosis than right-sided infection alone, due predominantly to its greater likelihood for invasion and abscess formation [7].

## 5. Prevention

The high increase of bacterial resistance throughout the last decades has produced a change in the IE guidelines from 2002. The same criteria for LSIE are applied to RSIE regarding the antimicrobial prophylaxis, being reserved only in patients with a high risk of endocarditis, particularly those with PVIE [5].

Nevertheless, there are some aspects that the last IE guidelines do not approach which are very relevant that need to be highlighted. One of the most critical issues is the quite strict aseptic measurements that healthcare professionals must take during routine procedures, especially invasive maneuvers in high-risk patients such as immunocompromised, hemodialytic (HD), cyanotic congenital heart disease (CHD) patients, etc.

The change in some hospital policies can diminish the incidence of bacteremia and IE, such as have been shown in some publications [17].

#### 6. RSIE in intensive care units (ICU)

There are few publications about the characteristics of RSIE in ICU. It is noteworthy that patients with IE admitted in ICU have a higher rate of morbidity and mortality than non-ICU patients. The only study describing the outcome of IDUs with RSIE needing ICU admission reported a mortality of 26% [2].

Some factors have been associated with a worse prognosis: acute respiratory failure requiring mechanical ventilation, shock, Simplified Acute Physiology Score (SAPS II) ≥ 20, and Sequential Organ Failure Assessment (SOFA) ≥ 3 [2, 5].

#### Right-Sided Infective Endocarditis DOI: http://dx.doi.org/10.5772/intechopen.85019

Other elements that play an essential role at the 30-day survival are age <45 years, Charlson score < 3, endocarditis diagnosed before ICU admission, aminoglycoside use, the presence of septic pulmonary embolism, and a single surgical indication for patients needing a surgical procedure [2].

Reasons for admission to the ICU were a congestive cardiac failure (64%), septic shock (21%), neurological deterioration (15%), and cardiopulmonary resuscitation (9%). Younger patients have a better prognosis because they usually present a minimal dysfunction of the right-sided valve, low risk of pulmonary embolism, and reasonable response to appropriate antibiotic therapy [2].

Opposite to the last IE guidelines, which no longer recommend the aminoglycosides in the treatment of native valve staphylococcal endocarditis, Georges et al. found a better survival in their patients treated with a combination of penicillins or vancomycin with gentamicin [2].


**6. Conclusions**

The concept of performance has been understood through different perceptions resulting from different disciplinary approaches, artistic fields or cultural contexts. Due to this conceptual openness and the diversity of creative practices, performance, as an action

before an audience, offers great potential for experimentation through the confluence of sound and visual media.

With its technological appropriation and expansion into other media, performance has stood out among the creative practices of recent decades, allowing a decentralization of the body/performer, thus opening up to other media and other materialities, such as sound or image. In the context of this decentralization, throughout this essay, we have sought to rethink and reflect on the notion of the connections between performer, spectator and religious place.

Through audiovisual mediation, we have verified that presence is produced in live performative moments and that sound and image become expressive processes in the production of these effects of presence since it is these that most obviously contribute to the production of meaning and the manifestation of the artistic work. In this way, audiovisual media should be seen as a bridge between art objects and not as an artistic destination, allowing dialogue and communication between different artistic realities.

The performative moments promote new possibilities, recursive processes, repetitions, nonlinear structures, simultaneous events and combinations of languages, where time, performative space and the performativity developed between the performer and the spectator are related with greater freedom and with the cooperation of different media, approximating them to moments that promote a symbolic liturgy.

In these live audiovisual performative moments, sound and image become convergent expressive processes, configuring the production of effects of presence and enhancing the representation of memory. The articulation between sound and live image also stimulates the creation of new narratives, making them denser and more immersive in artistic figuration, reflecting the complementarity of space and time, and opening new performative paths that are developed and experienced in live audiovisual performances, namely in religious places.

In the site-specific projects developed as part of this research, we start from the theme of memory as a phenomenon that allows the present creation of an absence, and we assume that the work of memory seems to imply a work of representation. This work of representation also involves a process of remembering that precedes a process of constructing sounds and images. These sounds and images are understood as tools in the living experience of memory construction, promoting a performativity of memory during the live sound and visual performances presented in performative moments.

During these performative moments of the site-specific projects that have been developed, the performative aspects of memory are highlighted, focusing on how memory is represented, shaped and influenced by various social, cultural, religious and spatial factors. These moments play a crucial role in the process of perception and apprehension, making use of the spatial qualities of places as they stimulate multiple senses, evoke emotional and psychological responses, take into account contextual meaning and encourage audience engagement.

The places chosen for fieldwork are spaces where particular intangible qualities can be revealed as a kind of quality that makes them special places. They are places that seek to create a spiritual connection and strengthen religious ontological positions in the world, where there is an interaction with the sacred and where the meaning and significance of human existence are intensified. This embodied perception of space in these religious places, through the performativity of memory, has an impact on the public because it promotes a sense of belonging and identity, evokes emotional and spiritual involvement, reinforces rituals and memories, allows for symbolic (re)interpretations and encourages a deeper understanding of the formation of place, our presence in religious places and our role in human life.

Throughout the development of this research and the development of site-specific projects, these (re)interpretations raised some issues about the perception and understanding of site-specific performances through the mediation of nonverbal means in religious places, to which we sought to respond.

In this sense, we observed that the performativity of memory, as an autobiographical concept, can be enhanced through live audiovisual performances in religious places by incorporating narratives and testimonies that have a connection to the place and by integrating sound and images that evoke memories and autobiographical experiences, highlighting the individual and subjective nature of memory in the spatial context of the place itself.

We have established that the performativity of memory in religious places can also promote a spatial 'self' through live audiovisual performances, creating dynamic, immersive and physical experiences in the spatial context of the religious place. This is achieved through the use of visual elements that can transform the architectural features of the place, evoke symbolism or represent narratives and iconography of the place itself, creating a deeper connection to the place and the memories related to it. The sound elements reinforce this spatial 'self', evoke emotional responses and trigger memories connected with the rituals and practices of the place. The confluence of sound and image also stimulates a multisensory experience in the here and now, reinforcing the sense of presence and connection of a spatial 'self' of the public to the place, grounding this spatiality in a contingent performative memory.

Finally, we argue that the construction of this spatial 'self' in live audiovisual performances in religious places, compelled by the performativity of memory, involves processes of social and artistic reconfiguration that contribute to transforming not only the social dynamics within the community but also the artistic representations of memory. Performative moments in religious places provide a platform for the community to shape its collective memory, contributing to the reconfiguration of social dynamics within the community and the recognition of diverse perspectives, thus fostering a sense of belonging and cohesion. These moments also involve artistic reconfigurations of practices, rituals and artistic forms, as they promote reinterpretations, representations or juxtapositions of narratives, symbolisms and religious aesthetics because of the multiple, contested, fluid and uncertain natures of these places. By reconfiguring artistic expressions, audiovisual performances stimulate creativity, artistic exploration and the formation of new aesthetic approaches that reflect contemporary sensibilities while respecting the identity of religious places.

From the residual artifacts produced and the feedback from the audience, collected during the conversations held after the performative moments, we also observed that the aesthetic and performative configurations used in audiovisual artistic creations of a place can have an impact on the most individual manifestations of religion, religiosity and religious belief, influencing the interpretation and creation of meaning, evoking emotional and spiritual responses, facilitating embedded engagement and promoting personal transformation and transcendence.

With this research through artistic practice, we also seek to anchor another sketch in the territories of performance, located between theory and practice, and the studies of religion in its multiple phenomena, traditions and grammar, questioning the aesthetic place of both today as essential tools for discovering new ways of understanding the contemporary culture and future directions on the aesthetic and performative configurations used in audiovisual artistic creations in religious places.

Due to the increasing interest in developing audiovisual artistic creations in religious places, the future directions on the aesthetic and performative configurations can include the development of immersive environments within religious places improving the experience of virtual pilgrimages or engaging in interactive narratives that enhance spiritual journeys, of interactive installations that can engage worshipers by allowing them to actively participate in the audiovisual experience. These future directions can also embrace multimedia storytelling through the use of multimedia platforms to convey stories, memories, religious narratives and personalized experiences with the use of wearable technology with curated content tailored to an individual's spiritual interests or beliefs, enhancing their engagement and understanding. Furthermore, and considering the above-mentioned conclusions, we believe it is important that future research work deepens the concept of spatial

self through its (re)construction based on ritual and belief and focusing on individual and collective remembrance processes.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The Archdiocese of Braga, Conciliar Seminary of Braga, Minor Seminary of Braga, Collegiate Church and Parish of St Martin—Cedofeita, *Schola Cantorvm* Collegiate Church of Cedofeita, CITER—Research Centre for Theology and Religious Studies, Faculty of Theology of the Portuguese Catholic University, Portuguese Catholic University, CEIS20—Centre for Interdisciplinary Studies of the University of Coimbra, SELMA—Centre for the Study of Storytelling, Experientiality and Memory of the University of Turku, Institute of Education and Citizenship, Flying Thoughts— Association for the Promotion of Ideas, Braga Media Arts.

**Conflicts of Interest:** The author declares no conflict of interest.


3.1.1. Superoxide Dismutase

Superoxide dismutase (SOD), which belongs to the enzymatic defense system, changes the superoxide radical anion to H2O2 by oxidative decay. Another function of SOD is to protect dehydratase from free radical superoxide inactivation. There are three forms of SOD in humans. SOD-1, a copper-zinc containing SOD (Cu, Zn-SOD), is present in the cytosol and specifically catalyzes dismutation in a pH-independent medium [42]. SOD-1 protein is a homodimer composed of eight antiparallel beta strands and two metal atoms that catalyze the conversion of toxic O2 − anions to H2O2 and O2. Specifically, copper minerals play a crucial role in the catalytic function of this enzyme, while zinc is important for structural integrity [43]. SOD-1 plays an important role as a first line of defense by detoxifying superoxide radicals. In addition, the lack of this enzyme exhibited a pronounced susceptibility to paraquat toxicity. SOD-2, a manganese containing SOD (Mn-SOD), is found in the mitochondrial matrix and reduces the superoxide radical anion generated in the electron transport chain [44]. A detailed analysis revealed that the SOD-2 subunit needs one metal atom and that it is functionally disabled in the absence of Mn atoms in the active site. SOD-2 attracts O2 − and turns positive on the active side. The active metal provides electrons directly to O2 − then reduces one molecule of O2 − and one proton to be converted to form H2O2 (Figure 2). The amount of SOD-2 is different in each cell type, depending on the number of mitochondria. Specifically, the presence of SOD-2 is essential for the survival of aerobic cells and the development of cellular resistance to oxidative stress. SOD-3, an extracellular SOD (EC-SOD), also contains copper and zinc in its structure, is synthesized inside the cell and secreted into the extracellular matrix [45]. SOD-3 enzyme is not induced by its substrate or other oxidants and is regulated to coordinate with cytokines, rather than as a response of individual cells to oxidants [46].

In neurodegenerative diseases, SOD-1 and SOD-2 genes appear to be disrupted and/or mutated. SOD-1 gene mutations produce diverse cellular changes such as alteration of gene expression, unusual protein interactions, caspase activation, mitochondrial dysfunction, and cytoskeletal abnormalities in familial ALS [47]. Overexpression of SOD-1 protects neurons against the neurotoxic effects of amyloid beta (Aβ), and loss of SOD-1 accelerates aging-related pathologies and reduces lifespan in mice [48–50]. SOD-1 deficiency in an AD model showed that it was associated with augmented Aβ oligomerization and memory impairment mediated by oxidative stress [51]. Overexpression of SOD-2 by treatment with sodium orthovanadate could rescue synaptic failure and neuronal cell death in the hippocampus after kainic acid (KA)-induced oxidative stress; moreover, an increase in SOD-2 protected the neuronal death from oxidative injury [52]. Impaired SOD-2 is a common potential pathogenesis

related to oxidative stress in PD and AD [6]. In human amyloid precursor protein (hAPP) transgenic mice with over 50% reduced SOD-2 activity, increased SOD-2 protects the age-related brain against hAPP/Aβ-induced impairments [53]. Extracellularly administered SOD was effective in inhibiting cell death and restoring healthy mitochondrial morphology in a monosodium glutamate-induced excitotoxicity disease model [54]. An increase in SOD-2 can be expected to assist or improve neuronal function and vascular pathology in AD as a therapeutic effect.