**Acknowledgements**

This publication is supported by the European Union through the European Regional Development Fund (ERDF) and by the french region of Brittany, Ministry of *Metal 3D-Printing of Waveguide Components and Antennas: Guidelines and New Perspectives DOI: http://dx.doi.org/10.5772/intechopen.106690*

Higher Education and Research, Rennes Métropole and Conseil Départemental 35, through the CPER Project SOPHIE/STIC & Ondes, and also by the region of Brittany under grant SAD volet. Additional funding comes from the European Space Agency, the Centre National d'Études Spatiales, the companies Thales Alenia Space, Thales Group, and SWISSto12.


**3. The role of obesity in the development of type 2 diabetes**

The decrease in insulin action indicates insulin resistance, the main hallmark of T2DM [38]. Several factors play a role in the development of insulin resistance, with obesity probably being the most important one [39]. During the last three decades, obesity has reached an epidemic stage in all age groups [40]. Increased intake of energy-dense foods containing a high percentage of fat and carbohydrates, combined with a lack of physical activity, leads to a net positive energy balance and represents the primary cause of obesity. The first stages of obesity are hypertrophy and hyperplasia, where adipocytes try to meet the demand to store excessive energy. When levels of free fatty acids and triglycerides exceed the metabolic capacity of adipose tissue, they accumulate as ectopic fat in non-adipose tissue such as the liver, pancreas, skeletal muscles, and heart [41]. The regional distribution of adipose tissue is particularly important for the development of disorders of glucose and lipid metabolism [42, 43]. The fat infiltration in the liver and pancreas in the absence of excess alcohol intake is termed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreas disease (NAFPD), respectively [44]. Due to fat accumulation in hepatocytes, NAFLD leads to inflammation, fibrosis, cirrhosis, and liver cancer and critically affects insulin sensitivity in the liver [44–46]. NAFPD plays a similar role in the dysfunction of the endocrine and exocrine pancreas leading to exacerbation of acute pancreatitis and increasing the susceptibility to pancreatic cancer [46–50]. Although the concept of the NAFPD was introduced only a few years ago [51], the correlation between fat infiltration and pancreas was first described almost a century ago on

obese cadavers having larger pancreata compared to non-obese cadavers [52, 53]. Importantly, over the last decade, it has been demonstrated convincingly that most of the morphological, functional, and clinical features of T2DM are reversible with sufficient weight loss and that these positive changes depend on the level of hepatic and pancreatic fat reduction [54–56].

Although insulin resistance is one of the main features of T2DM, it is not sufficient for the development of T2DM. Despite increasing insulin resistance, present long before the onset of diabetes, individuals with preserved beta cell capacity can stay normoglycemic for several years due to compensatory insulin hypersecretion. Furthermore, a certain proportion of individuals with insulin resistance never develop T2DM. The idea has been put forward that there may be a personal fat threshold or an individual level of susceptibility to developing T2DM at a given body mass index, with the main mechanisms behind this attractive hypothesis being varying degrees of fat accumulation in the liver and the pancreas, together with varying individual responses to this accumulation [57]. An obese subject with insulin resistance can secrete 2–5 times more insulin compared to lean nondiabetic individuals in response to a glycemic load, but when the adaptive capacity of the beta cells fails, T2DM occurs [58]. Several studies have shown that the first phase of insulin secretion is primarily affected, resulting in impaired glucose tolerance. During the progression of T2DM, the second phase of insulin secretion is further lost. Post-translational defects in insulin synthesis also occur, resulting in increased proinsulin secretion, and by the time the diagnosis of T2DM is made, the beta cell function is already typically reduced by 80% [59]. This beta cell failure is responsible for transitioning from an insulin-resistant compensated state to overt T2DM and remains to be elucidated in details. It probably involves an initially inadequate beta cell mass and an insufficiently increased response of the existing beta cells to increased insulin demand [60]. Noteworthy, the susceptibility of beta cells themselves to developing insulin resistance may play an important pathophysiological role [61]. Individuals with T2DM can display changes in beta cell mass, either due to a decrease in beta cell proliferation or/and an increase in cell apoptosis [62]. In T2DM patients, the apoptosis rate is increased severalfold compared to normoglycemic individuals [63], a phenomenon confirmed by ultrastructural analysis using TEM [64]. Furthermore, during T2DM gradual dedifferentiation of beta cells occurs in animal models, while the role of dedifferentiation during the development of human T2DM is controversial and less well-studied [63, 65–68]. Chronic exposure of islets to elevated levels of glucose, fatty acids, and amino acids results in ER stress due to increased insulin synthesis and secretion [69]. The protein folding capacity of ER becomes exceeded, which leads to the activation of the so-called unfolded protein response (UPR) and consequently to the inhibition of protein translation [70, 71]. Gluco- and lipotoxicity cause a vicious cycle of continuous deterioration of the glucometabolic state and eventually impair insulin secretion and increase apoptosis. In T2DM, not only the islet cells are affected, but also the pancreatic acinar cell viability and growth decrease, leading to increased apoptosis and replacement by fat [72, 73]. Importantly, intracellular fat in acinar cells may affect beta cell function in a paracrine manner through the release of adipokines. It is also likely to play a role in pancreatic carcinogenesis, seems to be associated with changes in innervation, and may initiate an acinar-to-adipocyte trans-differentiation [56].


**2. MRI of the mouse: Challenges for cardiac image-based mouse phenotyping**

#### **2.1. The mouse as a research model**

344 Practical Applications in Biomedical Engineering

science and translational research.

frequency reserve), for comparative studies.

image-based phenotyping.

balancing anesthetic, Nitrous Oxide.

Despite the existence of a plethora of cardiac functional techniques for characterization of mechanical structure, function and dysfunction, a parallel need exists for development of invasive and non-invasive tools and techniques to describe the left ventricular (LV) tissue material properties as these relate to the: (a) mechanical pumping function of the LV; (b) myocardial oxygen demand defining myocyte metabolic status; (c) coronary blood flow and its auto-regulation; (d) arhythmogenic risk; (e) cell-signaling pathways responsible for growth and remodeling during development and disease. Reinforcing basic physiology work, invasive catheterization experiments [Georgakopoulos 1998] have also allowed determination of inotropic and lusitropic cardiac status, while Magnetic Resonance Imaging (MRI) experimentation, methodologies and technology advances have facilitated migration of such work to a non-invasive imaging platform, with tremendous potential for future basic

Specifically, advances in MRI techniques (myocardial spin tagging [Zerhouni 1988, Axel 1989], DENSE [Aletras 1999], and harmonic phase imaging [Osman 1999]) have been introduced over the last decades to quantify cardiac function, allowing myocardial tracking, motion and strain quantification in normal and genetically engineered mice [Rockman 1991, Franco 1999, Brede 2001, Yang 2002, Engel 2004, Wilding 2005]. Critical to such work has been the validation of the underlying hypothesis of morphological and functional scaling from mouse to human (through consideration of global cardiac function, circulatory control, blood flow distribution, Ca2+ storage and cycling, myosin light chain distribution, and force

This chapter provides an overview of the major physiological issues and challenges for mouse MR imaging and discusses the most recent and major advances in conventional and new cardiac Magnetic Resonance imaging strategies, that ultimately allow quantification of motion, global, and regional cardiac function, strain, and elasticity, characterizing inotropic and lusitropic contractile function and dysfunction in humans and transgenic mice for

Specifically, this chapter attempts a detailed reference to the mouse as a research model, focusing on its genetic background and homology with the human genome and to the developmental and morphological differences between mouse and man, thus addressing cellular and global organ similarities and differences. As a basic determinant of structure, cardiac functional differences are associated, justified by carefully-controlled indices that determine integrative physiological control and functional activities, including metabolism, perfusion, angiogenetic, collateral flow, and coronary reserve. The importance and impact of anesthesia for image-based phenotyping in patho-physiological status is addressed with brief references to the possible mechanisms and cellular and sub-cellular target sites of anesthesia action. The section is complemented with recent findings on heart rate variability (as a result of the widely used inhalational anesthesia use) under optimal anesthesia conditions using isoflurane and long term physiological stability elicited from the use of the

A historical overview of the evolution of mouse cardiac MRI is also attempted (in direct correlation with the evolution and progress of human clinical cardiac MRI, radiofrequency The mouse emerged as an attractive animal research model following the rapid advances in experimental molecular biology techniques that allowed targeted mutagenesis in single genes [Capecchi 1989], in addition to the tremendous success for extraction, manipulation, and use of embryonic stem cells [Koller 1989]. Practical and ethical advantages were also associated with mice, such as their stable genetic lines, immune system, short gestation periods, low cost, and ease of use. Initial research strides were supported by US National initiatives including the Human and Mouse Genome projects administered through the National Institutes of Health (NIH) for cloning and mapping the entire human and mouse genomes [Collins 2003, Gregory 2002], efforts that were successfully completed in 2003.

Todate, multiple thousands of different knockout mice have been constructed (by individual Institutions, Laboratories, or National or International Consortia), most of which affect cardiovascular function. As attempts to match genotype to phenotype continue, an increasing number of knockout or loss-of-function mice is expected to be generated.

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

[Webb 1996]. While availability of data on the cardiomyofiber structure is scarce, a prior publication [McLean 1992] indicates some fiber orientation differences, primarily on the

**Figure 2.** Relative size scales of the human, adult, and mouse embryo [Courtesy of the Duke Center for In Vivo Microscopy, an NIH/NIBIB National Biomedical Technology Resource Center (P41 EB015897)].

Prominent differences also exist for the conduction system and coronary anatomy. In contrast to the human where the sino-atrial (SA) node is distinctly located on the right atrium, in the mouse it lies on the superior vena cava (SVC), at the juncture of the SVC with the right atrium. Coronary anatomy exhibits branching of a septal coronary artery from the left coronary system supplying the left anterior ventricular wall, while the right coronary artery branches into a right coronary and a circumflex vessel supplying the posterior

Cardiomyocytes are reported to have lengths of approximately 80-100 μm along their major axis, and lengths of 10-20 μm along their minor axis [Doevendans 1998, Smaill 1991). Eightyfive percent (85%) of the total number of cardiac cells (amounting to 7-10 million approximately) are interstitial while the remaining 15% that represent cardiomyocytes occupy 90% of the available total ventricular tissue volume [Doevendans 1998]. Also important is an increased capillary to fiber ratio (of the order of 1.4) in the mouse, a direct necessity for the higher energetic and metabolic demands compared to rats, canine, or humans, (with a fiber ratio of the order of 1-1.1) [Sabbah 1995, Przylenk 1983, Olivetti 1989,

middle layer of the myocardium.

ventricular wall [Doevendans 1998].

*Cellular size and content*

The Current Status, Challenges, and Future Perspectives 347

However, despite the usefulness, practicality, and low costs associated with the study of the mouse, important genetic, developmental, morphological, and physiological differences exist between mouse and man [Doevendans 1998, Schaper 1998]. The section that follows addresses succinctly common and distinctly differing features and functional differences in mouse and man and discusses the mechanisms of anesthesia effects on the mouse physiology and cardiac contractile machinery.

#### *2.1.1. Genetic background and gene homology*

Through various structural genomics attempts to map and compare human and mouse genomes [Schaper 1998, Gregory 2002], an overall homology of more than 85% and an identity of more than 80% were recorded [Schaper 1998], suggestive of the increased conservation during differentiation of the two species. Based on such findings, it is shown that the homeobox (hox) genes (transcription factors responsible for development), other transcription factors that bind to promoters encoding acute phase genes, and heat shock proteins, exhibit increased identity with humans. Based on Schaper et al. [Schaper 1998], however, structural genomics shows that (except primates) all other species (including mouse, rat, horse, bovine, etc) are equidistant from man, and evidence is thus inconclusive for the choice of the best species (based only on genetic homology and protein identity) for assessment of cardiovascular function and dysfunction.

#### *2.1.2. Developmental and morphological differences between mouse and human*

#### *Cardiac dimensions*

Indicatively, the human heart weighs around 250-300 g (left and right ventricular [RV, LV] and atrial chambers), and has an intrinsic rhythm of around 60-70 beats per minute (bpm), while the murine heart has a weight of 0.2-0.3 g and beats at a rate of 600-700 bpm. Additionally, the most evident external morphological difference between the adult mouse heart and the human heart is its shape and size (Figure 2). Developmental differences also exist; human development starts during the 3rd week of gestation and lasts approximately 7 months to complete, while mouse cardiac development spans a little more than 2 weeks. At human birth, most of the cardiac organ development has been completed while in the infant mouse cardiac development may still be in progress.

#### *Cardiac anatomy*

No major differences exist in the outer morphology, ventricular structure, or valves. Noted differences exist, however, in atrial and venous parts. Specifically, the left superior caval vein drains directly into the right atrium in the mouse, whereas the pulmonary vein has an opening in the left atrium [Doevendans 1998], and a secondary atrial septum is lacking [Webb 1996]. While availability of data on the cardiomyofiber structure is scarce, a prior publication [McLean 1992] indicates some fiber orientation differences, primarily on the middle layer of the myocardium.

**Figure 2.** Relative size scales of the human, adult, and mouse embryo [Courtesy of the Duke Center for In Vivo Microscopy, an NIH/NIBIB National Biomedical Technology Resource Center (P41 EB015897)].

Prominent differences also exist for the conduction system and coronary anatomy. In contrast to the human where the sino-atrial (SA) node is distinctly located on the right atrium, in the mouse it lies on the superior vena cava (SVC), at the juncture of the SVC with the right atrium. Coronary anatomy exhibits branching of a septal coronary artery from the left coronary system supplying the left anterior ventricular wall, while the right coronary artery branches into a right coronary and a circumflex vessel supplying the posterior ventricular wall [Doevendans 1998].

#### *Cellular size and content*

346 Practical Applications in Biomedical Engineering

physiology and cardiac contractile machinery.

*2.1.1. Genetic background and gene homology*

assessment of cardiovascular function and dysfunction.

mouse cardiac development may still be in progress.

*Cardiac dimensions*

*Cardiac anatomy*

*2.1.2. Developmental and morphological differences between mouse and human*

Indicatively, the human heart weighs around 250-300 g (left and right ventricular [RV, LV] and atrial chambers), and has an intrinsic rhythm of around 60-70 beats per minute (bpm), while the murine heart has a weight of 0.2-0.3 g and beats at a rate of 600-700 bpm. Additionally, the most evident external morphological difference between the adult mouse heart and the human heart is its shape and size (Figure 2). Developmental differences also exist; human development starts during the 3rd week of gestation and lasts approximately 7 months to complete, while mouse cardiac development spans a little more than 2 weeks. At human birth, most of the cardiac organ development has been completed while in the infant

No major differences exist in the outer morphology, ventricular structure, or valves. Noted differences exist, however, in atrial and venous parts. Specifically, the left superior caval vein drains directly into the right atrium in the mouse, whereas the pulmonary vein has an opening in the left atrium [Doevendans 1998], and a secondary atrial septum is lacking

Todate, multiple thousands of different knockout mice have been constructed (by individual Institutions, Laboratories, or National or International Consortia), most of which affect cardiovascular function. As attempts to match genotype to phenotype continue, an

However, despite the usefulness, practicality, and low costs associated with the study of the mouse, important genetic, developmental, morphological, and physiological differences exist between mouse and man [Doevendans 1998, Schaper 1998]. The section that follows addresses succinctly common and distinctly differing features and functional differences in mouse and man and discusses the mechanisms of anesthesia effects on the mouse

Through various structural genomics attempts to map and compare human and mouse genomes [Schaper 1998, Gregory 2002], an overall homology of more than 85% and an identity of more than 80% were recorded [Schaper 1998], suggestive of the increased conservation during differentiation of the two species. Based on such findings, it is shown that the homeobox (hox) genes (transcription factors responsible for development), other transcription factors that bind to promoters encoding acute phase genes, and heat shock proteins, exhibit increased identity with humans. Based on Schaper et al. [Schaper 1998], however, structural genomics shows that (except primates) all other species (including mouse, rat, horse, bovine, etc) are equidistant from man, and evidence is thus inconclusive for the choice of the best species (based only on genetic homology and protein identity) for

increasing number of knockout or loss-of-function mice is expected to be generated.

Cardiomyocytes are reported to have lengths of approximately 80-100 μm along their major axis, and lengths of 10-20 μm along their minor axis [Doevendans 1998, Smaill 1991). Eightyfive percent (85%) of the total number of cardiac cells (amounting to 7-10 million approximately) are interstitial while the remaining 15% that represent cardiomyocytes occupy 90% of the available total ventricular tissue volume [Doevendans 1998]. Also important is an increased capillary to fiber ratio (of the order of 1.4) in the mouse, a direct necessity for the higher energetic and metabolic demands compared to rats, canine, or humans, (with a fiber ratio of the order of 1-1.1) [Sabbah 1995, Przylenk 1983, Olivetti 1989, Doevendans 1998]. The duration of the cell cycle (once G1 is entered) is reported to be almost the same in mouse and man [Schaper 1998].

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

elastance (ES), and the end-systolic pressure volume relationship) and lusitropic (minimum developed ventricular pressure rates - dP/dtmin, Weiss and Glantz relaxation constants, and the end-diastolic pressure-volume relationship), left ventricular contractile indices [Constantinides\_ABME 2011, Doevendans 1998]. Recent MRI findings also support similar torsional patterns, as reported by normalized (to left ventricular lengths) twist and torsional angles [Henson 2000, Zhou 2003, Liu 2006, Zhong 2010], however, limited and less steep responses in the force-frequency relationship-response of the mouse compared to humans [Stull 2002] refers to altered calcium kinetics [Stuyvers 1997] and handling under stress.

In consideration of the various morphological and anatomical comparisons listed, the murine cardiovascular system (under normal physiological conditions) resembles relatively closely evoked responses in larger mammals. As mentioned, numerous cardiovascular indices in mice match corresponding values in rats and humans, predicted by allometric

At the integrative physiological level, the major blood pressure regulating systems, namely the baroreceptor reflex [Ma 2002] and the renin-angiotensin system (regulating electrolyte

However differences do exist, including the increased sensitivity of blood pressure to anesthesia and temperature, especially under conditions of stress [Barbee 1992, Rosenblum 1997, Sarin 1990, Janssen 2004, Constantinides\_ILAR 2011], higher resting cardiac sympathetic

Overall, under physiological conditions, evidence supports that bioenergetically and hemodynamically the mouse scales linearly with larger mammals and humans [Dobson 1995, Nielsen 1958, Phillips 2012], exhibiting a similar maximal aerobic capacity across species [Phillips 2012]. Preliminary evidence for allometric scaling to heart size in mechanical kinematic performance has also been presented [Popovic 2005, Zhong 2010]

Given all considerations, extrapolations of inferences from mice to man is appropriate under physiological conditions, however, similar attempts in pathological models or states may be

Even if advances in telemetric techniques have allowed the pursuit of mouse studies under conscious conditions to a large extent, most of the research (terminal, invasive, or noninvasive imaging) studies utilize anesthetics. Anesthetics, however, are known to cause severe cardio-depression [Hart 2001] with adverse physiological effects on hormonal release, centrally to the heart and peripherally to the vasculature [Price 1980, Ohnishi 1974] at the cellular level, affecting calcium entry through L-type Ca2+ channels, the calcium

balance) [Cholewa 2001] seem to resemble closely those in larger mammals.

*Allometric scaling of function, energetics, and metabolism*

**2.2. The impact of anesthesia for mouse studies**

tone [Janssen 2000, Janssen 2002], neurotransmitter release [Ehmke 2003], and others.

supported by preliminary comparative mouse-human results in this present work.

*Integrative physiological control*

scaling laws.

indeed risky.

The Current Status, Challenges, and Future Perspectives 349

#### *2.1.3. Functional physiological differences*

#### *Cardiovascular metabolism*

Energetic requirements in biological organisms are often assessed by their oxidative capacity, myosin ATPase and SERCA activities [Blank 1989] with a commensurate increased demand in small animals, such as rodents. In compensation of such increased energetic demand, an increased volume density of mitochondria is reported by Doevendans et al. [Doevendans 1998] in mice (37.9%) compared to humans (25.3%), with similar myofibril density (approximately 50%). However, recent findings by Phillips et al. [Phillips 2012] argue in favor of a constant density of mitochondria across species (approximately 21%), yet an increased enzymatic activity of mitochondrial enzymes in mice and a smaller dynamic range of metabolism is reported. Also of interest are the relative patterns of cardiac myosin chain isoforms (αα, ββ, αβ), a mouse αα-isoform compared to a human-ββ isoform dominance [Sheuer 1979], and a developmental switch in mice compared to humans, resulting in higher myosin ATPase activity. Noteworthy and more important is the increased basal activity of metabolic enzymes (Complex V) [Phillips 2012] and the smaller energetic reserve in mice compared to humans [Blank 1989, Phillips 2012], raising concerns for the appropriateness of the mouse as a proper model for comparative pharmacologic (doputamine, dipyridamole) stress studies in ischemia-infarction-reperfusion models, compared to human disease [van Rugge 1992, Wiesmann\_Circ\_Res 2001, Williams 2001].

#### *Perfusion, angiogenesis-collateral flow, coronary reserve*

Based on the extensive number of literature publications that focused on the elucidation of the basic principles of cardiovascular physiology (during the early and latter half of the 20th century), including the autoregulation of blood flow in rats and canine [Feng 2001, Sandgaard 2002], important differences exist in mouse and man with regard to perfusion, capillary density [Stoker 1982, Rakusan 1994], total blood volume (2.5 ml in the mouse compared to 400-500 ml in humans), relative distribution of blood flow in the capillary bed and redistribution capability subject to stimuli (temperature, anesthesia) [Barbee 1992, Rosenblum 1997, Sarin 1990, Constantinides 2011], angiogenetic capacity and formation of collateral vessels, as well as the resting coronary reserve, as factors that primarily project to ischemia-reperfusion studies (or other cardiovascular pathology models) and comparative analyses between pigs, canine, and man.

#### *In vivo cardiac function*

While direct comparative studies between mouse and man are still few, nevertheless published results favor similar hemodynamic and global cardiac functional indices, including blood pressure [Janssen 2002, Constantinides, 2011], inotropic (ejection fraction [EF], maximum developed ventricular pressure rates - dP/dtmax, stroke work (SW), preload adjusted maximum power (PAMP), Preload recruitable stroke work (PRSW), end-systolic elastance (ES), and the end-systolic pressure volume relationship) and lusitropic (minimum developed ventricular pressure rates - dP/dtmin, Weiss and Glantz relaxation constants, and the end-diastolic pressure-volume relationship), left ventricular contractile indices [Constantinides\_ABME 2011, Doevendans 1998]. Recent MRI findings also support similar torsional patterns, as reported by normalized (to left ventricular lengths) twist and torsional angles [Henson 2000, Zhou 2003, Liu 2006, Zhong 2010], however, limited and less steep responses in the force-frequency relationship-response of the mouse compared to humans [Stull 2002] refers to altered calcium kinetics [Stuyvers 1997] and handling under stress.

#### *Integrative physiological control*

348 Practical Applications in Biomedical Engineering

*Cardiovascular metabolism*

almost the same in mouse and man [Schaper 1998].

*Perfusion, angiogenesis-collateral flow, coronary reserve*

analyses between pigs, canine, and man.

*In vivo cardiac function*

*2.1.3. Functional physiological differences*

Doevendans 1998]. The duration of the cell cycle (once G1 is entered) is reported to be

Energetic requirements in biological organisms are often assessed by their oxidative capacity, myosin ATPase and SERCA activities [Blank 1989] with a commensurate increased demand in small animals, such as rodents. In compensation of such increased energetic demand, an increased volume density of mitochondria is reported by Doevendans et al. [Doevendans 1998] in mice (37.9%) compared to humans (25.3%), with similar myofibril density (approximately 50%). However, recent findings by Phillips et al. [Phillips 2012] argue in favor of a constant density of mitochondria across species (approximately 21%), yet an increased enzymatic activity of mitochondrial enzymes in mice and a smaller dynamic range of metabolism is reported. Also of interest are the relative patterns of cardiac myosin chain isoforms (αα, ββ, αβ), a mouse αα-isoform compared to a human-ββ isoform dominance [Sheuer 1979], and a developmental switch in mice compared to humans, resulting in higher myosin ATPase activity. Noteworthy and more important is the increased basal activity of metabolic enzymes (Complex V) [Phillips 2012] and the smaller energetic reserve in mice compared to humans [Blank 1989, Phillips 2012], raising concerns for the appropriateness of the mouse as a proper model for comparative pharmacologic (doputamine, dipyridamole) stress studies in ischemia-infarction-reperfusion models, compared to human disease [van Rugge 1992, Wiesmann\_Circ\_Res 2001, Williams 2001].

Based on the extensive number of literature publications that focused on the elucidation of the basic principles of cardiovascular physiology (during the early and latter half of the 20th century), including the autoregulation of blood flow in rats and canine [Feng 2001, Sandgaard 2002], important differences exist in mouse and man with regard to perfusion, capillary density [Stoker 1982, Rakusan 1994], total blood volume (2.5 ml in the mouse compared to 400-500 ml in humans), relative distribution of blood flow in the capillary bed and redistribution capability subject to stimuli (temperature, anesthesia) [Barbee 1992, Rosenblum 1997, Sarin 1990, Constantinides 2011], angiogenetic capacity and formation of collateral vessels, as well as the resting coronary reserve, as factors that primarily project to ischemia-reperfusion studies (or other cardiovascular pathology models) and comparative

While direct comparative studies between mouse and man are still few, nevertheless published results favor similar hemodynamic and global cardiac functional indices, including blood pressure [Janssen 2002, Constantinides, 2011], inotropic (ejection fraction [EF], maximum developed ventricular pressure rates - dP/dtmax, stroke work (SW), preload adjusted maximum power (PAMP), Preload recruitable stroke work (PRSW), end-systolic In consideration of the various morphological and anatomical comparisons listed, the murine cardiovascular system (under normal physiological conditions) resembles relatively closely evoked responses in larger mammals. As mentioned, numerous cardiovascular indices in mice match corresponding values in rats and humans, predicted by allometric scaling laws.

At the integrative physiological level, the major blood pressure regulating systems, namely the baroreceptor reflex [Ma 2002] and the renin-angiotensin system (regulating electrolyte balance) [Cholewa 2001] seem to resemble closely those in larger mammals.

However differences do exist, including the increased sensitivity of blood pressure to anesthesia and temperature, especially under conditions of stress [Barbee 1992, Rosenblum 1997, Sarin 1990, Janssen 2004, Constantinides\_ILAR 2011], higher resting cardiac sympathetic tone [Janssen 2000, Janssen 2002], neurotransmitter release [Ehmke 2003], and others.

#### *Allometric scaling of function, energetics, and metabolism*

Overall, under physiological conditions, evidence supports that bioenergetically and hemodynamically the mouse scales linearly with larger mammals and humans [Dobson 1995, Nielsen 1958, Phillips 2012], exhibiting a similar maximal aerobic capacity across species [Phillips 2012]. Preliminary evidence for allometric scaling to heart size in mechanical kinematic performance has also been presented [Popovic 2005, Zhong 2010] supported by preliminary comparative mouse-human results in this present work.

Given all considerations, extrapolations of inferences from mice to man is appropriate under physiological conditions, however, similar attempts in pathological models or states may be indeed risky.

#### **2.2. The impact of anesthesia for mouse studies**

Even if advances in telemetric techniques have allowed the pursuit of mouse studies under conscious conditions to a large extent, most of the research (terminal, invasive, or noninvasive imaging) studies utilize anesthetics. Anesthetics, however, are known to cause severe cardio-depression [Hart 2001] with adverse physiological effects on hormonal release, centrally to the heart and peripherally to the vasculature [Price 1980, Ohnishi 1974] at the cellular level, affecting calcium entry through L-type Ca2+ channels, the calcium

binding sensitivity of the contractile proteins to calcium, on conduction and excitability, and possibly on other sarcoplasmic reticular sites [Price 1980]. Also prominent are effects on the central and peripheral nervous system, but most notable are effects on the metabolism (through mitochondrial vasomotor changes in coronary circulation and perfusion, vasodilation, and blood flow changes in the microvasculature [Kober 2005], possibly synergistic to Nitric Oxide), and the decoupling of oxidative phosphorylation manifested through myocardial oxygen consumption changes.

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

**Figure 3.** Schematic representation of a typical myocyte with indicative (highlighted) target sites of

effects, especially for prolonged imaging studies often exceeding 45 minutes in duration. Apart from physiological indices of hormonal release, respiration and metabolism, carefully controlled cardiac indices (such as heart rate, ejection fraction, arterial pressure, and heart variability) ensure proper conditions of study of the cardiovascular system avoiding detrimental hypotension-induced blood volume changes, metabolic and contractile downregulation, and arrhythmogenicity. Heart variability (HRV) analyses have also been applied for phenotypic screening of transgenic mice, study of heart rhythm mediators through signaling pathways as well as the effects of pharmacologic intervention on intrinsic heart rhythm and arrythmogenesis [Thireau 1997, Bernston 1997, Gehrmann 2000]. Standardization of HRV analyses tools for mice have, however, been limited due to the numerous data acquisition types and analysis techniques employed. Most importantly, variability of HRV is dependent on the type of anesthesia being used, that may also be further influenced by anesthetic balancing agents such as nitrous oxide (N2O), medical air, and oxygen. Interpretation of HRV results has also been difficult [Hoit 2004], due to their dependence on a number of factors including aging, posture, circadian variability, and the duration of the sampling periods used, with recent evidence supporting the fact that the primary contribution of autonomic activity in the mouse is due to the sympathetic tone, in contrast to the parasympathetic vagus contribution [Janssen 2002, Janssen 2000,

inhalational anesthesia.

Constantinides\_IEEE 2010].

The Current Status, Challenges, and Future Perspectives 351


*Article* **The Hydrodynamic Dispersion Characteristics of Coral Sands**

#### **Xiang Cui 1,2, Changqi Zhu 1,\*, Mingjian Hu 1 , Xinzhi Wang 1 and Haifeng Liu 1**

Received: 10 July 2019; Accepted: 24 August 2019; Published: 28 August 2019

**Abstract:** Dispersion characteristics are important factors affecting groundwater solute transport in porous media. In marine environments, solute dispersion leads to the formation of freshwater aquifers under islands. In this study, a series of model tests were designed to explore the relationship between the dispersion characteristics of solute in calcareous sands and the particle size, degree of compactness, and gradation of porous media, with a discussion of the types of dispersion mechanisms in coral sands. It was found that the particle size of coral sands was an important parameter affecting the dispersion coefficient, with the dispersion coefficient increasing with particle size. Gradation was also an important factor affecting the dispersion coefficient of coral sands, with the dispersion coefficient increasing with increasing d10. The dispersion coefficient of coral sands decreased approximately linearly with increasing compactness. The rate of decrease was −0.7244 for single-grained coral sands of particle size 0.25–0.5 mm. When the solute concentrations and particle sizes increased, the limiting concentration gradients at equilibrium decreased. In this study, based on the relative weights of molecular diffusion versus mechanical dispersion under different flow velocity conditions, the dispersion mechanisms were classified into five types, and for each type, a corresponding flow velocity limit was derived.

**Keywords:** coral sands; porous media; model test; dispersion; mechanical dispersion; molecular diffusion


**6. Religious Specialists**

The evidence for gods and goddesses as well as cultic space and associated practices implies the existence of religious specialists (priests, diviners, prophets, etc.) and rituals (offerings, divination, ecstatic utterances, etc.) about which we know little specific.64 One indication of a tradition of religious specialists close to Ammon comes from the famous site of Deir ގAlla where the plaster inscription of Balaam son of Beor, a seer (*h. zh*) known from the Bible (Numbers 22–24) was found. The function of room EE335 (the room containing the Balaam texts written on the wall plaster) at Tall Deir ގAlla is generally considered to be religious in nature because of the content of the text itself. The benches in the room also suggest a cultic function (in connection with the texts), because other known sanctuaries have benches in them,65 but the room was otherwise empty of artifacts.66 The entrance to the room

62 On the excavations of the relevant buildings (102, 113, 200, 300, 700, 800, 900, 910), see (Daviau 2003, chp. 6–9).

63 For figurines found in tombs and other sites in Ammon see (Clark 2017, pp. 379–81; Dabrowski 1997; Dabrowski 2000, 2009; Daviau 2002, pp. 51–73; Dornemann 1983, pp. 131–40; Herr 2014, pp. 400–7; Herr and Platt 2002, pp. 393–99; Platt 1989, p. 361; Platt and Herr 2002, pp. 166–69).

64 Texts from the biblical book of Jeremiah suggest the titles of some of these religious specialists amongst the peoples surrounding Israel (Jeremiah 27:9, 49:3), but it is impossible to know whether these titles represent categories native to the Ammonites (Hübner 1992, p. 276). Presumably, Ammonite religion conformed to the general trends in Levantine religion, and so some of these titles were relevant to the Ammonites. A non-provenanced seal (Ø*CAI*, no. 1b) that is partially damaged contains the name *bdmlkm*, which some have suggested can be reconstructed as ގ*bdmlkm*, "servant of Milkom," and thus may represent a priest. The reconstruction is not certain though, and even if it is, the name does not necessarily indicate profession.

65 Notably, the bench room at Kuntillet ގAjrud (where plaster texts were also located on the walls), and Lachish cult room 49 (Zevit 2001, pp. 298–306).

66 (Ibrahim and van der Kooij 1991, pp. 20–21).

also provided public access.67 The rest of the excavated areas appear to be rather modest storage and work areas,68 thus not giving any specific clues to the function of room EE335 except to say that it was not related to any items obviously sponsored by the state. The text discovered and reconstructed from the wall plaster that had fallen to the floor presents Balaam's oracular vision from ގEl of what the Šaddayin gods were going to do, which apparently involves upheavals of the natural order of things.69 In addition to Balaam being a seer, Combination 1: line 11 mentions a priestess (*khnh*). The proximity of Deir ގAlla to Ammon suggests that these regular categories of religious specialists were probably also known in Ammon.


**1. Introduction**

The ecumenical relations in Romania are currently going through a challenging phase. Some even consider it a crisis of the ecumenical dialogue in its institutionalised form (See: Plaatjies van Huffel 2017; Davids 1999). The relationship between the orthodox and the evangelical Christians in Romania is no different, and, so far, there have been no official dialogues between the two communities. There are many possible causes for the lack of cooperation, but they seem to be different from those affecting the ecumenical dialogue at a global level. Both Christian communities are responsible for the current situation. On the one hand, evangelicals motivate their lack of openness towards dialogue with the orthodox through the historical wounds caused by the persecutions on the part of the orthodox Christians towards evangelicals. On the other hand, the orthodox are more reserved because of the aggressive proselytism practiced by the evangelicals in some cases, but also because evangelical theology is relatively new in Romania (in comparison to orthodox theology), which sometimes gives birth to a condescending attitude towards the evangelicals. When presenting the history of the evangelicals in Romania in the second half of the XIXth century, Dorn Dobrincu talks about the persecutions the baptist and pentecostal evangelicals went through, caused both by the state and the historical churches (Dobrincu 2018, pp. 48–77). On the other hand, the accusations regarding proselytism from the part of the evangelicals have been commonplace in the orthodox environments for a long time now. The orthodox thus claim that the evangelicals use any means (more or less honest/fair) to attract orthodox believers to their churches. (Mănăstireanu 2018, p. 271)

Still, there have been several initiatives to encourage a dialogue between the two communities. From personal relations among theologians to conferences open to scholars belonging to both traditions, these initiatives sometimes materialized in notable theological research studies (See: Oxbrow and Grass 2021, 2015; Grass et al. 2012; Zondervan et al. 2010). The purpose of this article is to offer an inventory of some convergent theological topics, more specifically those identified by evangelical theologians in Eastern orthodox

**Citation:** Sonea, Cristian. 2021. Ecumenical Convergences: Romanian Evangelicals Exploring Orthodoxy. *Religions* 12: 398. https://doi.org/ 10.3390/rel12060398

Academic Editors: Bradley Nassif and Tim Grass

Received: 30 April 2021 Accepted: 26 May 2021 Published: 31 May 2021

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

**Copyright:** © 2021 by the author. 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/).

theology. The article is an attempt to offer some answers to three evangelical authors who present their views on how orthodox theology approaches topics such as the authority of the scriptures (Paul Negrut,), the orthodox soteriology (Emil Bartos,) and the orthodox ecclesiology (Dănut, Mănăstireanu). These topics include important points of convergence, as well as some differences, so they could constitute a good theological ground for official dialogue between the Romanian evangelical and orthodox communities.

#### **2. What Is the Meaning of Ecumenical Convergence?**

Generally speaking, the term convergence refers to the effort made by two entities in order to reach the same point or to achieve the same goal. In other words, the process is initiated with the purpose of reaching unity by accommodating two separate realities. From a theological point of view, we use the word convergence when referring to the relations between Christianity and non-Christian religions. So, on the one hand, theological convergence is a process that refers to the necessity of finding common ground when interacting with a different religious tradition, and, on the other hand, it is a notion used to describe the encounter between two different realities (Dhavamony 2003, p. 245). In an ecumenical context, convergence involves the complex effort of the divided Christian communities to reach unity. The purpose of the institutionalised ecumenical movement is to offer a common Christian witness to the world. Thus, the declared aim of the ecumenical movement is to achieve the visible unity of all Christians. For this purpose, all those involved in the ecumenical dialogue, based on their spiritual, liturgical or sacramental experiences and inspired by their own traditions, elaborate various ecumenical syntheses that although not always the result of theological consensus do however represent factors of theological convergence, in hope of a future Christian unity (Leus,tean 2002, pp. 40–41).

There is a risk of interpreting the hermeneutics of ecumenical convergence as an attempt to level out the differences between the evangelicals and the orthodox, in the name of unity. However, this type of approach does not postulate in any way the absence of divergences, which are of course numerous and, in most cases, well known both by the evangelicals and the orthodox. In fact, the differences are emphasized to such a degree, in the Romanian context, that the more radical representatives of the two communities go as far as denying any convergence. That is why I decided to give priority to the ecumenical convergence here and to place it at the very basis of the ecumenical dialogue and perhaps a future study could discuss the theological differences as well.

Therefore, this particular concept—ecumenical convergence—represents the filter through which the present study analyses the positions on various theological topics of several theologians belonging to the two traditions. More specifically, I started by identifying evangelical theologians who published research on orthodox theology, and I then tried to synthetize and offer a critical evaluation of the convergent elements I found in their works. For this particular research, I selected only three authors for the following reasons: first of all, it would have been impossible to offer an extensive account of all the evangelical authors who wrote about orthodox theology, even if I had chosen to organize the material thematically. The second reason is connected to the particularities of evangelical theology, in which personal theological approaches do not have to be accepted on a general level, so personal views can and should be emphasized anyway. The third reason has to do with a certain degree of openness towards the dialogue of the three authors, which made it easy for me to identify the convergences. From the very beginning, I would like to state that the arguments presented in this paper can be included within the framework of an inclusivist orthodox ecclesiology, adopting George Florovsky's theological opinion regarding the limits of the church. Florovsky argues that the charismatic limits of the church can be mystically found in other Christian communities as well (See: Florovsky 1933, pp. 120–29). I will also mention Dumitru Stăniloae here, according to whom although non-orthodox confessions did indeed separate from the church, they kept a connection with her and are, in a sense, contained by her, to the extent to which they did not completely part from the Tradition of the Church (Stăniloae 1997, vol. 2, pp. 275–76).

### **3. Hallmarks of the Orthodox-Evangelical Dialogue**

Besides the interest that Romanian evangelicals have for the orthodox faith in a country that is mostly orthodox, we also acknowledge the more general interest evangelicals have towards traditional faiths.

Thus, Daniel Clendenin notices that the evangelicals have promoted an ahistorical faith, out of ignorance, because of a superficial understanding of sola scriptura, or due to the conviction that "Bible believers" should and can keep the distance from a corrupt society. At the initiative of Robert Webber, Donald Bloesch, and Thomas Howard, the evangelicals organised a conference for those who had a certain appreciation for the "orthodox evangelicals" and issued a document entitled "The Chicago Call: An Appeal to Evangelicals" (1978). Among other things mentioned in the document, we find the idea that evangelicals have neglected history and allowed themselves to be led by a sectarian spirit and proposed a return to a faith connected to patristic theology, councils, creeds, and "the catholicity of historic Christianity" (Clendenin 2003, p. 178). Similarly, in 1936 at the International Congress of the orthodox theologians in Athens, George Florovsky was urging the participants to go "back to the Fathers of the Church!" and he expressed his belief that the divisions among Christians can only be overcome "by a return to the common mind of the early Church." (Gavrilyuk 2015, p. 2).

Again, part of the same trend of returning to the primary sources, we find the story of Peter E. Gillquist who, together with a group of colleagues started studying church history and became acquainted with the earliest forms of Christianity. In 1973, they started a network of house churches in the United States, with the purpose of restoring the "ancient church", which they called the New Covenant Apostolic Order. After some research about the early church, they then started practicing a more liturgical type of worship and became interested in the idea of apostolic succession. This eventually determined most members of the group to join the Antiochian Orthodox Christian Archdiocese of North America in 1987. Thanks to Gillquist's efforts, seventeen parishes with 2000 members converted to the Antiochian Archdiocese and they became known as the Antiochian Evangelical Orthodox Mission (Gillquist 1989, pp. 5–8).

Apart from these quests for the traditional forms of Christianity, another event that marked the relations between the two traditions was the Canberra Assembly of the World Council of Churches, from 1991. The topic of the Holy Spirit's presence and activity in creation led to a heated debate regarding "spirits", stimulated particularly by Chung Kyung-Hyung's plenary presentation. Two of the groups participating in the conference were extremely critical towards Chung Kyung-Hyung's presentation: the orthodox and the evangelicals. The two groups expressed their concern in open letters that were read out loud to the other participants. The orthodox remarked that "some have the tendency to easily affirm the presence of the Holy Spirit in many movements or evolutions without proper discernment" and warned against "the tendency to wrongly identify the personal spirit, the spirit of the world or other spirits with the Holy Spirit" (Pirri-Simonian and Beek 2012, p. 6). They also brought up other subjects such as the dialogue with other religions and the understanding of salvation through Jesus Christ. In their letter, on the other hand, the evangelicals insisted that "a lot of discernment is necessary in order to identify the Spirit with the Spirit of Christ" and they pleaded for a high Christology as the only authentic Christian basis in dialogue with those "belonging to other faiths" (Pirri-Simonian and Beek 2012, p. 6). They also remarked upon the many "engagements and theological preoccupations they had in common with the orthodox" and asked to "start a dialogue between the evangelicals and the orthodox as soon as possible" (Pirri-Simonian and Beek 2012, pp. 6–7). After the event, three important consultations took place: one in 1993, in Stuttgart, with the topic: "The Bible and the Tradition", one in 1995, in Alexandria, with the topic: "The Proclamation of Christ today" and another one in 1998, in Hamburg, with the topic: "The return to God—Joy in hope"(Pirri-Simonian and Beek 2012, pp. 15–18). The meetings continued at the Ecumenical Institute from Bossey in 2000, 2002, 2006 (Grass et al. 2012). The first meeting (2000) dealt with the topic of salvation and concentrated on the question whether

salvation is the result of a single moment when an individual is "born again", or if it is a continuous process or perhaps both. In 2002, the topic of the meeting was the role and the place of the Bible in the two traditions, while in 2004, the meeting dealt with the nature and the purpose of the Church. The last meeting, organised in 2006, approached the more sensitive issue of anthropology (Sauca 2012, pp. 3–4). In 2013, another series of consultations started, as part of the Lausanne-Orthodox Initiative, which is continuing until today (Consultations 2021). These consultations are oriented specifically towards mission, and have been documented in Oxbrow and Grass (Oxbrow and Grass 2021, 2015).

#### **4. Romania—A Christian Country for Both: Orthodox and Evangelicals**

In comparison to other European countries, Romania has a very high percentage of believers. Special Eurobarometer, 493, published in 2019 by the European Commission, indicates that Romania is the country with the smallest number of atheists in Europe: 1% (Discrimination in the European Union 2019), and according to the Special Eurobarometer, 73.1, from 2010, on the topic of biotechnology, Romania had a 92% of believers, most of them Christian, coming second in Europe, while the first place was occupied by Malta (Biotechnology 2010). It is thus obvious that religious practices in general, and especially Christian religious practices occupy an important part in the life of most Romanians. Although the number of practicing Christians is smaller than the number of those who simply declare themselves to be Christian, Romanians still seem to be very attached to their old traditions and they tend to integrate culturally or educationally many of the Christian values.

Around 324, Eusebius of Caesareea writes about the beginnings of Christianity on the Romanian territory and I will note here that his position is officially accepted and adopted by the Romanian Patriarchy. According to this tradition, Saint Apostle Andrew went from Asia to Scythia Major and then to Scythia Minor (present-day Dobrogea, Romania), and he preached in some of the Greek towns on the Black Sea shores (Păcurariu 1991, p. 13). Although this account has been contested by some theologians (including some Romanian theologians) (Stan and Turcescu 2007, pp. 47–48), who considered it to be part of a so-called protochronism (from proto-chronos, meaning "first in time"), a tendency that can be identified in many countries from the Balkans, and which promotes the idea that the ethnogenesis of the Romanian people coincides with the process of Christianisation (Stan and Turcescu 2007, p. 48). Interestingly, the apostolic origin of Romanian Christianity is also assumed by some in the evangelical communities. The former president of the Penticostal Chrisitian Community, Pavel Rivis, Tipei, writes in Cuvântul Adevărului (the official magazine of the Romanian Pentecostal Community) about the apostolic origin of Pentecostalism on the Romanian territory: "We generally talk about a period of 85 years that have passed since the first Pentecostal church was founded in Romania, at Păulis, , Arad county, on 10 September 1922, but the beginnings of Pentecostalism can be traced back much earlier than that [ ... ]. The Apostle Andrew was neither catholic, nor orthodox, but he was surely a Pentecostal as he was baptised with the Holy Spirit." (Rivis,-Tipei 2007, pp. 3–4).

According to the latest census, the majority of the Romanian population is orthodox (86.5%). Additionally, the numbers indicate that the Romanian Orthodox Church has the second-highest number of orthodox believers after the Russian Orthodox Church. According to the same census, the evangelical communities, including pentecostals, make up for 3.3% of the entire population and they represent the only Christian community that had registered a growth in the number of believers since the previous census. In the 2002 census, 1.49% of the population was Pentecostal, while in 2011, the percentage increased with 0.41%, to a total of 1.9%, as well as an increase in the number of followers with 43,476 (INS 2011). Allen Anderson notes that the more conservative sources claim that the number of Romanian Pentecostals is somewhere around 300,000, while other sources claim it is close to 800,000 which would turn Romania into the most pentecostal country in Europe (Anderson 2004, p. 100).

Apart from the numbers, which are obviously important, it is also worth mentioning that in the collective mentality of the Romanians, the Christian faith is also part of their ethnic identity: regardless of confession, they all agree that the Romanian nation was "born Christian". So, although the first evangelical communities appeared at the beginning of the 20th century (Dobrincu 2018, p. 42), they still seem to be inclined to define their own theology as rooted in the Romanian culture (Rogobete 2001, p. 262, note 14). We can thus identify the influence of the traditional Churches in some of their teachings and practices. Just to give a few examples, in some Romanian evangelical communities, such as the Romanian Evangelical Church (the so-called tudorists who continue a movement initiated by the former orthodox priest Teodor Popescu), infant baptism is still practiced. Another similarity concerns the organisation of the ecclesial structure in the evangelical communities in comparison with the consecrated ordained members of the ecclesial body in the traditional churches. Here is an example:

"The deacon is in charge of the administration of the offerings received by the church. He can officiate Lord's Supper, he can perform the blessing of children or funerals, if the pastor is not able to perform them. The presbyter can officiate all services, at the recommendation of the pastor. The pastor officiates all services and is in charge of the pastoral care of a local church." (M ˘arturisirea de credint,a˘ 2021, p. 22)

"The bishop can perform all Holy Sacraments and all church services [ ... ]. The priest receives, from the bishop, through ordination, the three gifts: of teaching, sanctifying and leading [ ... ]. The deacon serves as a help for the priest and the bishop." (Belu et al. 2011, p. 57)

I am not going to discuss here the theological differences, which are obvious. However, we cannot ignore the similarities regarding the relations among various sacerdotal positions. The pastor, in this case, seems to have a role that is similar to that of an orthodox bishop, who is the leader of a local church or bishopric. The presbyter, who can officiate all religious services, at the recommendation of the pastor, is similar to the priest in the orthodox tradition, who performs all liturgical services, with the consent of the bishop, while the deacon helps the other members of the clergy. Obviously, not all evangelical communities have this kind of organisation and also, even those that do have it do not necessarily admit that it is an influence of the Orthodox Church, but rather say that it has biblical roots.

The similarities can be explained through the fact that the evangelical communities once belonged to the traditional churches and then separated from them. In fact, their conversion to the evangelical movements was perceived as sheep-stealing, as a result of proselytism, while the evangelicals regarded it as a return to biblical Christianity. This is actually the main reason why the relations between the two Christian communities have often been tense. Thus, the evangelical theologians who show interest in orthodox theology, do so with the declared purpose of finding reconciliation with the other Christian traditions, in this case with the orthodox, but also because they are making an attempt to define a Romanian evangelical theology (Rogobete 2001, p. 262, note 14). We are yet to find out whether the orthodox are receptive or if they are willing to answer with the same kind of attitude. According to Bradley Nassif, "the country holds much promise for constructive relations. At present, however, the dialogue in Romania remains weak and indirect, consisting mostly of a growing awareness of the need to explore the points of contact between each other. Academically speaking, there are more evangelical students of Romanian orthodoxy than there are orthodox students of Romanian evangelicalism" (Nassif 2000, pp. 29–31).

In 2018, the Coalition for the Family, an association of several organizations of the main religious denominations in Romania had the initiative to propose a referendum in order to change the definition of marriage in the Romanian constitution. While in the Romanian constitution marriage was defined as the union between spouses, the Coalition suggested that marriage should be defined as the free union between a man and a woman,

to be more specific "the stable union between one man and one woman". Although the referendum failed due to low turnout, it did succeed in bringing together most Romanian Christian denominations. On this occasion, the Baptist Teofil Stanciu offered a short overview of the relations between the orthodox and the evangelicals for the past three decades. Stanciu explains that Christians belonging to various denominations were united under one cause because they suddenly discovered they had common moral values they wanted to defend. What was interesting, he notes, was that this recent discovery was not preceded by official dialogues between the orthodox and the evangelical leaders on the hot topics of the present-day society. They did not decide together what their position was regarding these issues. There were, however, inter-confessional interactions among academics in universities, but without much echo in the actual communities of believers. Another form of conversation, Stanciu adds, was constituted by the Ph.D. dissertations written by evangelicals under the guidance of orthodox theologians due to the lack of post-graduate programmes available in the evangelical faculties and institutes. However, the debates in the public arena, especially those related to moral issues, determined many to favour the Christian element of their identity, rather than their specific confession. Social media played an important part in this, as well as the global evolutions signalled by the press and the perceived persecutions against Christians. All these, Stanciu notes, gave birth to temporary trans-confessional solidarity. On the positive side, he explains, there is a dialogue in the academia (less influential), and another one on a wider scale, but perhaps more superficial, on the moral issues of the society. Otherwise, the lack of communication is still probably the rule, whether it is because of refusal of mutual recognition, or because of plain indifference. Finally, Stanciu appreciates the fact the orthodox and the evangelicals found some common ground in the current debates from the public arena, but he worries that they might remain stuck in the ideological or political realm. Although certain political, civic or social benefits can result from this, the theological dimension should not be ignored, as it is at the basis of any other initiative. We must find a way, he concludes, to put into practice, "in a creative but realistic way, the concept of unity in diversity" (Stanciu 2019).

#### **5. Convergent Theological Topics**

The divergences between the orthodox and the evangelicals are often intensely discussed in the sermons or other public speeches of the leaders of the two communities. Thus, topics such as infant baptism vs. adult baptism, sola Scriptura vs. the authority of the Tradition, sacramental priesthood vs. universal priesthood, the veneration of Holy Theotokos, the honoring of saints, icons and relics, as opposed to Christ as the only intercessor are just a few of the topics a simple believer can often hear being discussed in church. Besides these differences that surely exist, there are also a lot of convergences, much more rarely discussed, such as the authority of the Scriptures in the life of the Church, the teachings about salvation or the understanding of the church as koinonia.

#### *5.1. The Authority of the Bible in the Romanian Orthodox Church in the Work of Paul Negrut,*

The Romanian evangelical theologians approach a wide range of topics when expressing their views on orthodoxy, such as the authority of the Bible in the Church (Negrut, 1994), the theology of Stăniloae and theosis (Rogobete 2001), Scriptures (Mănăstireanu 2006); eco-theology (Maris, 2009), ecclesiology (Mănăstireanu 2012), justification (Florut, 2018), the theology of participation in God (Oprean 2019), salvation, grace and charismas (S, tefănică 2019), the role of women in Church (Sabou 2012), the ecumenical dialogue (Druhora 2020).

I will start with the classic debate concerning the place and the authority of the Bible in Church. In Paul Negrut,'s view, the debate started with "the translation of Scriptures into modern Romanian by Dumitru Cornilescu and the tension between Scripture and Tradition emphasized in the work of Teodor Popescu" (Negrut, 1994, p. 4), a deacon and a priest who embraced the evangelical principles, which led to their exclusion from the orthodox clergy. "From the interplay between the orthodox paradigm of revelation–communion– deification and the Protestant paradigm of revelation–justification–sanctification adopted

by Cornilescu's movement there emerged within Romanian orthodoxy new hermeneutical communities which emphasize both the mystical and the ethical dimensions of biblical Christianity. Consequently, since Scripture is perceived as the "Book of the community", both laity and hierarchy participate in episteme and praxis." (Negrut, 1994, p. 341)

Negrut, notes that Cornilescu regarded Scripture "as the only source of theological epistemology and the supreme authority in matters of faith and practice". Thus, he continues, Cornilescu "believed that the authority to maintain a balanced relation between episteme and praxis within the Christian community is sola scriptura. Although such a belief represents a radical shift from the orthodox view, the Romanian Orthodox Church avoided any open theological debates with Cornilescu regarding biblical authority, preferring instead to reject his teachings on the grounds that they were Protestant and thus heretical" (Negrut, 1994, p. 79).

Although Bible occupies a central place in the Orthodox Church, it is not considered the unique source of theological epistemology. According to Orthodox theology, the unique source is Christ, Who can be known by the community of faith. This living relationship with God is called Tradition in the Orthodox Church. Christ was known by the members of the first Christian communities, before the first books of the biblical canon were written. Thus, in the orthodox view, the Bible is a written part of the Tradition. It does play a normative role in the sense that the truth of faith cannot contradict the Scriptures, but it is not the only source of theological epistemology. The orthodox Church never embraced Dumitru Cornilescu's and Teodor Popescu's views, which does not mean that the Bible plays a less important part in the life of the orthodox communities. The Romanian Orthodox Church has used the Romanian language in Church services as a liturgical language ever since the 17th century, which made it possible for everybody to access both the actual text and the interpretations of the Bible. A biblical and a liturgical tradition in the Romanian language developed early on, which allowed lay people to read the Bible in their own language. This aspect would be relevant in a bilateral dialogue between the orthodox and the evangelicals as the centrality of the Scriptures constitutes a topic of ecumenical convergence. The special place the Bible occupies in the Romanian tradition has been consolidated by the presence of a group inside the Romanian Orthodox Church called the "Lord's Army". The group has a pronounced evangelical character and although it was initially considered a separatist movement (David 1998, pp. 166–68), it eventually remained inside the Church. Within this considerably large group of orthodox Christians, the reading of the Bible occupies an important part of their church life.

Additionally, the "two source" theory, which placed the source of Divine Revelation in the Scripture and the Tradition and which had been adopted by the Romanian Orthodox Church (Negrut, 1994, p. 164) was later on corrected by Dumitru Stăniloae and Dumitru Popescu, according to whom, the Source of the Revelation is the on-going work of the Son, the Word of God and of the Holy Spirit that are seen as the hands of God that reveal themselves in history (Stăniloae 1996, vol. 1, p. 32) through actions, words and images (Stăniloae 1996, vol. 1, pp. 28–29). As for the New Testament, the Word revealed Himself and, through the Holy Spirit, He was initially passed on by oral tradition and then He continued to be transmitted this way even after the books of the New Testament were written. Thus, Tradition has a wider meaning, preceding and including the Bible, which is simply the written record of the oral tradition (Popescu 2005, p. 66), but they both have one source: the Holy Trinity. This correction places both Tradition and the Scriptures within the limits of the Church and they appear to be woven into a whole through the work of the Holy Spirit.

There are of course different ways in which we can understand the authority of the Bible in the orthodox and the evangelical traditions, but the interaction between them in Romania made the Romanian orthodox biblical tradition consider the Scriptures as a criterion of validity for Tradition, while in the evangelical tradition, there are voices such as that of Dănut, Mănăstireanu that emphasize the necessity of Tradition, not just for the purpose of preserving a Christian lifestyle, but also from the perspective of continuity (Mănăstireanu 2006, p. 55).

Thus, in the Romanian context, the Bible as an authority for faith, life and practice is an important element of ecumenical convergence. Contemporary orthodox Bible scholars identified in this area some common benefits for the two traditions. As far as "Bible literacy is concerned", the orthodox have a lot to learn from the evangelicals, if they want to make "the Gospel of Christ clearer and more central to the life of the orthodox Christians" (Tofană 2015, p. 10), while on the other side, the appeal to the patristic authority in interpreting the Scriptures would prevent personal interpretations from causing separations in the body of the Church (Tofană 2015, pp. 13–14).


3.2.3. FTIR Spectroscopy

The FTIR spectra depicted in Figure 6 show peaks at 3530 cm−1 (\*), which are characteristic of the hydrogen-bonded water in the crystal for both coated and uncoated nano co-crystals, [54,55]. The stretching band at 1635 cm−1 (@) is due to the carbonyl moiety (O=C–NR2) and is characteristic for 3TC and AZT. It partially overlaps with the N–H (bending) band at 1607 cm−1 (→). The stretching vibration of the imine group (R2-C=NR) is observed at 1648 cm−1 (#). Characteristic bands for AZT are observed at 2170 cm−1 (‡) and 1652 cm−1, due to –N3 and –N–H stretching vibrations. A comparison of the wavenumbers for the co-crystal and the OPT-NCC are reported and plotted in Table S2 and Figure S2 respectively and the spectra for the NCC, AZT and 3TC are depicted in Figure S3 in the Supplementary Information.

**Figure 6.** FTIR absorption spectra of the uncoated NCC (black) and the OPT-NCC (orange).


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*Use of Selected Antioxidant-Rich Spices and Herbs in Foods*

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Food Agric. 2002;82:1645-1651.

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[98] Khanna NM. Turmeric-Nature's precious gift. Curr Sci.

1999;76:1351-1356.

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*Antioxidants - Benefits, Sources, Mechanisms of Action*

[87] Ho S, Chang K, Lin C. Antineuroinflammatory capacity of fresh ginger is attributed mainly to 10-gingerol. Food Chem.

[88] Stoilova I, Krastanov A, Stoyanova A, Denev P, Gargova S. Antioxidant activity of a ginger extract (Zingiber officinale). Food Chemistry.

[89] Mao QQ, Xu XY, Cao SY,

Nutr Rev. 2013;71:245-254.

[91] Palatty PL, Haniadka R,

2013;53:659-669.

Valder B, Arora R, Baliga MS. Ginger in the prevention of nausea and vomiting: A review. Crit Rev Food Sci.

[92] Do MT, Kim HG, Choi JH, Khanal T, Park BH, Tran TP, Jeong HG. Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells. Food Chemistry. 2013;141(3):2591-2599. https://doi. org/10.1016/j.foodchem.2013.04.125.

[93] Abraham A. The trend in export, import and production performance of black pepper in India. International

Mathematics. 2018;118(18):4795-4802.

[94] Tipsrisukond N, Fernando LN, Clarke AD. Antioxidant effects of essential oil and oleoresin of black pepper from supercritical carbon dioxide extractions in ground pork. J Agric Food Chem.

Journal of Pure and Applied

1998;46:4329-43333.

Gan RY, Corke H, Beta T et al. Bioactive Compounds and Bioactivities of Ginger (Zingiber officinale Roscoe). Foods,

[90] Marx WM, Teleni L, McCarthy AL, Vitetta L, McKavanagh D, Thomson D et al. Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review.

2013;141:3183-3191.

2007;102(3):764-770.

2019;8(6):185.

Antifungal Activities of Spices. International Journal of Molecular

Sciences. 2017;18(6):1283.

2015;30(8):542-550.

[80] Bozkurt M, Sezgic M, Karakol P, Uslu C, Balikci T. The Effect of Antioxidants on Ischemia-Reperfusion Injury in Flap Surgery. Antioxidants, Intech Open 2019.

[81] Tapsell LC, Hemphill I, Cobiac L, Sullivan DR, Fenech M, Patch CS et al. Health benefits of herbs and spices: the past, the present, the future. Medical Journal of Australia. 2006;185(S4).

[82] Ranjbar A, Ghasmeinezhad S, Zamani H, Malekirad AA, Baiaty A, Mohammadirad A et al. Antioxidative stress potential of Cinnamomum zeylanicum in humans: a comparative cross-sectional clinical study. Therapy.

[83] Ghosh T, Basu A, Adhikari D, Roy D, Pal A. K. Antioxidant activity and structural features of *Cinnamomum zeylanicum*.2015; 323 Biotech, 5(6),

[84] Bi X, Lim J, Henry CJ. Spices in the management of diabetes mellitus. Food

[86] Muhammad DRA, Dewettinck K. Cinnamon and its derivatives as potential ingredient in functional food-A review. International Journal of

Chemistry. 2017;217:281-293.

Food Properties. 2017;1-27.

[85] Jayaprakasha GK, Rao LJM. Chemistry, Biogenesis, and Biological Activities of Cinnamomum zeylanicum. Critical Reviews in Food Science and Nutrition. 2011;51(6):547-562.

2006;3(1):113-117.

939-947.

[79] Mousavi G. Study on the effect of black cumin (Nigella sativa Linn.) on experimental renal ischemia-reperfusion injury in rats. Acta Cirurgica Brasileira.

**404**

[96] Pizzale L, Bortolomeazzi R, Vichi S, Überegger E, Conte LS. Antioxidant activity of sage (Salvia officinalis and S fruticosa) oregano (Origanum onites and O indercedens) extracts related their phenolic compound content. J Sci Food Agric. 2002;82:1645-1651.

[97] Nakatani N, Inatani R, Ohta H, Nishioka A. Chemical constituents of pepper and application to food preservation. Naturally occurring antioxidative compounds. Environ Health Perspect. 1986;67:135-147.

[98] Khanna NM. Turmeric-Nature's precious gift. Curr Sci. 1999;76:1351-1356.

**407**

eugenol

**1. Introduction**

**Chapter 20**

**Abstract**

Compounds

*Cinnamomum zeylanicum*:

Morphology, Antioxidant

*Asel Chandula Weerasekera, Kanchana Samarasinghe,*

*Cinnamomum zeylanicum* is one of the oldest spices used for culinary purposes in Asian countries. Its extracts have demonstrated a positive impact on controlling the progression of disease pathologies due to antioxidant, anti-inflammatory, antimicrobial, anticancer, anti-mutagenic, anti-tyrosinase and antidiabetic characteristics. *C. zeylanicum* also has its unique variations which makes it necessary to distinguish it from other species of cinnamon. Phenolic compounds such as cinnamaldehyde, eugenol, carvacrol, cinnamic acetate and thymol are the main compounds that can be found in essential oils of *C. zeylanicum*. However, cinnamaldehyde and eugenol act as the main bioactive antioxidant compounds found in *C. zeylanicum* because of their active functional groups in the structures. There are many examples of the use of *C. zeylanicum* extracts for medicinal purposes, specifically cinnamon metabolite proanthocyanidins which suppress inflammatory compounds and help pathways such as insulin signaling. Moreover, the bioactive compounds in essential oils of this plant are

used against many pathogenic (including food-borne) and spoilage bacteria.

and India including other regions of tropical Indochina and Madagascar (**Figure 1**). This is one of the oldest traditional spice species used for culinary purposes in South Asian countries [1, 2]. Additionally, according to toponymical and historical evidence, *C. zeylanicum* has been used for medicinal purposes since the establishment of Aryan settlements in the Anuradhapura kingdom [3]. Moreover, the indigenous species of Ceylon cinnamon has been used in the Ayurveda system of Sri Lanka [3, 4]. Ethnopharmacological studies show that

**Keywords:** Alzheimer's disease, Ayurveda, cinnamaldehyde, Ceylon cinnamon,

*Cinnamomum zeylanicum* (family Lauraceae), known as 'Ceylon cinnamon' or 'true cinnamon', grows as an ever-green tree native to Sri Lanka (earlier Ceylon),

Properties and Bioactive

*Heethaka Krishantha Sameera de Zoysa,*

*and Viduranga Yashasvi Waisundara*

*Thushara Chathuranga Bamunuarachchige*

## **Chapter 20**