**11. References**

176 Congenital Heart Disease – Selected Aspects

Freedom from systemic AV valve regurgitation and ventricular dysfunction was significantly higher after anatomic repair. The authors concluded that anatomic is superior to physiologic repair in patients with two adequately sized ventricles. However high risk groups such as those patients with RV dysfunction or the need for LV training warrant careful selection prior to undergoing anatomic repair. Taken together, these outcomes favor anatomic over classic /physiologic repair with careful preoperative assessment of TR for the

Patients with ccTGA require outpatient follow-up every 1-2 years by a pediatric or adult congenital cardiologist. Symptomatology, ventricular function, and valvar insufficiency should further guide frequency of follow-up. It is recommended an ECG be performed at each visit to monitor for AV block with periodic consideration of Holter monitor. Cardiopulmonary exercise testing is performed to assess overall function as well as response to medical or surgical therapy. RV function in the unrepaired or physiologically repaired ccTGA patient must be closely monitored with serial echocardiography even in asymptomatic patients (Bos et al., 2006). Cardiac MRI with cine data used to quantify RV volume, mass, and ejection fraction is the best modality to serially quantify RV function, and

Pregnancy in the ccTGA patient is generally well tolerated except in the presence of maternal NYHA class III-IV symptoms, moderate or severe AV valve regurgitation, or poor ventricular function (EF<40%). Evaluation of pregnancy outcome in 22 women with ccTGA revealed 50 live births in 60 total pregnancies (83%). However, the rate of miscarriage in the ccTGA mothers was higher than the general population (Connolly et al., 1999). A recent cohort of patients by Gelson and colleagues (2011) revealed high maternal and neonatal morbidity in women with systemic right ventricles with a significant number of babies born small for gestational age. Although cyanosis in women with ccTGA has been shown to be a risk factor for miscarriage, the women in the cohort of Gelson et al. were normally saturated (Gelson et al., 2011; Thierrien et al. 1999). The risk of congenital heart defects in the offspring

Patients for which heart transplantation may be considered are those with end-stage RV failure, significant LV dysfunction and pulmonary valve abnormalities precluding successful DS operation, or uncontrollable arrhythmia (Duncan & Mee, 2005). For patients undergoing surgical intervention, poor preoperative EF of the systemic ventricle has been

Although debate continues over efficacy and long-term follow-up of physiologic vs. anatomic repair for ccTGA, recent outcomes data favor anatomic correction in which systemic function is restored to the LV. Management considerations specific to this population of complicated patients include type and timing of surgical intervention to

shown to predict the eventual need for transplantation (Beauchesne et al., 2002).

purpose of risk stratification.

**9. Follow-up and special considerations**

should be performed every 3-5 years.

of mothers with ccTGA has not been defined.

**10. Conclusions and special considerations**

**9.1 Pregnancy**

**9.2 Heart transplant**

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**8**

**Proximal Anomalous Connections**

Pierre Aubry1, Xavier Halna du Fretay2, Patrick A. Calvert1,3, Patrick Dupouy4, Fabien Hyafil5, Jean-Pierre Laissy6 and Jean-Michel Juliard1

Isolated proximal **ANO**malous connections of **COR**onary arteries (ANOCOR) are not rare with an angiographic prevalence and tomographic prevalence of 0.5% and 1.3% respectively, in adult populations. The diagnosis of ANOCOR is sometimes fortuitous in adults undergoing a coronary angiography to detect a coronary artery disease (CAD). The absence of diagnosis in young people may have severe consequences with sudden death occurring frequently during intensive exertion. The prognosis depends mainly on the initial course of the ectopic coronary vessel. Preaortic course with intramural segment is recognized as high risk for sudden death in children or young adults. Management of ANOCOR with intramural course may be difficult in patients >35 years of age and with no evidence of myocardial ischemia. The mechanisms of life-threatening cardiac events are still not well understood even if anatomical risk factors are identified. Fortunately, most cases of ANOCOR are simply incidental anatomical findings. Multidetector computed tomography (CT) is recognized as the best imaging technique for identifying ANOCOR. Intravascular ultrasonography (IVUS) may help to quantify the severity of high-risk ANOCOR. In the ACC/AHA 2008 guidelines for the management of adults with congenital heart disease, surgical repair is the treatment of choice for high-risk ANOCOR (Warnes et al. 2008). However, this therapeutic management is based on little solid data with limited long-term follow-up. Percutaneous coronary intervention (PCI) has been proposed in some ANOCOR. The limited experience of most angiographers in detection of ANOCOR may explain non infrequent misdiagnoses with erroneous interpretations of ANOCOR. Large-scale prospective multicenter studies are needed to improve screening and imaging strategies and to better define the treatment of these potentially lethal congenital coronary abnormalities.

**1. Introduction**

**of Coronary Arteries in Adults**

*1Department of Cardiology, Bichat Hospital, Paris 2Department of Cardiology, Foch Hospital, Suresnes 3Department of Cardiology, Papworth Hospital*

*4Department of Interventional Cardiology and*

*Cardiovascular Imaging, Hôpital Privé d'Antony, Antony 5Department of Nuclear Medicine, Bichat Hospital, Paris 6 Department of Radiology, Bichat Hospital, Paris,*

 *NHS Foundation Trust, Cambridge,*

*1,2,4,5,6France 3United Kingdom*

Congenitally Corrected Transposition of the Great Arteries (SLL). *Pacing and Clinical Electrophysiology*, Vol. 33, No. 1, (January 2010), pp. e4-7, ISSN 1540-8159.


**5. Mechanism of action of select bioactive phytochemicals**

#### **5.1 Bixin**

Bixin constitutes the main pigment of the industrial annatto obtained from the seed coat of *Bixa orellana* [34]. This phytochemical belongs to the relatively small family of apocarotenoids; it was the first cis-carotenoid to be isolated from natural sources [35]. However, it was not until 1961 that its chemical structure and stereochemistry were determined through nuclear magnetic resonance spectroscopy studies [36].

This phytochemical compound shows pleiotropic bioactivities with healthpromoting properties. It was recently demonstrated that bixin caused arrest of Hep3B cell line at G2/M checkpoint of the cell cycle and the molecular mechanism of action was demonstrated by a modeling study, which was based in the favorable

 binding of bixin to domains of Bax BH3 and FasL proteins [37]. Consequently, bixin should be used for developing agents to combat human hepatocellular carcinoma. Bixin is also a potent activator of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which is the master regulator of the cellular antioxidant response protecting the skin against various environmental stressors including UV radiation and electrophilic pollutants [38–40]. The protective effects against solar UV-induced skin damage are due to the NRF2-dependence of bixininduced antioxidant and anti-inflammatory effects [39]. In addition, bixin displays molecular activities as antioxidant, excited-state quencher, peroxisome proliferatoractivated receptor α/γ agonist, and Toll-like receptor 4/nuclear factor kappa-lightchain-enhancer of activated B-cell antagonist. Together, these bioactivities may be important to the improvement of skin barrier function and environmental stress protection [40].

### **5.2 Crofelemer**

 Crofelemer previously known as SP-303 is a large proanthocyanidin oligomer isolated from the bark latex of the plant *Croton lechleri* Müll. Arg. [41]. Initial studies have demonstrated the immense antiviral activity of crofelemer against a gamma of DNA and RNA viruses such as respiratory syncytial virus, influenza A virus, parainfluenza virus, herpesvirus types 1 and 2, and hepatitis A and B viruses. The antiviral mechanism implies the direct interaction of crofelemer to components of the viral envelope, blocking both the viral attachment and the cell invasion [41]. More recently, crofelemer is used as a first-in-class antidiarrheal medication, and its efficacy has been investigated *in vivo* assays [42] and in patients with HIV-associated diarrhea, diarrhea of various infectious etiologies, as well as diarrhea-predominant irritable bowel syndrome [43]. Crofelemer was recently approved by the FDA to treat diarrhea in HIV/AIDS patients on antiretroviral therapy [44].

The mechanism of action as antidiarrheal of this proanthocyanidin oligomer consists in the dual inhibitory action on two structurally unrelated prosecretory intestinal Cl− channels, which are responsible for chloride secretion and subsequent luminal hydration. The first target is an extracellular site of the cystic fibrosis transmembrane regulator (CFTR) Cl− channel (∼60%, IC50 ∼ 7 μM), which produces a voltage-independent block with stabilization of the channel closed state. The second target is the intestinal calcium-activated Cl− channel (CaCC) by a voltage-independent inhibition mechanism (>90%, IC50 ∼ 6.5 μM) [45].

#### **5.3 Linalool**

An abundant (~90%) essential oil of the leaves of *Aniba rosaeodora* [46, 47] that is used in the traditional medicine of the Peruvian and Brazilian Amazon for its effects on the central nervous system, such as sedative, anticonvulsant, and antidepressant [19, 47, 48]. Additionally, linalool has anti-inflammatory [49], anticancer [50–52], antihyperlipidemic, antinociceptive, analgesic, anxiolytic, and neuroprotective properties [53]. Several studies have demonstrated a gamma of anti-infectious activity like antiviral [54], antibacterial [55–57], antifungal [58, 59], and antileishmanial [55, 60, 61].

The anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells were recently revealed by Rodenak-Kladniew et al. [50] (**Figure 4**). According to these researchers, linalool in a dose-dependently blocked cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by

*Medicinal Plants of the Peruvian Amazon: Bioactive Phytochemicals, Mechanisms of Action… DOI: http://dx.doi.org/10.5772/intechopen.82461*

**Figure 4.**

*Anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells.*

mitochondrial membrane potential loss, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation

#### **5.4 Mitraphylline**

A pentacyclic oxindolic alkaloid that was isolated from the alkaloid fraction of the dried inner bark of *Uncaria tomentosa* (Willd. ex Schult.) DC; it represents the most abundant phytochemical (40%) of the alkaloid fraction [62]. Several investigations have demonstrated the immunoregulatory activity of this compound or the pentacyclic oxindolic alkaloid-enriched fraction [63–67].

The mechanism of action as immunoregulator of mitraphylline consists in both to protect cells against oxidative stress and to elicit a response via an NF-kβdependent mechanism. The first mechanism is based on the inhibition of the inducible nitric oxide synthase gene expression; consequently, nitrite formation and programmed cell death are avoided. Finally, in the second mechanism, the inhibition of NF-kβ signaling permits the abrogation of the release of pro-inflammatory cytokines such as TNFα, IL-6, IL-1 α, IL-1β, IL-4, IL-17, and IFN-α [63–67].

#### **5.5 Quercetin**

A polyphenol categorized as a flavonol, one of the five subclasses of flavonoid compounds. This bioactive phytochemical is biosynthesized and accumulated in

tissues and organs of several medicinal plants of the Peruvian Amazon such as *Annona montana*, *Bauhinia longifolia*, *Bertholletia excelsa*, *Genipa americana*, *Inga edulis*, *Mauritia flexuosa*, *Myrciaria dubia*, *Oenocarpus bataua*, *Solanum sessiliflorum*, *Theobroma bicolor*, *T. cacao*, and *T. grandiflorum* [68–70]. Quercetin exhibits multifaceted therapeutic applications for multiplicity of unrelated acute and chronic human ailments like allergy, arthritis, asthma, bacterial and viral infections, cancer, cardiovascular diseases, inflammation, obesity, diabetes, mood disorders, neuropathologies, and other health problems [71–76].

 This multiple health beneficial properties of quercetin are attributed to their particular mechanism of action based on inhibition of several key proteins and enzymes (**Figure 5**). For example, a recent research showed that this compound is a potent inhibitor of 25 human serine/threonine kinases [77]. The multitarget inhibitor explains its beneficial pleiotropic effects on humans. This flavonoid-type inhibitor is effective against xanthine oxidase, appropriate for the treatment of hyperuricemia, gout, and inflammatory disease states. The inhibitory mechanism is based on the favorable steric complementarity of the conjugated three-ring structure of quercetin with the active site of xanthine oxidase. The enzyme-quercetin binary complex is stabilized by van der Waals forces and hydrogen-bonding interactions with both binding and catalytic amino acid residues, respectively [78, 79]. Recently, Hamilton et al. [80] have demonstrated that quercetin is a competitive inhibitor of glucose uptake by GLUT1. These researchers showed that the inhibitory effect is simply by binding of quercetin to the surface of GLUT1 [80]. Finally, several structural studies by X-ray diffraction have corroborated the inhibitory complex of quercetin with several human protein kinases [81–83].

## **5.6 Taspine**

An alkaloid isolated for the first time by Vaisberg et al. [84] from the bark latex of the plant species *Croton lechleri* Müll. Arg. Previous *in vitro* and *in vivo* investigations have demonstrated that taspine promotes early phases of wound healing in a dose-dependent manner [84, 85]. Taspine was also demonstrated to activate the pro-apoptotic cascade, which oligomerizes Bak/Bax into pores that result in the release of cytochrome c and consequently apoptosis in HCT116 colon carcinoma cells [86]. Similar results were reported for an *in vivo* study conducted with ZR-75- 30 human breast cancer xenografts in athymic mice [87].

The mechanism of action of taspine as a topoisomerase inhibitor was revealed recently. Initially, using *in vitro* assays, Fayad et al. [86] observed the inhibition of both topoisomerases I and II by taspine. Castelli et al. [88] corroborated the

**Figure 5.**  *Inhibitory complex of quercetin with selected human kinase targets.*

*Medicinal Plants of the Peruvian Amazon: Bioactive Phytochemicals, Mechanisms of Action… DOI: http://dx.doi.org/10.5772/intechopen.82461*

inhibitory action of taspine on purified topoisomerase I and provided the molecular details of the inhibitory action. These researchers showed that taspine inhibits the catalytic process (cleavage and religation), and molecular docking simulations showed that the formation of the complex enzyme-taspine is accomplished by the interaction in the proximity of the active site preventing the cleavage reaction. While, that the religation inhibition is explained by DNA intercalation of the inhibitor with the enzyme-DNA-binary complex.


**Author details**

Anthony Anukam\* and Jonas Berghel Environmental and Energy Systems, Department of Engineering and Chemical Sciences, Karlstad University, Karlstad, Sweden

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**Author details**

*Recent Advancements in the Metallurgical Engineering and Electrodeposition*

Based on the above studies, the following conclusions can be drawn.

and austenite grain size and structures become homogeneous.

1.Both Trial 4 (without Ce) and Trial 7 (with Ce) weld metals are responds in austempering heat treatment at 300 and 350°C for 1.5, 2 and 2.5 h holding time. At 300°C microstructure shows needle shape bainitic ferrite with retained austenite however at 350°C shows feathery shaped bainitic ferrite with retained austenite. Ce content in weld metal to refine the bainitic ferrite

2.Volume percentage of retained austenite and its carbon content changed with changing the austempering temperature and holding time. At 300°C shows less amount of retained austenite with higher amount of bainitic ferrite. However at 350°C shows higher amount of retained austenite with comparatively less amount of bainitic ferrite. Retained austenite also varied with varying the austempering holding time at respective temperature and shows maximum retained austenite content at 2 h holding time at each austempering temperature for both the weld metals. However, Ce content in weld metal to enlarge the process windows to delay the stage I reaction and shows more amount of retained austenite at each austempering

3.The microhardness of weld metal shows lower value at 350°C, presence of higher amount of retained austenite than 300°C austempering temperature. With changing the austempering holding time, the hardness values are changed and show lower hardness value at 2 h holding time with respective austempering temperature. Ce content in weld metal decreased the hardness value and shows at both the temperature, presence of higher amount retained austenite and homogeneous microstructure. Tensile test result shows failure take place from the base metal for both Trial 4 and Trial 7 weld metals at 300 and 350°C for 2 h holding time to indicate the 100%

4.Charpy impact values are changes with changing the austempering temperature with changing the amount of retained austenite in weld metal. 350°C shows higher impact value for both weld metals presence of higher amount of retained austenite. Ce in weld metal to improve the Charpy impact value as a result of refine the microstructure and increasing the amount of retained austenite. Maximum Charpy impact value shows at Trial 7 weld metal at 350°C

5.Fatigue strength of both welded joints was improved with improving the austempering temperature. At 350°C feathery shaped bainitic ferrite with higher amount of retained austenite illustrate higher fatigue strength than needle shaped bainitic ferrite with small amount of retained austenite at 300°C. Presence of Ce content in weld metal Trial 7 weld metal shows higher fatigue strength at both austempering temperature due to lower hardness and

6.Fatigue fracture surface shows at 300°C temperature predominantly mixture with dimple and reverse pattern quasi-cleavage types fracture, however at 350°C shows dimple types fracture to indicates ductile in nature. Ce content

**4. Conclusion**

temperature.

joint efficiency.

austempering conditions.

higher Charpy impact value.

**144**

Tapan Sarkar Metallurgical and Material Engineering Department, Welding Technology Centre, Jadavpur University, Kolkata, India

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**Preface to "Advances in Micro- and Nanomechanics"**

Material science, including the field of nanotechnologies, requires the consistent development of a theoretical and experimental basis for better understanding of small-scale material behaviour. Current advances in the field have resulted in the rapid development of microand nano-electromechanical systems (MEMS and NEMS). Among examples of these, it is worth mentioning nanosensors, actuators, filters and energy harvesters.

For the design and modelling of these systems, various enhanced models of continuum and structural mechanics can be applied. Here we mention strain and strain gradient elasticity, other nonlocal models, surface elasticity, micropolar, microstretch, couple-stress and micromorphic continua among others.

Manufacturing and further experimental studies of material at small scales also require advanced techniques, as discussed in this Special Issue of *Nanomaterials*. These techniques include, but are not restricted to, magnetron sputtering, nanoindentation, optical, scanning electron and atomic force microscopy, and X-ray microtomography Raman spectroscopy.

This reprint could be useful for both theoreticians and experimentalists working in the field of micro- and nanomechanics.

> **Victor A. Eremeyev** *Editor*

### *Editorial* **Advances in Micro- and Nanomechanics**

**Victor A. Eremeyev**

Department of Civil and Environmental Engineering and Architecture (DICAAR), University of Cagliari, Via Marengo, 2, 09123 Cagliari, Italy<EMAIL_ADDRESS>or<EMAIL_ADDRESS>
Recent advances in technologies of design, manufacturing and further studies of new materials and structures result in an essential extension of classic models of continuum and structural mechanics. For example, nowadays it is well established that material properties at small scales could be size-dependent. In the literature, various approaches were proposed for studying such phenomena. It is worth mentioning stress and strain gradient elasticity, surface elasticity, media with internal degrees of freedom, and nonlocal continua among others. These models can successfully describe various sized effects.

Another direction in the mechanics of materials, close-related to the aforementioned enhancements, addresses theoretical and experimental studies of material properties for media with complex internal microstructure. In particular, the great interest is the determination of effective properties of new composite materials and further analysis of their dependence on the microstructure.

Let us also note that at micro- and nano-scales one can observe a more rich picture of electromechanical couplings. The latter may play an important role in material response. For example, so-called flexoeffects relate electric polarization or magnetization to gradients of strains. So both flexoelectricity and flexomagneticity bring us another example of strain gradient models. Being sometimes even negligible at the macro-scale, these properties may be dominant at the nanoscale. This gives a possibility to use such materials as elements of MEMS and NEMS, such as energy harvesters, sensors, and actuators.

This special issue "Advances in Micro- and Nanomechanics" collects several papers that have presented theoretical, numerical, and experimental studies of materials and structures at small scales. It is rather natural to expect new phenomena in nanometer-sized thin-walled structures such as nanowires and nanofilms.

The new model of a nanowire embedded into an elastic substrate was proposed in [1]. Here surface energy was taken into account as in the Gurtin–Murdoch surface elasticity as well as a nonlocality according to the strain gradient approach. For the derivation of the governing equations, the virtual force technique was applied.

Experimental studies of thin films were presented in [2–4]. Here, films were produced with magnetron sputtering and further analyzed using various techniques such as atomic force microscopy and nanoindentation. As a result, microstructural, nanomechanical, and tribological properties were discussed in more detail. The residual stress-driven technique was applied to the determination of Young's modulus of nanofilms in [5]. Here authors proposed a new relatively simple approach based on the consideration of deformations of bilayer cantilevers. The analysis of the thermal stability and hardness of nanocrystalline Ni thin films was given in [6]. Here it was shown that the addition of cysteine results in improved hardness of films.

Properties of nanoparticles and related composites were investigated in [7,8]. Fracture strength and local hardness of spherical particles made of B4C and TiC were estimated in [7]. In [8], nanoparticles of NiO/C applied for the manufacturing of nanocomposites for supercapacitors were investigated using X-ray diffraction and other techniques.

Biomechanical studies of coatings were discussed in [9]. Here authors discussed the mechanical properties, microstructure, and composition of enamel and dentine at the initial stages of caries. Here X-ray microtomography, optical, Raman, atomic force, scanning electron microscopy, and nanoindentation were simultaneously applied.

**Citation:** Eremeyev, V.A. Advances in Micro- and Nanomechanics. *Nanomaterials* **2021**, *11*, 274. https://doi.org/10.3390/ nano12244433

Received: 28 November 2022 Accepted: 8 December 2022 Published: 13 December 2022

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

**Copyright:** © 2022 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/).

Magneto-electro-elastic coupling was studied in [10,11]. In [10], linear vibrations and buckling of nanoplates in a hygro-thermal environment were analyzed. To this end, a strain gradient nonlocal approach was used. Finally, using a variational approach nonlinear deformations of a nanobeam considering piezo- and flexomagneticity were studied in [11]. The content of the SI reflects the state of the art in the field of micro- and nanomechanics.

It combines new theoretical models with modern experimental studies of materials.

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

#### **References**


*2.2. Surface Characterization*

The Brunauer–Emmett–Teller BET surface areas were determined by nitrogen adsorption-desorption at 77 K. All nitrogen adsorption–desorption isotherm curves and variations of the specific surface areas are depicted in Figure 4. According to the International Union of Pure and Applied Chemistry (IUPAC) standard, the catalysts exhibited the IV type isotherm showing that the materials were essentially mesoporous. The fresh sample exhibited H4 hysteresis loop which corresponded to the narrow slit-like pores, whereas the hysteresis loops of spent (90 min) and spent/regenerated (SP-180, 360, and 720 min) samples had the characteristic of a type H3 loop. Compared to fresh and not regenerated samples, the spent/regenerated samples showed a lower amount of nitrogen adsorbed at the high relative pressure (P/P0 = 1), which suggests a strong decrease in the mesoporosity because of the aggregated pores between the CNTs. In addition, as is shown in Figure 4, the displacement of the hysteresis loops toward the lower partial pressures is an indication of the porosity's evolution.

**Figure 4.** N2 adsorption-desorption isotherms and variation of specific surface areas for fresh, spent, and spent/regenerated catalysts at different reaction times.

BET surface areas of spent and spent/regenerated samples were relatively small compared to that of the fresh sample. They decreased linearly with the time of CMD reaction in the following order: fresh-sample (122 m2/g) > SP-90 min (109 m2/g) > SP-180 min (74 m2/g) > SP-360 min (64 m2/g) > SP-720 min (61 m2/g). During the CMD reaction or oxidative regeneration process, the formation of new phases (such as Co and Fe metallic species, CoCx, carbon, and θ-Al2O3, etc.) caused the blocking of the pores with the subsequent loss of surface area as evidenced by XRD analysis. This result was consistent with AAS findings, which showed an increase in the mass of carbon deposited with the number of reaction cycles. The decline in catalyst activity might be related to the reduction in porosity which occurred during the decomposition process.

#### *2.3. H2-TPR and TG Analysis*

Hydrogen temperature programmed reduction experiments were carried out in 100 to 1000 ◦C temperature range under a hydrogen atmosphere. H2-TPR profiles of fresh, spent, and spent/regenerated 15Co–30Fe/Al2O3 samples are shown in Figure 5a,b. Figure 5a is for fresh catalyst, whereas Figure 5b is for the spent catalyst. The reduction profiles can be classified into three regions. In region I (200–450 ◦C), the reduction of hematite (Fe2O3) to Fe3O4 and the reduction of Co3O4 to CoO take place. In region II (450–710 ◦C), the reduction of Fe3O4 to FeO and the reduction of CoO to Co occur. In region III (710–900 ◦C), the reduction FeO to Fe happens. Similar results were observed by other investigators [49–51].

**Figure 5.** (**a**) H2-TPR for fresh catalyst, (**b**) H2-TPR for used catalyst, and (**c**) thermogravimetric (TG) profiles, of 30Fe-15Co/Al2O3 catalysts at different regeneration temperatures.

From the XRD analysis, the possible reducible phases in fresh sample were the following: Fe3O4, CoAl2O4 spinel, and probably some amorphous (or highly dispersed) Fe2+ and Co2+ species which could not be detected easily by XRD. Al2O3 was non-reducible under this work's conditions due to the high binding energy between Al and O. Large differences in H2-TPR profiles were observed that depended on the time of reaction and the number of decomposition-oxidation cycles. However, for all samples, the reduction peaks observed below 450 ◦C were ascribed to the reduction of Co2+ species to nanoparticles of metallic cobalt, whereas the peaks observed between 450 and 900 ◦C were ascribed to the reduction of Fe3+ species of metallic iron. In the case of the SP-360 min and SP-720 min samples compared to other samples, several reduction peaks were observed at low and high temperatures; they could be ascribed to successive steps of the reduction to cobalt and iron species and/or to the presence of various types of Co and Fe species of different interactions with the support or with different particle size. Indeed, it is well known that the increase in the degree of the agglomeration and consequently the size of metal oxide particles could cause a decrease in the metal-support interaction and make reduction easier. From H2-TPR results, it should be pointed out that the H2 consumption decreased with the increasing reaction time (or the number of decomposition-regeneration cycles), probably because of the increase in the encapsulation rate of metallic particles in a zero-valence state that makes their oxidative regeneration difficult due to their inaccessibility to hydrogen molecules. This could justify the lower reducibility of both SP-360 min and SP-720 min samples. During the H2-TPR process, a hydrogasification of carbon deposits could also happen at temperatures above 700 ◦C by releasing methane (C(s) + 2H2 → CH4). An analysis of gaseous effluents (using, for example, mass spectrometry) is however necessary to assess this hypothesis.

TGA results of spent and spent/regenerated catalysts are shown in Figure 5c that shows a weight change in the temperature range 100–850 ◦C. All samples displayed weight loss (WL) from 500 to 850 ◦C which was related to the combustion of different kinds of carbon (cobalt carbide amorphous carbon and carbon nanotubes). The TGA curves showed that the weight loss decreased in the order WL(SP-90 min) > WL(SP-720 min) > WL(SP-360 min) > WL(SP-180 min). As expected, the highest weight loss was observed in the spent and not regenerated sample (SP-90 min). Comparing the regenerated samples, it was found that SP-180 min exhibited the lowest weight loss, indicating that the accumulation of encapsulating carbon deposition (difficult to remove) increased with the increasing number of decomposition-oxidation cycles. This result corresponded to the XRD finding which exhibited a more intense peak of carbon for samples having undergone several decomposition–regeneration cycles. In the case of SP-720 min, a change was noticed in the slope of the TGA curve, which suggested two kinds of coke deposit may be related to the more abundant presence of cobalt carbide over this catalyst.

#### *2.4. Catalysts Behavior under CMD-Regeneration Cycles*

In most cases, during CMD reaction, carbon encapsulates the active sites and this carbon accumulation is responsible for catalyst deactivation. To increase the catalyst lifetime, regeneration cycles by gasification using oxygen as an oxidizing agent was introduced as has been described before. The regeneration step obviously required the interruption of the production process for 10 min. The catalytic activity of catalysts was determined by evaluating methane conversion and hydrogen yield obtained during the CMD process. In the present work, Weight hourly space velocity (WHSV) is calculated from the feed gas consisting of 15 mL/min of CH4 and 10 mL/min of N2 and weight of catalyst 0.3 g, as follows:

$$\text{WHSV} = \frac{(15+10)\text{ mL/min} \times 60\text{ min/h}}{0.3\text{ g-cat}} = \frac{25 \times 60\text{ mL/(h)}}{0.3\text{ (g-cat)}} = 5000\text{ mL/(h\cdot g\text{-cat.})}$$

The methane conversion obtained here for regenerated catalysts is above 60%. Zhou et al. conducted an Fe catalyst for CMD and investigated the effect of space velocity on the methane conversion. When a space velocity (3750 mL/g-cat/h), close to the one used in the present work (5000 mL/g-cat/h), was considered, they found a methane conversion of about 38% [52].

Figure 6 compared the evolution, with time of stream (TOS), of the methane conversion obtained over the fresh catalyst and the spent catalysts subjected to successive cycles of CMD/regeneration. As can be seen, the results were not the same after the regeneration cycles. Only the points on the curve at 90, 180, 360, and 720 min corresponding to the samples SP-(90, 180, 360, 720 min) were considered. As is shown, the methane conversion decreased, as the reaction time was increased, in the order of 68% (90 min, zero cycle) > 63% (180 min, after two cycles) > 62% (360 min, after four cycles) > 56% (720 min, after eight cycles). This degradation of catalytic activity and loss of stability of the catalysts (about Δ% = 12% from 90 to 720 min of TOS) was due probably to irreversible deactivation caused by covering and encapsulating of active sites by deposited carbon. The same trend was observed in the BET surface area which decreased when the number of decomposition/regeneration cycles was increased, as is shown in Figure 3. On the other hand, it was shown that the reducibility of catalysts decreased when the number of decomposition/oxidation cycles was increased; this was attributed to the blocking of metallic particles (in the oxidation state zero) by the formation of encapsulating carbon species, consequently leading to the loss of active sites and catalyst deactivation. From these results, it could be concluded that the degradation of physicochemical and catalytic properties was essentially related to carbon formation that was not completely removed after repetitive oxidative regeneration steps. Therefore, the higher the amount of carbon deposited, the lower the catalytic activity.

Through this study's experiments, the authors were able to verify that significant catalyst deactivation occurred toward higher regeneration times (involving a succession of cycles) despite a very interesting catalytic formulation. The formation of cobalt carbide CoC2 may then complicate the regeneration of metal catalysts (Figure 1), as reported in the literature [52].

**Figure 6.** Time on stream (TOS) yield of hydrogen versus different regeneration times with 15%Co–30%Fe/Al2O3 spent-catalyst. TOS conditions: Tregeneration-activation = 500 ◦C; Treaction = 700 ◦C; (WHSV = 5000 mL/H·g-cat), total flow rate = 25 mL/min and CH4/N2 = 1.5.

Figures 6–8 present, respectively, the evolution with time on stream (TOS) of H2 yield and the coproduced carbon on SP-(90, 180, 360, 720 min) samples. The hydrogen production by 67.8% (90 min) > 66.8% (180 min) > 63.7% (320 min) > 57.7% (720 min) followed the same evolution as the methane conversion. Similar to the conversion of methane, the hydrogen yield was affected by the number of regeneration cycles. It decreased with the increase in the regeneration number, but to a lesser extent. On the other hand, in the case of the carbon deposit, an increasing trend of carbon with the increase in the regeneration number was observed: 1.2 (180 min) < 1.5 (320 min) < 3.2 (720 min).

As reported by some authors [53], the catalyst deactivation mechanism rests on progressive pore blocking by carbon deposition. The carbon formation involved in the first step is the dissociative adsorption of methane on the metal surface (iron and cobalt) producing hydrogen and carbon atoms. The adsorbed carbon atoms could dissolve and diffuse through the metal. Those on the surface form, thereby encapsulating carbon, blocking the access of methane to the active sites, and causing a reduction of activity, as proposed by the following steps. During CMD reaction, the carbon may chemisorb firmly as a monolayer or physically adsorb in multilayers while releasing hydrogen [54]. In either case, this blocks the reactants from reaching the metal surface. The behavior is complex, because the carbon threads may grow from the top surface of the metal particles or the carbon may spread into the metal and form bulk carbides (e.g., formation of CoC2), as observed in the study's XRD. According the H2-TPR conclusions, it can be stated that methane molecules may be formed through the reaction between carbon encapsulating particles and chemisorbed hydrogen gases.

The formation of encapsulating carbon on the metallic surface could be limited by Cads + H2 → CH4 reverse reaction (with H2 produced by reaction or added to the feed). This step was favored in the presence of a high hydrogen concentration in the feed which depended on the methane conversion. Besides coke deposition, the sintering of metallic active phase (Co, Fe) occurred during CMD reaction and oxidative regeneration process and was the second factor responsible for catalyst deactivation. Similar to carbon deposition, sintering brings about the loss of surface area and porosity. Despite the coke deposits and many oxidative treatments, the present catalysts remained active with a methane conversion and hydrogen yield exceeding 56% and 58%, respectively (after eight reaction cycles).

Further tests were needed to optimize the regeneration step to eliminate quantitatively the carbon deposits and improve the catalytic performance.

**Figure 7.** Comparison of different H2 yields (%) obtained from 90, 180, 360, and 720 min of reaction (the white bar is a limit between each regeneration cycle).

**Figure 8.** Carbon yields obtained after 90, 180, 360, and 720 min of reaction.


*4.2. The Main Challenges of New-Type Urbanization and Rural Revitalization in the New Era*

The strategic coupling and coordinated management of new-type urbanization and rural revitalization is the implementation of "people-oriented" development and the only way to urban–rural integration. The review of overseas research, and the experiences and evolution of urban–rural relations and urbanization processes in Western countries are valuable, and have reference significance to China. However, it is not appropriate for China to adopt Western models completely because there are many differences in urbanization processes between China and developed countries. First, the urbanization in developed countries is gradual, with the evolution of industrialization over a long period of time, and the urbanization of the population, the urbanization of land and industrialization are synchronous. By contrast, before reform and opening up, there was mostly no process of urbanization in China. Then, urbanization experienced a high speed and large scale after reform and opening up. This means that cities in China need to receive large-scale populations from rural areas within a short time and face a rapid increase in the urban public services required by the urban population. The fact that the urbanization of the population, the urbanization of land and industrialization are not synchronous is resulting in the appearance of peri-urbanization. Second, population mobility and settlement in cities face different extents of difficulty in China. The former is related to economic conditions and own needs. The latter is limited because settlement in cities needs to meet the requirements of the household registration systems in different cities, especially in megacities. Except for the roles that government play in the process of urbanization, the national conditions, systems and demand in Western countries and China are different. In such a unique environment, there are many problems brought about by rapid urbanization. The traditional urbanization mode of China shows the important characteristics of "large-scale spatial production", "peri-urbanization", "complexity of multiple factors" and "serious urban–rural isolation", some of which hinder the healthy development of urbanization. Thus, taking Western experiences and models as reference, China should change the urbanization mode considering individual characteristics and needs. The traditional urbanization model, in which space production is taken as the core and population and industrialization are considered as playing leading roles, must be changed. Further urbanization should promote and implement new-type urbanization and a rural revitalization strategy with good human life, local culture, social justice and

civil rights, being "people-oriented" at its core and gradually forming a mode of new-type urbanization with Chinese characteristics and rural revitalization.

The principal contradiction facing China in the new era has changed into the contradiction between unbalanced and inadequate development and the people's ever-growing needs for a better life. The contradiction is mainly concentrated in the agricultural and rural areas, so the evolution of urban–rural relations determines the overall change in social contradictions. Due to the existence of historical laws and geographical inertia, there will be the following major challenges and trends in urban–rural relations in China by 2050:

The geographical characteristic of "one side adjacent to the sea" will still be the main factor for the regional imbalance of urban–rural relations in China. Because most of the coastal areas in the world are still in periods of rapid development, the advantages of foreign trade and the urbanization of coastal areas in China will continue, while the inland areas are still facing the constraints of water resources and development paths, so it will be difficult to change the situation of the imbalance in development between the eastern and the western areas in the short term.

The unbalanced and insufficient development in space will continue to embody the characteristics of the "Hu Line" as the geographical boundary. The "Hu Line" not only reflects the long-term demographic geographical pattern of China, but also profoundly reflects the spatial differences in society, the economy, culture and other aspects in China. The east and west of this line have historical inevitability and realistic stability. Therefore, breaking through the current situation of the spatial imbalance of the "Hu Line" will be a long-term process.

**The exploration of development paths and transformation driven by innovation.** It is crucial to have talent attraction and technological innovation, as well as the transformation of the development mode. In particular, great importance should be attached to the impact of science and technology on the urban–rural relations and regional development. With the continuous promotion of information technology, the Internet has greatly changed the spatial distance of urban–rural areas and different regions, which provides a basic guarantee for the development of emerging industries in rural and inland areas, promoting rural revitalization and inland development into a new era of diversified development.

**Deepening the reform of the system and mechanism is the key measure.** The proposal of "Rural Revitalization" in the new era has brought important strategic advantages for the integration of urban and rural development, and agricultural and rural areas are even at an unprecedented national strategic height. China will accelerate the reform of the system and mechanism for the integrated development of urban and rural areas to achieve balanced and full development. In July 2014, the State Council agreed to establish an inter-ministerial joint meeting system to promote new-type urbanization with The Letter of State [2014] No. 86, which requires that under the leadership of the State Council, the National Development and Reform Commission should take the lead in comprehensively promoting the implementation of the national new-type urbanization plan and the policy formulation (Figure 4). The State Council held six meetings to summarize and deploy the key tasks of the annual work, which played an important role in effectively promoting the implementation of the national new-type urbanization plan and coordinating and solving major problems. In July 2019, the State Council further agreed to establish an interministerial joint conference system for urbanization and urban–rural integration development, which is the system design and guarantee expected to play an important role in accelerating the high-quality development of urbanization and urban–rural integration. In addition, the evolutionary history of urban–rural relations is basically consistent with the changes in Chinese history and culture, so an urban–rural integration system and cultural system with Chinese characteristics are important parts of the overall development of urban and rural areas.

**Figure 4.** Evolution of inter-ministerial joint meeting on urbanization and integrative development of urban–rural relations (collected from relevant reports).


**1. Introduction**

Beekeeping in Algeria is part of agricultural life. It is practiced in mountainous regions such as the Aures Mountains, Kabylie, and Dahra, in the coastal plains, and the valleys of the big wadis, but it is more intensive in the northern part of the country where the flora provides resources for honey throughout most of the year [1]. Beekeeping plays an important role in the rural areas of the Mediterranean region due to the suitable climatic conditions and high biodiversity. Highly valued honey supplies are a welcome income for farmers and hobby beekeepers [2].

The composition of this food, obtained by bees from nectar, honeydew, or both sugary resources, is highly dependent on honeybee activity and the biogeography of the area in which it was produced. So, physicochemical properties such as color, pH, electrical conductivity, sugar content, organic acids, ash content, polyphenols, flavonoids, and other phytochemicals differ with different environmental conditions and plant communities visited by honeybees [3].

The Mediterranean region of Algeria is an outstanding biogeographical crossroads that resulted from a complex history and highly heterogeneous environmental factors [4]. Algeria has significant plant biodiversity, with about 3150 species [5], of which more than 500 species are endemic and characteristic of the Mediterranean basin, the Atlas Mountains, the high steppe plateau, the large Saharan plateau, and the mountainous massifs of the Algerian Sahara [6]. The melliferous area in Algeria is estimated at 797,122 hectares with a predominance of forests and maquis, natural meadows, orchards with orange fruits, and other crops.

The main honey sources in the area are trees like *Eucalyptus* and some wild herbaceous plants, mainly from the *Apiaceae* (*Foeniculum*, *Daucus*, *Coriandrum*, *Eryngium*, *Pimpinella*), Asteraceae (*Galactites tomentosa*, *Centaurea*, *Echinops*), *Brassicaceae*(*Brassica* and *Sinapis*), and *Fabaceae*(*Hedysarum*, *Ononis natrix*, *Trifolium*, *Melilotus*) families [7–9]. Some plants, such as*Ziziphus lotus*, or grown plants, such as *Helianthus annuus* or *Citrus*, were also named as important plants sources for honey production [10]. In this context, the main honey types produced in the country are *Eucalyptus*, *Citrus*, forest (honeydew), jujube, sunflower, rosemary, and wild mustard. However, the production of other rare or less known honey types was mentioned in some papers [11,12].

The country is considered a traditional consumer of honey, but national production does not achieve self-su fficiency, so to cover the relevant needs, large quantities of honey are imported every year from countries such as China, India, and Saudi Arabia. The lack of national legislation and unknowns about Algerian honey characteristics have a negative impact on the scarce development of Algerian beekeeping. In the absence of specific legislation, there are also no requirements to assess the quality or geographical and botanical origin of honey in the market. Therefore, consumers and local producers are not protected against frauds, and honey of good quality is not valorized. Improving knowledge in the characteristics of local production is the main course of action for their valorization and to link agricultural products with the territory in which they were produced. These studies facilitate the recognition of specific properties with botanical origin and allow di fferentiating local production from imported honey. Currently, there is no designation of origin for local honey that would contribute to valorizing Algeria honey production.

Some authors studied the characteristics of honey produced in Algeria and found di ffering results as to the pollen content [8–10,13], physicochemical attributes and pollen profile of samples from di fferent areas [7,14–16], their botanical origin [9,11,17–19], antibacterial and antioxidant activity [20], or specific compounds such as sugars and phenolic or volatile compounds [21,22]. However, honey production in Algeria remains poorly studied. On the basis of these facts, this paper aimed to provide scientific information on the botanical origin and physicochemical profile of honey samples from di fferent bioclimatic areas of Algeria.

### **2. Material and Methods**

### *2.1. Study-Area Bioclimatology*

The territory of Algeria is composed of four principal structural units. Near the coast, in the north, there is a narrow region with several hills and plains named Tell. This region is densely populated and constitutes the main agricultural land in the country. It has a Mediterranean climate with mild winters and moderate rainfall. Mean annual temperatures are close to 22 ◦C in summer and 10 ◦C in winter. Rainfall is abundant along this coastal area, increasing the amount of annual precipitation from 400 to 670 mm in the west to near 1000 mm in the east. These weather conditions determined a subhumid-humid climate tendency.

In the central area, several mountain chains were determined as the high plateau area that separates the Mediterranean area from the Saharan Atlas and the desert. This is a highly diverse area dominated in the plains by steppelike morphology. This region is characterized by a semiarid-to-arid climate with irregular and low precipitation (200–400 mm); its bowl profile explains the presence of many salt lakes (called "chotts") collecting surface water. It continues to the south with the Saharan Atlas that delimits the Sahara desert. The Saharan Atlas is formed by three massifs that are the source of watercourses that supply the wells of oases along the northern edge of the desert; the massifs are Biskra, Laghouat, and Béchar. The Sahara is a windy and very arid area with a continental climate, high thermal amplitude, and extremely poor precipitation of no more than 130 mm.


Shear-Wave Elastography in Diffuse Thyroid Diseases

*Cristina Mihaela Cepeha, Andreea Borlea, Corina Paul, Iulian Velea and Dana Stoian*

#### **Abstract**

The diagnosis and evaluation of diffuse thyroid pathologies is often a challenge for clinicians. Ultrasonography has an essential contribution in thyroid imaging, but elastography adds more accuracy. Frequently used in the evaluation of thyroid nodules, elastography has become a necessary tool in assessing the risk of malignancy. Diffuse thyroid pathologies such as Graves' disease, chronic autoimmune thyroiditis, and subacute thyroiditis, are diagnosed based on laboratory tests completed with imaging. Recently it has been shown that elastography is useful in the evaluation and differentiation of these cases due to the differences in elasticity. This chapter describes the general principles of shear-wave elastography, examination technique, features found in diffuse thyroid disease, but also the limitations of this type of investigation for a better understanding of its use in assessing diffuse thyroid pathology.

**Keywords:** thyroid, elastography, shear-wave elastography, ultrasonography, diffuse

#### **1. Introduction**

Optimal thyroid function is necessary for growth and development as well as for reproductive function. Iodine deficiency is the leading cause of thyroid dysfunction. In areas unaffected by iodine deficiency, thyroid dysfunction is due to autoimmunity. Thyroid pathology can be divided into nodular and diffuse pathology. One in 20 Americans will develop a thyroid disorder in their lifetime, with women being seven times more affected than men [1, 2]. In this chapter, we will address diffuse thyroid diseases (DTD) that can be divided into non-autoimmune (subacute thyroiditis, silent thyroiditis) and autoimmune diseases such as Hashimoto thyroiditis (HT) and Graves' disease (GD) [3].

Hashimoto thyroiditis is also known as chronic autoimmune thyroiditis (CAT) is considered the most common endocrine disorder, and autoimmune pathology, as well as it represents the most common cause of hypothyroidism. HT can be divided into primary and secondary based on its etiology. Primary HT includes classic form, juvenile form [4], fibrous form, painless thyroiditis, Hashitoxicosis, and IgG4-related form [5]. Secondary HT is often iatrogenic, for example, caused by interferon [6] or monoclonal antibodies [7]. The diagnosis is established by correlating the clinical manifestations with the presence of antithyroid peroxidase (ATPO) antibodies and

antithyroglobulin (ATG) antibodies correlated with the ultrasound aspect. Symptoms may vary from dysphonia, dysphagia, and dyspnea to systemic symptoms of hypothyroidism or may even be absent. The antibodies listed earlier are found in over 95% of HT cases, thus being an important diagnostic criterion [8]. The ultrasound image usually reveals hypoechogenicity and heterogeneity (**Figure 1**).

The presence of fibrous septae may explain the pseudolobulated appearance of the parenchyma. Micronodules may also be present. Increased vascularity may be observed using color Doppler. The volume of the thyroid gland is often increased, but can be normal or even decreased, atrophic in the final stages of the disease [9, 10].

Graves' disease is characterized by the presence of thyrotoxicosis, ophthalmopathy, and goiter, although not all three characteristics are always present. In iodinesufficient areas, GD accounts for 70–80% of cases of thyrotoxicosis, being more frequent in women over 50 years old. Symptoms of hyperthyroidism include irritability, palpitations, weight loss, shortness of breath, tremor, heat intolerance, sweating, and excessive fatigue. The diagnosis is usually based on anti-TSH-receptor antibodies (TRAB) correlated with the ultrasound appearance [11–13]. The echogenicity is usually decreased, and the appearance is not homogenous. Increased volume and high blood flow may also suggest the diagnosis [10, 12, 14].

**Figure 1.** *US image of a patient with CAT.*

#### *Shear-Wave Elastography in Diffuse Thyroid Diseases DOI: http://dx.doi.org/10.5772/intechopen.102636*

Subacute thyroiditis (SA) is usually caused by a viral infection with symptoms including mild fever, swelling, and pain in the neck area, irradiating to the ear or jaw and fatigability. Thyroid stimulating hormone (TSH) is usually suppressed and inflammatory markers are elevated [15]. The presence of focal or diffuse hypoechoicity together with diminished vascularization may suggest the diagnosis if it is associated with the mentioned symptoms [16].

Post-partum thyroiditis (PPT) occurs in the first year after giving birth and may occur after an induced or spontaneous abortion. PPT prevalence may vary from 1 to 18%, but usually is reported approximatively 5%. In general, PPT has two evolutionary stages, transient thyrotoxicosis due to tissue destruction followed by the phase of hypothyroidism with or without restauration to euthyroidism [17]. Ultrasonography (US) shows the hypoechogenic inhomogeneous texture of the thyroid with decreased vascularity [18].

The ultrasonographic examination is the most sensitive imaging method for evaluating the thyroid. The most important indications of the US are: confirmation of the presence of thyroid nodules, their measurement and characterization, evaluation of diffuse tissue changes, detection of post-operative residual tumors, screening for the patients at high-risk (multiple endocrine neoplasia, history of thyroid cancer, and neck irradiation), and the guidance of the fine needle aspiration (FNA). US is widely available, non-invasive, and reproducible [19–21].

A relatively new imaging technique is elastography, which adds value by assessing tissue elasticity. There are more types of elastography, but the two most used are strain elastography (SE) and shear-wave elastography (SWE). SE evaluates the stiffness by applying external pressure which deforms the tissue. The deformation is named strain. The pressure being exerted by the operator, SE requires longer training to obtain high-quality images. To measure the stiffness, SWE uses shock waves generated by the machine. Both methods have advantages and disadvantages [22, 23]. SWE will be further described in detail, emphasizing the principles, technique, and the value of this method as well as the peculiarities of diffuse thyroid diseases.

### **2. Shear-wave elastography**

#### **2.1 Principles**

SWE technique relies on the production and detection of shear-waves. The wave propagation velocity depends on tissue elasticity. Tissue deformation generated by the production of waves produces changes in the echo pattern. Tissue motion is monitored among the US probe in multiple locations. Shear waves are generated at low frequencies (10–2000 Hz) and their speed (~1–50 m/s) is related to tissue density [22, 24]. SWE is used for evaluation of various tissues: liver [25–27], kidney [28, 29], breast [30, 31], thyroid [32–34], prostate [35], and muscles and tendons [36]. There are three types of dynamic elastography: transient elastography (TE), point shearwave elastography (pSWE), and 2D-SWE [37].

Transient elastography, usually used for measuring liver stiffness, uses a mechanical push. The wave velocity is proportional to tissue fibrosis. The usefulness of TE was demonstrated in many studies [38, 39].

Compared to the previous technique, point shear-wave elastography has the advantage of image guidance so the operator can choose the best acoustic window to perform the measurements. It is an acoustic radiation force impulse (ARFI)-based

method that displays the elasticity as a numerical output (the average speed of shear wave within a region of interest [ROI], expressed in meters per second) [40, 41].

In 2D-SWE, multiple ARFI pulses generate shear waves on a larger area. The machine creates a colored map to display the stiffness. By convention, red is considered stiff and blue is considered soft. Quantitative results are expressed in meters/ second (wave propagation speed) or kilo-Pascals (kPa). 2D-SWE is a reproductible, quantitative, and operator-independent technique (**Figure 2**) [42, 43].


*2.3. Formulation Yield*

The formulation yield was calculated by relating the total formulation weight (actual yield) to the mass of the component excipients used in the preparation of the formulation (theoretical yield). The constituting excipient plus the model drug and produced RDS formulation were weighed as separate entities using a laboratory scale balance (Kern EG 620-3NM, Kern and Sohn, GmbH, Balingen, Germany). The percentage yield was calculated using Equation (1) below:

$$\% \text{Yield} = \frac{\text{Actual yield (g)}}{\text{Theoretical yield (g)}} \times 100\tag{1}$$

#### *2.4. Physicochemical Characterization of the Reconstitutable Dry Suspension*

#### 2.4.1. Particle Size, Polydispersity Index, and Zeta Potential

Measurement of particle size (PS) and polydispersity index (PDI) was based on the principle of dynamic light scattering using the Nano series Zetasizer (Malvern Instruments Ltd, Malvern, UK). For each quantification, RDS samples were re-dispersed in deionized water, appropriately diluted, and sonicated (Table-type Supersonic Cleaner KQ118, Nanjing T-Bota Scietech Instruments and Equipment, Co, Ltd., Nanjing, China) for 15 min at 37 ± 0.5 ◦C. All measurements were performed as three independent replicates with 10 readings per sample at a measurement angle of 173◦ and temperature of 25 ◦C. Zeta potential (ZP) is an indicator of particle surface charge, which determines particle stability in dispersions [23,24]. It was computed based on the Smoluchowski equation [25] using the Nano series Zetasizer with RDS samples dispersed in deionized water and placed in disposable folded capillary zeta cells maintained at 25 ◦C. For statistical relevance, samples were measured in triplicate with 20 runs per measurement cycle.

### 2.4.2. Visualization of Surface Morphology

The surface microstructure of the RDS was observed under a JEOL Transmission Electron Microscope (TEM) (JEM-2100 LaB6 200 kV Transmission Electron Microscope, JEOL, MA, USA). About 1 mg of the test sample was dispersed in ethanol and spotted on a carbon coated copper grid. Ethanol

was allowed to evaporate under atmospheric conditions prior to sample loading into the TEM viewing stage (JEOL JEM-2100 LaB6 200 kV Massachusetts, USA). The Gatan Digital Micrograph Software was used to facilitate sample viewing.


**8. The photoelectric effect without photons** [Ragazas 2010k]

Photoelectric emission has typically been characterized by the following experimental facts *(some of which can be disputed, as noted)*:

*Explanation of the Photoelectric Effect without the Photon Hypothesis:* Let be the rate of radiation of an incident light on a metal surface and let be the rate of absorption of this radiation by the metal surface. The combined rate locally at the surface will then be . The radiation energy at a point on the surface can be represented by 0 ( ) *t Et Ee* , where *E*0 is the intensity of radiation of the incident light. If we let be the *accumulation of energy* locally at the surface over a time pulse , then by *Characterization 1* we'll have that *E* . If we let Planck's constant *h* be the *accumulation of energy* for an electron, the

number of electrons *ne* over the pulse of time will then be *ne h* and the energy of an electron *Ee* will be given by

$$
\Delta E\_e = \frac{\Delta E}{n\_e} = h(\nu - a) \tag{10}
$$

Since 0 0 0 *u e* 1 *E e du E* , we get the *photoelectric current I* ,

The Thermodynamics *in* Planck's Law 707

The graphs in Fig. 5 match the above experimental data to various graphs (in red) of

*A=0.13 b=1.98 c=5.95 d=0,07 A=0.09 b=2.07 c=4.88 d=0.09 A=0.05 b=1.41 c=3.04 d=0.18*

The above graphs (Fig. 5) seem to suggest that Eq. (11) agrees well with the experimental data showing the asymptotic behavior of the (photocurrent) v (energy) curves. But more

> 0

= %-change of

0

*h* (Planck's constant being the minimal

0

*x*

*t t E h h*

= "distance per cycle of change" and

*x*

and

0 *t*

 .

that can be

= 'cycle of change'. For

**9. Meaning and derivation of the De Broglie equations** [Ragazas 2011a]

= "cycle of change per time". We can rewrite these as 0

0 *h h*

*x x*

*p*

and

(a) (b) (c)

systematic experimental work is needed.

corresponding *x* and *t* we can write,

measured) we get the *de Broglie equations:*

( , ) ( ,) *x t xt* . We can write

Fig. 4.

Fig. 5.

Consider 0 00

> 0 *t*

Taking limits and letting 0

equation (12)

$$I = \frac{n\_c}{\tau} = \frac{\eta}{h\tau} = E\_0 \left| \frac{e^{(\nu - \alpha)\tau} - 1}{h(\nu - \alpha)\tau} \right| \tag{11}$$

The absorption rate is a characteristic of the metal surface, while the pulse of time is assumed to be constant for fixed experimental conditions. The quantity *e* 1 *h* in

equation (10) would then be *constant*.

Combining the above and using (10) and (11) we have *The Photoelectric Effect:*

*kT Note:* Many experiments since the classic 1916 experiments of Millikan have shown that there is photoelectric current even for frequencies below the threshold, contrary to the explanation by Einstein. In fact, the original experimental data of Millikan show an asymptotic behavior of the (photocurrent) vs (voltage) curves along the energy axis with no clear 'threshold frequency'. The photoelectric equations (10) and (11) we derived above

agree with these experimental anomalies, however. In an article Richard Keesing of York University, UK , states,

*I noticed that a reverse photo-current existed … and try as I might I could not get rid of it.*

*My first disquieting observation with the new tube was that the I/V curves had high energy tails on them and always approached the voltage axis asymptotically. I had been brought up to believe that the current would show a well defined cut off, however my curves just refused to do so.*

*Several years later I was demonstrating in our first year lab here and found that the apparatus we had for measuring Planck's constant had similar problems.*

*After considerable soul searching it suddenly occurred on me that there was something wrong with the theory of the photoelectric effect … [Keesing 2001]*

In the same article, taking the original experimental data from the 1916 experiments by Millikan, Prof. Keesing plots the graphs in Fig. 4.

In what follows, we analyze the asymptotic behavior of equation (11) by using a function of the same form as (11).

$$f(\mathbf{x}) = \frac{A\left(e^{b(\mathbf{x}-c)} - \mathbf{1}\right)}{\mathbf{x} - c} + d \tag{12}$$

*Note: We use d since some graphs typically are shifted up a little for clarity.*

Fig. 4.

706 Thermodynamics – Interaction Studies – Solids, Liquids and Gases

1 *ne e I E h h*

would be negative and so there will be no photoelectric current. (by (10) above) *(see*

by *Conclusion* 7 **Section 3**.

3. If *Ee* is taken to be the kinetic energy of a photoelectron, then for incident light with

4. The photoelectric current is almost instantaneous ( 9 10 sec. ), since for a single

*Note:* Many experiments since the classic 1916 experiments of Millikan have shown that there is photoelectric current even for frequencies below the threshold, contrary to the explanation by Einstein. In fact, the original experimental data of Millikan show an asymptotic behavior of the (photocurrent) vs (voltage) curves along the energy axis with no clear 'threshold frequency'. The photoelectric equations (10) and (11) we derived above

*I noticed that a reverse photo-current existed … and try as I might I could not get rid of it. My first disquieting observation with the new tube was that the I/V curves had high energy tails on them and always approached the voltage axis asymptotically. I had been brought up to believe that the current would show a well defined cut off, however my curves just refused to do so. Several years later I was demonstrating in our first year lab here and found that the apparatus*

*After considerable soul searching it suddenly occurred on me that there was something wrong*

In the same article, taking the original experimental data from the 1916 experiments by

In what follows, we analyze the asymptotic behavior of equation (11) by using a function of

*bx c A e f x d x c*

1

(12)

current *I* is proportional to the intensity *E*0 of the incident light. (by (11) above)

assumed to be constant for fixed experimental conditions. The quantity

Combining the above and using (10) and (11) we have *The Photoelectric Effect:*

2. The energy *Ee* of a photoelectron depends only on the frequency

less than the 'threshold frequency'

*kT*

intensity *E*0 of the incident light. It is given by the equation *E h e*

 0

(11)

 *e* 1

and not on the

where *h* is

*h*

the kinetic energy of a photoelectron

and fixed metal surface, the photoelectric

is a property of the metal surface. (by (10)

is

in

>

is a characteristic of the metal surface, while the pulse of time

The absorption rate

above)

frequency

*Note below)*

the same form as (11).

1. For incident light of fixed frequency

Planck's constant and the absorption rate

photoelectron we have that 9 10 sec. *h t*

agree with these experimental anomalies, however.

Millikan, Prof. Keesing plots the graphs in Fig. 4.

In an article Richard Keesing of York University, UK , states,

*we had for measuring Planck's constant had similar problems.*

( )

*Note: We use d since some graphs typically are shifted up a little for clarity.*

*with the theory of the photoelectric effect … [Keesing 2001]*

equation (10) would then be *constant*.

The graphs in Fig. 5 match the above experimental data to various graphs (in red) of equation (12)

Fig. 5.

The above graphs (Fig. 5) seem to suggest that Eq. (11) agrees well with the experimental data showing the asymptotic behavior of the (photocurrent) v (energy) curves. But more systematic experimental work is needed.


*4.12. Flow Cytometry Analysis of Apoptosis*

Cell apoptosis was evaluated by plating RTCC1 and J82 cells (105 cells each) with sh*LacZ* or sh*MAP1B* for 24 h, followed by 15 min of incubation using an Annexin V-FITC kit (BD Biosciences, Franklin Lakes, NJ, USA) that contained propidium iodide. The percentages of cells at late apoptosis were calculated from three independent experiments.