**1. Introduction**

The accuracy of intraocular lens (IOL) power calculation is a matter of great importance in cataract surgery [1,2]. IOL power is determined by three factors: preoperative biometric data (axial length (AL), anterior chamber depth (ACD), and mean corneal power (K)), the IOL power calculation formula, and the IOL constant [3]. Cataract surgeons have aimed to create an IOL formula for the determination of the ideal refractive outcome. The prediction of postoperative ACD or effective lens position (ELP) is the most important process in IOL power calculation, and IOL power calculation error is, for the most part, due to errors in predicting ELP [4].

Although more than 10 years have passed since the concept of the Haigis formula was introduced, it still shows high predictive accuracy [5,6]. The T2 formula, using only AL and K for ELP, shows the highest predictive accuracy [5,7]. However, there is an important limitation that the two formulas above are designed based on multiple linear regression analysis [8,9]. A multiple linear regression analysis, in principle, requires the independence of explanatory variables. However, ACD and K have significant relationships with AL, which can cause errors. Statistically, the explanatory variables used in ELP prediction are considered to have a collinearity problem [10,11].

**Citation:** Yoo, Y.-S.; Whang, W.-J. Conditional Process Analysis for Effective Lens Position According to Preoperative Axial Length. *J. Clin. Med.* **2022**, *11*, 1469. https:// doi.org/10.3390/jcm11061469

Academic Editor: Nobuyuki Shoji

Received: 31 January 2022 Accepted: 27 February 2022 Published: 8 March 2022

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

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

Hayes presented dozens of models in PROCESS macros for conditional process analysis [12–14]. Conditional process analysis includes not only independent variables, but also the concept of a mediating variable and a moderating variable. Using this method, we can solve the problem of multicollinearity and identify relationships between explanatory variables and develop a more accurate structural equation model for a dependent variable.

In this study, considering that the formula yielding excellent accuracy differs according to AL, we divided a total of 621 eyes into four groups according to AL. We determined the ideal model for predicting ELP in each group on the basis of conditional process analysis and the results were compared with existing IOL formula derived from a multiple linear regression analysis.

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

This retrospective case series study included 621 eyes of 621 patients who underwent uneventful and micro-coaxial phacoemulsification cataract surgery without any intraoperative complications between March 2018 and September 2019. None of the patients had a history of ocular disease, previous ocular surgery, or general disorders affecting the cornea. Exclusion criteria were amblyopia, corneal opacity, glaucoma, retinal disease, history of ocular inflammation, history of ocular trauma, and history of exposure to other intraocular surgeries. The study methods adhered to the tenets of the Declaration of Helsinki for use of human participants in biomedical research. The Institutional Review Board (IRB #SC20RASI0071) for Human Studies at Yeouido St. Mary's Hospital approved this study, and informed consent was exempted by IRB of Yeouido St. Mary's Hospital.

Preoperative biometric measurements, such as K of anterior surface, ACD, and AL, were obtained with an IOLMaster optical biometer (version 5, Carl Zeiss, Oberkochen, Germany) to calculate IOL power. All procedures were performed by two surgeons (H.S. Kim and W.J. Whang). All patients underwent cataract surgery through a 2.2 mm micro coaxial incision under topical anesthesia (proparacaine hydrochloride 0.5%, Alcaine, Alcon). After performing continuous curvilinear capsulorhexis with an intended diameter of 5.0 mm and hydrodissection, phacoemulsification of the nucleus was performed using an OZil torsional handpiece with the Centurion vision system (Alcon, Fort Worth, TX, USA). Following phacoemulsification, the intraocular lens (ZCB00, Johnson & Johnson Vision, Santa Ana, CA, USA) was inserted into the capsular bag using an injector and disposable cartridge system before removing the ophthalmic viscosurgical device. Finally, a balanced salt solution was injected into the corneal incision site with stromal hydration. After the surgery, postoperative antibiotic and corticosteroid eye drops were used four times daily and tapered over a month.

Subjective refraction was measured 3 months postoperatively with manifest refraction by an experienced ophthalmologist (J. Y. Lee) and ELP was back-calculated using the following thin-lens formula [15]:

$$\text{IOL power} = \frac{1336}{\text{AL} - \text{ELP}} - \frac{1336}{\frac{1336}{\text{Z}} - \text{ELP}}$$

$$\text{Z} = \frac{(nc - 1) \times 1000}{r} + \frac{1000}{\frac{1000}{\text{PostR} \times \text{R}} - VD}$$

where *nc* is the fictious corneal refractive index (1.3315), *r* (millimeter) is the mean value of the preoperative corneal radius, *PostRx* is the postoperative spherical equivalent, and *VD* (millimeter) is the vertex distance.

The 621 eyes were stratified into 4 subgroups to investigate the appropriate structural equation model according to the preoperative AL:

The ELP prediction error was defined as the value calculated by subtracting the predicted ELP from the back calculated ELP based on the thin-lens formula described above. Conditional process analysis was defined as the method for calculating ELP prediction in the present study. The accuracy of refractive outcomes (prediction error (PE), median absolute error (MedAE), and mean absolute error (MAE)) using conditional process analysis was compared to those using the Haigis formula. Refractive outcomes using the Haigis formula were calculated using an optimized IOL constant for the IOLMaster (ZCB00; a0 = −1.302, a1 = 0.210 and a2 = 0.251 based on ULIB site) and the zeroing of ME was performed based on the analysis methods suggested by Hoffer et al. [16]. PE was defined as the actual postoperative spherical equivalent minus the predicted spherical equivalent using the IOL power actually implanted. MedAE and MAE were the median and the average from the absolute value of the PE, respectively. The percentages of eyes with PE within ±0.25 D, ±0.50 D and ±1.00 D were also obtained.


**9. References**

http://www.vnwatersectorreview.com/detail.aspx?pid=107&r=5#4

**4**

*Portugal*

**Risk Assessment of Cyanobacteria and**

**of** *Planktothrix* **spp. Monitoring**

*Nacional de Saúde Dr. Ricardo Jorge, Lisboa,*

*Universidade Nova de Lisboa, Caparica,*

Catarina Churro1,2, Elsa Dias1 and Elisabete Valério2

**Cyanotoxins, the Particularities and Challenges**

*1Laboratório de Biologia e Ecotoxicologia, Departamento de Saúde Ambiental, Instituto*

Cyanobacteria are a diverse well adapted group of organisms that presents amazing morphological diversity. Cyanobacteria can be unicellular or colonial (filamentous, spherical or amorphous) (Fig. 1). Since cyanobacteria have cells larger than normal bacterial cells and behavior more similar to algae, they were classified under the microalgae for a long time and acquire the name of blue-green algae or Cyanophyta (Whitton & Potts 2000). Cyanobacteria is a phylum of bacteria that obtain their energy through photosynthesis. The name "cyanobacteria" comes from their coloration (cyano = blue). The vegetative cell wall is of Gram-negative type and in some species the peptidoglycan layer is considerably thicker than in other bacteria. Many unicellular and filamentous cyanobacteria possess an "envelope" outside the lipopolysaccharide (LPS) "outer membrane", which is called: sheath, glycocalyx, or capsule, and depending on the consistency, gel, mucilage or slime. The sheaths of cyanobacteria are predominantly polysaccharide, but a part of its weight may be polypeptides, and depending on the species, some types of sugar residues may be involved

Fig. 1. Optical microscopy photographs of cyanobacteria presenting different morphologies.

The arrow indicates the heterocyst cell in *Anabena circinalis*.

**1. Introduction**

(Castenholz, 2001).

*2Centro de Recursos Microbiológicos (CREM), Faculdade de Ciências e Tecnologia,*


**5. Dermatan Sulfate**

DS is found in the cornea, where it maintains optical clarity, and in the sclera, where it helps to maintain the eye's overall shape [93]. Further, it is found in blood vessel walls, heart valves, and the umbilical cord during pregnancy where it plays a key role in regulation of the extracellular matrix [93]. Its composition is very similar to that of CS, as demonstrated by its former name CS type B, however I-iduronic acid a C5 epimer of glucuronic acid, substitutes for hexuronic acid found in CS [50]. Sulfation is found on C4 or C6 of the galactosamine ring and sulfation levels increase with age [93].

DS has been implicated in the development of many pathologies, such as cancer metastasis [94], connective tissue diseases [95], and inhibited neuron regeneration [96]. Research focusing on DS in tissue engineering is sparse, with the bulk of research focusing on discovery of its functions and some research focusing on DS, modified DS, and DS proteoglycans as therapeutics or as a targeting mechanism for drug delivery [97–101]. This lack of exploration can likely be attributed to two key factors: the recent reclassification of DS from chondroitin sulfate B, and the extreme complexity of DS synthesis and physiological interactions. DS interactions are based upon the composition and sulfate functionalization patterns of the chain allowing for a high diversity of patterns and potential interactions similar to those seen for CS. For example, xyloside-primed dermatan sulfate from breast carcinoma cells has cytotoxic effects and this behavior is only exhibited by DS of a defined disaccharide composition [102]. This is the first example of cytotoxic effects of dermatan sulfate and highlights the complexity of cell interactions with sulfated GAGs. There has, however, been some research focusing on the use of DS in tissue engineering. DS proteoglycans are key moderators of fibrinogenesis and K.M., et al. have shown that this behavior can be recapitulated in vitro when combining DS with collagen scaffolds. Collagen fibril formation was shown to be dependent on DS concentration, with low concentrations resulting in disorganized fibrils and higher concentrations resulting in more organized, but less dense fibrils [103]. A more unique use for DS in tissue engineering may be in surface modification of implantable devices. DS, when combined with chitosan in a multi-layer coating on polyethylene terephthalate surface show high surface wettability and inhibited biofilm formation, two important factors in implantable devices such as vascular prosthetics [104].

It has also been shown recently that mouse embryonic stem cells undergo neuronal differentiation via activation of signal-regulated kinase 1/2 and human neural stem cells undergo neuronal differentiation and neuronal migration in the presence of DS [105]. This lends some promise to the use of DS to drive stem cell differentiation in neuronal tissue engineering constructs similar to the use of HA and CS as mentioned previously.


**2.1. Synthesis of supramolecular systems of water-soluble polysaccharides and their stability in aqueous solutions**

In the course of this study, different conditions of mechanochemical synthesis and various complexing agents have been tried and compared in terms of efficacy. The complexing agents were: arabinogalactan (AG), a water-soluble larch polysaccharide derived from *Larix sibirica* Ledeb. and *Larix gmelinii* (Rupr.), fibregum (FG), a glycoprotein of acacia gum, fruit pectin (PC), hydroxyethyl starch (HES200/0,5), dextrans (D) 10. 40. 70, and ß-cyclodextrin (CD), the latter chosen as standard for being widely used in pharmaceutics. The mixtures of powdered components (polysaccharides/complexing agents and drugs) were dispersed in ball mills at greater or lower intensities in laboratory planetary- and rotary-type mills, respectively. Milder rotary milling was predominantly applied because the molecular-level mixing in a planetary mill, common to laboratory studies of mechanochemical modification of drugs [9], may partly destroy the material and pose scaling problems. The materials processed by nondestructive rotary milling [10, 11, 21], instead, interact to produce solid dispersed systems of components (composite aggregates of superdispersed particles), and the process is easily scaled onto industrial flow mills.

The obtained compositions were checked for drug contents to avoid unwanted chemical reactions. Formation of supramolecular complexes was identified from changes in solubility of drugs in the water solution of the compositions [22].

Dissolution and complexing of poorly water-soluble drugs can be illustrated by such simplified equations:

$$\mathsf{Drug}\_{\mathsf{solid}} \leftarrow \succ \mathsf{Drug}\_{\mathsf{solution}} \tag{1}$$

$$\text{Drug}\_{\text{solution}} + \text{CA}\_{\text{solution}} \leftarrow \succ(\text{Drug} \cdot \text{CA})\_{\text{solution}} \tag{2}$$

Equilibrium, according to (2), is given by

574 The Complex World of Polysaccharides

properties of starting materials:

3. composite materials: aggregates of powdered particles.

micelles) that enclose drug molecules and provide their solubility.

and synthesis of polyfluorinated aromatic compounds [19, 20].

**Figure 1.** Mechanochemical transformations in mixtures of solids organic substances.

report the results of pharmacological testing.

in various mills.

medium);

components;

This difficulty may be surmountable with solid-state chemistry approaches, specifically, with mechanochemical transformations in mixtures of solids [9-11]. Unlike the liquid-phase synthesis, mechanochemical treatment is a simpler single-stage process going without solvents or melts and respective additional procedures. The flow chart in Fig. 1 shows a simplified sequence of transformations the powder mixtures experience during dry milling

There may be three types of main products relevant to our study, depending on the

1. "molecular dispersions", or solid solutions of drugs in excess filling (dispersion

2. supramolecular complexes or products of chemical reactions between the

In fact, they all are solid dispersions that form supramolecular structures (complexes or

Generally, solid-phase processes have a number of advantages in laboratory and technological uses as they yield, in a shorter time, materials which the classical liquid-phase technology can never provide and allow avoiding problems associated with melts or solvents and side reactions. The high potentiality of mechanical activation was proven in our previous studies [12-14], e.g., on quick-dissolving pharmaceutical compositions [15-18]

In this synopsis we present techniques for synthesizing supramolecular complexes of poorly soluble drugs with water-soluble polysaccharides or with glycyrrhizic acid (a plant-derived glycoside), describe physicochemical properties of their solid forms and solutions, and

$$\mathbf{K\_{DCA}} = \left[ \left( \mathbf{Drug} \cdot \mathbf{CA} \right) \text{solution} \right] / \left[ \mathbf{Drug} \text{solution} \right] \ge \left[ \mathbf{CA} \text{solution} \right] \tag{3}$$

where Drugsolid is the drug in a crystalline solid phase, in equilibrium with the solution; Drugsolution is the drug existing in the free form in the solution; CAsolution is the free complexing agent in the solution; (Drug **.** CA)solution is the complexing agent-drug complex in the solution; KDCA is the constant of supramolecular complexing.

The value Drugsolution corresponds to the thermodynamic equilibrium solubility in the absence of complexing agents. In the case of complexing, the total concentration of the dissolved drug Cdrug equals the sum its free and bound forms.

$$\text{C\_{Drug}} = \text{[Drug\_{solution}]} + \text{[(Drug\_ CA)\_{solution}]} \tag{4}$$

Thus, the solubility increase of a drug in the solution (X) in the presence of a complexing agent is

$$\mathcal{X} = \mathbb{C}\_{\text{Drug}} / \text{[Drug}\_{\text{solution}}] = 1 + \mathbb{K}\_{\text{DCA}} \cdot \text{[CA solution]} \tag{5}$$

In our view, X is a good proxy of binding strength in the supramolecular complexes drugs may form with various water-soluble polymers.

All poorly soluble drugs we studied have shown a notable solubility increase when became incorporated into compositions with complexing agents. Table 1 below shows solubility data reported in [22-32] as far as published for the first time in this review.

The binding strength in the complexes grows in the series "dextran 70 < dextrans 40 and 10 ~ < HES < ß-cyclodextrin, fibregum < pectin < arabinogalactan". Complexing of pectin with mezapam and clozapine most probably occurs by acid-base reactions, which accounts for quite a high binding strength. However, other complexing agents lack acid-base groups and the interaction mechanism is most likely "hydrophobic", as in the case of cyclodextrin complexes. Thus, the mechanochemical treatment strengthens considerably the drug binding in compositions. The solubility of drugs increases, depending on the way of mixing, in the series "mixing without milling < high-rate milling < low-rate milling.

The obtained compositions were analyzed by X-ray powder diffraction and thermal methods. All non-processed mixtures showed X-ray and thermal features typical of crystalline drugs, which disappeared or decreased markedly after milling. Therefore, drugs in the ground mixtures partly or fully loose their crystallinity, possibly, as their solid phase becomes disordered and their molecules are dispersed into the excess solid phase of complexing agents, with formation of solid solutions or supramolecular complexes. In the latter case, the solubility changes evidence that the analyzed compositions form more strongly bound complexes when form in the solid phase than in the solution.

## **2.2. Molecular dynamics and structure of arabonigalactan complexes**

AG-drug systems were investigated by 1Н NMR spectroscopy [22] for the molecular dynamics of complexes and the mobility of arabinogalactan (AG) molecule fragments. NMR relaxometry is applicable to molecular complexes as the spin-lattice and spin-spin relaxation times (T1 and T2, respectively) are highly sensitive to interactions and diffusion mobility of molecules. As a molecule becomes bound in a complex, its diffusion mobility slows down, and the proton relaxation times decrease notably. In the case of rapid complexsolution molecular exchange, the NMR signal decays according to the mono-exponential law. Otherwise, if the exchange is slower than the relaxation time, the kinetics is biexponential:

$$A(t) = P\_1 \cdot \exp(-t/T\_{21}) + P\_2 \cdot \exp(-t/T\_{22}) \tag{6}$$

may form with various water-soluble polymers.

agent is

milling.

the solution.

biexponential:

Thus, the solubility increase of a drug in the solution (X) in the presence of a complexing

In our view, X is a good proxy of binding strength in the supramolecular complexes drugs

All poorly soluble drugs we studied have shown a notable solubility increase when became incorporated into compositions with complexing agents. Table 1 below shows solubility

The binding strength in the complexes grows in the series "dextran 70 < dextrans 40 and 10 ~ < HES < ß-cyclodextrin, fibregum < pectin < arabinogalactan". Complexing of pectin with mezapam and clozapine most probably occurs by acid-base reactions, which accounts for quite a high binding strength. However, other complexing agents lack acid-base groups and the interaction mechanism is most likely "hydrophobic", as in the case of cyclodextrin complexes. Thus, the mechanochemical treatment strengthens considerably the drug binding in compositions. The solubility of drugs increases, depending on the way of mixing, in the series "mixing without milling < high-rate milling < low-rate

The obtained compositions were analyzed by X-ray powder diffraction and thermal methods. All non-processed mixtures showed X-ray and thermal features typical of crystalline drugs, which disappeared or decreased markedly after milling. Therefore, drugs in the ground mixtures partly or fully loose their crystallinity, possibly, as their solid phase becomes disordered and their molecules are dispersed into the excess solid phase of complexing agents, with formation of solid solutions or supramolecular complexes. In the latter case, the solubility changes evidence that the analyzed compositions form more strongly bound complexes when form in the solid phase than in

AG-drug systems were investigated by 1Н NMR spectroscopy [22] for the molecular dynamics of complexes and the mobility of arabinogalactan (AG) molecule fragments. NMR relaxometry is applicable to molecular complexes as the spin-lattice and spin-spin relaxation times (T1 and T2, respectively) are highly sensitive to interactions and diffusion mobility of molecules. As a molecule becomes bound in a complex, its diffusion mobility slows down, and the proton relaxation times decrease notably. In the case of rapid complexsolution molecular exchange, the NMR signal decays according to the mono-exponential law. Otherwise, if the exchange is slower than the relaxation time, the kinetics is

1 21 2 22 *A*( ) exp( / ) exp( / ) *t P tT P tT* (6)

**2.2. Molecular dynamics and structure of arabonigalactan complexes**

[CAsolution] (5)

X = CDrug /[Drugsolution] = 1 + KDCA .

data reported in [22-32] as far as published for the first time in this review.

1 – To determine the solubility of the drug, machined mixture of complexing agent/drug, in amounts of 0.4 grams, as well as the linkage of individual substances which are equivalent to their content in the above mixture was dissolved in 5 ml of water while stirring with a magnetic stirrer at +25 ° C till reaching constant concentration. The concentration of drug in the solution was analyzed by HPLC.

2 – mixing without mechanical treatment;

3 – treatment in a planetary mill, acceleration 40 g;

4 – treatment in a rotary ball mill, acceleration 1 g;

**Table 1.** Increase in water solubility of some drugs as a result of complexing.

The fast component P1 and the slow component P2 correspond, respectively, to the shares of molecules in the complex and in the solution. Typical T2 values are 0.5-1 s for molecules in the solution and 0.03-0.09 s for those bound in the complex. Shorter T21 times mean lower mobility of drug molecules in the latter case.

Similar considerations apply to the mobility within polymers when parts of a macromolecule differ in mobility, possibly, controlled by their spin and conformations.

#### *2.2.1. T2 measurements*

578 The Complex World of Polysaccharides

Nifedipine

Dihydroquercitin

Quercitin

Ibuprofen

Albendazol

Carbenazim

Simvastatin

of drug in the solution was analyzed by HPLC. 2 – mixing without mechanical treatment; 3 – treatment in a planetary mill, acceleration 40 g; 4 – treatment in a rotary ball mill, acceleration 1 g;

Hydroxyethylstarch(1/10)4 0.04/0.222 5.5 [23] Beta-cyclodextrin (1/10)3 0.04/0.60 15.1 [23] Glycyrrhizic acid (1/10)3 0.04/0.088 2.2 [29]

Arabinogalactan (1/10)3 0.18/1.24 6.9 [26] Arabinogalactan (1/20)3 0.18/2.46 13.7 [26] Glycyrrhizic acid (1/10)3 0.18/0.92 5.1 [30]

Arabinogalactan (1/10)4 0.65/3.75 5.9 [23,27] Hydroxyethylstarch(1/10)4 0.65/1.97 3.0 [23]

Arabinogalactan (1/10)3 0.019/0.21 11.6 [28] Arabinogalactan (1/20)3 0.019/1.28 71.0 [28]

Arabinogalactan (1/10)2 0.03/0.036 1.2 [29] Arabinogalactan (1/10)4 0.03/0.85 28.4 [29] Hydroxyethylstarch (1/10)4 0.03/0.08 2.6 [29] Glycyrrhizic acid (1/10)3 0.03/0.441 14.7 [29]

Arabinogalactan (1/10)4 0.003/0.174 58.0 [32] Hydroxyethylstarch(1/10)4 0.003/0.094 31.3 [32]

Arabinogalactan (1/10)4 0.009/0.146 16.2 [32] Hydroxyethylstarch(1/10)4 0.009/0.020 2.1 [32]

Glycyrrhizic acid (1/10)3 0.0012/0.314 260 This article Arabinogalactan (1/10)3 0.0012/0.044 36,7 This article

article

article

Beta-Carotene Arabinogalactan (1/40)3 < 0.001/2.65 > 2000 [25], This

Warfarin Arabinogalactan (1/40)3 0.021/0.111 5.3 [31]

Contaxantine Arabinogalactan (1/40)3 < 0.001/2.64 > 2000 [25], This

1 – To determine the solubility of the drug, machined mixture of complexing agent/drug, in amounts of 0.4 grams, as well as the linkage of individual substances which are equivalent to their content in the above mixture was dissolved in 5 ml of water while stirring with a magnetic stirrer at +25 ° C till reaching constant concentration. The concentration

**Table 1.** Increase in water solubility of some drugs as a result of complexing.

Fibregum(1/10)4 0.65/5.72 8.8 [23,27]

*Arabinogalactan* shows biexponential relaxation patterns. The calculated parameters for arabinogalactan and AG-drug complexes are listed in Table 2.

1 - T2 measurements were performed for the aromatic protons of drug molecules, to an accuracy of ± 10%

2 – solvent D2O;

3 - solvent 70% D2O + 30% CD3OD;

**Table 2.** Spin-spin relaxation times of protons for arabinogalactan and drug molecules in solutions1

The short relaxation times may correspond to the interior protons and the long times may represent the exterior protons of the polymer compound. Mechanical activation in a planetary mill increases the molecular mobility of the interior fragments but decreases their percentage. A relatively narrow ~ 6 kHz band in the 1H NMR spectra of AG powder, which stands out against a broad line associated with dipole-dipole interaction non-averagable in solids, represents a mobile phase with its integral intensity up to ~ 15% of the number of hydrogen nuclei in the sample. The mobile phase may correspond to fragments of AG macromolecules, possibly, side chains, as one may reasonably hypothesize given that water content in AG never exceeds 2 wt.%. This very fact appears to facilitate AG-Drug molecular complexing on mechanical activation of solids.

*AG-Drug systems* most often exhibit distinct biexponential kinetics as evidence that the drug molecules are either free or bound in complexes with AG. The bound molecules are more abundant and less mobile in milled samples, while the free ones keep almost invariable NMR relaxation times. The characteristic 1H NMR bands of clozapine and mezapam move to low field on complexing, possibly because the molecules become protonated at the account of minor remnant uronic acid present in AG, the shift being likewise greater in the milled samples. However, no complexing-related shifting appears in the cases of indomethacin and diazepam. The life time of drug molecules in complexes with AG must to be ~> 100 ms, judging from the conditions of slow exchange.

The system AG-diazepam offers an illustrative example. Solutions of these mixtures not subjected to mechanical treatment show mono-exponential relaxation behavior, but with shorter times than in free diazepam, likely as a result of rapid solution-complex molecular exchange. The milled mixtures, on the contrary, have biexponential kinetics corresponding to slower exchange of molecules and stronger binding.

Thus, dynamic NMR spectroscopy of all Drug-AG solutions indicates formation of supramolecular drug-polysaccharide complexes, like the data on solubility increase. Most likely, the complexing sites are at side chain spaces in the branching macromolecules. Unlike cyclodextrins, ensembles of polysaccharide molecules (including arabainogalactan) are micro-heterogeneous in mass and structure. As a result, molecular modeling of the complex is very difficult. The binding mechanism appears to lie mainly with hydrophobic interactions [33, 34] which are typical of guest-host cyclodextrin complexes. A certain support to this hypothesis comes from stronger binding of highly lipophilic drugs which are almost insoluble in water. In this case, the branched structure of AG macromolecules [35, 36] is especially favorable for complexing. However, Coulomb interactions may contribute as well in the presence of acid-base groups in polysaccharides and drugs [37].


**Oral and Maxillofacial Tissue Engineering with Adipose-Derived Stem Cells**

Morikuni Tobita and Hiroshi Mizuno

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55899


**1. Introduction**

The risk management market provides many opportunities for mitigating financial risks in construction. The risk management process consists of identifying risks, measuring risks and then deciding how to handle the risks. Once identified, risks can be avoided, retained or transferred (The A-R-T of Risk Management). There are ways of doing this, such as retaining, mitigating the risk through actions that reduce the frequency and/or severity of the risk consequence, or contractually transferring the risk to another party, either through insurance or contractual risk transfer agreements.

This chapter focuses primarily on transferring the economic (financial) consequences of losses that result from risk realization in the construction industry. We particularly explore available optimal financial risk transfer techniques, including various insurance products, and methods for transferring the financial consequences of risk realization through contractual agreements. We conclude with a section on indemnifying the financial considerations associated with new and evolving risks such as changing technology.

**32**

*Risk Management in Construction Projects*

[1] International Association of Oil and Gas Producers (IOGP). Guideline for the Development and Application of Health, Safety and Environment Management Systems. Report No.

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[13] Ridley J, Channing J. Safety at Work. 7th ed. U.K.: The Elsevier Ltd; 2008

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[18] Hu Y et al. '2+1' Programme: An Efficient HSE Risk Management Mode for Frontline Workers. Saarbrucken: Lambert Academic Publishing; 2016

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[6] Hu Y et al. The principle and application

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[8] Acfield AP et al. Integrating safety management through the bowtie concept—A move away from the safety case focus. In: Proc. of the Australian Safety System Conference. 2012

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DPA\_Section\_11.pdf

and Technology. 2010

Gas Industry. 2010

Construction contracts are often written with incentive clauses based on the contracted for completion date. When construction is finished ahead of schedule the contractor is rewarded a pre-specified amount per day. If the project finishes after the deadline, a pre-specified penalty is assessed for each day late. Thus, risk realization in the construction process can have twofold financial consequences: direct and indirect costs of liability and damages. We cover direct losses to property, liability to contractors, business interruption coverage (e.g., delay in start-up or completion insurance and contingent business interruption in supply chain management), worker's compensation liability, and other important insurance mechanisms pertinent to construction risk management.


*Edited by Rebecca L. Aft*

This book presents novel in interesting find by multiple accomplished investigators in breast cancer. These chapters elucidate new mechanisms of breast cancer cell death as well as discuss new pathways for therapeutic targeting.

ISBN 978-953-51-0145-1

Targeting New Pathways and Cell Death in Breast Cancer

Photo by Dr\_Microbe / iStock

## Targeting New Pathways and Cell Death in Breast Cancer

*Edited by Rebecca L. Aft*

**TARGETING NEW**

Edited by **Rebecca L. Aft**

**INTECHOPEN.COM**

**PATHWAYS AND CELL**

**DEATH IN BREAST CANCER**

## **TARGETING NEW PATHWAYS AND CELL DEATH IN BREAST CANCER**

Edited by **Rebecca L. Aft**

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http://dx.doi.org/10.5772/1744 Edited by Rebecca L. Aft

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Bulent Ozpolat, Thomas T. Chen, Maria Chen, Chun-Mean Lin, David Liu, Jeremy Haakenson, Mark Kester, Hsin-Ling Yang, Ou-Cheng Hseu, Yang, Lin-Tao Jia, Paul Davis, Faith Davis, Hung-Yun Lin, Shaker A Mousa, Aleck Hercbergs, Mary Luidens, Jordan, Philipp Y Maximov, Shiaw-Yih Lin, Leila Green, Fazlul Sarkar, Aamir Ahmad, Zhiwei Wang, Raza Ali, Bassam Bitar, Farah Logna, Main Maitah, Bin Bao, Shadan Ali, Dejuan Kong, Yiwei Li, Zhou, Xiaofang Zhang

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First published in Croatia, 2012 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

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*Edited by Patricia Bozzetto Ambrosi, Rufai Ahmad, Auwal Abdullahi and Amit Agrawal*

*"Brain circulation is a true road map that consists of large extended navigation territories and a number of unimagined and undiscovered routes."*  Dr. Patricia Bozzetto Ambrosi

This book combines an update on the review of cerebrovascular diseases in the form of textbook chapters, which has been carefully reviewed by Dr. Patricia Bozzetto Ambrosi, Drs. Rufai Ahmad and Auwal Abdullahi and Dr. Amit Agrawal, high-performance academic editors with extensive experience in neurodisciplines, including neurology, neurosurgery, neuroscience, and neuroradiology, covering the best standards of neurological practice involving basic and clinical aspects of cerebrovascular diseases. Each topic was carefully revised and prepared using smooth, structured vocabulary, plus superb graphics and scientific illustrations. In emphasizing the most common aspects of cerebrovascular diseases: stroke burden, pathophysiology, hemodynamics, diagnosis, management, repair, and healing, the book is comprehensive but concise and should become the standard reference guide for this neurological approach.

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New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review

Published in London, UK © 2020 IntechOpen © DancingMan / iStock


**3.1 The sting balance description**

An aerodynamic balance has been developed to measure drag and lift forces in the MARHy operating flow conditions. The main difficulty comes from the fact that operating conditions concerns rarefied regime with low density flows, giving force values estimated between 1mN and 1 N. Aerodynamic balances applied to supersonic wind tunnels are ranged in two main balance groups' internal and external balances. Internal balances [32] are a test model extension and located inside the test section, on the contrary, external [33] are placed outside the test section and the model is supported with thin wires. For the present study, a sting balance was designed to measure drag and lift forces applied to the waveriders in supersonic and hypersonic flows. The design of this device had to meet to several constraints: be able to measure small forces values around mN, to have an aerodynamic design to not obstruct the test section and ability to measure aerodynamic model forces with different incidence angles without changing the balance calibration. This sting balance is composed in two parts, drag and lift modules as showed on **Figure 2**. The principle adopted for force measurement is based on the deformation of thin slats equipped with strain gauges, deforming when the test model is an incoming flow.

The drag module as can be seen on **Figure 3** is designed in three parts: upper part, slats, and lower part in order to facilitate manufacturing. There are six slats arranged in three rows and two columns. Indeed, many configurations have been dynamically simulated with a CAO software to optimized de number of lamelles, their arrangement and their thickness. The **Figure 3** shows the deformation of the drag module slats when subjected to a horizontal force. The results showed that this configuration is the best compromise to optimize the bending, and to minimize the

*Experimental Analysis of Waverider Lift-to-Drag Ratio Measurements in Rarefied… DOI: http://dx.doi.org/10.5772/intechopen.100328*

**Figure 1.** *3D CAO design of the waverider used in this experimental work.*

**Figure 2.** *View of the sting balance two modules, drag and lift.*

lateral and vertical deformations. Indeed, other configurations such as a row of three wider slats showed lateral and vertical deformations that could weaken the balance of the sting, optimizing the bending which is the most important part for this module.

The drag slats are 0.2 mm thick and made of AISI 304 steel to avoid plastic deformation. Once all the components of the drag module are assembled, the lower

**Figure 3.** *Detail of the drag module and simulation of the strain stresses.*

part is static and only the upper part is mobile. Therefore, the most sensitive part of the slats is the upper area, where the strain gauges will be placed. The strain gauges are glued to the central slat and there is one on each side to create a complete Wheatstone bridge. The lifting module is made up of a single part and there are only two superimposed slats. This module is also made of AISI 304 and it measures 10 cm. The purpose of having two superimposed slats is to reduce the bending of the heavy test models when the flow is deactivated. Indeed, if the test model creates a bending due to its mass, it can have an impact on the lift values in the presence of the flow. The maximum mass of the test model that this sting balance can support is 140 g. This lift module, like the drag module, has a full Wheatstone bridge with two strain gauges per side, as shown in **Figure 4**.

Drag module measurements are dependent on the position of the balance center of gravity (COG). A change in the position of the center of gravity will change the measurement of the associated forces for the same test model and flow conditions. To avoid this problem, a counterweight is placed at the back of the balance and its position is adapted according to the mass of the test model. The higher the mass of the test model, the further the counterweight will be from the drag module. On the contrary, if the test model is light, the counterweight will be closer so that the center of gravity is always aligned with the two slats equipped with strain gauges.

**Figure 4.** *Detail of strain gauges of the lift module.*

*Experimental Analysis of Waverider Lift-to-Drag Ratio Measurements in Rarefied… DOI: http://dx.doi.org/10.5772/intechopen.100328*

Another important point for this type sting balance is to avoid that the flow has a direct impact on the deformation of the slats. Indeed, if the drag and lift modules are in the flow without protection, the drag and lift values will be overestimated. In addition to the shock produced by the presence of the test model, a second shock can be created on the drag module itself and increase the deformation of the slats and thus the drag value. To solve this problem, a cover was modeled and installed. It is dimensioned to allow the drag and lift modules to deform without touching the cover which could create friction and in turn distort the measurements. On the other hand, this cover also allows to protect the strain gauges from the temperature increase caused by the shock in hypersonic flow condition. For the experimental conditions of this work in supersonic regime, the shock does not produce any heating.

To validate this sting balance, we have performed a study with spheres in order to compare our experimental results with those of the literature. In his study, Aroesty determines the drag coefficients for spheres in a supersonic flow at Mach 4 and low density and establishes a curve that relates the drag coefficients of the spheres with the Reynolds number after shock Re2 [34]. In our case we measured the drag forces for spheres of different diameters in the three flow conditions at Mach 4. **Figure 5** plots the experimental data from Aroesti and our experimental results. As shown in the graph, the drag coefficients for the sting balance are consistent with the reference values. The numerous preliminary tests we have conducted have shown that without the stinger cover, the drag coefficients for small diameter spheres (less than 15 mm) and low Re2 (less than 200) are indeed overestimated as explained in the previous paragraph. For larger diameter spheres, the results are close to the Aroesty values without the protective cover. This is due to the fact that the shock created by the large diameter spheres is large enough to protect the scale elements that will be in the wake, which is not the case for the small diameter spheres.

**Figure 5.** *Drag coefficients of spheres in near rarefied regime: Aroesty and Noubel data.*

## **3.2 Strain gauges**

Strain gauges are used to measure the slat deformation. It is a sensor whose resistance varies with the applied force, then it converts force into an electrical resistance which can then be measured [35]. Strain gauge elements are electrically connected to form a Wheatstone bridge circuit used for the measurement of static or dynamic electrical resistance. The output voltage of the Wheatstone bridge is expressed in millivolts output per volt input. At the end a calibration curve of the lift and drag modules will convert the out put signal in a mesure of the corresponding fonce expressed in newton. For the experimental conditions of the MARHy wind tunnel forces are estimated between 1 mN and 1 N so strain gauge need to have a high gauge factor. There are essentially two types of strain gauges, the so-called semiconductor strain gauges whose gauge factor is greater than 180 and the metallic strain gauges whose gauge factor is between 2 and 3. In order to optimize the measurement of forces we have opted for the first type, however they are very sensitive to the value of excitation applied which can easily damage them [36, 37]. For this balance, the gauge used is the KYUOWA: KSPB-2-1 K-E4, with an excitation voltage of 1 Volts.

### **3.3 Calibration procedure**

Calibration of the balance is necessary to convert the electrical signal from by strain gauges into applied force. The purpose of calibration is to reproduce known forces on the sting balance and relate them to the variation of the measured voltage. We designed a calibration bench composed of a digital newton meter mounted on a motorized micrometric displacement, which aligned with the lift or drag modules, apply a stable and known force in the same geometric configuration as those of the experience. Both during calibration and during wind tunnel experiments, the models are screwed onto the model holding sting so as to align their center of gravity with the end of the sting. Finally a curve is obtained expressing the force as a function of the voltage measured for each module: drag and lift. The accuracy of the force measurement on the lift and drag module is estimated at 0.1 mN.

A counterweight is added so that the position of the center of gravity remains constant regardless of the size and mass of the model. This preserves the calibration performed with the balance provided that, during wind tunnel measurements, the balance's center of gravity is in the same position as during calibration. For this purpose, the position of the counterweight is adjusted for each test model.

It should be noted that if the aerodynamic forces are to be studied as a function of the angle of incidence of the test model with respect to the flow, it must be ensured that the center of gravity remains unchanged. For this reason, the balance is positioned horizontally so that the angle of incidence in the horizontal plane (x-y) is changed and the position of its center of gravity is not affected [38].

## **4. Experimental conditions**

#### **4.1 Marhy facility description**

The first version of the wind tunnel, then named SR3, was built in 1961, at the Aerothermic Laboratory. Since 2000, this wind tunnel, renamed MARHy, has been installed at the ICARE Laboratory of the CNRS in Orléans, and many technical improvements have been made.

In particular the pumping unit which is a key element allowing to ensure in continuous mode without time limit low density flows with Mach numbers ranging *Experimental Analysis of Waverider Lift-to-Drag Ratio Measurements in Rarefied… DOI: http://dx.doi.org/10.5772/intechopen.100328*

from 0.8 to 21. The two main components of the Marhy facility are the large capacity test chamber and the pumping unit. The wind tunnel consists of three main parts: the settling chamber, the test chamber and the collector-diffuser chamber as presented in **Figure 6**.

The facility is supplied with exchangeable nozzles to generate laminar subsonic, supersonic and hypersonic stationary flows [39]. Only the supersonic configuration is described in this paper.

Subsonic and supersonic conditions flows are generated by contoured nozzles, using air or nitrogen at ambient temperature. Nozzles are housed into the settling chamber, a cylinder of 2*:*6 m length and 1*:*2 m in diameter with a large access port at the bottom (200 *kg*), placed on a trolley with wheels on a guide rail for easy opening and closing. The relevant components of the facility MARHy in supersonic configuration is skecthed on **Figure 7**.

The divergent section of the nozzles opens into the experimental chamber, a cylindrical test section with a diameter of 2 m and a length of 3.5 m.

This chamber is placed perpendicular to the direction of the flow, so that there is enough space on either side of the flow to install diagnostic systems and supports without disturbing the flow. The experimental chamber is large enough to allow the

**Figure 6.** *The wind tunnel MARHy and the pumping group.*

**Figure 7.** *Sketch of the wind tunnel MARHy in supersonic configuration.*

integration of specific instrumentation such as probe supports, electron gun and aerodynamic balances and to avoid interactions between the flow and the wall of the wind tunnel. Two rounded bottoms laterally close the cylinder, one of them is provided with a door of 1*:*2 m in diameter, giving access to the interior of the experimental chamber as can be seen in **Figure 8**. Four port flanges with a diameter of 0.6 m, closed by optical windows made of quartz and fluorine, are distributed around its cylindrical section. Six other smaller diameter flanges are available for instrumentation.

The pressure in the experimental chamber is recovered by means of a central diffuser to match the test section pressure to the inlet pressure for the vacuum pumps, specially at hypersonic operating conditions. The collector-diffuser is a 1.4 m diameter cylinder connects the experimental chamber to the pumping group by means of a motorized butterfly valve with a diameter of 1.5 m. The pumping group consists of 2 primary pumps, 2 roots-type intermediate pumps and 12 rootsvacuum pumps,ensuring continuous operation. The number of pumps commissioned depends on the operating conditions of the flow (Mach number and static pressure).

**Figure 8.** *View of the experimental chamber of the facility MARHy.*

*Experimental Analysis of Waverider Lift-to-Drag Ratio Measurements in Rarefied… DOI: http://dx.doi.org/10.5772/intechopen.100328*


*3.1. Soil Properties*

In this study, there was no significant difference in soil texture (p = 0.09) across the cropping systems and soil was sandy-clay loam or sandy-clay depending on their silt content (Table 2). Soil pH varied significantly (*p* = 0.03) between the cropping systems and soil under MCRC exhibited the lowest pH values. The soil under MCRC was classified as acidic while the soil under other cropping systems were classified as slightly acidic. Soil bulk-density (BD) values were significantly higher for the surface depth layers of 0–10 and 10–20 cm in the soil under fallow (5YF and Ab10YF) and teak plantation than the soil under cropping (MCRC and YMI). However, for the sub-layer depths (20–30 and 30–40), regardless of the cropping system, BD values increased with YMI showing the lowest BD while MCRC, TP, 5YF and Ab10YF exhibited the highest values.

**Table 2.** Soil properties under the different cropping systems.

MCRC: maize–cotton relay cropping; 5YF: 5-year fallow; Ab10YF: above 10-year fallow; YMI: yam–maize intercropping system; TP: teak plantation; BD: bulk density. Means that do not share a letter are significantly different at α = 0.05. ns non-significant at 5%; \* *p* value significant at 5%.


**1. Introduction**

The treatment of choice for symptomatic, persistent or enlarging periapical lesion after conventional re-root canal treatment is surgical endodontic treatment, which is aimed at resecting the root end and then creating a barrier at the apical end of the root with an inert material [1–3]. The goal of this treatment protocol is to salvage the tooth and prevent it

**Citation:** Ahmed, M.A.; Mughal, N.; Abidi, S.H.; Bari, M.F.; Mustafa, M.; Vohra, F.; Alrahlah, A. Factors Affecting the Outcome of Periapical Surgery; a Prospective Longitudinal Clinical Study. *Appl. Sci.* **2021**, *11*, 11768. https://doi.org/10.3390/ app112411768

Academic Editor: Gianrico Spagnuolo

Received: 23 August 2021 Accepted: 22 November 2021 Published: 10 December 2021

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

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

from further damage by limiting the entry of microbes and their byproducts into the canal system, thus promoting the health of the tooth.

The success of surgical endodontic treatment mainly relies on the absence of clinical signs and symptoms and radiographic resolution of periapical lesions. Studies have shown that multiple factors may influence the outcome of periapical surgery such as age, gender, smoking, type of root-end filling material, size of the preoperative periapical lesion, and the presence of pretreatment signs and symptoms [3,4].

Smoking is considered one of the risk factors that can impede periapical healing. Smoking disturbs healing by limiting the supply of oxygenated blood and nutrients to the periapical area [5]. This in turn makes periapical tissue more susceptible to bacterial infection [6]. Additionally, it alters the synthesis of collagen, expedites bone loss, and interferes in the tissue repair process around the periapical area [7,8]. Furthermore, smokers have restricted defense mechanisms due to the deficiency of several immunological factors such as Tumor necrosis factor alpha (TNF-α) and Human beta defensin-2 (hBD-2) [9].

There have been numerous studies investigating the size of preoperative periapical lesions with periapical wound healing. It was observed that fibroblasts proliferate into a large bony defect after periapical surgery and form scar tissues instead of allowing osteoblasts for osseous regeneration [10], which in turn disrupts healing. However, the involvement of several molecular and cellular factors makes it more intricate [11]. Few studies have reported a better healing outcome with smaller lesions [3,12,13] while others find no statistically significant difference in outcome in relation to the size of periapical lesions [14,15].

The presence of preoperative signs and symptoms indicates the acute stage of periapical lesion. Acute lesions usually present with pain and swelling while chronic lesions are usually asymptomatic with or without the presence of sinus tract. A consensus has been observed that the presence of preoperative clinical signs and symptoms do not significantly influence postoperative healing [16,17] however, vice versa has also been reported in some studies [3,18].

In light of conflicting evidence and lack of prospective studies regarding the factors that determine the successful outcome, the current study was designed to evaluate the various preoperative factors affecting the outcome of surgical endodontic treatment.


**4. Conclusions**

A simplified real-time forecast method and a simplified method for the estimation of return levels of storm surge in semi-enclosed basins are proposed. Both the two approaches are mixed. Indeed, results coming from a physics-based approach are corrected by means of statistical corrections.

In both cases, the strategy is to estimate the dynamic response function of the basin to a unit wind stress. These functions may be used, following the theory of

*Simplified Methods for Storm Surge Forecast and Hindcast in Semi-Enclosed Basins: A Review DOI: http://dx.doi.org/10.5772/intechopen.92171*

linear dynamic systems, to compute the response of a considered semi-enclosed basin using whatever wind time series.

In this way, only the wind field role is considered, and the pressure field is not. In order to take into account all the meteorological parameters inducing the storm surge, a statistical correction for both models is proposed.

In the case of forecast models, the statistical correction have been made using a series of artificial neural networks trained with (a) the residual raw level time series, (b) recent residual level estimated at the POI on the basis of the measurements collected during 24 h before the forecast time and (c) the forecasted pressures along the basin as input neurons.

For the hindcast method, instead, the pressure field has been considered using the pressure anomaly and operating a statistical correction using a calibration coefficient.

The approaches allow to reduce the computational costs since the numerical simulations have to be done once and for all for each considered basin.

The two methods have been applied to two different points of interest in the Adriatic Sea revealing in both cases good reliability of the obtained results compared to their simplicity.

It has to be noticed that these approaches are devoted to study storm surges in the semi-enclosed basins and are not able to correctly reproduce storm surges due to very rapid meteorological events (i.e. hurricanes).


Preface

This book consists of chapters that summarize the scientific research that connects functional foods with the active components and important health benefits. The health benefits of functional foods should be based on accurate scientific data and the issues of safety and efficacy should be taken into consideration. We must remember that functional foods are foods and not drugs or dietary supplements and any adverse effects with other pharmaceuticals should be thoroughly studied. In the Introductory Chapter 1, we see that it is important to communicate to the consumers the definitions of functional foods, the categories and how they can be prepared and used in our daily diet. In recent years, there has been growing interest in plant sources, vegetables, fruits, and medicinal plants rich in vitamins, fibers, and various categories of phytochemicals that have beneficial effects on human health, such as preventing or reducing the risk of chronic diseases. Olive oil is considered as a key component of the Mediterranean diet due to its fatty acid, especially monounsaturated fatty acid oleic acid, vitamin, and polyphenol composition. There are over 200 minor components in olive oil with biological activities. The most abundant antioxidants in olive oil are tocopherols, β-carotene, lutein, squalene, and lipophilic and hydrophilic phenols. Chapter 2 "Olive Oil: Antioxidant Compounds and Their Potential Effects On Health" overviews the chemical composition and health effects of the active components in olive oil. In Chapter 3 "Olive Oil Phenols", the structure and the significant biological activities of the four most abundant phenols in extra virgin olive oil (oleocanthal, oleacein, lingstroside aglycon, and oleuropein aglycon) are extensively described. An olive-oil-rich diet protects human health from cardiovascular diseases (cardiometabolic markers such as blood pressure, glycaemia, and dyslipidemia, LDL cholesterol, and LDL oxidation), type-2 diabetes, obesity, cancer, inflammation, and oxidative stress. The challenges of the new development of probiotic fermented products based on vegetables and fruits are presented in Chapter 4 "Fermented Functional Beverages" using scientific data from research studies. The scientific data, including the methods and the results, is presented in Chapter 5 "Functional Properties of Snack Bars" describes extensively the development of snack bars, which are consumer-friendly, with bioactive ingredients, and functional properties. Fish belongs to the basic food group of a healthy diet and is rich in important fatty acids, proteins, vitamins, and minerals. These are the key issues addressed in Chapter 6 "Fish as an Important Functional Food for Quality Life". New food processing technologies have been developed in order to stabilize the final functional product and preserve its bioactive properties and these are being used by food manufacturers. This is the key issue of Chapter 7. "Instant Controlled Pressure-drop DIC as a Strategic Technology for Different

Types of Natural Functional Foods". It is a process that improves both performance of the drying process and high-quality functional foods.

#### **Dr. Vasiliki Lagouri**

**1**

Section 1

Introduction

Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens, Greece

Section 1 Introduction

**3**

**Chapter 1**

Foods

*Vasiliki Lagouri*

**1. Functional foods definitions**

of foods not as supplements [1].

chemo-preventive effects" [4].

for functional food.

of any of them.

Introductory Chapter: Functional

The first definition of functional foods has been established in Japan. In 1991,

A second definition of functional foods developed by the "Functional Food Science in Europe" (FUFOSE): "Functional food is a food with certain beneficial effects on one or more target functions in the body beyond the basic nutritional effects with a result the improved health state and well being or reduction of risk of diseases. It is consumed as a part of a normal diet and is not used in the form of pill

Recently, the Functional Food Center (FFC) introduced a new definition for functional foods as: "Natural or processed foods that contains known or unknown biologically-active compounds; which, in defined, effective non-toxic amounts, provide a clinically proven and documented health benefit for the prevention, management, or treatment of chronic disease" [3]. In this definition, first functional foods can be natural or processed. Second, bioactive compounds, which are considered to be the source of the functionality of the foods, are secondary metabolites occur in food usually in small amounts that act synergistically to benefit health. Specifically, bioactive compounds may "exert antioxidant, cardio-protective and

US does not have a formal definition for functional foods. Τhe terms nutraceuticals or dietary supplements or medical foods are often used, thus functional foods cannot be regulated differently from other food products. Despite the government agencies, national and international organizations proposed their own definitions for functional food. The lack of a consistent definition between countries has led to unregulated publishing of health claims in functional foods and there exists an overall unclear definition of what "functional food" is between scientists, government officials, and the consumers. It is imperative that the food scientists should reconsider the meaning of functional food and agree upon a new formal definition

In practice, a functional food can be a natural food, a food to which a healthpromoting component has been added or from which a component for specific health reasons has been removed, a food in which a component has been modified by technological or chemical means to provide a specific health benefit, or a food in which the bioavailability of a component has been modified, or a combination

Although the terms "nutraceutical" and "functional food" are used commonly around the world, there is no consensus on their meaning. According to

the Japanese law entered the work definition "foods for specified health use" (FOSHU) which allowed the first health claims on the food labeling. The FOSHU can be foods which exhibit health effect, used as foods in a diet, and are in the form

or capsule or any other form of dietary supplement" [2].

#### **Chapter 1**

## Introductory Chapter: Functional Foods

*Vasiliki Lagouri*

#### **1. Functional foods definitions**

The first definition of functional foods has been established in Japan. In 1991, the Japanese law entered the work definition "foods for specified health use" (FOSHU) which allowed the first health claims on the food labeling. The FOSHU can be foods which exhibit health effect, used as foods in a diet, and are in the form of foods not as supplements [1].

A second definition of functional foods developed by the "Functional Food Science in Europe" (FUFOSE): "Functional food is a food with certain beneficial effects on one or more target functions in the body beyond the basic nutritional effects with a result the improved health state and well being or reduction of risk of diseases. It is consumed as a part of a normal diet and is not used in the form of pill or capsule or any other form of dietary supplement" [2].

Recently, the Functional Food Center (FFC) introduced a new definition for functional foods as: "Natural or processed foods that contains known or unknown biologically-active compounds; which, in defined, effective non-toxic amounts, provide a clinically proven and documented health benefit for the prevention, management, or treatment of chronic disease" [3]. In this definition, first functional foods can be natural or processed. Second, bioactive compounds, which are considered to be the source of the functionality of the foods, are secondary metabolites occur in food usually in small amounts that act synergistically to benefit health. Specifically, bioactive compounds may "exert antioxidant, cardio-protective and chemo-preventive effects" [4].

US does not have a formal definition for functional foods. Τhe terms nutraceuticals or dietary supplements or medical foods are often used, thus functional foods cannot be regulated differently from other food products. Despite the government agencies, national and international organizations proposed their own definitions for functional food. The lack of a consistent definition between countries has led to unregulated publishing of health claims in functional foods and there exists an overall unclear definition of what "functional food" is between scientists, government officials, and the consumers. It is imperative that the food scientists should reconsider the meaning of functional food and agree upon a new formal definition for functional food.

In practice, a functional food can be a natural food, a food to which a healthpromoting component has been added or from which a component for specific health reasons has been removed, a food in which a component has been modified by technological or chemical means to provide a specific health benefit, or a food in which the bioavailability of a component has been modified, or a combination of any of them.

Although the terms "nutraceutical" and "functional food" are used commonly around the world, there is no consensus on their meaning. According to

#### *Functional Foods*

the Bureau of Nutritional Sciences, of the Food Directorate of Health Canada, the following definitions have been proposed: A functional food is similar in appearance to, or may be, a conventional food, is consumed as part of a usual diet, and is demonstrated to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional functions. Nutraceutical is a product produced from foods but sold in powders, pills, and other medicinal forms not generally associated with food and demonstrated to have physiological benefits or provide protection against chronic disease. Functional food is clearly a different category than a nutraceutical, a pharmafood, or a dietary supplement. It is a food not a drug since it has beneficial health effects usually disease preventive and not therapeutic properties [5].

### **2. Functional foods categories**

The functional foods of plant or animal origin according to their action can be categorized as:

Functional foods can be in many forms. Some may be conventional foods with bioactive components that can now be identified and linked to positive health effects. Some may be fortified or enhanced foods, specifically formulated to reduce disease risk. Consumers can already choose from a wide variety of foods that contain functional components either inherently (e.g., soy protein, fish, olive oil) or through fortification (e.g., folate-fortified milk). As additional bioactive components are identified, the opportunities for developing functional foods will be broad [7]. Foods that naturally provide a bioactive substance may be enhanced to increase the level present in the food (e.g., eggs with increased levels of omega-3 fatty acids). On the other side, foods that do not naturally contain a bioactive substance can be fortified (e.g., calcium-fortified orange juice).

#### **3. Functional foods development**

According to the FCC, a few steps have been suggested to be followed in order to bring the functional foods to the market [3]:

**5**

**Author details**

Vasiliki Lagouri

Athens, Greece

provided the original work is properly cited.

\*Address all correspondence to<EMAIL_ADDRESS>
*Introductory Chapter: Functional Foods DOI: http://dx.doi.org/10.5772/intechopen.82304*

scientific basis for these regulations [9].

4.Development of the appropriate food vehicle.

5.Marketing the product to the public and educating about the health benefits.

Scientific understanding of the way in which specific food components affect body processes involved in health and well-being enables the development of markers that could confirm the impact of the new food products and could also be used in their safety assessment [8]. The development of functional foods using the innovative food technology and biochemical methods can offer beneficial effects to the consumers for well-being and reduction of the risk of disease. The design and the operation of such studies need to be carefully performed in order to give the scientific evidence for the approval of the health claims and the successful production of new functional foods. The development of functional foods, with their accompanying health claims, will proceed with progress in food regulation, which is the means to guarantee the validity of the claims as well as the safety of the food. Science in itself cannot be regulated and functional food science provides only the

6.Long-term studies on populations for the overall product effectiveness.

7.Measurement of the public attitudes toward functional food.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of

*Functional Foods*

therapeutic properties [5].

categorized as:

vegetables).

**2. Functional foods categories**

the Bureau of Nutritional Sciences, of the Food Directorate of Health Canada, the following definitions have been proposed: A functional food is similar in appearance to, or may be, a conventional food, is consumed as part of a usual diet, and is demonstrated to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional functions. Nutraceutical is a product produced from foods but sold in powders, pills, and other medicinal forms not generally associated with food and demonstrated to have physiological benefits or provide protection against chronic disease. Functional food is clearly a different category than a nutraceutical, a pharmafood, or a dietary supplement. It is a food not a drug since it has beneficial health effects usually disease preventive and not

The functional foods of plant or animal origin according to their action can be

1.Vitamins and minerals fortification (e.g., vit C, folic acid, calcium, iron).

2.Cholesterol reduction (e.g., omega-3 fatty acids, phytosterols).

4.Probiotics, prebiotics, and synbiotics (e.g., yoghourt, kefir, fruits,

5.Phytochemicals (e.g., phenolic compounds, carotenoids, lycopene) [6].

Functional foods can be in many forms. Some may be conventional foods with bioactive components that can now be identified and linked to positive health effects. Some may be fortified or enhanced foods, specifically formulated to reduce disease risk. Consumers can already choose from a wide variety of foods that contain functional components either inherently (e.g., soy protein, fish, olive oil) or through fortification (e.g., folate-fortified milk). As additional bioactive components are identified, the opportunities for developing functional foods will be broad [7]. Foods that naturally provide a bioactive substance may be enhanced to increase the level present in the food (e.g., eggs with increased levels of omega-3 fatty acids). On the other side, foods that do not naturally contain a bioactive substance can be

According to the FCC, a few steps have been suggested to be followed in order to

1.Study the link between the particular food component and health benefits.

3.Human studies which involve human appropriate dosages of bioactive com-

2.In vitro and in vivo studies with nonliving and animal specimens.

3.Dietary fiber (e.g. nondigestible carbohydrates and lignin).

fortified (e.g., calcium-fortified orange juice).

bring the functional foods to the market [3]:

pounds and testing for adverse side effects.

**3. Functional foods development**

**4**

4.Development of the appropriate food vehicle.

Scientific understanding of the way in which specific food components affect body processes involved in health and well-being enables the development of markers that could confirm the impact of the new food products and could also be used in their safety assessment [8]. The development of functional foods using the innovative food technology and biochemical methods can offer beneficial effects to the consumers for well-being and reduction of the risk of disease. The design and the operation of such studies need to be carefully performed in order to give the scientific evidence for the approval of the health claims and the successful production of new functional foods. The development of functional foods, with their accompanying health claims, will proceed with progress in food regulation, which is the means to guarantee the validity of the claims as well as the safety of the food. Science in itself cannot be regulated and functional food science provides only the scientific basis for these regulations [9].

### **Author details**

Vasiliki Lagouri Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Greece

\*Address all correspondence to<EMAIL_ADDRESS>
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Shimizu T. Health claims on functional foods: The Japanese regulations and an international comparison. Nutrition Research Reviews. 2003;**16**(2):241-252

[2] The European Parliament and the Council of the European Union. Regulation no 1924/2006 of the European parliament and of the council on nutrition and health claims made on foods. Official Journal of the European Union. 2006;**404**:9-25

[3] Martirosyan DM, Singh J. A new definition for functional food by FFC: What makes a new definition unique? Functional Foods in Health and Disease. 2015;**5**(6):209-223

[4] Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, et al. Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer. The American Journal of Medicine. 2002;**113**:71-88

[5] Health Canada Policy Paper: Nutraceuticals/Functional Foods and Health Claims on Foods, Therapeutic Products Programme and the Food Directorate from the Health Protection Branch 1998

[6] Roberfroid MB. In: Gibson GR, William CM, editors. Functional Foods Concept to Product. 1st ed. Abington Hall, Abington, Cambridge: Woodhead Publishing; 2000. pp. 9-25

[7] O'Donnell CD. Ten trends in nutraceutical ingredients. Prepared Foods. 2003;**172**:89-92

[8] Aggett PJ et al. Scientific concepts of functional foods in Europe consensus document. British Journal of Nutrition. 1999;**81**:Sl-S27

[9] Roberfroid MB. A European consensus of scientific concepts of functional foods. Nutrition. 2000;**16**:689-691

Section 2

Functional Foods - Properties

and Technology

7

Section 2


**Author details**

Rabeeya Saeed1 , Salman Sharif1 \* and Faridah Amin2

1 Liaquat National Hospital and Medical College, Karachi, Pakistan

2 Indus Hospital and Health Network, Karachi, Pakistan

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.