E numbers of food additives.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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\r\n\r\n\tThis book provides the reader with an overview of the latest developments in the anatomy of paranasal sinus and sino-nasal system disorders and focuses on the most important evidence-based developments in rhinology. The book will emphasize six different sections namely 'Normal anatomy and anatomical variations', 'Arterial supply of nasal cavity', 'Radiology of paranasal sinuses', 'Frontal/anterior and posterior ethmoid/maxillary/ sphenoid sinusitis', 'Orbit and lacrimal system' and ' Pituitary and para sellar region'. General otolaryngologists, rhinologists, anatomists, specialist related services, and general practitioners with interest in otolaryngology will find this book useful and of interest.
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He was an ENT registrar at the Royal Infirmary, Middlesbrough, the United Kingdom in 1993 and subsequently a JW Fulbright scholar at the University of Pittsburgh, the USA in 1997. Dr. Gendeh has written 95 scientific papers in peer-reviewed journals with more than 478 citations, HI of 13, and editor of 8 books and 7 book chapters.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"67669",title:null,name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh",profilePictureURL:"https://mts.intechopen.com/storage/users/67669/images/system/67669.png",biography:"Dr. Balwant Singh Gendeh is a senior consultant ENT surgeon with sub-specialty interest in rhinology (allergy, sinonasal diseases, endoscopic sinus, anterior and ventral skull base surgery, and functional and cosmetic nasal surgery). He was an ENT registrar at the Royal Infirmary, Middlesbrough, United Kingdom in 1993 and subsequently a JW Fulbright scholar at the University of Pittsburgh, USA in 1997. During his Fulbright experience, he also worked at the Hospital of the University of Pennsylvania (HUP), Philadelphia and St Joseph’s Hospital, Chicago, USA with sub-specialty interest in rhinology and aesthetic nasal surgery. Dr. BS Gendeh retired as a consultant ENT surgeon at the National University of Malaysia Medical Center (UKMMC) in 2014, and is presently a Visiting Professor at the Department of Otorhinolaryngology-Head and Neck Surgery at UKMMC and is a resident ENT consultant at Pantai Hospital Kuala Lumpur since 2014. Due to his vast contribution to the academia in research and clinical publication, he was elected as a Diploma of Fellowship Academy of Medicine Malaysia (FAMM) in October 2000, International Fellow of the American Academy of Otolaryngology Head and Neck Surgery in April 2004, Fellow of the Academy of Sciences Malaysia (FASc) in April 2016 and as Fellow of Malaysian Scientific Association (FMSA) in September 2017. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"56648",title:"Introductory Chapter: Introduction to Food Additives",doi:"10.5772/intechopen.70329",slug:"introductory-chapter-introduction-to-food-additives",body:'\nFood additives are utilized in the preparation and processing of almost all types of food in order to give favorable attributes to the food we eat. Very simply, it is a substance which is added to food to enhance its flavor, appearance, or other favorable quality. In fact, the food protection committee of the US national research council defined food additives as “A substance or a mixture of substances other than a basic food stuff that is present in a food as a result of an aspect of production, processing, storage, or packaging” [1]. According to US FDA (Food and Drug Administration), a food additive is “any substance, the intended use of which results or may reasonably be expected to result–directly or indirectly–in its becoming a component or otherwise affecting the characteristics of any food” [2]. Although the term ‘food additives’ has been used frequently at present, its utilization has been practiced since ancient times; and probably dating back to much earlier than the hunter-gatherer era. Even though food additives confer much benefit to all sectors, such as the manufacturers, retailers, and customers, utilization of food additives must be carried out extremely cautiously.
\nAdditives, for the most part, are synthetic chemicals. Present day consumers are turning to natural ingredients and bio-based additives due to adverse effects caused by some chemicals. Therefore, plant-derived substances are gaining a foot hold as preservatives, colorants, flavors, and even as antibacterial agents [3, 4].
\nAlmost all safe-to-use food additives are given ‘E numbers’ by the European Food Safety Authority. In order to get to this status, the food additive must pass all the safety checks. Following are the general categories of food additives and their E numbers. However, when one food additive has more than one function, it is given only one E number. Chemical compounds and other species are constantly added to the list of safe-to-use food additives as the food additives pass the safety checks. An up to date list of food additives and their E numbers could be obtained from official UK food standards agency web site https://www.food.gov.uk/science/additives/enumberlist#toc-1. The general list of E numbers of food additives is given in Table 1 [5].
\nBlock of numbers | \nFood additives | \n
---|---|
E100-E199 | \nColors | \n
E200-E299 | \nPreservatives | \n
E300-E399 | \nAntioxidants and acidity regulators | \n
E400-E499 | \nThickeners, stabilizers and emulsifiers | \n
E500-E599 | \nAnticaking agents | \n
E600-E699 | \nFlavor enhancers | \n
E700-E799 | \nAntibiotics | \n
E900-E999 | \nGlazing agents and sweeteners | \n
E1000-E1599 | \nAdditional chemicals | \n
E numbers of food additives.
Chemical | \nOdor | \n
---|---|
Diacetyl, acetylpropionyl, acetoin | \nButtery | \n
Isoamyl acetate | \nBanana | \n
Benzaldehyde | \nBitter almond, cherry | \n
Cinnamaldehyde | \nCinnamon | \n
Ethyl propionate | \nFruity | \n
Methyl anthranilate | \nGrape | \n
Limonene | \nOrange | \n
Ethyl decadienoate | \nPear | \n
Allyl hexanoate | \nPineapple | \n
Ethyl maltol | \nSugar, cotton candy | \n
Ethylvanillin | \nVanilla | \n
Methyl salicylate | \nWintergreen | \n
Acid | \nDescription | \n
---|---|
Glutamic acid salts | \nThis amino acid’s sodium salt, monosodium glutamate (MSG), is one of the most commonly used flavor enhancers in food processing. Mono- and diglutamate salts are also commonly used. | \n
Glycine salts | \nSimple amino acid salts typically combined with glutamic acid as flavor enhancers. | \n
Guanylic acid salts | \nNucleotide salts typically combined with glutamic acid as flavor enhancers. | \n
Inosinic acid salts | \nNucleotide salts created from the breakdown of AMP, due to high costs of production, typically combined with glutamic acid as flavor enhancers. | \n
5’-Ribonucleotide salts | \nNucleotide salts typically combined with other amino acids and nucleotide salts as flavor enhancers. | \n
According to the US FDA, “A color additive is any dye, pigment, or substance, which when added or applied to a food, drug or cosmetic, or to the human body, is capable (alone or through reactions with other substances) of imparting color” [2]. Food colors are used as food additives mainly to yield better sensory effects, specifically appearance contentment. The reasons for adding colors to food are manifold. First, color may be lost due to the processing and storage conditions of food, and thus food colors are added to compensate such loss of color. Second, food items with natural colors may show a variation of color, and thus food colors are added to correct such variations in color. Third, food colors may be added to further improve the natural color of the food. Fourth, food colors are added to give color to food items with no color [2].
\nThere are two types of food colors, certified colors and colors exempt from certification. The certified colors are synthetic compounds. They are usually more effective than natural compounds and they do not introduce off-flavors to the foods. Colors derived from natural sources are exempt from certification. These compounds are more expensive than synthetic compounds. Yet, the colors exempt from certification may give off-flavors to the foods [2].
\nHealth effects of food colorants are a major concern among the consumers and regulatory bodies; and thus, carrying out toxicity studies determining health effects are considered very significant today. A recent study revealed that Allura Red AC lacks genotoxicity after the European Food Safety Authority showed its concern on this matter [6]. In addition to toxicity studies, remedies for the adverse effects of food colorants are being evaluated. For example, Rafati et al. demonstrated that the negative effects caused by tartrazine in mice could be mitigated by the simultaneous administration of vitamin E [7].
\nAlthough food colors are added to enhance organoleptic appeal of the foods, naturally occurring food colors such as curcumin and riboflavin possess other beneficial health effects. In fact, curcumin exhibits numerous bioactivities such as antioxidant, antimicrobial, and anticancer [8, 9]. Riboflavin, also, acts as an antioxidant, and it is linked to several health benefits [10]. Numerous strategies have been explored to increase the stability of natural colorants due to beneficial health effects or general lack of toxicity of these compounds [11, 12]. As expected, novel sources of natural colorants are being explored due to the positive attributes of natural colorants [13]. In addition, encapsulation techniques and other innovative methods are being explored in order to improve numerous properties of food colorants as opposed to directly add food colorants in food [14].
\nThe list of colors usually used in food manufacturing is stated below [5].
\nList of colors: Curcumin, Riboflavin, Riboflavin-5’-phosphate, Tartrazine, Quinoline yellow, Sunset Yellow FCF, Orange Yellow S, Cochineal, Carminic acid, Carmines, Azorubine, Carmoisine, Amaranth, Ponceau 4R, Cochineal Red A, Erythrosine, Allura Red AC, Patent Blue V, lndigotine, Indigo Carmine, Brilliant Blue FCF, Chlorophylls and chlorophyllins, Copper complexes of chlorophyll and chlorophyllins, Green S, Plain caramel, Caustic sulphite caramel, Ammonia caramel, Sulphite ammonia caramel, Brilliant Black BN, Black PN, Vegetable carbon, Brown FK, Brown HT, Carotenes, Annatto, Bixin, Norbixin, Paprika extract, Capsanthin, Capsorubin, Lycopene, Beta-apo-8’-carotenal (C30), Ethyl ester of beta-apo-8’-carotenoic acid (C30), Lutein, Canthaxanthin, Beetroot Red, Betanin, Anthocyanins, Litholrubine BK.
\nFood preservatives have become an indispensible part of the food industry today. In simple terms, a food preservative is any substance that hinders food deterioration caused by microbes, enzymes, or any other chemical reaction. Millions of people suffer from hunger as a result of lack of enough food [15] and thus, the advantages of using food preservatives in food processing are plenteous. Food preservatives along with other food additives are under strict control by numerous governing bodies. A short account of the governing system is given under Section 11.
\nMost artificial food preservatives impart negative health effects at high doses. For instance,
Natural preservatives are an appealing alternative to artificial preservatives, especially with respect to health effects. A novel trend is to explore and utilize essential oils such as clove essential oil and eugenol extracted from cloves, limonene extracted from citrus fruits, and essential oil extracted from cinnamon as food preservatives of numerous food items including fresh cut produce, juices, and fish [3, 18–20]. As expected, encapsulated natural food preservatives including thyme essential oil and curcumin have shown favorable properties such as sustained release and enhanced antioxidant and antimicrobial properties [21, 22]. In addition to natural products, fermented milk products have shown promise as food preservatives [23]. The reasons for utilizing natural products and nonsynthetic products as food preservatives include imparting health benefits to the consumers and gaining “clean label” advantage.
\nNumerous approaches are being taken to find novel food preservatives with ameliorated properties. For instance, peptides have been used successfully as potential food preservatives [24]. Once a peptide food preservative is identified, mass production may be carried out using biotechnology. Combinations of food preservatives have also been studied to discover the combined effect and the possibility of substituting synthetic food preservatives by such combinations. For example,
Some food preservatives used in food manufacturing are listed below [5].
\nList of preservatives: Sorbic acid, Potassium sorbate, Calcium sorbate, Benzoic acid, Sodium benzoate, Potassium benzoate, Calcium benzoate, Ethyl p-hydroxybenzoate, Sodium ethyl p-hydroxybenzoate, Sodium methyl p-hydroxybenzoate, Sulfur dioxide, Sodium sulphite, Sodium hydrogen sulphite, Sodium metabisulphite, Potassium metabisulphite, Calcium sulphite, Calcium hydrogen sulphite, Potassium hydrogen sulphite, Biphenyl; diphenyl, Nisin, Natamycin, Hexamethylene tetramine, Dimethyl dicarbonate, Potassium nitrite, Sodium nitrite, Sodium nitrate, Potassium nitrate, Propionic acid, Sodium propionate, Calcium propionate, Potassium propionate, Boric acid, Sodium tetraborate; borax.
\nAntioxidants play a pivotal role in the food industry, combating oxidative stress on oxygen-sensitive species. The antioxidants used in the food industry are either hydrophilic, lipophilic, or amphiphilic, protecting various types of ingredients. Certain antioxidants function also as acidity regulators. Examples include ascorbic acid and citric acid. Acidity regulators are also an essential group of food additives as lowering the pH of the food usually assists to retard microbial attack.
\nAlthough antioxidants are deemed to confer numerous health benefits to the humans, synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) have shown negative health effects [26]. On the contrary, some reports have shown chemoprevention properties of those synthetic carcinogenic antioxidants [27]. Again, the issue of toxicity is dealt with by adhering strictly into the ADI published by the governing bodies worldwide including the US FDA. Although the results of synthetic antioxidants are inconsistent, numerous natural antioxidants have the ability to function as nontoxic anticarcinogenic compounds. Examples include ferulic acid, caffeic acid, curcumin, vitamin E, polyphenolic catechins, and carnosol [28].
\nAs with other food additives, the trend is to utilize and seek for natural food antioxidants. Both pure antioxidants and plant extracts are used and explored these days. Moreover, encapsulation of pure antioxidants and plant extracts showing antioxidant properties is carried out to obtain improved attributes such as improved stability and sustained release of those bioactive compounds [29, 30]. The liposomal encapsulation of the
A list of antioxidants used in food manufacturing is stated below [5].
\nList of antioxidants: Ascorbic acid, Sodium ascorbate, Calcium ascorbate, Fatty acid esters of ascorbic acid, Tocopherols, Alpha-tocopherol, Gamma-tocopherol, Delta-tocopherol, Propyl gallate, Octyl gallate, Dodecyl gallate, Erythorbic acid, Sodium erythorbate, Tertiary-butyl hydroquinone (TBHQ), Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), Extracts of rosemary, 4-Hexylresorcinol.
\nAcidity regulators such as citric acid, tartaric acid, and phosphoric acid are numbered together with antioxidants in the E numbering system [5, 31]. This approach is very logical as certain acidity regulators, such as citric acid, exhibit antioxidant properties. In fact, citric acid has imparted favorable effects on food, functioning as an acidity regulator and antioxidant simultaneously [32]. What’s more, food acidity regulators have shown advantageous combined effects with other food additives on food. Antibrowning effect of citric acid together with ascorbic acid and nitrogen on banana smoothies is an example [33].
\nThe list of acidity regulators commonly used in food manufacturing is stated below [5].
\nList of acidity regulators: Sodium lactate, Potassium lactate, Calcium lactate, Citric acid, Sodium citrates, Potassium citrates, Calcium citrates, Tartaric acid (L-(+)), Sodium tartrates, Potassium tartrates, Sodium potassium tartrate, Phosphoric acid, Sodium phosphates, Potassium phosphates, Calcium phosphates, Magnesium phosphates, Sodium malates, Potassium malate, Calcium malates, Metatartaric acid, Calcium tartrate, Adipic acid, Sodium adipate, Potassium adipate, Succinic acid, Triammonium citrate, Calcium disodium ethylene diamine tetra-acetate; calcium disodium EDTA.
\nThickeners, stabilizers, emulsifiers, and gelling agents have become an integral part in the current food manufacturing industry. Thickeners increase the volume, change the viscosity, and increase the processability of the food items. Stabilizers, as the name implies, stabilize the food products; sometimes through the utilization of fillers. Emulsifiers assist in the miscibility of otherwise immiscible substances possible. For instance water-in-oil or oil-in-water emulsions used in the food industry are made utilizing emulsifiers. Gelling agents mainly contribute to the viscosity and sensory properties of the food products. In sum, all thickeners, stabilizers, emulsifiers and gelling agents contribute to the stability and palatability of the food product.
\nThis category of food additives also consist of natural and synthetic compounds. In fact, lecithin that assists in emulsification and stabilization for most food products is mostly extracted from soy bean, and thus it is a natural additive [34]. However, numerous studies are being conducted evaluating the positive effects of synthetic lecithin [35]. Alginate functioning as both a thickener and gelling agent is another natural food additive in this group [36]. Apart from the natural compounds, synthetic emulsifiers such as polysorbates constitute an important component of this group. Although considered food grade, several health concerns have arisen regarding such artificial emulsifiers [37].
\nA list of thickeners-stabilizers-emulsifiers-gelling agents used in food manufacturing is listed in Tables 2 and 3 [5].
\nList of thickeners-stabilizers-emulsifiers-gelling agents: Lecithins, Alginic acid, Sodium alginate, Potassium alginate, Ammonium alginate, Calcium alginate, Propane-1-2-diol alginate, Agar, Carrageenan, Processed eucheuma seaweed, Locust bean gum; carob gum, Guar gum, Tragacanth, Acacia gum; gum Arabic, Xanthan gum, Karaya gum, Tara gum, Gellan gum, Konjac, Soybean hemicellulose, Cassia gum, Polyoxyethylene sorbitan monolaurate; Polysorbate 20, Polyoxyethylene sorbitan mono-oleate; Polysorbate 80, Polyoxyethylene sorbitan monopalmitate; Polysorbate 40, Polyoxyethylene sorbitan monostearate; Polysorbate 60, Polyoxyethylene sorbitan tristearate; Polysorbate 65, Pectins, Ammonium phosphatides, Sucrose acetate isobutyrate, Glycerol esters of wood rosins, Cellulose, Methyl cellulose, Ethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, Ethyl methyl cellulose, Carboxy methyl cellulose, Crosslinked sodium carboxy methyl cellulose.
\nAs the name implies, the role of anticaking agents is to prevent lumping or caking in food. These agents are added mostly for powders or granulated material. Among the numerous advantages of using anticaking agents include: sustenance of sensory attributes, easiness of packaging, efficient transportation, and simplicity to yield high quality products for consumption. Depending on the food product involved, either water-soluble or organic solvent-soluble anticaking agents are used.
\nAnticaking agents frequently used in food manufacturing are stated below [5].
\nList of anticaking agents: Calcium Aluminum Silicate, Calcium Phosphate tribasic, Calcium Sili-cate, Calcium Stearate, Cellulose, Magnesium Carbonate, Magnesium Oxide, Magnesium Silicate, Magnesium Stearate, Microcrystalline Cellulose, Propylene Glycol, Potassium Ferrocyanide, Trihydrate, Silicon Dioxide, Sodium Aluminum Silicate, Sodium Ferrocyanide, decahydrate.
\nFlavors and flavor enhancers are of extreme importance in the food industry as it is what makes the food sensational. Flavor is perceived by the taste and smell via chemical senses. Also, the chemical irritants perceived in the mouth and throat, temperature and texture are factors affecting the flavor of a food. Nowadays, both natural and artificial substances are used as food flavors Table 2. The basic universally recognized flavors include: sweet, sour, tangy, bitter, umami, hot, that can be perceived through the tongue. On the other hand, the number of sensations that can be perceived through the nose (smell) is limitless. As a result, the food industry is ever growing utilizing different combinations of taste and smell. What’s more, there is another group of chemical substances that do not impart any flavor in to the food product but enhance the existing flavor in the food Table 3. These flavor enhances are highly valued in the food industry as these substances contribute significantly into cost reduction in food manufacturing. Flavors and flavor enhancers frequently used in food manufacturing are stated [38].
\nFlavors and flavor enhances also are evaluated for their health effects by numerous scientists worldwide. Further, extraction of numerous novel natural flavors is being carried out around the globe as a result of the higher inclination of the customers to such natural compounds [39]. There has been much criticism on the health effects of glutamate—a much consumed flavor enhancer. However, mixed results have been published and there is no evidence to prove that glutamate possesses negative health effects, according to a recent report [40]. Like almost all other food additives, encapsulation, for instance microencapsulation and emulsification, is used as means of enhancing the properties of food flavors [41, 42].
\nAntibiotics are being used in the food industry today to increase the shelf life of numerous food items, especially perishable food items including milk [43]. Although not directly added during food processing, nonvegetarian food may contain a certain amount of antibiotics since antibiotics are frequently used in animal production. However, any antibiotic used for human therapeutic purposes or for animal feed additive are banned for use in the food industry. Tetracycline is a classic example. Maximum permissible amounts of such antibiotic residues have been declared and much emphasis is given to regular monitoring of antibiotic residues in food [44]. Moreover, the antibiotics used in the food industry show slower activity than those used for therapeutic purposes [45]. Antibiotics frequently used in food manufacturing are stated below.
\nList of antibiotics: Nisin, Natamycin, Subtilin, Tylosin Phytoncides.
\nPhytoncides are antibiotics obtained from plants. Examples include: mustard oil, thyme, cinnamaldehyde, eugenol, etc. [46].
\nAntibiotics permitted as food additives are being experimented heavily, especially to engineer more potent variants [47]. Further, encapsulation has become a common technique to enhance the desirable properties of antibiotics. For instance, coated liposomes encapsulating nisin has shown improved sustained release properties beneficial for applications in the food sector [48].
\nGlazing agents may be either natural or synthetic. They are used mainly for preservation of food items by forming a thin coat around it [49]. A list of glazing agents frequently used in food industry is stated below [5].
\nList of glazing agents: Stearic acid, Beeswax, Candelilla wax, Carnauba wax, Shellac, Microcrystalline wax, Crystalline wax, Lanolin, Oxidized polyethylene wax, Esters of colophonium, Paraffin.
\nThe most commonly used sweetener used in the food industry is sucrose as it is readily available. Thus, the performance of other sweeteners is frequently measured against that of sucrose [50]. Glucose is also frequently used in the food industry, especially in the manufacturing of confectionaries [51]. However, substitutes for common sugars, natural or artificial, are in high demand due to the prevalence of diabetes mellitus among a significant proportion of people worldwide. Other requirements for sugar substitutes include weight loss, dental care, and reactive hypoglycemia. In addition, using sugar substitutes is cost effective since the sugar substitutes are many times (sometimes more than 100 or even 1000 times) sweeter than sucrose [52]. A list of sweeteners frequently used in food manufacturing is stated below [5, 53].
\nList of sweeteners: Sorbitol, Sorbitol syrup, Mannitol, Acesulfame K, Aspartame, Cyclamic acid and its Na and Ca salts, lsomalt, Saccharin and its Na - K and Ca salts, Sucralose, Thaumatin, Neohesperidine DC, Steviol glycoside, Neotame (as a flavor enhancer), Salt of aspartame-acesulfame, Maltitol, Maltitol syrup, Lactitol, Xylitol, Erythritol.
\nThe European Food Safety Authority has grouped some food additives as ‘additional chemicals’ as those chemicals cannot be grouped together with other food additives. As indicated in Table 1, these chemicals are numbered from E1000 to E1599. Even though these chemicals may function as other food additives, they have different properties and thus treated differently. For instance, invertase having the number E1103 functions as emulsifiers-stabilizers-thickeners-gelling agents but is in a special category.
\nA list of other chemicals frequently used in food manufacturing is stated below [5].
\nList of other chemicals: Polydextrose, Polyvinylpyrrolidone, Polyvinylpolypyrrolidone, Polyvinyl alcohol, Pullulan, Basic methacrylate copolymer, Oxidized starch, Monostarch phosphate, Distarch phosphate, Phosphated distarch phosphate, Acetylated distarch phosphate, Acetylated starch, Acetylated distarch adipate, Hydroxyl propyl starch, Hydroxy propyl distarch phosphate, Starch sodium octenyl succinate, Acetylated oxidized starch, Starch aluminum Octenyl succinate, Triethyl citrate, Glyceryl triacetate; triacetin, Propan-1-2-diol; propylene glycol, Polyethylene glycol.
\nFood additives are under strict control of numerous governing bodies. In the European Union, the governing bodies are the European Food Safety Authority (EFSA) and the European Commission, Parliament and Council. These bodies are accountable for the safety assessment, which includes toxicological studies and dietary exposure assessment, authorization which includes maintaining and publishing data bases of food additives permitted to be used in the EU, and control which is involved in legislation and labeling of food additives. The U.S. Food and drug administration (US FDA) is the main governing body of food additives in USA, and almost all other countries have their own governing bodies of food safety. Food and Agriculture Organisation (FAO) and the World Health Organisation (WHO) work together in the international arena via a Joint Expert Committee on Food Additives (JECFA) [54–57].
\nJoint Expert Committee on Food Additives from 1961 has taken initiative of matters regarding the acceptable daily intake (ADI) level. “ADI is a measure of the amount of a specific substance (originally applied for a food additive, later also for a residue of a veterinary drug or pesticide) in food or drinking water that can be ingested (orally) on a daily basis over a lifetime without an appreciable health risk”. “ADIs are expressed usually in milligrams (of the substance) per kilogram of body weight per day.” [58]
\nAll of these food additives are used to fine tune the food items to yield a superb food product having sensational attributes. In addition, the preservative effect that the food additives impart is of utmost importance. Further, food safety governing bodies worldwide have set maximum levels to be used in the food industry for all approved food additives. Thus, health risk is at a low level. However, it is advisable to change ones diet time to time so that the subject is not exposed to the same food additives for lengthy periods of time. This practice also may not be essential if the customer pays attention to the recommended daily intake of the ingredients.
\n“Innovation is change that unlocks new value” according to Jamie Notter [59]. Adding food additives to enhance the attributes of food is an ancient concept of value addition of food practiced from as early as the hunter-gatherer era. In the modern era, the demand is greater than the supply, and innovation is the change that satisfies the demand by all the sectors, such as the manufacturers, retailers, and customers. While using food additives to enhance the attributes of food, it is of prime importance that guidelines by the relevant food safety authorities are followed since synthetic and natural compounds with various health effects are widely used as additives. Deviations from food safety regulations may result in serious negative outcomes. As a result, any party breaching rules and guidelines regarding food additives will have to face serious consequences, including harsh court decisions against them. In sum, considering the health effects and regulations regarding food additives are extremely significant although utilizing food additives have enabled the beings to enjoy a plethora of various food products.
\nThe biological phenomena could be explained by classical physics, and most of these phenomena are characterized by cycles. Usually, the time period required to “complete a cycle” is not constant. The study of time period fluctuations represents a way to assess interactions between other systems and the intrinsic properties of the same system.
\nThe light/dark cycle (circadian rhythm) and the cyclic seasons that divide the year by changes on weather, ecology, and hour of daylight allowed the evolution of life on earth [1]. These series of events have influenced the organisms inducing cycles that are essential for life (hormonal, organ function, behavior, production of neurotransmitters, reproduction, and others); all cycles are fluctuations related to several biological phenomena. The study and knowledge of the fluctuations of biological phenomena are valuable to analyze the intrinsic properties of a system and the interaction with other cyclic systems [2].
\nThe quantification of biological variability has been used to study several physiological phenomena, among them, fluctuations on the heart rate using the RR interval period of the electrocardiogram (ECG). The heart rate variability (HRV) is a useful health indicator [3], and in this chapter we detail how this tool is used for the prognosis and diagnosis of metabolic diseases.
\nAll organisms present dynamic and complex oscillations in their function. The time between every oscillation is called period, and it represents biological rhythms. These rhythms regulate all physiological processes with periods of milliseconds as neuronal activity, seconds as the heart rate, hours as hormone release, monthly as the ovarian cycle, and annually as the growth and migration. The biological rhythms are present in all levels of biological organization at the molecular, organelle, cell, and tissue levels; these organizations are present in vertebrates, invertebrates, and plants (Figure 1).
\nVariability biologic system. All organisms develop the variability of biological systems for environmental adaptation. Physiological and metabolic processes depend on the interaction between the central and peripheral rhythms.
The study of period variations is essential because these fluctuations represent the interaction of the cycles with other systems or alterations on the intrinsic properties of the same system, individual and interspecific variability [4].
\nThe periods can oscillate only under the influence of an external periodic signal originating exogenous rhythms; these allow changes in the variability of biological rhythm associated with external environmental synchronizer [5]. However, when the light/darkness external synchronizer is removed, a self-sustaining oscillation is shown, so it is said that the system has an autonomous endogenous rhythm.
\nThe biological rhythms with a periodicity of 24 h are denominated circadian rhythms (
The autonomous nervous system (sympathetic and parasympathetic) regulates the cardiovascular system that involves the heart rate variability. The relevance that the intermittent oscillations of peripheral clocks modulate the variability of the central clock is fundamental for health process. The coordination and communication among peripheral and central clock are essential for metabolic, enzymatic, molecular, and physiological process.
\nThe heart rate (HR) is determined by the activity of the sinoatrial node. The electrical activity propagates to the atria and then to the atrioventricular node, and, finally, the electrical activity reaches the ventricles triggering its contraction from apex to base. Any change in the origin and propagation of this electrical activity is denominated arrhythmia. The contraction and relaxation of cardiac tissue is a process named heartbeat. It is a cyclical event, the beats per minute produce the heart rate. Heart rate is a parameter that serves to diagnose some health problems in patients. When HR is increased, it is called tachycardia and the decrease of HR is called bradycardia. Tachycardia is related to exercise, emotions, the fight or flight phenomenon, among other activities. Bradycardia is related to sleep and rest. To measure HR there are several methods that are used in the clinic, like pulse taking, auscultation, and electrocardiography.
\nThe interaction of the organisms with its environment causes changes in the metabolic requirements of the multiple tissues that are depending on the circulating blood to supply oxygen and nutrients and remove metabolic waste, i.e., age, physical conditioning or exercise, behavior (emotions, pathologies, spice that is being studied, activity that takes place when the HR is taken, hemorrhages, heart attacks, addictions). In response to these demands, the heart adapts its interbeat intervals.
\nThese intervals vary thanks to the intrinsic properties of the heart (spontaneous activity of the sinoatrial node [6] and atrial and ventricular electrical properties along with extracellular matrix composition) and especially the influence of the autonomic nervous system (ANS), a communication pathway between the heart and the whole body. This system modulates the spontaneous activity of the sinoatrial node and conduction system of the heart (Figure 2).
\nHeart rate variability sources. The time interval variations between consecutive heartbeats are result of the interaction between the autonomous nervous system modulation and intrinsic properties of the heart regulating its function.
The ANS regulates heart rate, visceral activities, and glandular functions to keep homeostasis. The ANS innervation on the heart can be divided in sympathetic (SNS) and parasympathetic (PNS) nervous system. They both have opposing effects on the heart activity. The sympathetic nervous system is responsible for the “fight or run” response, increasing the myocardium contractile properties and the rate of spontaneous activity of the sinoatrial node (SAN), the natural pacemaker of the heart, augmenting the heart rate. On the other hand, the parasympathetic nervous system has an inhibitory effect on the peacemaker and atrioventricular node (NAV) activity (see Figure 2), adjusting to rest states by means of a decrease in the heart rate [2].
\nSympathetic innervation secretes norepinephrine, a neurotransmitter that links to β1 receptors on the cardiac sarcolemma activating G proteins. This union induces a conformational change that dissociates the αs subunit activating adenylyl cyclase. The activated adenylyl cyclase catalyzes the conversion of ATP to AMPc, which joins directly to ionic channels responsible for the hyperpolarization activated pacemaker current (If) increasing the SAN depolarization rate. This stimulus also increases the opening probability and the inward calcium current enhancing the strength of cardiac contraction. Parasympathetic innervation releases acetylcholine, a neurotransmitter that binds to M2 receptors on the cardiac sarcolemma activating inhibitory G proteins, inducing a conformational change in Gi protein that dissociates the αi subunit inhibiting adenylyl cyclase leading to a decrease in the formation of AMPc, thus decreasing the SAN depolarization rate. The dynamical interaction between SNS and PNS enables the heart to fulfill the organism requirements in the short and long term.
\nSince the heartbeat is a cyclic phenomenon that repeats continually as a result of the interaction between spontaneous SAN activity [7], passive and active properties of the myocardium, conduction system, and ANS influence, it can be regarded as a result of the interaction of multiple coupled systems that oscillate. This complex nonlinear interaction reflects on interbeat interval variability; such phenomenon is called heart rate variability.
\nThe interbeat intervals are usually assessed as the time between the R-wave peaks of the ECG signal (RR time series). This registry is consequence of the spatial and temporal sum of the electrical activity of the whole heart, and each wave is characteristic of specific electrical events. The R wave is representative of the QRS complex, which is the result of the ventricular transmural depolarization heterogeneity [8]. In view on the fact that the time from the start of the depolarizing wave at the sinoatrial node to the ventricle depolarization can account as other oscillation sources, inter-beat interval indicated by the PP interval (depolarization of the atria) can provide some insights that can be concealed by the RR interval (Figure 2).
\nHRV analysis is a valuable noninvasive method to quantify modifications caused by aging, disease progression, and other physiologic or pathologic changes. These alterations influence the oscillating systems or the way they couple, as sympathetic and parasympathetic heartbeat modulation besides intrinsic properties of the heart that rely on extracellular matrix, sarcolemma composition (ionic channel density and kinetics, gap junction density, lipid composition), myocyte size, adipocyte, and fibroblast distribution. The etiology of these alterations is often related to metabolic diseases [9].
\nTo analyze HRV using the ECG signal, we used the R waves of the QRS complex. The evaluation of the time between an R-wave peak (R1) and the next immediate R-wave peak (R2), the time interval between the appearance of an R wave and the next (t1–2) will be called heart period. The RR intervals are organized in chronological order, with an organized set of numbers. This set will be called the “heart activity time series.”
\nThe heart rate (number of beats per unit of time) can be estimated as the inverse of the time period. When the frequency is stable, it is always the same, so are the period and the time series. When the time series is plotted against its order appearance, a time series graph is obtained [10]. The times series values determine the shape of the graph. When the frequency is constant, the graph is a parallel line to the time axis. And in the case that the frequency has variations (HRV), the graph is like in Figure 3.
\nHeart rate variability analysis. (A) Time series with chronological order and (B) Poincaré plot of time series.
The time series has all the information of the variability of system; then, to determine that two time series are similar, numerical values were allocated to this variability. The first tool used was RR time series spectral analysis, this technique is based on the use of all periodic signals consisting of sums of sine and cosine functions with different frequencies and amplitudes, with the purpose to determine which frequencies are involved in the formation of the time series [10]. The frequencies obtained by this mathematical tool have been associated to the nervous system, breathing, and other physiological functions. The frequencies and power spectrum of the different components of the time series are the parameters used to quantify the variability with this method [11].
\nThe disadvantage (if it can be considered as one) of using this method is that not everybody is expert in Fourier series; therefore it’s difficult to analyze, interpret, and perform. The second tool we use is the Poincaré plots. They require graphing the time series as follows: the first RR1 interval is assigned as x value, and then the value of the RR2 interval is assigned as y; this ordered pair is plotted on a Cartesian coordinate axis. Now we consider RR2 as x, and RR3 as y to plot it. After that the rest of the RR intervals are graphed in the same way, where the x is the RR(i) interval and the y is the interval RR(i+1); we plot each RR interval against the next immediate one. The resulting graphs are converted into spot stains; this chart is known as Poincaré plot (Figure 3). Now the question is how to quantify the spots. Before we give an answer to the problem, we will first describe the advantages of Poincaré plot.
\nFirst of all, it is important to mention that the heart rate will be 1/RRi; consequently the analysis of the interval variations gives us information of the heart rate variation. That is, the Poincaré plots give us information about changes in heart rate even if this parameter is not explicitly represented in this graph. As above mentioned, the frequency (F) is the inverse of the time period (T), hence F*T = 1.
\nIn the plot we trace the identity straight line RR(i+1) = RR(i), this line divides the plane into three parts: one where the RR(i+1) is equal to RR(i) (blue line in Figure 3), another where RR(i+1) > RR(i) which is the top of the identity line. And the third where RR(i+1) < RR(i) which is the part that is under the identity line (Figure 3). Therefore, just by looking at the point localization, we can say that the next interval has a higher value, i.e., the frequency is less. In other words, when the points fall above the identity straight line, the period i + 1 is greater and the further the point is from the identity line, the value of the period i + 1 will be greater; otherwise when the points are under the identity graph, the period i + 1 will be smaller, and the frequency will be higher [3].
\nThe distance between the points and the identity straight line tells us what the instantaneous (or sequential) changes of the RR interval will look like, as mentioned in the short term [12]. As an example, we will mention that when the distance from the points to the identity straight line is zero RR(i+1) = RR(i), there are no changes in the interval, but if this distance becomes greater, the variation between RR is greater. These distances are called D1i; the D1i distances that are above the identity straight line will be positive and those below will be negative in such a way that the average of these distances are zero, but the standard deviation of these distances (SDD1) will be different from zero, and this parameter will be used to characterize the width of the Poincaré plot. The width or SDD1 will be used to determine the variability of D1; this parameter is related to the short-term variability of the RR, and this relates to the interaction of the sympathetic system and the heart. To calculate SDD1 all distances from points to the identity line are calculated the average and standard deviation [3, 13]. Thus it is found that
\nAll D1i distances are added and divided by the number of distances to get the average; the standard deviation to the latter is called SDD1. SDD1 is a parameter that characterizes short-term variability.
\nSecondly, calculate the distance from all points to the perpendicular line that crosses the identity line at the coordinate point of the mean value (RRm, RRm). This distance is called D2j (Eq. (2) and Figure 3). All D2j distances are added and divided by the number of distances to get the average; the standard deviation to the latter is called SDD2.
\nThe RR variability changes can be obtained based on the RR time series without using explicitly the time:
\nwhere \n
By obtaining the values of SDD1 and SDD2, we quantify the variability of the heart rate in the short and long term. This data defines the coefficient of variability as SDD1/SDD2.
\nUsing the Poincaré plots, the quantification of the variability in the heart rate is determined by calculating SDD1, SDD2, and the SDD1/SDD2 ratio. The advantage of this method is that the calculation of these parameters is clearly arithmetic, and just by looking at the Poincaré, plot you have an idea of how the variability is given.
\nA biological marker or biomarker is any substance, structure, or process that is objectively measured and evaluated as an indicator of normal biological processes. The biomarkers in the medical science field play essential role for disease detection, pathogenic responses, and therapeutic intervention. These markers are observational side products with potential utility in clinical and research studies [14]. Additionally they are used in new treatment strategies for clinical management. The biomarker field opens the opportunity to originate new knowledge in the complex health scheme.
\nMetabolic alterations cause metabolic diseases as result of changes in chemical reactions in the organism by several enzyme deficit, developing alterations like lipid metabolism disorders. These diseases are associated with synthesis and degradation of fatty acids. The principal and general symptoms of metabolism injury are lethargy, weight alteration, inflammatory process, seizures, and jaundice.
\nFor the last decade, the cardiovascular diseases have been the first cause of death worldwide, and the deadly arrhythmias have increased in the industrialized countries; this fact is related to lifestyle and metabolic alterations such as sedentarism and diet [15, 16]. Obesity and metabolic syndrome are disorders associated with metabolic modifications.
\nThe metabolic syndrome has been described as a cluster of several signs like abdominal obesity, hyperglycemia, dyslipidemia, and high blood pressure (Figure 4). These factors predispose to develop cardiovascular diseases, and each component is strongly correlated with CVD. An opportune diagnosis is necessary to know the progression of MeS and predisposition to develop lethal risks. HRV analysis is a tool to assess cardiac function in patients with several pathologic conditions. However, relationships between HRV and cardiac rhythm with changes in MeS have not been found, improving considerably the prognostic and diagnostic of MeS, as well as the side effects.
\nThe metabolic syndrome increases the heart rate variability. (A) The cluster signs of MeS increase the risk to develop cardiovascular diseases (CVD) and diabetes mellitus. (B) ECG of control and MeS rats, showing lower heart rate in MeS rats. (C) Poincaré plots exhibiting lower balance between parasympathetic and sympathetic systems. (D) Fourier analysis indicating that lower frequencies predominate in MeS rat RR time series.
The ECG is a biomarker for early diagnosis of metabolic diseases [3], and to asses HRV, a five random minute interval must be measured and analyzed. When more time is analyzed, the characteristic SDD1 and SDD2 will be lost [3]. In humans, the MeS showed changes in RR intervals; SDD1 or short-term variability was modified in young adults, while in woman and elderly human, the alterations were vagal as sympathovagal balance (SDD1 and SDD2 [17]).
\nAlso, spectral analysis with Fourier transform was used for the 24-h ECG record; this analysis showed that in human, the high frequencies (HF 0.15–0.40 Hz), which represents sympathetic modulation, were lower only in women with metabolic syndrome [18] and at low frequencies (LF 0.04–0.15 Hz), which represent parasympathetic modulation, heart rate was not altered by MeS. Furthermore, individual components of the MeS were highly correlated with imbalance cardiac autonomic system; the obesity modifies sympathetic nervous system [19]; hyperglycemia alters parasympathetic system [20]; and microalbuminuria, dyslipidemia, and hypertension do not alter neither of them but decrease LF/HF index (see Figure 4) [21, 22].
\nRats with obesity and hypertension presented similar cardiovascular changes as humans: a decrease in parasympathetic system without any increase in sympathetic modulation [23], and only temporary alterations in sympathetic nervous system were reported in rats with high sucrose diet, insulin resistance, and visceral fat (epididymal fat) [24]. However, the rats with high sucrose diet showed higher LF than control [25], and also the heart rate was decreased showing sinus bradycardia and a threefold increase of heart rate variability, SDD1 15 ± 0.4, and SDD2 69 ± 1, compared with control animals 5.5 ± 0.1 and 26 ± 0.1, respectively. In addition, sinoatrial node doubled its variability as shown in the SDD1/SDD2 index = 0.25 for control condition and MeS: SDD1/SDD2 = 0.55 [26]. In genetically modified rats, cardiac alterations were observed independently on individual characteristic of MeS (see Figure 4).
\nThe cardiac arrhythmias in diabetes mellitus are due to structural and functional remodeling, which are alterations in the architecture of the heart that include fibrosis, fat deposition, hypertrophy, modification in the utilization, and production of energy. In addition, electrical activity remodeling includes failure in electrical conduction, dysregulation in ion channels and gap junctions [27], and all these changes are added to the autonomic imbalance between the sympathetic and parasympathetic nervous systems until it becomes cardiac autonomic neuropathy (CAN), which is recognized as a risk for development of atrial fibrillation and sudden cardiac death (see Figure 5)[28].
\nRelations between alterations in DM and cardiac arrhythmias. The alterations in the architecture of heart tissue and functions produce a decrease in HRV during diabetes, which increment the risk of arrhythmias.
In order to realize clinical diagnosis of CAN, the performing cardiac autonomic reflex test or neuropathy Ewing’s battery is recommended. It consists of the assessment of the HRV in rest condition, while standing, during paced deep breathing, during sustained muscle contraction with the use of a handgrip dynamometer (handgrip exercise), and during and after a provoked increase in intrathoracic/abdominal pressure (maneuver of Valsalva) (see Figure 5) [29, 30].
\nUnfortunately, these tests have limitations: patients must be aware so they can perform each of the tests, and it is necessary to suspend medications that could alter the results of the test (e.g., the avoidance of medications that cause hypotension, such as diuretics, tricyclic antidepressants, and vasodilators) [31].
\nDue to these disadvantages, the measurement of HRV has been used as an alternative for CAN diagnosis in recent years because it is a noninvasive test, it does not provoke pain in the patient, the analysis is performed in a short time, it is reliable, and it is a low-cost technique. In addition, this methodology allows the HRV analysis to be performed in less time because it is not necessary to have specialized knowledge in statistics or mathematics since the values of SDD1, SDD2, and SDD1/SDD2 are obtained by means of relatively simple arithmetic calculations and it does not need specialized software to perform them [3]. Another improvement is that the Poincaré plot analysis can be done with only 100 RR intervals, which excludes the use of a Holter registry without reducing the reliability and sensitivity of the test [32].
\nSeveral authors have reported a decrease in HRV in patients with DM types 1 and 2 regardless of the method used to measure it (frequency-domain HRV or time domain). The decrease in HRV in diabetic patients is associated with an early phase of the evolution of CAN. There is a loss of parasympathetic function with a relative increase of sympathetic function causing an imbalance of the sympathetic/parasympathetic tone (without parasympathetic denervation). The patient experiments an increase in resting heart rate. In the next stage, sympathetic denervation takes place increasing the risk of arrhythmias [33]. Despite the existence of a large number of studies on HRV in diabetic patients, we still do not have a relationship that allows us to know the stage of damage in which the autonomic nervous system is found.
\nOn the other hand, we have validated the use of HRV and the measurement of SDD1, SDD2, and the Poincaré SDD1/SDD2 index (Eqs. (1) and (2)) as a biomarker for diagnosis and prognosis of cardiac autonomic neuropathy. For this purpose, a model of type 1 diabetes pharmacologically induced by STZ was used. This model was developed in CD1 mice in which the progress of disease is allowed for 10 weeks without insulin administration (the time compared with human 8 years of disease progression), which produces a decrease in the values of SDD1 (1 vs. 0.9), SDD2 (1.3 vs. 0.8), and SDD1/SDD2 (0.8 vs. 1.1) compared to the control (Figure 6) [32].
\nPoincaré plots of interval RR of ECG. The HRV in conditions of control vs. 8 years of DM development. The influence of the ANS allowed maintaining the balance of an elliptical shape.
In this stage of the disease, no decrease in heart rate was reported, which suggests that CAN was in the early stages. However, after a time period equivalent to 15 human years of DM induction without hypoglycemic treatment CAN, a decrease in HRV is developed (Figure 6). Additionally, in this second stage, mice showed denervation in the pacemaker tissue [13]. We conclude that the use of HRV and Poincaré plots could detect CAN even in early stages of the disease, and therefore it will allow introducing therapeutic maneuvers to control the symptoms and delay the damage to the ANS due to DM.
\nThe periodic oscillations in biological phenomena are quantified with the purpose to use them as a health indicator (biomarker) in mammalian. By means of the ECG interval analysis, HRV is quantified using RR and PP time series. Poincaré plots were constructed, and three indicators were obtained: SDD1, SDD2, and SDD1/SDD2 index. The behavior of these indicators is related with health or metabolic disease. In MeS, a sympathovagal imbalance was reported, and the parasympathetic system showed alterations with a twofold increase in SDD2 indicator. Furthermore, the three indicators were decreased by DM. These biomarkers have the advantages of being based on a noninvasive tool, being objective, and being obtained by easy arithmetic calculus. In addition, the shape of the Poincaré plots offers qualitative information by only looking at it.
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