A summary of the early phases of the glaucoma surgical treatment.
\r\n\t
",isbn:"978-1-80356-363-3",printIsbn:"978-1-80356-362-6",pdfIsbn:"978-1-80356-364-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"969d1c6315b04584c2f011e03dad69c2",bookSignature:"Dr. Mansoor Zoveidavianpoor",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11929.jpg",keywords:"Drilling Performance, Drilling Tools, Well Design, Drilling Procedure, Rotary Drilling, Directional Drilling, Measuring-While-Drilling, Smart Well Technology, Environment Protection, Geothermal Drilling, Sustainable Drilling Fluids, Carbon Sequestration",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2022",dateEndSecondStepPublish:"March 18th 2022",dateEndThirdStepPublish:"May 17th 2022",dateEndFourthStepPublish:"August 5th 2022",dateEndFifthStepPublish:"October 4th 2022",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Zoveidavianpoor has over 18 years of multidisciplinary oil and gas experience, built upon his technical, operational, and management roles in the industry and academia. He is a member of the Society of Petroleum Engineers (SPE), the Energy Institute, UK and is registered as a chartered petroleum engineer. He has published more than 50 publications on International peer-reviewed Journals and conferences, has contributed to 5 textbooks, and served in many scientific committees.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"92105",title:"Dr.",name:"Mansoor",middleName:null,surname:"Zoveidavianpoor",slug:"mansoor-zoveidavianpoor",fullName:"Mansoor Zoveidavianpoor",profilePictureURL:"https://mts.intechopen.com/storage/users/92105/images/system/92105.jpg",biography:"Dr. Mansoor Zoveidavianpoor has over 24 years of experience, built upon his technical, operational, and management roles in the industry and academia. Mansoor holds a BSc degree in Geology, MSc, and Ph.D. degrees both in Petroleum Engineering. He was involved in different disciplines such as project management, geology, flow assurance, piping construction, artificial intelligence, environmental engineering, drilling and production engineering, He has lectured several courses at the University Technology Malaysia (UTM), Petroleum University of Technology (PUT), and Islamic Azad University (IAU). He is a member of the Society of Petroleum Engineers (SPE) and registered as a Chartered Petroleum Engineer at Energy Institute, and EIA subject specialist at DOE Malaysia. He has published more than 50 publications on International peer-reviewed Journals and conferences, has contributed to 5 textbooks, and served in many scientific committees. Currently, he is working as an Associate Professor at UTM and involved in several consultancies in petroleum engineering and energy transition. 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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:"43995",title:"The History of Detecting Glaucomatous Changes in the Optic Disc",doi:"10.5772/52470",slug:"the-history-of-detecting-glaucomatous-changes-in-the-optic-disc",body:'At the present time it is much easier to recognize and to assess glaucomatous changes at the optic nerve than it used to be. This is possible thanks to modern devices and imaging techniques that allow much faster and better diagnosing. Even today, the single most important thing in this matter is to know the characteristics of the normal -healthy optic disc (Figure 1.). The appearance of the optic disc, as in the other biological variables varies widely among healthy individuals. This fact complicates the recognition of the pathological changes.
Today modern glaucoma diagnostic is unimaginable without technological support, when it comes to discovering as well as for following up glaucoma optic neuropathy.
With standard clinical exam aside, there is a number of imaging devices that we use in everyday practice, and to mention a couple i.e. CVF, HRT, GDX, OCT, PACHIMETRY, FUNDUS PHOTOS, CDI… and we agree that without the help of this wide technological spectrum of supporting diagnostic devices we could not be able to diagnose the disease or to track the glaucoma changes. Just stop for a second and remember how it was in the old days? Let’s take a glance of the old days and how it all started?
There was the time when ophthalmologist did not have those sophisticated imaging devices; they even did not have slit lamps… despite the fact that they were glaucomatologists!
This chapter is dedicated to the pioneers of ophthalmology and glaucomathology; their legacy for future glaucomatologists.
The term optic disc is frequently used to describe the portion of the optic nerve clinically visible on examination. This, however, may be slightly inaccurate as ‘disc’ implies a flat, 2 dimensional structure without depth, when in fact the ‘optic nerve head’ is very much a 3 dimensional structure which should ideally be viewed stereoscopically.
Healthy optic disc
Every disease has its history, as much in diagnosing-discovering it, as in quality and adequate treatment. History of the diseases categorized today under the term “glaucoma” may be divided into three major periods. First period is the earliest and it stretches from approximately 400 BC up until 1600 AD; during the course of this period the term “glaucoma” was used to refer to a general group of blinding ocular diseases without the distinctions that historians now can recognize. During the middle period from the beginning of the 17th century to the middle of the 19th century the cardinal signs of glaucoma, separately and in combination, were described in published texts. Finally, the third period starts with the introduction of the ophthalmoscope (Helmholtz, 1854) to the present.
First period (400 BC to 1600 AD)
Etymology of the term glaucoma is that it derives from the Greek word ‘‘glaukos’’, which appears in the Homer’s notes, where it is mentioned as -a sparkling silver glare, later used for colours such as sky-blue or green. As a diagnosis by physicians, glaucoma is first mentioned in Hippocrates\'
It is interesting that most authors, by the Roman era, used the term
However, Archigenes, who practised at Rome in the time of Trajan (98-117 AD), used the term “ophthalmosglaucos” for a curable blindness that was not caused by cataract.
Archigenes revealed that he used the juice of the deadly nightshade, a mydriatic, in the treatment of this condition, adding, “the instilled juice of nightshade makes black the grey eyes.”
Galen (129-216 AD), (Figure 3.) defined glaucoma as a condition in which changes in fluids of the eye caused the pupil to become grey. He also refers to the mydriatic effect of nightshade.
Aetius, the physician of the emperor Justinian (482-565) AD, and a great Ophthalmologist, identified two forms of glaucoma, one a curable condition of the lens and the other an incurable condition that involved an effusion in which the pupil becomes thickly coagulated and dried.
Hippocrates (c.460 B.C.-c. 370 B.C.), a famous Greek physician, and the father ofMedicine, who first used the term \'glaucosis\' in his work \'Aphorisms\' to describe,conditions correlated with blindness and possibly glaucoma
Anatomy of the Eye, according to Galen as the Arabs transferred to the West
Second period (1600 TO 1854)
This period is marked by the rising awareness among ophthalmologists that technology is a key to a proper diagnostic.
Glaucoma became more distinct when it comes to adult or elderly patients with the emergence of four characteristics: (1) the consistent failure of cataract operations to improve vision, (2) the clinical appearance of eyes in terminal stages of the disease, (3) a specific history indicating self-limited forerunners of the severe disease, and (4) the elevated intraocular pressure.
Important breakthrough in ophthalmology is marked with the anatomic findings of Brisseau (1707) and the introduction of the process of lens extraction by Daviel (1752). This led to a search for the site of glaucoma in other structures of the eye and to concentration on clinical signs that could be helpful in distinguishing between cataract and glaucoma. Since a majority of the eyes in which the diagnosis of glaucoma was made in the 18th century were in an advanced stage of visual loss and iris atrophy after one or several acute attacks or after a prolonged chronic course, the clinical picture was dominated by congestion (varicosities) of the anterior ciliary veins, a dilated, poorly reacting pupil, and a varying degree of nuclear lens opacity. On examination with the light sources of that period, a greenish reflection could often be obtained; since this seemed to point to the real location of the disease, it became a prominent sign listed in the literature of the 181h and early 191h centuries.
The clinical features of advanced glaucoma, occasionally preceded by attacks of blurred vision that recurred with a high degree of uniformity, was first recorded in St. Yves\' “Treatise of the Diseases of the Eyes” (1741) and was described in more detail by Weller (1826).
It is a well known fact that elevation of the intraocular pressure as a distinct sign of ocular disease, recognizable by undue resistance of the eyeball to indentation by the physician\'s finger, was first clearly mentioned in the “Breviary” of the itinerant English oculist Banister (1626). In 1738 an equally clear reference to hardness of the eye appeared in the independent writings of Johann Platner, professor of anatomy, surgery, and therapeutics at the University of Leipzig. As a distinct clinical symptom, hardness of the eyeball was apparently generally known and accepted in the 1820s, as one may judge from the almost simultaneous but independent texts by Demours of France (1818), Guthrie of England (1823), and Weller of Germany (1826).
William Mackenzie[1] had a great influence on European and American ophthalmology through his personal teaching and through his textbook, between 1830. and 1854. He distinguished between acute and chronic glaucoma and gave a detailed description of the course of the latter from a stage 1 characterized just by a greenish hue reflected from the pupil to a stage 6 in which the eyeball, after perforation of a corneal ulcer in absolute glaucoma, has become atrophic. Mackenzie was well aware of the abnormal hardness of the glaucomatous eye from the second stage on; also, he apparently was the first to recommend a form of posterior sclerotomy to relieve the abnormal hardness.
Duke-Elder in his
Third period (1854. to the present day)
With Eduard Jaeger, the grandson and son of distinguished Austrian ophthalmologist, began modern ophthalmology and modern ophthalmic exam. He was the first investigator who described and documented with the picture, ophthalmoscopic appearance of the glaucomatous disc in the literature. It was a picture from the monocular indirect ophthalmoscope, on which was described the glaucomatous disc as a swelling of the papillary tissues with respect to the surrounding retina[3].
Just a few months later, Albrecht von Graefe also described a prominence of the papilla in glaucoma[4]. His description of the optic disc, specially his description of the pulsation of the arteries in the glaucomatous eyes, became reliable and, at time, reliable indicator of elevated intraocular pressure. The ring-shaped zone around the disc was officialy named -
Later, pathological findings confirmed ophthalmoscopic findings of the optic disc depression, what was interpreted as an effect of the elevated intraocular pressure, or-
Early classification of glaucoma was made at von Graefe’s clinic.
First type of glaucoma was acute or inflammatory, which characterized with self-limited prodromal attacks of misty vision (in 70 % of the cases), patient is seeing rainbows around the candle flame; attacks increased in severity, length and frequency until the real disease suddenly erupted in the form of an acute attack of inflammation and severe reduction of vision. Partial vision recovery with temporary remission mostly occurred spontaneously or responding on a treatment with large doses of opiates, antiphlogisthics and paracenthesis. Many penetrating exams were carried out during the remissions. After analysis of all phases of this type of glaucoma, von Graefe made a concept according which an acute glaucoma is:”achoroiditis or an iridochoroiditis, with diffuse impregnation of vitreous and aqueous with exudative material which caused the rise in pressure through an increase in volume.”
Second type was the chronic glaucoma. Prodromal attacks were without any sign of irritation, congestion or swelling; lengthen gradually and fused in a chronic form, characterized with the anterior ciliary veins dilatation, shallow anterior chamber, iris atrophy, glaucomatous cupping, arterial pulsation in the fundus; followed with reduction in vision.
The third type von Graefe simply named amaurosis with excavation of the optic nerve, and for him it was not in a group of glaucomatous diseases[6]. Normal anterior segment, with optic disc excavation, which lead to the vision impairment.
Completing this classification, von Graefe used the designation
In the late period of his research (1861.), von Graefe declared that an exclusion of amaurosis with the optic disc excavation from the group of glaucoma diseases was a mistake[7]. This correction he credited to Doners of Utrecht, his friend, who found a palpable tension among many eyes with so-called amaurosis with optic nerve excavation to be significantly above normal. Doners, after his research, prepositioned a term
It is interesting that von Graefe discovered also an ocular hypertension patients among his amaurosis with optic nerve excavation cases. He accepted Doner’s term glaucoma simplex. His posterity, first of all Schnabel[8], had verb his amaurosis with optic nerve excavation, implying that it was an optic nerve disease unrelated to elevated intraocular pressure.
Theory of inflammation, that von Graefe’s proposed as a cause of intraocular pressure rise and a name of that type of glaucoma held until the clinical discovery of the angle closure mechanism in the 20th century. Some of the alternative terms that were used are: “irritative” (de Wecker[9]), “congestive” (Hansen-Grut), and, much later, “uncompensated” (Elschnig).
The Anglo-Saxon literature preferred terms as acute, subacuteand chronic glaucoma
Finally, von Graefe in his last communication (1869), for the first time introduced a terms
In the late 1850s, German anatomist Heinrich Mueller[10] was the first who granted ophthalmoscopically observed depression of the optic disc. In his theory that was a result of an abnormally increased vitreous pressure acting upon the lamina and forcing it to recede. Mueller and his followers assumed that the receding lamina had taken the entire papilla with it, placing the nerve fibres on a steadily increasing stretch or pressing them against the sharp edge of the excavation. Consequence of that was optic nerve atrophy.
Considering that this concept was not uniform for all glaucomatous eyes (in some cases pathologists confirmed the lamina cribrosa displacement, in others not), the theory was add to the basic pressure hypothesis and was widely accepted but also a new ophthalmoscopic and pathologic facts of glaucoma were revealed.
Austrian ophthalmologist Isidor Schnabel (1842-1908)[8] was the first to describe in detail the nerve fibre breakdown with the formation of cavities as a characteristic of the glaucomatous process in the optic nerve. It was the earliest sign and for a long time the only glaucomatous change. In later stages the atrophy affected all portions of the optic nerve up to the entrance of the central vessels. In his opinion, cavernous atrophy was
Another perspective on the origin and nature of the glaucomatous optic neuropathy was introduced by Priestley Smith[11]. The glaucomatous cup is not a purely mechanical result of exalted pressure, but is in part at least, an atrophic condition which, though primarily due to pressure, includes vascular changes and impaired nutrition in the area of the disc and around its margin which require a considerable time for their full development.
This Priestley Smith\'s original notion that the rise in pressure may cause damage to the tissues of the disc through its influence on blood circulation is valid until the present day.
Previously mentioned essence of glaucoma, recognized in the mid-1850s, attributed to excessive formation of intraocular fluid or hyper secretion and assumed to eider a type of choroiditis (von Graefe) or a secretory neurosis (Donders).
The clear concept of the eye mechanisms that were involved in the intraocular pressure production, in that time, was not plain. German anatomist Schwalbe12 began in 1860s the experimental study of the fluid exchange of the eye, searching the lymphatics in the anterior segment. When the dye is injected into the anterior chamber of the eye, in aqueous solution or suspension, it appears promptly in veins on the surface of the globe! His conclusion was that the anterior chamber is a lymphatic space in open communication with anterior cilliary veins.
Theodor Leber13 also injected dyes into the anterior chamber of the eye of a rabbit, and discriminated certain border structures. This disclosure stimulated many investigators of that time, including Leber, to investigate a cannular system and Schwalbe, to investigate the anterior chamber angle in animals. Thus Leber discovered normal outflow (on a fresh enucleated mammalian eye), he presented it as a filtration through the trabecular meshwork and a flow through ciliary and vortex veins.His conclusion was that the rate of outflow was, in principle, proportional to the perfusion pressure, except during an initial period, when the perfusion fluid took up the space occupied in the living eye by blood. He actually determined filtration coefficients, the forerunners of today\'s coefficients of aqueous outflow.
Since this outflow was from fresh enucleated eyes at the pressures prevailing in the living eye, Leber reasoned that the same process of outflow must also take place in the normal living eye. To maintain a stable in vivo pressure, the steady loss of fluid must be compensated for by steady formation of an equal amount of fluid, which Leber believed could also take place through a process of filtration. Thus, the filtration theory of aqueous formation and elimination was born. In a few human eyes enucleated in far-advanced stages of glaucoma, Leber found very low filtration coefficients which indicated abnormal resistance to aqueous outflow[14]. This finding fitted in well with the first detailed pathologic report on the condition of the chamber angle in far-advanced glaucoma[15]: “The most important finding in genuine glaucoma is the circular adhesion of the iris periphery to the periphery of the cornea or the obliteration of the space of Fontana.”*
Considering that in either case glaucoma could result from an inflammatory or an obstructive process within the angle or from pressure from behind. It was realized almost immediately that the peripheral anterior synechiae could be either the cause or the effect of glaucoma. Pathologic specimens which supported these mechanisms were identified and reported. The theory that glaucoma was principally a disorder of aqueous outflow (referred to generally as the Leber-Knies theory) rapidly gained ground.
The essence of the Leber’s (Leber-Knies) filtration theory has stood the test of time. Leber’s best apprentice, Erich Seidel, in 1920’s, made some necessary additions to this theory, including the effects of the colloidosmotic pressure of the plasma proteins and of active transfer processes in the formation of aqueous[16].
Interesting appendage is that the essence of the Leber’s theory, the idea, admittedly without experimental proof, of a steady directional circulation of fluid through the chambers of the eye had been expressed by earlier observers, specifically William Porterfield, more than 100 years before Leber.
During 1880s and 1890s, it was observed that chronic inflammatory glaucomas composed two thirds of all glaucomas. Angle closure glaucomas were dominant. Priestley Smith measured the horizontal corneal meridian in normal eyes 11.6mm and in glaucomatous eyes 11.2mm[17], what expressed dominance of the angle closure glaucoma in that period. 1888. Priestley Smith also introduced the concept of a predisposition to glaucoma, which consists in progressive narrowing of the circumlental space with age, due to the steady growth of the lens in eyes with small corneas. Anatomicaly, the ciliary processes in states of hyperaemia are crowded forward, pressing the iris against the anterior angle wall. This based on a Smith\'s experiment on the animal that a small excess of pressure in the vitreous chamber (as little as 4 mm Hg) makes the lens and the suspensory ligament advance in such a manner as to close the angle of the anterior chamber.
Next step was the discovery of shallowness of the anterior chamber as an important role in the mechanism of the acute glaucoma (in the eyes with acute inflammatory glaucoma)[18]. The description of the mechanism: if the pupil dilates in an eye with shallow anterior chamber, the iris, particularly with its thicker portion, can occlude the filtration angle and, thereby, raise the intraocular pressure. If contraction of the sphincter frees the filtration space, the event remains a prodromal attack. At a certain level of intraocular pressure the ocular veins are compressed at their place of entry into the sclera; venous stasis develops with increased transudation; that, and not inflammation, is the true nature of glaucoma.[18]
The Revolution on this field came in 1920.when Curran [19](Kansas City) and Seidel [16](Heidelberg), on the basis of astute clinical observations, independently announced the concept of the relative pupillary block.
Curran\'s paper[19]: "normally the aqueous passes through the pupil from the posterior to the anterior chamber, but it is here contended that in glaucoma this passage is impeded on account of the iris hugging the lens over too great a surface extent. Some of the aqueous gets through while some passes back, forcing the lens and the iris still more forward. "
Ophthalmoscopy, the most important single invention in ophthalmology, that had shaped its evolution, was introduced by Hermann von Helmholtz in December of 1850.[20],[21]However, Jan Purkinje (known for the Purkinje images) had described the complete technique and published it in Latin in 1823,[22]but his audience apparently was not yet ready and his publication went unnoticed. A quarter of a century later, however, the situation changed.
The ophthalmoscope was not based on any radically new concepts. Rather, it combined the appropriate application of various known principles with recognition of its potential impact and presentation to an appropriate audience. Under the leadership of men like Bowman in London, Donders in Holland, and von Graefe and von Helmholtz in Germany, ophthalmology emerged as the first organ-based specialty in medicine.
Several workers had tried to visualize the inside of the eye but had fallen short of putting it all together. Kussmaul (known for “Kussmaul\'sairhunger”) described the imaging principles in a thesis in 1845[23]but failed to solve the illumination problem. Cumming[24](1846) in England and Brücke[25](1847) in Germany had shown that a reflection from the fundus could be obtained by bringing the light source in line with the observer, but they failed to solve the imaging problem. Babbage,[26]the English mathematician, reportedly constructed an ophthalmoscope in 1847, but his ophthalmologist friend did not recognize the importance and did not publish it until 1854, when von Helmholtz\' instrument was well known.
In the fall of 1850, von Helmholtz tried to demonstrate the inside of the eye to the students in his physiology class. On December 6, he presented his findings to the Berlin Physical Society[20]; on December 17, he wrote to his father[27]:
Helmholtz\' monograph on ophthalmoscopy was published in 1851 and soon was widely circulated. The next year there were several important improvements contributed by other workers. Rekoss,[28]von Helmholtz\' instrument maker, added two movable disks with lenses for easier focusing. Epkens, working with Donders in Holland,[27] introduced a perforated mirror for increased illumination. Ruete[29] in Germany did the same and also developed the indirect method of ophthalmoscopy. With these basic components in place, future generations provided technical improvements. In 1913, Landolt[30] listed 200 different types of ophthalmoscopes.
If the patient\'s fundus is properly illuminated, the field of view is limited by the most oblique pencil of light that can still pass from the patient\'s pupil to the observer\'s pupil (Figure 4.). In direct ophthalmoscopy the retinal point that corresponds to this beam can be found by constructing an auxiliary ray through the nodal point of the eye.[30] The point farthest from the centerline of view that can still be seen is determined by the angle α, that is, the angle between this oblique pencil and the common optical axis of the eyes.
Field limits in direct ophthalmoscopy. The maximum field of view is determined by the most oblique pencil of rays (shaded) that can still pass from one pupil to the other.
Angle α, and therefore the field of view, is increased when the patient\'s or the observer\'s pupil is dilated or when the eyes are brought more closely together.
The more peripheral pencils of light use ever-smaller parts of each pupil. This means that, even if the patient\'s fundus is uniformly illuminated, the luminosity of the fundus image gradually decreases toward the periphery, so that there is no sharp limitation to the field of vision. In practice, therefore, the effective field of vision is determined by the illuminating system not by the viewing system. Most ophthalmoscopes project a beam of light of about one disc diameter.
Even with appropriate illumination, direct ophthalmoscopy has a small field of view (Figure 5.) shows that of four points in the fundus, points one and four cannot be seen because pencils of light emanating from these points diverge beyond the observer\'s pupil. To bring these pencils to the observer\'s pupil, their direction must be changed (Figure 6). This requires a fairly large lens somewhere between the patient\'s and the observer\'s eye. This principle was introduced by Ruete[29]in 1852 and is called indirect ophthalmoscopy to differentiate it from the first method, in which the light traveled in a straight, direct path from the patient\'s eye to the observer.
Limited field of view in the direct method. Peripheral pencils of light do not reach the observer\'s pupil.
Extended field of view in the indirect method. The ophthalmoscopy lens redirects peripheral pencils of light toward the observer.
The use of the intermediate lens has several important implications that make indirect ophthalmoscopy more complicated than direct ophthalmoscopy.
The primary purpose of the ophthalmoscopy lens is to bend pencils of light toward the observer\'s pupil. Figure 3 also demonstrates one of the most characteristic side effects of this arrangement: Compared with the image in direct ophthalmoscopy, the orientation of the image on the observer\'s retina is inverted. For the novice, this often causes confusion in localization and orientation. Figure 3 further shows that in this arrangement the patient\'s pupil is imaged in the pupillary plane of the observer. In optical terms the pupils are in conjugate planes.
The most important changes are related to the change from candle light to gas light, to external electric light and, finally, to built-in electric light sources.[31]
Although the older generation found it difficult to adapt to the new instrument, the younger generation did so eagerly. One of them was Eduard von Jaeger (1828 to 1884) from Vienna, best known for his print samples that were based on the print catalogue of the Vienna State Printing House. He was the son of a well-known ophthalmologist and an artistically gifted mother. In 1855, at the age of 27, he published his first atlas; he continued to add to his collection of authoritative fundus paintings until his death in 1884.[32]
Although not generally considered as a method of ophthalmoscopy, fundus examination with the slit lamp offers an important addition to the traditional methods of direct and indirect ophthalmoscopy. It offers the advantage of high-power magnification through the microscope and flexible illumination with the slit-lamp beam. With appropriate contact lenses, it can offer higher magnification than direct ophthalmoscopy and a field several times wider than indirect ophthalmoscopy. These methods have become particularly important in combination with laser treatment.
Because the slit-lamp microscope has a fixed focus on a plane approximately 10 cm in front of the objective and because the image of the fundus of an emmetropic eye appears at infinity, the fundus cannot be visualized without the help of additional lenses. There are several options.
A negative lens placed in front of the objective of the microscope can move the microscope focus to infinity. The practical application of this principle was worked out by Hruby[33],[34]of Vienna (1942) with a lens known as the Hruby lens.
The optical principle is best understood if the lens is considered in conjunction with the eye, rather than as a part of the microscope. Parallel rays emerging from an emmetropic eye are made divergent by the Hruby lens and seem to arise from the posterior focal plane of that lens (Figure 7A.) For a -50-D lens, this would be 20 mm behind the lens (the usual Hruby lens is -55 D). The slit-lamp microscope is thus looking at a virtual image of the fundus in a plane somewhere in the anterior segment and must be moved a little closer to the patient than it would be for the regular external examination.
To estimate the field of view in this method, it may be assumed that only rays emerging parallel to the axis will reach the objective of the microscope and the observer\'s eye. When emerging from the eye, these rays must have been aimed at the anterior focal point of the Hruby lens. (Figure 7B), in which these rays are traced back to the retina, shows that the field of view (a) is proportional to the pupillary diameter as seen from the anterior focal point of the lens. This field is of the same order of magnitude as the field in direct ophthalmoscopy; it is largest when the lens is closest to the eye.
Hruby lens. A. The fundus image (F\') is formed in the posterior focal plane of the lens. B. The field of view is proportional to the size of the pupil as seen from the anterior focal point of the lens.
With the lens close to the cornea, the fundus image will be close to the fundus plane and approximately actual size. The magnification to the observer is thus largely determined by the magnification of the microscope. At 16×, the magnification is about equal to that of direct ophthalmoscopy; at higher settings, the magnification is greater. Binocular viewing and slit illumination are advantages over direct ophthalmoscopy, even at similar magnification. Limitation to the posterior pole is a disadvantage.
When the Hruby lens is moved progressively closer to the eye, it will eventually touch the cornea and become a contact lens. If the curvature of the posterior lens surface equals the curvature of the anterior corneal surface, the image formation will not change, but two reflecting surfaces will be eliminated, and image clarity will increase.
The use of a contact lens for fundus examination was perfected by Goldmann[35]of Berne, Switzerland (1938). His contact lens is known for the three mirrors incorporated in it. These mirrors positioned at different angles make it possible to examine the peripheral retina with little manipulation of the patient\'s eye or of the microscope axis (Figure 8).
Three mirror contact lens by Goldmann. Two of the three mirrors are shown. They allow visualization of different parts of the fundus.
The refractive power of the cornea is eliminated in the contact lens. The only effective refractive element left would seem to be the far less powerful crystalline lens. The retina is situated well within the focal length of this lens, and the crystalline lens will therefore form a virtual image of the fundus (F) in a plane (F\') behind the globe. How can the microscope focus on an image that far back? We overlooked one other refracting surface: the plano front surface of the contact lens. F\' is seen through plastic and vitreous. To the observer in air F\' appears at F", through the same effect that makes a swimming pool appear shallower than it is. Because of this, the microscope again must focus on a plane inside the globe. As with the Hruby lens, magnification is largely determined by the microscope.
Thus, contact lens fundus microscopy extends our range of examination methods to details beyond the reach of ordinary direct ophthalmoscopy.
The use of the Hruby lens and Goldmann contact lens is comparable to direct ophthalmoscopy, because no real intermediate image is formed. The equivalent of indirect ophthalmoscopy can be achieved by focusing the microscope on the real image formed by a high-power plus lens.
El Bayadi[36]introduced the use of a +60-D lens for this purpose. The inverted image formed by this lens is situated 16 mm (0.0167 m) in front of it. A practical problem with some older slit lamps is that they cannot be pulled back far enough to observe this image.
Compared with the Hruby (-55 D) lens, the El Bayadi (+60 D) lens offers the same major advantage as does indirect ophthalmoscopy: a larger field of view. With proper placement of the lens, the field is about six disc diameters (40 degrees), compared with the one- or two-disc diameter field of the Hruby lens.
With a 60-D lens the aerial image is as large as the fundus; thus the magnification is approximately equal to the microscope magnification (similar to that with the Hruby lens).
Can the field of view be widened even further? This is possible by using a contact lens of very high plus power with some additional optical tricks.Figure 9 illustrates the RodenstockPanfunduscope, based on a design by Schiegel.[37]
The unit contains a high plus contact lens, which forms an inverted fundus image (F\') located inside a second, spherical glass element.
In this arrangement, as in the previous example of a high myope (Figure 10), the image-forming and field-widening functions of the ophthalmoscopy lens are separated again. The contact lens forms the image; the spherical element serves to flatten the image and to redirect the diverging pencils of rays toward the observer. Because these elements are so close to the eye, the field of view can be very wide. Indeed, without moving the lens, the view reaches 200 degrees, that is, from equator to equator, 4 to 5 times the diameter (16 times the area) of regular indirect ophthalmoscopy or of the El Bayadi lens.
Contact lens arrangement for wide-angle indirect biomicroscopy. A high-power contact lens forms an inverted image (F\') inside a spherical element, which redirects the light toward the observer.
Indirect ophthalmoscopy of a high myope. The myopic eye forms its own aerial image (dotted lines) without the help of the ophthalmoscopy lens. Without the lens, only the central part of this image would be visible (dashed lines, limited by the patient\'s pupil). With lens (solid lines) the image is limited by the lens rim.
The size of the image inside the front lens is 70% of the retinal size; for detailed examination, therefore, 50% more microscope magnification is required than with the other slit-lamp methods. However, the principal use of this lens is not for its magnification but for its overview, an overview previously achievable only in fundus drawings or photocompositions.
Similar contact lens arrangements are used in specially designed fundus cameras that allow fundus photography of areas 100 degrees or more in diameter. With lenses such as these, the spectrum of our examining methods can be extended not only toward higher magnification than with direct ophthalmoscopy but also, at the other end, toward an overview of the fundus considerably beyond that obtainable with regular indirect ophthalmoscopy.
As the technology to calculate, design, and manufacture lenses with aspheric surfaces has improved, it has been possible to make lenses with higher powers and better light gathering abilities. The number and variety of lenses for indirect ophthalmoscopy and of contact lenses for slit-lamp microscopy has grown accordingly.
Fundus cameras have greatly improved the ability to document and follow fundus lesions. Eduard von Jaeger often spent countless hours drawing a single fundus, but today a photographic image is available in a fraction of a second. For reasons mentioned earlier, fundus cameras are built on the principle of indirect ophthalmoscopy. The observer\'s lens and retina are replaced by a camera lens and film. Because all components are enclosed in a rigid housing, more accessories can be built in. This includes a dual illumination system, which includes a constant light source for focusing and a flash for photography, and filters such as for fluorescein angiography. Rather than placing the viewing and illumination beams side by side, the illumination beam generally uses the periphery of the pupil and leaves the center for the observation beam.[38]
An angled glass plate that can be flipped to the right or to the left can be used to slightly deviate the observation beam to the right part or the left part of the patient\'s pupil to produce photo pairs that can be viewed stereoscopically.
Because newer lens designs have allowed the construction of wide-angle cameras, a special challenge has been to construct the optical system in such a way that the curved retina is imaged in a plane that can be captured on a flat film.
The optics of the eye are not perfect. Even if major errors are corrected with spherical and cylindrical lenses, small irregularities across the pupillary opening persist. The technique of adaptive optics was developed for astronomical telescopes to counteract image degradation by atmospheric irregularities. An adaptive optics system uses a grid to divide the pupillary opening into many small areas and determines a separate small correction for each area. The information is fed to a slightly deformable mirror with microactuators. Thus the image quality can be enhanced to the point at which the cone mosaic can be clearly visible. The setup is too laborious for use in routine photography. Because the corrective system has to be fixed in relation to the pupil, it cannot be implemented in glasses or contact lenses. However, the technique, also known as wavefront analysis, has found a place in the refractive sculpting of the cornea.[39]
Another important part of ophthalmic exam. First explored in by Trantas (1907.); then explored by Salzmann (1915-16.); Koeppe (1919-20.); and Troncoso (1925-30). Finally Otto Barkan (1887.-1958.) made gonioscopy a routine diagnostic method in the ophthalmologist\'s office, thereby bringing about the separation of the glaucomas due to the angle-closure mechanism from the open-angle glaucomas[40]that the elevation of the intraocular pressure depends of abnormal resistance to aqueous outflow caused by anatomic or functional changes within the outflow channels.
Not until the 1890s did open-angle glaucoma become well proved and accepted in theories.
Thanks to gonioscopy, started recognition of a type or types of glaucoma without obstruction of the angle by the iris.
In the first edition of the Graefe-SaemischHandbook of Ophthalmology (1877), Saemisch lists the following ocular diseases as frequently giving rise to secondary glaucoma: cicatricial ecstasies of the cornea, circular or total adhesions of the iris to the lens, iritis serosa, traumatic cataract, dislocations of the lens, intraocular tumours, hemorrhagic retinal processes (referring mainly, if not exclusively, to occlusions of the central retinal vein), and sclerectasia pastries (which probably referred to glaucoma in eyes with malignant myopia). Congenital hydrophthalmos was at the time also classified with the secondary glaucomas.
William Bowman introduced digital estimation of the ocular tension at the annual meeting of the British Medical Association in 1862. Estimation of the ocular tension by palpation became one of the ophthalmologist\'s special skills, and some ophthalmologists developed so much confidence in it that they viewed instrumental tonometry with suspicion.
The early beginning of instrumental tonometry, apparently made by von Graefe, who mentions preliminary trials of mechanical tonometers in a letter to Donders dated December 24, 1862. Unfortunately, none of these instruments, however, reached the drawing board stage.
The real beginning and the first tonometers actually produced and tested on human eyes were developed in Donders\' clinic in Utrecht between 1863 and 1868. They were instruments for use on the sclera. The scleral curvature at the site of tonometer application was determined first; it then served as a reference plane for the measurement of the depth of the indentation.
Impression tonometry had its drawbacks. The principal flaw was that the indentation, by displacing a significant amount of intraocular fluid, changes the pressure which is intended to measure; this was clearly expressed for the first time by AdoIf Weber in 1867. Weber was official inventor of the first applanation tonometer, which was intended to give a tension reading with only minimal fluid displacement. Despite its theoretic superiority, this instrument did not gain wide acceptance, because recognition of the point of perfect applanation without indentation proved to be difficult. Lately, the principles of applanation tonometry were explored by Maklakoff in 1885. andImbert and Fick, father and son, a few years later. It resulted a several new applanationtonometers, but only one of them, Maklakoff\'s model of 1892, has stood the test of time and has remained in use, mainly by groups in the USSR.
The beginning of the 20th century, digital tonometry was still a method of subjective assessment of the ocular pressure [41]. At that time neither applanation tonometer did not find widespread use in practice.Finally, in 1905.Schiøtz presented his impression tonometer and it did not take long for the instrument to acquire the epithet “the first clinically useful tonometer.” First major comprehensive reports of the clinical value of Schiotz tonometer began to appear in 1910. The essence of today\'s knowledge of the intraocular pressure in the normal and in the diseased human eye was acquired between 1910. and 1920. through the use of Schiøtztonometers.
Disadvantages of digital and instrumental tonometry, realized by the pioneers of these methods, addressed to the properties of the eyeball wall, especially elasticity, affected estimation of the intraocular pressure. Early experimental attempts in that time, to measure these properties and to eliminate them revealed new variables. Schiøtz wrote in 1920: “I can not imagine any method available for living eyes by which errors due to variations of the envelope could be eliminated.” [42]Thirty years later, the electronic form of his instrument came closest to yielding reasonable estimates of “ocular rigidity,” the term introduced by Friedenwald for the resistance that the in vivo eyeball offers to a change in intraocular volume [43].
Correcting readings taken with the Schiøtz tonometer for deviation of the particular eye from average ocular rigidity, the coefficient of ocular rigidity lost some of its clinical importance through the tremendous progress in applanation tonometry that occurred in the early 1950s through the work of Goldmann, Perkins, and Maurice.
The technology to estimate intraocular pressure (IOP) has evolved tremendously since Sir William Bowman emphasized the importance of ocular tension measurements in 1826. In an address delivered at the annual meeting of the British Medical Association, Sir William underscored the critical role that digital estimation of ocular tension played in his practice. In his address, Sir William stated that “it is now my constant practice, where defective vision is complained of, to ascertain almost at the first instant the state of tension in the eye...It is easy enough to estimate the tension of the eye, though there is a right and a wrong way of doing even so simple a thing... With medical men, the touch is already an educated sense, and a very little practice should suffice to apply it successfully to the eye.”[44]
Soon afterwards, digital tonometry became an essential clinical skill necessary to master by all ophthalmologists. When mechanical tonometry was first introduced in the late 1800s, many ophthalmologists felt so confident with their ability to estimate IOP by palpation that they viewed the new technology as inferior. Isador Schnabel, in an address to the Vienna Ophthalmological Society in 1908, was noted to state that although he did not object in principle to mechanical tonometry, he expected “…very little from this test since digital tonometry by an expert is a much more accurate test”.[45]
Although Grafe is credited with the first attempts to create instruments that mechanically measured IOP in the early 1860s, his proposed instruments were neither designed nor built. Rather, it was Donders who designed the first instrument capable of estimating IOP – albeit not accurately – with mechanical tonometry in the mid 1860s. The principle behind Donders’s instrument was to displace intraocular fluid by contact with the sclera. The ophthalmologist first measured the curvature of the sclera at the site of contact, and then used this measurement as a reference plane to measure the depth of indentation. Smith and Lazerat refined this technology in the 1880s, and the discovery of cocaine by Carl Koller in 1884 led the way to corneal impression tonometry soon thereafter. With the aid of a powerful corneal anesthetic agent, corneal tonometry became the definitive choice of IOP measurements because it offered a well – defined and uniform site of impression when compared with the sclera.
Impression tonometry’s major shortcoming was that it displaced so much fluid upon contact with the eye that the measured readings were highly variable and mostly inaccurate. What was needed was a way to displace a minimal amount of fluid to record IOP. This breakthrough came when Adolf Weber designed the first applanation tonometer in 1867, which gave a highly defined applanation point without indentation. After two decades of skepticism, the value of applanation tonometry was re-discovered when Alexei Maklakoff and others introduced new versions of applanationtonometers. In early 20th century, there were about 15 models of tonometers in use. In fact, Maklakoff’s 1892 model is the basis of applanation tonometry today. However, digital tonometry still remained the gold standard among most ophthalmologists in the early 1900s.
The first clinically useful mechanical tonometer was designed and introduced by HjalmarSchiotz in the early 1900s. The instrument was simple, easy to use, and highly precise. It was quickly accepted and became the new gold standard beginning the 1910s. Innovations in calibration led to its increased use, and a tremendous amount of knowledge about the normal and glaucomatous eye was quickly acquired. An adjustment for ocular rigidity was introduced by Goldmann in the 1950s, which led to the development of Goldmannapplanationtonometers. The Goldmanntonometers displace such little fluid that variations in ocular rigidity are mostly negligible. The electronic and non – contact tonometers used today rely heavily on the principles and instrumentation first introduced by Maklakoff, Schiotz and Goldmann.
Today, for the most part, digital tonometry has been replaced by sophisticated technologies to estimate IOP. Today’s instruments are incredibly accurate and easy to use. Yet, there is sometimes no good substitute for digital tonometry. For example, some ophthalmologists may prefer digital tonometry when estimating IOP in patients with keratoprostheses. In these situations, fingers that have mastered Sir William’s art are highly desirable. In fact, it is said that the famous Dr. Claus Dohlman, Harvard professor of Ophthalmology at the Massachusetts Eye and Ear Infirmary, remains as accurate in measuring IOP with his fingers as any ophthalmologist using the high-tech tonometers of today!
Modern diagnostic of glaucoma is unimaginable without perimetry. The merit for measurements of peripheral vision for the diagnosis and follow-up of ocular disease, as many other things in ophthalmology, is attributed to Albert von Graefe. With a primitive campimeter—a sheet of paper with radial rows of dots which served as stimuli—he was probably the first (1856) to plot paracentral field defects in chronic glaucoma and to use them in the evaluation of surgical results. Similar to von Graefe’s device, Haffmanns from Donder’s clinic discovered the greater frequency in glaucoma simplex of serious involvement of the upper half of the field, which gave rise to an easily detectable nasal step [46].
In 1857.Förster introduced the first perimeter, which placed accent on large targets, such as the 10/330, which permitted only very gross measurements. The observations of that time did suggest partial reversibility of field defects if the pressure was lowered substantially by an iridectomy or sclerotomy. 1889. was a very important year for a development of techniques most appropriate for glaucoma. Bjerrum presented 2-meter screen, the 2-meter test distance, and the 2- to 5-ram white test objects. He discovered the relative or absolute scotomas, circling the point of fixation and including the blind spot, which became the hallmark of chronic glaucoma. Conceptually, it means the beginning of the nerve fibre bundle theory of the glaucomatous optic nerve disease.
Further major step was the occurrence of small scotomas in the zone from 12° to 20° from the point of fixation, in early glaucomas, presented by Peter [47]. These scotomas, in the beginning were not connected with the blind spot, but they reached it later via expansion.
The construction of smaller isopters, another early glaucoma characteristic, presented in 1920s, was clearly established with Bjerrum’s technique. Bjerrum’s technique also confirmed the regression of early glaucomatous defects following normalization of pressure documented by instrumental tonometry. The close relationship between pressure and field of vision was demonstrated further by Samojloff\'s observations [48]of temporary enlargement of the blind spot concurrent with osmotically induced pressure elevations. By stereocampimetry with minute targets, Evans was able to detect a gross form of parallelism between diurnal pressure fluctuations and the size of paracentralscotomas[49].
Also in 1920s was noticed that among patients with glaucomatous defects close to the point of fixation (late stages of glaucoma optic neuropathy), a surgical procedure, particularly iridectomy, could have an untoward effect and lead to further rapid shrinkage of the visual field. The incrimination of the iridectomy referred originally to the period when the alternative, the sclerotomy, had proved relatively free of unfavourable effects on the visual field. Subsequent experience with filtering operations temporarily led to the distinction between two classes of glaucoma operations: 1) the less risky: cyclodialysis and sclerotomy and 2) the riskier: iridectomy, sclerectomy, and trephination.
The early treatment of glaucoma has its course of history (Table 1. and Table 2.).
Main discoveries where:
A curative action of the iridectomy in certain glaucomas7,[44],
The development of the filtering operations [50], and
The discovery of the first three ocular hypotensive drugs: eserine, pilocarpine, and epinephrine [51].
\n\t\t\t\t | \n\t\t|
1830 | \n\t\t\tMackenzie1 recommends scleral punctures to release vitreous and to relieve the pressure on the retina. | \n\t\t
1857 | \n\t\t\tvon Graefe\'s iridectomy6 almost overnight gains the position of | \n\t\t
1882 | \n\t\t\tde Wecker, in a paper on the “filtering cicatrix”9, expresses the concept that in the presence of elevated intraocular pressure, a properly executed corneoscleral incision can heal in a manner allowing intraocular fluid to “filter,” ie, be driven by a pressure gradient through the loose scar tissue into subconjunctival spaces. | \n\t\t
1891 | \n\t\t\tBader [52] finds the occurrence of an iris prolapse during or shortly after an iridectomy a favourable sign, auguring success of the operation. | \n\t\t
1903 | \n\t\t\tHerbert reports on a series of subconjunctival fistula operations in which he purposely leaves the iris in the operative incision. The report includes the first detailed description of the transformation of the epibulbar tissues that become exposed to the steady flow of aqueous [53]. | \n\t\t
1905 | \n\t\t\tHeine first reports on the operation of cyclodialysis[54], based on Fuchs\' [55] and Axenfeld\'s[56] observation of the association between postoperative choroidal detachment, a tear or tears in the insertion of the ciliary muscle at the scleral spur, and hypotony. | \n\t\t
1906 | \n\t\t\tLagrange first reports on his iridosclerectomy[50]. | \n\t\t
1909 | \n\t\t\tFreeland and Elliot independently substitute the trephine for Lagrange\'s scissors. | \n\t\t
1913 | \n\t\t\tAt the first international review of glaucoma surgery the pronouncement is made that chronic glaucoma can only be arrested by establishing a filtering cicatrix in connection with the anterior chamber. The iridectomy loses its status of | \n\t\t
1915 | \n\t\t\tThe abexterno incision is introduced by Foroni[58]. | \n\t\t
1920 | \n\t\t\tSeidel demonstrates the transconjunctival passage of aqueous after trephining procedures[16]. | \n\t\t
A summary of the early phases of the glaucoma surgical treatment.
\n\t\t\t\t | \n\t\t|
1863 | \n\t\t\tArgyll Robertson and von Graefe study the effect of extracts of the calabar bean on pupil and accommodation. Von Graefe finds the miotic effect useful in that it facilitates the iridectomy. | \n\t\t
1876 | \n\t\t\tLaqueur[59] reports “a definite drop of the elevated tension after repeated installations of physostigmine in five cases of glaucoma simplex and in one case of secondary glaucoma.” | \n\t\t
1876 | \n\t\t\tWeber studies the mechanisms underlying the hypotensive effect of physostigmine in rabbits and in man and advises caution in its use because of the marked swelling and engorgement of the ciliary processes caused by the drug [60]. | \n\t\t
1877 | \n\t\t\tLaqueur gives the first clear-cut account of the successful termination by use of physostigmine of attacks of acute glaucoma and of the prevention of recurrences [61]. | \n\t\t
1877 | \n\t\t\tWeber introduces pilocarpine with the hope that it will replace the iridectomy in some of the chronic and simple glaucomas and that it will serve to make up for the insufficient effect of the latter in many other cases [62]. | \n\t\t
1898 | \n\t\t\tThe hypotensive effect of topically administered adrenal extracts is discovered. | \n\t\t
1902 | \n\t\t\tDarier reports significant lowering of pressure in some glaucomas, induced by adrenaline alone or in combination with physostigmine[51]. | \n\t\t
1909 | \n\t\t\tExtensive clinical use of adrenaline has confirmed the beneficial results, but it has also brought to light the clear-cut untoward effects, ie, the drug may cause further elevation of pressure and even precipitate acute attacks in certain eyes. | \n\t\t
1923 | \n\t\t\tHamburger reintroduces adrenaline; new, more potent, more stable preparations for topical use are becoming available. Untoward effects in certain eyes are rediscovered [63]. | \n\t\t
1932 | \n\t\t\tGonioscopy furnishes the answer to the unfavorable response of certain eyes to topical adrenaline. | \n\t\t
A summary of the early phases of the glaucoma medical treatment.
Fructose is a common form of sugar found naturally in fruits, honey, and table sugar. It is often used as an additive to modern foods and drinks. Its sweetening effects and low costs of production have made fructose increasingly popular [1, 2]. Fructose consumption has increased since the 1970s. Mean fructose intake per person increased approximately 32% from the 1970s to early 2000s. Of note, total carbohydrate intake over that period increased by 41%, indicating an increase in glucose consumption as well [3]. In a 2008 study analyzing fructose consumption of 21,483 people, the mean fructose intake per capita was about 54.7 g/day (10.2% of total caloric intake/day) [1]. Dietary Guidelines for Americans 2015–2020 recommended that average intake of added sugars should be less than 10% of total calories per day [4]. Worldwide the consumption of sugar varies by age, setting and county. Among different European countries, for example, intake ranges widely, from 7 to 25% of total energy intake [5].
Fructose intake in the diet has been linked to certain human diseases [6, 7, 8, 9, 10]. However, the precise role of fructose in disease is poorly understood and some findings are still controversial. There are numerous studies associating fructose with negative impacts on multiple components of metabolism in animals and humans [11, 12, 13, 14]. The past few decades of research have expanded our understanding of fructose, yet there is still much to learn. It is important to establish an accurate scientific understanding of fructose and its implications on human health because of its increasing popularity worldwide. This chapter focuses on up to date findings related to the metabolism and the role of fructose in human disease, including hypertension, hyperglycemia, metabolic syndrome, free oxygen radicals, retinopathy, diabetes, and cancer.
Fructose is one of three major monosaccharides consumed by humans, in addition to glucose and galactose. Its catabolism produces the same energy content as glucose, 4 kilocalories per gram. Fructose is found as a monosaccharide in honey and fruits. It is found as part of the disaccharide sucrose in cane sugar, used to make table sugar. Sucrose is comprised of glucose bound to fructose in a 1:1 ratio (Figure 1). Fructose, a potent sweetener, is also artificially added to foods and sugar-sweetened beverages (SSB), often in the form of high fructose corn syrup (HFCS). HFCS refers to the fructose content relative to corn syrup, which is entirely glucose, rather than the fructose content relative to other sweeteners. Indeed, as in sucrose and in honey, most HFCS compounds used as food additives contain nearly the same 1:1 ratio of glucose to fructose. Therefore, it is important to understand that concerns pertaining to fructose consumption might also be inferred to a wide range of sweeteners, not only HFCS.
Structural formula of the sucrose, glucose and fructose. Sucrose is a disaccharide consisting of one glucose and one fructose molecule. Hydrolysis breaks the glycoside bond converting sucrose into glucose and fructose.
Digestive and intestinal brush border enzymes break down polysaccharides and disaccharides into monosaccharides—fructose, glucose, or galactose. Free fructose is absorbed directly from the intestinal lumen and is transported into circulation primarily by glucose transporter 5 (GLUT5) and glucose transporter 2 (GLUT2). Once in the portal circulation, almost all absorbed fructose enters the liver [15]. Fructose is transported into hepatocytes primarily via hepatic GLUT2. In addition, other family members of glucose transporters are involved in fructose absorption and metabolism [16]. After ingestion into liver, fructose is metabolized to either glucose [17], glyceraldehyde or acetyl CoA [18]. The liver distributes energy to other cells in the form of glucose, lactate, and triglycerides or converts this energy into hepatic glycogen or fat (Figure 2) [19, 20].
Fructose metabolism in hepatocyte: After absorption from intestine, fructose is taken by hepatocyte via the glucose transporter 2 (GLUT2) and rapidly converted to fructose-1-phosphate (F-1-P) by fructokinase. F-1-P is then metabolized to glyceraldehyde or dihydroxyacetone phosphate (DHAP) via aldolase B (Ald-B). Glyceraldehyde will be further converted to glyceraldehyde-3-phosphate and acetyle CoA, finally will convert to fat acids, lactate or ATP. In liver, F-1-P also can convert into glucose and glycogen via DHAP and glyceraldehyde-3-p to improve glycogenesis. In addition, intracellular phosphate levels decrease stimulates formation of uric acid and increases the level of uric acid at blood. F-6-P; fructose-6 phosphate, G-6-P; glucose-6-phosphate; G-1-P, glucose-1-phosphate.
Extrahepatic fructose metabolism is generally considered minimal. Extrahepatic cells do not express fructokinase, so fructose metabolism must be catalyzed by hexokinase in these cells. Hexokinase has a much higher affinity for glucose than fructose. Thus, conversion from fructose to fructose 6-phosphate proceeds slowly in extrahepatic cells, preventing them from playing a large role in fructose metabolism [21].
Under diabetic conditions, excess glucose may enter the polyol pathway and can be converted to exogenous fructose (Figure 3). In this pathway, aldose reductase reduces glucose to sorbitol and NADPH is oxidized to NADP+. Sorbitol dehydrogenase then oxidizes sorbitol to fructose, which produces NADH from NAD+ [6, 22, 23]. The polyol pathway can result in NADH/NAD+ redox imbalances in diabetes [22]. Excessive activation of this pathway increases reactive oxygen species (ROS), and decreases nitric oxide (NO) and glutathione, promoting microvascular damage to the retina, kidney and nerves [24, 25, 26, 27].
Polyol pathway: Under normal physiological conditions, glucose is used for energy (ATP) production via glycolysis. In diabetes, excess glucose enters the polyol pathway. Aldose reductase reduces glucose to sorbital and oxidizes NADPH to NADP+, then sorbitol dehydrogenase oxidizes sorbitol to fructose, which produces NADH from NAD+.
By comparing the aorta of rats exposed to fructose with controls exposed to mannitol and testing them with the superoxide anion scavenger superoxide dismutase (SOD), fructose has the effect of inducing NADPH-derived superoxide anion production. SOD incubation increased the response to acetylcholine in the fructose-exposed group. The group exposed to fructose showed a leftward shift in the concentration-response curve to acetylcholine when apocynin was added, but the group exposed to mannitol did not. Additionally, the concentration response curves for both groups to phenylephrine were shifted to the right after SOD incubation, but this effect was greater in the fructose-exposed group [28]. In addition, it was found that high-fructose diet (HFrD) increased ROS 2.8 times in the aorta of rat [29]. Another study found that fructose increased blood pressure, superoxide anion, and expression of NADPH oxidase subunits p47phox and p22phox in rat endothelium [30].
Fructose can induce expression of the pro-inflammatory molecule intracellular adhesion molecule-1 (ICAM-1) on human and rat endothelial cells. This is due to a fructose-induced reduction of endothelial NO synthase (eNOS) expression [31]. Moreover, eNOS gene therapy helped repress the damaging the effect induced by a HFrD, indicating that eNOS has a protective effect [32]. HFrD can impair cardiac AKT/eNOS signaling. In contrast, estradiol can activate the Akt/eNOS signaling that is impaired by HFrD in rat heart [33].
The effect of topical fructose and dextrose on the adherence of leukocyte adherence in rat mesenteric venules was observed with intravital microscopy. The result showed that fructose induced significant inflammation, but dextrose did not. It was determined that fructose was mediating endothelial damage via ROS generation because the damage was blocked by NO donors spermine NONO-ate and antioxidant lipoic acid [34]. A recent study in human endothelial cells found that exposure to high fructose concentrations significantly affected gene expression, decreased the cellular angiogenic capability, and impaired endothelial vascular function [35].
Several articles have reviewed the effects of fructose on blood pressure (BP) [36, 37]. Various mechanisms have been proposed, including increased sympathetic activation [38], inflammation [31], endothelial dysfunction [39], increased uric acid stimulation [40], inhibition of eNOS system [32], increased salt and water retention [41, 42], increased homocysteine levels [43] and in utero programmed hypertension of offspring [44].
Few epidemiological studies have examined the association between fructose intake, uric acid, and BP levels. Some studies have conflicting conclusions about the relationship between fructose and blood pressure [45]. A cross-sectional epidemiological study using the data collected from the National Health and Nutrition Examination Survey indicated that a high intake of fructose of ≥74 g/day is associated with elevated BP in the adults without a medical history of hypertension [39]. Studies have shown that HFrD of 60% fructose chow in rats leads to hypertension [46]. Recent epidemiological studies [39, 45] and meta-analysis [47] have indicated that there is an association between fructose and BP. In addition, when fructose is provided in a beverage, there is an acute BP raising effect [37, 48]. Moreover, lowering sugar-sweetened beverages intake was significantly associated with reduced BP in adults with hypertension [49]. There may also be epigenetic impact, because the HFrD of pregnant women was associated with BP programming in the offspring [44, 50].
In a mouse model, high salt intake caused leptin resistance and obesity by stimulating endogenous fructose production and metabolism. It also raised BP and induced metabolic syndrome which was abrogated when fructose metabolism was blocked [51]. It was found that after 30 minutes of 40 mM fructose exposure on the rat aorta, with and without the endothelium lining, the contractile responses induced by phenylephrine (a selective α1–adrenergic receptor agonist) were increased in the rat aorta with endothelium present. This demonstrated that the effects of fructose on contractile response resulted from fructose acting on the endothelium and not the smooth muscle [28]. NO, an important vasodilator, was shown to have reduced availability when NO synthase was blocked with L-NAME. The result showed that a smaller shift occurred in NO production in the aorta segments exposed to fructose ranging from 0 to 40 mM concentrations. It was also shown that fructose increased activation of NADPH oxidase of the aorta, leading to production of superoxide anions and less NO bioavailability. The NO bioavailability may also be affected by hydrogen peroxide, which is known as an endogenous regulator of NO synthase [52]. Catalase, a hydrogen peroxide scavenger, was used to study the rat aorta segments. The results showed that catalase reduced the vasodilatory response to acetylcholine only in the rings incubated with mannitol, and not with fructose. This suggests that the vasodilator effects of hydrogen peroxide were impaired after fructose exposure. Additionally, catalase reduced the response to phenylephrine in the aorta incubated with fructose, suggesting that fructose increased hydrogen peroxide, leading to increased contractility [28]. Fructose may also reduce NO bioavailability by generating uric acid, which reduces NO levels by blocking L-arginine uptake, stimulating arginase, inhibiting eNOS, and by direct scavenging [53, 54]. Fructose can enhance expression of apical chloride/base exchanger Slc26a6 (PAT1, CFEX), which increased salt and water absorption, Slc26a6 and Glut5 play an essential role in fructose-inducing hypertension [41].
The National Health and Nutrition Examination Survey (NHANEX 2003 to 2006) examined the relationship between increased fructose intake and blood pressure in healthy adults. Their study consisted of 2253 diverse participants and showed that a high fructose intake (defined as >74 g/day) was associated with elevated blood pressure levels, both with and without adjusting for numerous risk factors. The results showed 26%, 30%, and 77% higher risk for the blood pressure cut offs: ≥135/85, ≥140/90, and ≥ 160/100 mmHg, respectively [39].
The conversion of fructose to fat in the liver (de novo lipogenesis) may be a modifiable pathogenic pathway [55]. Fructose uptake increases triglycerides by conversion to trioses-phosphate. Tests in rats [43, 46] and humans [18, 56] have shown that HFrD increase triglycerides. HFrD also increases fasting plasma triglycerides level and the diet significantly inhibited several pathways of lipid metabolism [57]. It increased plasma triglycerides in both males and females, but with a higher degree in males [58]. In obese individuals it increased triglycerides more than glucose [18].
In a rat animal model, HFrD for 5 weeks significantly increased plasma triglycerides (3.8-fold) and decreased high-density lipoprotein cholesterol by 14% [59]. Consuming fructose-sweetened beverages for 10 weeks has shown a significant increase in visceral adipose tissue, dyslipidemia, and an impaired glucose tolerance compared to the corresponding glucose cohorts, although weight gain was not different in either cohorts [60, 61].
The prevalence of overweight status and obesity in children has increased dramatically in recent decades. SSB is already a known risk factor for weight gain in children and adults [62, 63]. Numerous prospective cohort studies have illustrated that increasing intake of SSB contributes to obesity [62, 64, 65, 66], while reducing the intake of soft drinks can reduce weight [67]. HFrD promoted metabolic syndrome by inducing lipogenesis and causing triglyceride accumulation and insulin resistance [68]. Oxidative stress and inflammation due to HFrD also induced metabolic changes [6, 68]. Hyperhomocysteinemia is also associated with the changes seen in the individuals with metabolic syndrome [69]. Rats fed with high fructose for 5 weeks had 72% higher homocysteine levels compared to chow fed controls. Rats fed with HFrD developed metabolic syndrome, which includes hypertriglyceridemia and obesity [43].
The liver is essential for metabolism of proteins, fats, and carbohydrates. Liver disease may affect various components of metabolism and may contribute to metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) can result from excessive fat accumulation in the liver leading to liver damage and inflammation. NAFLD is a manifestation of metabolic syndrome. NAFLD affects about 30–40% of the adult population [70] and about 10% children [71]. Persistent liver damage can cause cirrhosis and hepatocellular carcinoma [72].
An imbalance in fatty acid synthesis, β-oxidation, and triglyceride exportation processes leads to the accumulation of fat in hepatocytes. Fructose is a substrate and inducer of hepatic de novo lipogenesis [6]. Fructose has a role in inducing fatty liver disease by stimulating carbohydrates conversion into fatty acids and blocking β-fatty acid oxidation [73]. As mentioned previously, fructose is converted into glyceraldehyde-3-phosphate by avoiding the rate-controlling step of glucose metabolism in hepatocytes. Thus, the consumption of high fructose increases the hepatic de novo lipogenesis [74]. Excessive lipogenesis causes hepatic inflammation, a key pathophysiologic feature of NASH [75]. These processes also increase mitochondrial coupling, leading to oxidative stress [74]. Numerous studies have shown that fructose uptake causes ATP depletion because it floods the hepatocytes with fructose-1-phosphate via fructokinase [76, 77, 78].
The effects of fructose consumption on NAFLD and metabolic syndrome have been studied [79, 80]. Increased fructose consumption has been suggested to contribute to NAFLD [81, 82]. A study on zebra fish showed that when treated with 4% fructose or glucose, only the fructose-treated larvae developed NASH [83].
Fructose intake also affects insulin sensitivity and has been shown to increase fibrosis severity in patients who have NASH [84]. Short term (9 days) high fructose intake of 25% of energy content was associated with increased hepatic fatty acid synthesis and liver fat in healthy men fed weight-maintaining diets [85]. There have been retrospective studies done on patients with NAFLD, showing that they correlate with a higher fructose intake, despite similar overall energy intake compared to healthy individuals. Another meta-analysis concluded that consumption of SSB plays a role in fatty liver disease [67]. However, results are not conclusive. A recent meta-analysis of six observational and 21 intervention studies concluded that the apparent association between indices of human health like liver fat and lipogenesis from fructose or sucrose intake appear to be confounded by excessive energy intake overall [86].
Increasing evidences show that Sirtuin 1 (Sirt1) plays a vital role in the development and rescue of NAFLD [87]. Sirt1 is a NAD+-dependent histone deacetylase and is considered to be a core regulator in fatty acid oxidation and lipogenesis [88, 89]. Sirt1 reduces liver steatosis, improves mitochondrial function, and restores insulin sensitivity, thereby improving blood sugar and lipid regulation [90]. In addition, Sirt1 has anti-inflammatory activity, anti-aging activity and reduces oxidative stress of the vascular endothelium. Enhancing Sirt1 activation can reduce lipogenic enzymes expression [91] and lipid accumulation in liver [92]. Ablating the Skirt1 activation can exacerbate liver fat accumulation and hepatic steatosis [93, 94]. Diet has been shown to be involved in the regulation of Sirt1. An unhealthy diet can increase the risk of NAFLD and obesity [93, 94]. Nutritional and lifestyle interventions can increase the activation of Sirt1 and improve NAFLD [94, 95]. Fructose decreases the expression and activity of Sirt1 in liver, and inhibits lipid metabolism [96], whereas increased Sirt1 activity can attenuate fructose-induced hepatic lipid deposition and prevent NAFLD [90]. In high-fat diet mice, activation of the AMPK/Sirt1 pathway significantly improved obesity, lipid accumulation and hepatic steatosis [97]. In addition, metformin has been proposed to alleviate NAFLD, since metformin can increase autophagy by increasing the expression and activation of the Sirt1 [92].
In recent years, Sirt1 activators and inhibitors have been extensively studied, including some human trails [98, 99]. Ongoing research data suggests that NAFLD may benefit from targeting Sirt1 therapy [98].
Fructose consumption can result in insulin resistance, an effect that is similar to glucose [13]. In rats, high fructose consumption resulted in increased visceral adipose tissue, insulin resistance and hypertension [100, 101]. A higher C-peptide is often associated with insulin resistance [102]. A study was conducted to evaluate the link between fructose intake and C-peptide level in women, and it found that the serum C-peptide concentration of the subjects with the highest intake of fructose was 13.9% higher than those with the lowest intake [103]. In rats fed with HFrD resulted in a complete metabolic syndrome including hyperinsulinemia [43].
Fructose also sensitized pancreatic beta cells to TNF-alpha induced necroptosis [104]. Fructose showed increased insulin resistance in both obese men and women, more notable in males [58]. Fructose increased visceral adipose tissue, plasma insulin, blood triglyceride level, and HOMA index. There was a decreased stimulation of protein kinase B signaling in fructose fed rats. Insulin induced GLUT4 presence on plasma membranes of cardiac cells was decreased by fructose diet [105].
The body’s use of insulin may be impaired by increased resistance in peripheral tissues, it is important to assess the effects of fructose on the insulin and the pancreatic beta cells. It is well known that hyperglycemia is detrimental to beta-cell viability, which is a large part of the pathophysiology of development for diabetes mellitus. One factor in the beta cell death is a mitochondrial channel called the permeability transition pore (PTP, or MTP). PTP is associated with mitochondrial dysfunction and directly involved in insulin resistance [106]. There is evidence that PTP inhibitors prevent the pancreatic β cell death induced by hyperglycemia [107]. Comparing the effects of fructose and glucose on PTP, the results show that even low concentration of fructose (2.5 mM) can induce PTP open, similar to 30 mM glucose [108]. This indicated that the possible role of fructose on PTP and in the development of beta cell damage.
In healthy people, acute increases in plasma glucose concentration inhibit endogenous glucose production. This regulation is disrupted in type 2 diabetes patients, causing inappropriate endogenous glucose production and hyperglycemia [109]. Hyperglycemia inhibits glucose production when an intracellular influx of glucose is catalyzed to glucose-6-phosphate via glucokinase [110]. In healthy individuals, there is an autoregulatory mechanism in which glucose phosphorylation suppresses glucose production, primarily by inhibiting glycogenolysis [111].
Studies show that fructose may have an impact on glucose level. In one study, dogs were fasted for 42 hours, then they were administered different amounts of IV fructose. Fructose exposure caused an increase in net hepatic glucose uptake, glycogen synthesis and hepatic lactate output, the experiments show that about 70% of H3- labeled glucose captured by the liver is incorporated into glycogen and deposited in liver [112]. This is significant because glucokinase is known to activate the glycogen synthase enzyme [113]. Fructose has a role in determining glucokinase activity, glucokinase has a major role in determining hepatic glucose uptake [112].
Other animal studies have shown that after two weeks of high fructose intake, blood glucose levels were significantly increased in healthy rats [114]. A study in humans has shown small amounts of fructose stimulated hepatic glucose uptake and hepatic glycogen synthesis. Under euglycemic hyperinsulinemia, low-dose fructose infusion increased net hepatic glycogen synthesis by 3 times via stimulating glycogen synthase flux [115]. Glucose-fructose co-ingestion will significantly increase hepatic glycogen repletion rates compared with glucose ingestion alone [116].
It is important to understand that although insulin resistance and pancreatic cell damage may develop in rats fed with HFrD as reported by some studies, the presentations might not always mimic type 2 diabetes found in humans or rats. For example, HFrD combined with high fat diet to induce T2D in rodents. These animals only developed early stage of diabetes but did not develop β-cell failure as seen in the late stages of T2D in humans [117, 118]. The animal could develop a nutritional tolerance after eating a fructose diet for 3 months, but these animals could be not used as suitable fructose-fed animal model for diabetes study due to no signs of insulin resistance and β-cell dysfunction [119]. A new and alternative rat model was created by using a 10% fructose-fed diet followed by 40 mg/kg of streptozotocin to induce beta cell toxicity. In this animal model, rats developed both insulin resistance and pancreatic β-cell dysfunction [120].
In humans, the epidemic of T2D and diabetes-related metabolic complications have been linked to fructose consumption [121, 122, 123, 124, 125]. Indeed, fructose as a highly lipogeneic monosaccharide, fructose intake increases the risk of impairing gluocse metabolism [63, 126]. However, results are conflicting. An excessive rate of endogenous glucose production is a major contributor to fasting hyperglycemia in diabetes. A study on human showed that infusion of small amounts of fructose during hyperglycemia partially corrected the regulation of glucose production and partially restored the ability of glucose to suppress glucose production in subjects with type 2 diabetes [127].
In diabetes mellitus, hyperglycemic condition increases the activity of polyol pathway; approximately 30% glucose can be converted to fructose via the polyol pathway. Persistent hyperglycemia increases fructose level and decreases NADPD/NADP+ ratio, leading to NO production decrease, ROS production increase, oxidative stress, and protein glycation increase. These events damage the microvascular system and are implicated in diabetic complications, especially in retinopathy, nephropathy, and neuropathy [22].
Hyperuricemia (HP) can cause metabolic, cardiovascular, and renal diseases [68]. Elevated level of uric acid can inhibit NO bioavailability; it also can promote smooth muscle cell proliferation and can activate the inflammation cascade, which can lead to damage of the endothelium of vessels [128, 129]. During fructose metabolism intracellular phosphate (PO4) is decreased, there is an activation of adenosine monophosphate deaminase which increases inosine monophosphate. Inosine monophosphate is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO). The end product of these processes is uric acid [130, 131] (Figure 4). Furthermore, the increased insulin levels due to fructose intake lead to renal reuptake of urate, resulting in reducing the excretion of uric acid through the kidneys and further increases the serum uric acid level [53, 132].
Fructose stimulates hepatic uric acid synthesis. Fructose is transported into liver via hepatic GLUT2 and is phosphorylated by fructokinase (F-K) to fructose-1-phosphate (F-1-P), which uses ATP as a phosphate donor and results in intracellular phosphate (PO4) depletion. Intracellular phosphate levels decrease stimulates the activity of hepatic AMP deaminase (AMPD). AMPD catalyzes AMP to inosine monophosphate (IMP). IMP is converted to inosine by 5′ nucleotidase (5′NT) and then inosine is further degraded to hypoxanthine by purine nucleotide phosphorylase (PNP). Hypoxanthine is degraded into xanthine by xanthine oxidase (XO), and finally produced uric acid is released into circulation.
A meta-analysis of animal research showed that there is a significant relationship between fructose feeding and HP [133]. Research has also shown that when rats fed with HFrD, elevated uric acid blocked acetylcholine-mediated arterial dilation [53]. Human can also develop HP after high fructose consumption [11, 40, 129]. SSB consumption was significantly associated with increased uric acid concentration in adult population [134]. However, a meta-analysis showed that uric acid concentration was reduced by using glucose instead of fructose [135].
Chronic uncontrolled hyperglycemia can cause microvascular damage which can manifest as diabetic retinopathy (DR). Pathological retinal findings include microaneurysms, capillary abnormalities, hyperpermeability, hypoperfusion, and neo-angiogenesis, which eventually can lead to loss of vision [136, 137].
Animal studies have showed that animals can develop metabolic syndrome while on fructose diet and can also develop choroidal neovascularization which can lead to exudative age-related macular degeneration [137, 138, 139]. The retinal neovascularization occurs as part of oxidative stress resulting in an activation and infiltration of phagocytic cells in the retina. High fructose diet can also modulate gene expression in the retina [138]. The genes are involved in the development of diabetic retinopathy [140]. Melatonin plays an important role in the maintenance of disc shedding, function of rod photoreceptors [141], and elongation of cone photoreceptors in the retina [142]. Melatonin also blocks apoptosis of retinal cells after experimentally induced ischemia [143]. Excessive fructose consumption leads to down regulation of melatonin, and decrease the effects of melatonin on anti-inflammation and anti-oxidative stress in the retina [144, 145].
The premature death of retinal pericytes is a pathophysiological hallmark of DR. One study showed that advanced glycosylated end-products (AGEs) can cause retinal pericytes dysfunction and death by reducing survival signals mediated by platelet-derived growth factor [146]. DR is also caused oxidative stress because of increased ROS production and antioxidant depletion [147]. Protein kinase C (PKC) also has an important role in diabetic retinopathy, PKC activation leads to upregulation of pro-inflammatory genes, loss of capillary pericytes and generation of ROS [148, 149].
Research studies have provided clinical and experimental evidence that fructose intake is associated with development of cancer, especially if consumed in large amounts [150]. Adenomatous polyposis coli (APC) genes can develop biallelic mutations and in combination with fructose intake can trigger or promote the colorectal cancer [151, 152]. The fructose transporter GLUT5 receptors are expressed on the cancer cells like colorectal and breast cancers indicated that fructose can be used as fuel by several types of cancers [153, 154]. Excessive intake of fructose can lead to increased formation of RDS production via formation of glycolaldehyde [155]. Glyoxal is an autoxidation product during fructose metabolism and also a contaminant in the food processing promoted intestinal tumor growth in mouse model.
Fructose was shown to be carcinogenic even if it was only 3% of total daily caloric intake which are mediated through activation of GLUT5 and phosphofructokinase. If fructokinase (ketohexokinase) which is the first enzyme involved in fructose is knocked out in mice the cancer growth can be suppressed [156, 157]. Fructose can also promote cancer growth via pentose phosphate and increases protein synthesis and also cause hepatic inflammation, nonalcoholic fatty liver disease and hepatocellular carcinoma [158, 159].
Fructose promotes cancer growth by formation of lactate, which is an end-product of fructose metabolism. Lactate is likely needed at several steps during the cancer growth including escape from the immune system, cell migration, metastasis and self-sustenance [160]. Lactate levels were found to be 40-fold high in glycolytic tumors and it correlates with cancer cell metastasis and poor survival [161]. Lactate also promotes angiogenesis in the tumors by inducing vascular endothelial growth factor (VEGF) in endothelial cells. If the lactate production is blocked by a chemical inhibitor or gene deletion, the angiogenesis and cancer cell proliferation is stopped [162, 163].
Fructose and uric acid have been shown to stimulate mitochondrial ROS production which is needed for tumor cell growth [164, 165]. During the rapid cell division cancer cells can suffer from hypoxic conditions and have to tolerate them to maintain viability and growth [166]. Fructose metabolism is useful in rapidly dividing cancer cells since during the glycolytic pathway it can use one molecule of ATP to generate 4 molecules of ATP from fructose-1,6-bisphosphate through pyruvate [167].
Fructose consumption may promote breast cancer cell line MDA-MB-468 to an aggressive type [168]. Fructose intake is associated with more aggressive cancer behavior and may promote metastasis [168, 169, 170]. Fructose also has a role in pancreatic cancer growth via the induction of transketolase flux [171]. Prostate cancer cell may also use fructose as the preferred energy source to support the cell proliferation and metabolism [172].
Human cells have the ability to produce fructose endogenously, which is also possible in the cancer cells [173]. Endogenous fructose production takes place through the polyol pathway by utilizing aldolase reductase. This enzyme is found in an activated state in various types of human cancers, including liver, breast, ovarian, cervical, and rectal cancers and helps in synthesizing fructose from glucose [174].
Fructose can promote cancer cell growth by providing fuel to make nucleotides, lipids, and energy, especially for cancers that express GLUT5 receptors. Low fructose diet and fructokinase inhibitors can be novel techniques to treat cancers. Furthermore, blocking uric acid and lactate production could also be targets of cancer prevention and treatment [175].
The past decade of research on fructose has expanded our understanding of role of fructose in disease. The imbalance between high fructose intake and low physical energy consumption is a possible reason of the deleterious health effect of fructose. The consumption of excess fructose may promote the development of metabolic disorders directly or indirectly. Dietary fructose intake has been linked with some human diseases, including hypertension, obesity, dyslipidemia, diabetes, non-alcoholic fatty liver syndrome, and certain type of cancers. Further investigation to gain a better understanding about fructose metabolism will be important to define a potential dietary intervention to reduce disease.
The authors declare that there is no conflict of interest.
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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. 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