Brief ICF Core set for Obesity [3].
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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\r\n\tElectromagnetic imaging is an emerging biomedical imaging modality, which when matured, might present an effective supplement to current imaging technologies for non-invasive assessment of functional and pathological conditions of tissues. This book aims to provide a state-of-art for the most relevant advancements in the development of electromagnetic sensing and imaging for non-invasive detection, by covering all aspects related to the design, modeling, and experimentation. The authors are welcome to submit original research and review articles reporting recent advances in the application of electromagnetic waves technologies in industry and bioengineering.
\r\n\r\n\tThe scope of this book will be the collection of new and/or review results exploring the use of electromagnetic waves for industrial and biomedical applications with particular focus on inclusion detection and medical treatment as well as a diagnostic tool for disease detection. Potential topics include but are not limited to the following: Electromagnetic sensing and imaging for industry applications, Electromagnetic sensing and imaging for biomedical applications, Microwave sensing and imaging , Non-invasive electromagnetic diagnostic tools, Usage of electromagnetic waves for probing organs and advanced MRI techniques, Theoretical modeling of electromagnetic wave propagation, Application of electromagnetic waves in advanced MRI techniques, RF sensors and coils, Biomaterials for wearable sensors, In vitro and in vivo testing.
",isbn:"978-1-83968-582-8",printIsbn:"978-1-83968-581-1",pdfIsbn:"978-1-83968-583-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"e57ef4b5bada0d966637cd303d76278f",bookSignature:"Distinguished Prof. Lulu Wang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9878.jpg",keywords:"Electromagnetic Sensing, Imaging, Biomedical Applications, Electromagnetic Measurements, Conductivity, Electromagnetic Induction Tomography, Electric Impedance Imaging, Microwave Imaging, Biomaterials, RF Coils, Electromagnetic Scattering Problems, Integral Equations",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 26th 2020",dateEndSecondStepPublish:"November 3rd 2020",dateEndThirdStepPublish:"January 2nd 2021",dateEndFourthStepPublish:"March 23rd 2021",dateEndFifthStepPublish:"May 22nd 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"With an M.E. (Hons.) and a Ph.D. degree from the Auckland University of Technology, New Zealand, Dr. Wang is the first author of over 60 peer-reviewed publications, received multiple national and international awards from various professional societies and organizations she is a member of (ASME, IEEE, AAAS, PSNZ, and IPENZ ).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang",profilePictureURL:"https://mts.intechopen.com/storage/users/257388/images/system/257388.jpg",biography:"Lulu Wang is a Full Professor of Biomedical Engineering at Shenzhen Technology University in China. She received the M.E. (First class Hons.) and Ph.D. degrees from the Auckland University of Technology, New Zealand, in 2009 and 2013, respectively. From 2013 to 2015, she was a Research Fellow with the Institute of Biomedical Technologies, Auckland University of Technology, New Zealand. In 2015, Dr. Wang became an Associate Professor of biomedical engineering with the Hefei University of Technology. In 2019, she became a Full Professor of biomedical engineering with the College of Health Science and Environmental Engineering, Shenzhen Technology University. Her research interests include medical devices, electromagnetic sensing and imaging, and computational mechanics. Over the past five years, Dr. Wang is the first author of 60 peer-reviewed publications, 2 ASME books, 7 book chapters, and 12 innovation patents. She has edited three books and two special issues of international journals. Dr. Wang is a member of ASME, IEEE, AAAS, PSNZ, and IPENZ. She has been an active scientific reviewer for numerous journals and international conferences. She received multiple National and International Awards from various professional societies and organizations.",institutionString:"Shenzhen Technology University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6835",title:"Computer Methods and Programs in Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"19f08ef15d97900c94dc8fb04f9afb5f",slug:"computer-methods-and-programs-in-biomedical-signal-and-image-processing",bookSignature:"Lulu Wang",coverURL:"https://cdn.intechopen.com/books/images_new/6835.jpg",editedByType:"Edited by",editors:[{id:"257388",title:"Distinguished Prof.",name:"Lulu",surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8347",title:"Computer Architecture in Industrial, Biomechanical and Biomedical 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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"}}]},chapter:{item:{type:"chapter",id:"55342",title:"Vitamin C Against Cancer",doi:"10.5772/intechopen.68746",slug:"vitamin-c-against-cancer",body:'The anticancer effects of vitamin C (ascorbic acid) are known since 1969, when Benade et al. published a paper showing that the sodium salt of this nutrient (sodium ascorbate) is highly toxic or lethal to Ehrlich ascites carcinoma cells in vitro [1].
A few years before this discovery, the American biochemist, Irwin Stone, had already published some interesting reports on the genetic origin of scurvy, the lethal disease produced by severe deficiency of vitamin C. He had also coined the term “hypoascorbemia,” to define the inability of humans and a few other species to synthesize vitamin C because of the lack of the enzyme L-gulonolactone oxidase (GLO), due to an “inborn error of carbohydrate metabolism.”
After decades of research in this field, Stone became convinced that given the lack of GLO, and the low amount of vitamin C introduced with food, man easily undergoes a condition of “chronic subclinical scurvy (CSS),” and CSS is our most widespread disease. The long-term biochemical outcome of CSS, according to the scientist, sets the stage for the development of the serious medical problems of later life, including, among others, cardiovascular diseases (CVDs), collagen diseases, and cancer. Clinical tests reveal that mega levels of vitamin C are useful in the prevention and treatment of cancer and other diseases. Moreover, to correct CSS at least 10 g of vitamin C per day depending upon the incident stresses is required. Under stress, the daily requirement of vitamin C may be up to 200–300 g/day.
Stone noted that in the past decades, “micro” daily levels of vitamin C had wiped out acute frank scurvy, but did not prevent the epidemic incidence of CSS, the more insidious and more dangerous, relatively asymptomatic form of scurvy. The full correction of CSS is, therefore, the first step in any preventive medicine procedure. Even though the recommended dietary allowances (RDA) [2] prescribe daily amounts of vitamin C in the order of a few milligrams, these, according to Stone, will only prevent the appearance of the terminal symptoms of scurvy, but will not do much else.
On this ground, Stone concluded that “vitamin C” is not a real “vitamin,” and proposed the use of the term “ascorbate,” to better define this missing human liver metabolite [3, 4].
Therefore, according to the scientist, cancer, as well as almost any other known human diseases, depends on both the inability of humans to synthesize vitamin C and the insufficient amount of the nutrient normally assumed with food, leading to a deficiency (“hypoascorbemia”), which, in the long term, transforms into CSS, thereby predisposing to all kind of diseases.
The evidence that among the mammals producing their own vitamin C, an unstressed 70 kg goat is capable of producing 13 g of this liver metabolite, [5] and much more under stress had convinced Stone that vitamin C RDAs were largely underestimated. Therefore, he proposed the use of mega doses or doses ranging from 300 to several thousand times, the amount suggested by the RDAs of the nutrient to treat and prevent different diseases including cancer [6].
However, although formally proposed by Stone, the therapeutic use of mega doses of vitamin C was not really a novelty.
In 1949, Frederick Klenner had reported the successful treatment of 60 cases of bulbar poliomyelitis, with high doses of vitamin C, administered by mouth and, simultaneously, by intramuscular and intravenous injection, continuously, for 72–96 hours, until the complete remission of the symptoms [7]. Klenner proposed his anti-Polio, vitamin C–based treatment after reading a series of studies published by Jungeblut, between 1935 and 1937 [8], but he also treated with success, a number of other viral diseases, by using the same high dose vitamin C protocol.
The plea for a substantial revision of the dosage of vitamin C used in clinics had already come from the Nobel Prize Albert Szent-Györgyi, the discoverer of vitamin C, who, in the introduction to the Stone’s book, “The healing factor,” wrote, “The medical profession itself took a very narrow and wrong view. Lack of ascorbic acid caused scurvy, so if there was no scurvy there was no lack of ascorbic acid. Nothing could be clearer than this. The only trouble was that scurvy is not a first symptom of lack but a final collapse, a premortal syndrome, and there is a very wide gap between scurvy and full health … But nobody knows what full health is! … Full health, in my opinion, is the condition in which we feel best and show the greatest resistance to disease. This leads us into statistics, which demand organization. However, there is another, more individual difficulty. If you do not have sufficient vitamins and get a cold, and as a sequence pneumonia, your diagnosis will not be “lack of ascorbic acid” but “pneumonia.” So you are waylaid immediately” [3].
Therefore, Szent-Györgyi had already warned the medical establishment about the need to radically review vitamin C RDAs (in the order of milligrams) that he considered sufficient to prevent scurvy, but largely insufficient to grant a condition of “full health.”
The twofold Nobel Laureate, Linus Pauling later formalized this concept, in an article published in 1974 [9]. In this article, Pauling, after illustrating in detail the arguments in favor of the use of mega doses of vitamin C to treat a number of different diseases, suggests that the RDA of 45 mg/day, be renamed minimum dietary allowance, and the recommended dietary intake be introduced, ranging from 250 to 4000 mg/day for adults.
In the same year, Cameron and Campbell published an article concerning the treatment of 50 patients with advanced cancer, with 10 g of vitamin C administered by vein for the first few days, and then by mouth, for the rest of their lives. The results of this study indicated that high doses of vitamin C are useful as a routine supportive measure to reinforce standard treatment of earlier and more favorable cases [10].
Two years later, Cameron and Campbell demonstrated that the use of the protocol proposed by Cameron and Pauling significantly prolonged the survival and improved the quality of life of terminal cancer patients [11], but their work raised a number of criticisms, especially focused on the randomization procedure. To respond to the critics, the authors decided to undertake a second investigation, but this new study further confirmed that patients on mega doses of vitamin C lived, on average, 251 days longer than the untreated controls [12]. The same authors [13] and a group of Japanese clinicians [14] later confirmed the results formerly obtained by Cameron and Pauling.
In an attempt to either duplicate or refute the results reported by Cameron and Pauling, the Mayo Clinic initiated another investigation, which seemed to disprove the efficacy of the mega doses of vitamin C against cancer [15]. However, according to Pauling, the inclusion criteria used by the Mayo Clinic scientists were not conformed to the ones he had used. In fact, the Mayo Clinic study included patients previously treated with chemotherapy that compromises the immune response, while a functioning immune system is, according to Pauling, a fundamental prerequisite for an effective anticancer action of mega doses of vitamin C.
Therefore, based on this and other criticisms, the Mayo Clinic group undertook a second clinical investigation that substantially confirmed the results of the first one [16], and this study represented, for the scientific community, the definitive evidence of the inefficacy of mega doses of vitamin C against cancer.
As an undoubted evidence of the biases affecting this study, it will be worth mentioning that the second clinical trial performed at Mayo included only patients affected by colorectal cancer (CRC), that are clearly not representative of the entire complex and variegated range of cancer types affecting humans. However, to remain confined to just CRC as a paradigm of cancer, it will be worth mentioning the recent reports showing that vitamin C in high doses kills BRAF and KRAS mutants of CRC, which are resistant to the standard chemotherapeutic regimens, thus, substantially disproving the results of the second Mayo Clinic investigation [17–19].
Vitamin C is an essential nutrient with a number of beneficial functions, for the organism, since it
helps the metabolism of tyrosine, folic acid, and tryptophan;
increases the elimination of cholesterol;
contributes to the synthesis of catecholamines;
helps the body to absorb and breakdown histamine;
enhances the absorption of nonheme iron;
promotes the synthesis of collagen (its most widely known physiological function);
neutralizes free radicals (it is a reducing agent, “scavenger” of free radicals, and a founder among the natural antioxidants);
protects the DNA from damage due to free radicals and mutagens;
reduces the risk of premature death;
fights off widespread environmental pollutants;
prevents the development of nitrosamines, and much more.
Vitamin C is ubiquitous, but humans, guinea pigs, some primates, a particular type of fruit-eating bat, the majority of fishes and birds do not produce it, and therefore they depend on diet for the assumption and use of this fundamental nutrient [20].
Regarding the anticancer properties of vitamin C, different authors have proposed various mechanistic explanations; among others:
As mentioned in the previous section, the hypothesis that vitamin C in high concentrations, administered by intravenous infusion, acts as a prooxidant, rather than antioxidant, leading to the formation of H2O2, with consequent oxidative damage to cancer cells, was formerly proposed in 1969 [1]. According to this hypothesis, vitamin C kills cancer cells through the intracellular generation of toxic hydrogen peroxide (H2O2) produced upon its oxidation by the cells themselves.
Although relevant for clinical cancer treatment, this discovery remained “hidden” for more than four decades, and the theory of the prooxidant activity of vitamin C in high concentration was proposed again 36 years later, though with no mention of the original work done in 1969 [21, 22].
The theory was further investigated, very recently, by Yun et al. [17–19] who defined the chain of events leading vitamin C to behave as a prodrug of H2O2 thereby killing selectively cancer cells, both in vitro and in vivo. Briefly, vitamin C in high doses administered by intravenous injection exerts its selective cytotoxic effect on cancer cells, because, after parenteral administration, it behaves as a peroxide delivery system for the generation of sustainable ascorbate radical and H2O2 in the extracellular space, with consequent oxidative damage to cancer cells (Figure 1). The selectivity of the cytotoxic effect of parenteral vitamin C depends on the fact that cancer cells, compared to their normal counterpart, show a reduced level of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase. The reduced level of antioxidant enzymes leads to cellular damage by accumulation of H2O2, with consequent intracellular redox imbalance and oxidative damage to different cellular structures.
Prooxidant effect of vitamin C (see text). Legend: Vit. C = vitamin C, ATP = adenosin triphosphate, DHAA = dehydroascorbic acid, GSH = glutathione, GSSG = glutathione disulfide, GAP = glyceraldehyde 3-phosphate, GAPDH = glyceraldehyde 3-phosphate dehydrogenase, GLUT = glucose transporter, NAD = nicotinamide adenine dinucleotide, ROS = reactive oxygen species, PARP = poly ADP-ribose polymerase.
Yun et al. [17–19] have recently showed that the death of KRAS and BRAF cell mutants of CRC is imputable to the oxidized form of vitamin C: dehydroascorbic acid (DHAA). DHAA competes with glucose, for intracellular uptake by glucose transporters (GLUTs), mainly one and four subtype receptors. Interestingly, both KRAS and BRAF activating mutations are responsible of the upregulation of GLUT1 expression in different types of cancer, including CRC, although the upregulation of GLUT1 expression is not always associated with increased sensitivity of tumor cell lines to the cytotoxic effects of DHAA.
Investigation into the metabolic makeup of KRAS and BRAF CRC-derived cell lines shows that there is an accumulation of glycolytic intermediates upstream glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and a contemporary depletion of the metabolites downstream GAPDH, indicating an inhibition or severe reduction of its enzymatic activity, which appears to be the key of the cytotoxic effect of DHAA.
In summary, the data reported by Yun et al. on the effect of DHAA on CRC cell lines indicate that in glycolysis-addicted KRAS and BRAF mutated cell lines, high amounts of DHAA enter the cancer cells, thanks to the overexpressed GLUT-1 receptors. DHAA is then reduced again to vitamin C inside the cells. The reduction of DHAA to vitamin C scavenges glutathione (GSH), thus inducing redox imbalance and oxidative stress. Oxidative stress, in turn, leads to inactivation of GAPDH, inhibition of glycolysis, and energetic crisis, which leads to cancer cell death.
According to this mechanistic explanation, vitamin C, functioning as a prooxidant, would induce an increase in the intracellular reactive oxygen species (ROS), which leads to increased DNA damage, with consequent activation of poly ADP-ribose polymerase (PARP), an enzyme necessary to repair damaged DNA. PARP activation would in turn consume NAD+, with NAD+ depletion and consequent ADP depletion, leading to energetic crisis and death of cancer cells [23].
The theory according to which vitamin C in high doses would act as a prodrug of H2O2, beyond being criticized by different authors, seems somewhat controversial and overlooks a few important aspects as follows:
Although reported in 2005 by Chen et al. [21, 22], it is not new, since, as we have seen, it had been already proposed by Benade et al. in 1969 [1]. Interestingly, while according to Benade, H2O2 forms inside the cell, starting from vitamin C, Chen et al. conclude that H2O2 is formed outside the cell, staring from DHAA. Our experience with high concentrations of vitamin C to treat, in vitro, retinoblastoma (Y79) (Figures 2 and 3) [24], uveal melanoma (C918, OCM1) [25], human promyelocytic leukemia (HL60) [26], and different human myeloid leukemia (HL60, U937, K562, NB4, NB4-R1, and NB4/As) cell lines [27] indicates that H2O2 forms inside the cells, rather than outside. In fact, in our experiments, the cytotoxic effect of vitamin C on cancer cells in culture persists for hours/days after the removal of vitamin C from the culture medium.
H2O2 is a metabolite normally produced by the cells of the body and usually overproduced by cancer cells. Therefore, H2O2 itself could be an optimal substitute for vitamin C, as an anticancer compound. In this regard, it could be useful remark that Reginald Holman, in 1957, published a paper in “Nature” showing that rat implanted with Walker 256 adenocarcinoma and treated by simply replacing their drinking water with 0.45% hydrogen peroxide showed a rate of cure of 50–60% [28]. The time for complete disappearance of the tumor varied from 15 to 50 days depending on the tumor size at the beginning of treatment. Holman’s work was based on the assumption (later confirmed by studies on vitamin C) that malignant cells are deficient in catalase, and as such unable to detoxify high fluxes of H2O2. As a consequence, an in vivo measurement of catalase activity in tumors would represent a useful diagnostic tool to predict which cancers will respond to pharmacological doses of vitamin C therapy (or H2O2) [29].
According to the prooxidant theory, vitamin C in high concentrations induces the production of H2O2 through a Fenton-like reaction (Figure 4). This reaction is the oxidation of organic substrates by iron and hydrogen peroxide. Trivalent iron (Fe3+) is fundamental for the reaction, but, since Fenton-like reactions are usually controlled, in vivo, because of iron sequestration by metal-binding proteins, the prooxidant effect of vitamin C, in vivo, is considered scarcely significant by different authors [30, 31], and other mechanisms should be hypothesized.
Cancer cells produce high amounts of H2O2, and high levels of this metabolite have been associated with key features in cancer, such as DNA alterations, cell proliferation, apoptosis resistance, metastatic spread, angiogenesis, and hypoxia-inducible factor 1 (HIF-1) activation. On the contrary, decreasing the cellular levels of H2O2 may reverse the malignant phenotype. Therefore, H2O2 can be either proapoptotic or antiapoptotic, either carcinogenic or anticarcinogenic, depending on its concentration and localization within the cell [32, 33];
According to the “Fenton chemistry,” invoked to explain the selective cytotoxic effect of vitamin C against cancer cells, trivalent iron (Fe3+) is necessary for the formation of H2O2, starting from vitamin C. However, some literature data seem to demonstrate that the exact opposite is true. In particular, Mojic et al. using two prostate cancer cell lines (LNCaP and PC-3) showed that iron at physiological concentrations in the cell culture medium and human plasma abrogates the anticancer/cytotoxic effects of vitamin C. According to these authors, iron at physiological concentrations promotes both production and decomposition of H2O2, the latter being mediated by a Fenton reaction, which prevents the accumulation of H2O2, thus abolishing the cytotoxic effect of vitamin C. Therefore, as the authors conclude, the in vitro investigations on the anticancer properties of vitamin C may have been overestimated because all suffered the bias of a low amount of Fe3+ in the culture medium, if compared to normal plasma and body fluids. To repeat in vivo the results obtained in vitro, the authors suggest that the simultaneous administration of vitamin C and chelating agents remove iron [34].
Vitamin C (ascorbate) readily undergoes pH-dependent autoxidation producing hydrogen peroxide, and catalytic metals accelerate the oxidation process. This means that catalytic iron is not strictly necessary for the production of H2O2, starting from vitamin C, and therefore, the Fenton reaction may not be essential for this purpose. The autoxidation, i.e., oxidation in the absence of catalytic metals, occurs via the ascorbate dianion (Asc2−). In particular, that at pH 7.0, 99.9% of ascorbate (vitamin C) is in the form of monoanion (AscH−). Asc2− increases by a factor 10, with one unit increase in the pH. Therefore, while the production of H2O2 may be scarcely relevant in the absence of catalytic iron (as in the “Fenton chemistry”), it may become considerable when the concentration of ascorbate is in the order of the millimoles, as in the case of the use of vitamin C as an anticancer compound. To give an example, an aqueous solution containing 20 mM of vitamin C in the form of sodium ascorbate (the sodium salt of the ascorbic acid) will contain 1 μM of Asc2− which, in turn, will result in a flux of H2O2 on the order of 10 nM/s in a typical cell culture experiment [35].
In most laboratory settings, autoxidation of vitamin C is due to adventitious catalytic metals, as part of the buffers used or contaminating of lab equipment. It is not by chance that the methods underpinning the “Fenton Paranoia” are in vitro methods using either isolated tissue cultures or d samples exposed to the air. Indeed, as reported by some authors: “… unless extreme care is taken, every time vitamin C is added to blood samples (and urine samples) outside the body there are a whole host of oxidative products and markers produced …” [36].
Both the antioxidant and prooxidant activities of vitamin C in high doses may not necessarily be mutually exclusive. Studies on chelation therapy have shown that 5 g of the sodium salt of vitamin C added to the ethylenediaminetetraacetic acid (EDTA) chelation cocktail results in acute oxidative stress, but this effect is transitory, and after multiple sessions of EDTA-based chelation treatment, a prolonged, protective, antioxidant effect of the treatment becomes evident [37]. These data confirm the evidence reported by Mojic et al.[34] regarding the inhibitory effect of iron on the prooxidant activity of vitamin C, and also the idea, formerly illustrated by Klenner, according to which vitamin C in high concentration may act as a “flash oxidizer” [38].
Flow cytometric analysis of Y79 human retinoblastoma cell line viability, after treatment with increasing concentrations of vitamin C (Asc) in vitro. C = control sample, Asc1 = vitamin C 1 mM, Asc3 = vitamin C 3 mM, Asc5 = vitamin C 5 mM, Asc7 = vitamin C 7 mM. Starting from a viability of about 74% (control sample), the percentage of viable cells after 1 hour of treatment with vitamin C and 18–24 hours of incubation are about 66% at 1 mM, 41% at 3 mM, 11% at 5 mM, and 9% at 7 mM of vitamin C.
Microphotographs of Y79 human retinoblastoma cell lines: A: hematoxylin/eosin staining of cultured Y79. Interestingly, cells in culture tend to form the typical Flexner-Wintersteiner «rosettes» (black arrows) commonly seen in pathology specimends (original magnification: 200×). B: May-Grunwald Giemsa staining showing morphological details: large cells with loose chromatin and highly basophilic cytoplasm (original magnification: 400×). C: Contrast phase microphotographs of Y79 human retinoblastoma cell lines in culture (control sample): cells tend to form clusters in culture (original magnification: 200×). D: Contrast phase microphotograph of Y79 human retinoblastoma cell lines after treatment with vitamin C 7 mM. At a concentration of 7 mM, vitamin C destroys the vast majority of cells in culture. A few residual cells appear swollen and necrotic (original magnification: 200×). E and F: Hoechst/PI staining of Y79 human retinoblastoma cell line in the culture. With Hoechst/PI, live cells not distinguishable in the black/withe caption. In the control sample (E), there is a clear prevalence of cells stained by the Hoechst dye (alive) while in the sample treated with 7 mM of vitamin C (F), the prevalent color is given by PI (dead cells)(original magnification: 200×).
Fenton reaction mediated by vitamin C. (1) Vitamin C (ascorbic acid, AscH2) reduces ferric ions (Fe3+) to ferrous ions (Fe2+). (2) Ferrous ion reacts with oxygen to produce superoxide. (3) Dismutation of superoxide leads to hydrogen peroxide. (4) Hydrogen peroxide reacts with ferrous ions to form hydroxyl radicals. Legend: Asc = ascorbic acid, vitamin C, Fe = iron, O = oxygen, H2O2 = hydrogen peroxide, OH = hydroxyl radical.
In summary, increasing the concentration of vitamin C with mega doses of the nutrient injected in vein may lead to a substantial increase in the spontaneous generation of H2O2, with toxic consequences to cancer cells, according to the chain of biochemical reactions more recently described by Yun et al., and briefly summarized herein. This does not mean that the administration of vitamin C in high doses by intravenous injection abrogates its antioxidant properties, but most probably that both prooxidant and antioxidant effects coexist. It rather implies that both antioxidant and prooxidant properties are simultaneously present in the molecule, the latter resulting more pronounced when the concentration of the nutrient reaches values in the order of millimoles (20 mM).
“Collagen” is a collective name to designate group of fibrous proteins that occur in vertebrates as the chief constituent of connective tissue fibrils and in bones. Many of the symptoms of scurvy (the syndrome of acute deficiency of vitamin C) depend on the defective production of collagen. Since the beginning of the history of this nutrient, scientists know that vitamin C is essential for the synthesis of collagen. Indeed, vitamin C is a cofactor of collagen prolyl-4-hydroxylase (C-P4H), the enzyme responsible for the formation of hydroxyproline, the essential component of collagen. Under conditions of vitamin C deficiency, C-P4H loses its activity, and the organism does not form collagen properly, with consequent connective tissue deterioration, as it happens in scurvy (Figure 4).
Prolyl-hydroxylases are an entire family of enzymes, also known as 2-oxoglutarate-dependent dioxygenases (2-OGDDs) with a wide range of biological functions [39], and members of this family include HIF-hydroxylases [40]. These vitamin C–dependent enzymes are of extreme importance in tumor biology since hypoxia and induction of HIFs are a hallmark of many tumors [41].
HIF is a heterodimeric transcription factor discovered in 1991 [42]. In normal oxygen pressure conditions (“normoxia”), the HIF-1α unit is downregulated by vitamin C–dependent hydroxylases, while in hypoxic conditions, such as those so frequently found in solid tumors, there is a repression of the hydroxylation of HIF-1α, with consequent increase of HIF-dependent gene transcription, neoangiogenesis, and tumor growth and progression. The important consequence of the central role of vitamin C in the synthesis of HIF-1α hydroxylases is that low levels of vitamin C promote tumor growth and progression (as already hypothesized by Stone, Szent-Györgyi, and Pauling), by reducing HIF-1α hydroxylation, thereby stabilizing HIF-1α [43], and high levels of HIF render cancer cells more sensitive to vitamin C–induced toxicity [44].
Recently, Kuiper et al. have confirmed the above data by finding an inverse relationship between intratumor levels of vitamin C and HIF activity in both endometrial cancer and CRC [45–47].
For a better understanding of the centrality of the relationship between hypoxia and HIF in tumor biology, we must consider that cancer hypoxia (a very common feature in cancer) is associated with HIF activity that mediates angiogenesis, epithelial-mesenchymal transition (EMT), stem cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy [48]. Therefore, attempts to downregulate HIF synthesis and activity may represent a step forward in the search of an effective and selective anticancer drug [49, 50].
Is vitamin C such a molecule?
The current evidence shows that vitamin C has a close relationship with the function of HIF, and therefore, being a natural compound, it is the best-suited, natural molecule for the purposes of inhibiting cancer growth through HIF-mediated mechanisms.
Tian et al. note that the overexpression of HIF greatly enhances vitamin C–induced toxicity on cancer cells, since HIF increases the intracellular uptake of oxidized vitamin C through its transcriptional target GLUT1, synergizing with the uptake of its reduced form through sodium-dependent vitamin C transporters (SVCTs) [44].
Other authors, working with human leukemia cell lines, showed that vitamin C inhibits the growth of human leukemic cells not only through the generation of H2O2 but also and more importantly through the downregulation of HIF-1α transcription [51].
Further important insights into the role of HIF have come from studies of three tumorigenic models in vivo, showing that the antitumorigenic effects of antioxidants such as N-acetylcysteine (NAC) and vitamin C are not due to their ability to squelch DNA damage and genomic instability mediated by ROS but due to their capacity to downregulate HIF levels [52].
These results are of extreme interest for the following reasons:
Whether we consider its prooxidant activity, leading to cancer cell damage through the generation of H2O2 or its antioxidant (more typical) activity, leading to the enzymatic breakdown, and nonenzymatic downregulation of the HIF, vitamin C in high doses always shows the characteristics of a simple, natural, and effective anticancer molecule;
Antioxidants (all of them!) have anticancer effects;
Vitamin C and other antioxidants may have a role as adjuvant therapy to prevent progression or recurrence of HIF-dependent tumors;
Vitamin C may show anticancer properties even when administered by mouth, with caution about the dose, which must be sufficiently high.
Recent investigations have shown that ascorbate therapy has a significant effect on the expression of several genes relevant to the development or inhibition of cancer. In particular, the reduced expression of tumor-promoting genes, such as HIF, and the increased expression of tumor-suppressor genes, such as p53, support the notion that vitamin C can act as a potential agent for the suppression of tumor development [53].
As we have seen, vitamin C has a number of beneficial biological functions, many of which are related to its action as an electron donor for adjusting the redox state of iron-containing enzymes. Recent studies have implicated Fe2+-dependent oxidative modification activities in normal tissue homeostasis and experimentally induced reprogramming. The loss of these activities is associated with epigenetic defects and compromised cell differentiation or developmental potential (Figure 5).
Hypoxia stabilizes HIF-1α as the rate of prolyl-hydroxylases (PHD)-mediated hydroxylation of a subunit is limited. HIF-1α accumulates in the cytoplasm and passes into the nucleus, where it binds to HIF1-β. Cofactor p300 allows the binding to hypoxia response elements (HREs) of target genes involved in angiogenesis, metabolism, pH regulation, proliferation, and metastasis. Vitamin C, as a cofactor of PHD, determines increased degradation of HIF1-α and, as a consequence, inhibits the expression of genes activated by HIF1-α.
One of the most important properties of Fe2+-2OG-dependent dioxygenases is their susceptibility to environmental factors (as we have seen in the case of HIF-hydroxylases). Vitamin C is necessary to maintain the function of these enzymes, and different oncometabolites can inhibit their activity.
Recent studies show that vitamin C may enhance reprogramming of pluripotent stem cells, and the available data suggest a strong link between vitamin C, dioxygenase function, and stem cell differentiation, that is of great relevance for human disease [54]. In fact, vitamin C (in the form of sodium ascorbate), as a member of Fe2+- and 2OG-dependent dioxygenases, plays a critical role in the demethylation of DNA and histone, as a cofactor for a group of enzymes termed methylcytosine dioxygenase ten-eleven translocation (TET, including TET1, TET2, and TET3) and some Jumonji-C (JmjC) domain-containing histone demethylases [55, 56].
(Note 1: TET1 catalyzes the conversion of the modified DNA base 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1 produces 5-hmC by oxidation of 5-mC in an iron and alpha-ketoglutarate-dependent manner [8]. The conversion of 5-mC to 5-hmC has been proposed as the initial step of active DNA demethylation in mammals.)
(Note 2: TETs belong to the Fe2+- and 2OG-dependent dioxygenase superfamily.)
Given its role as an essential cofactor of enzymes involved in epigenetic gene regulation/expression, vitamin C can be involved in embryonic development, postnatal development, aging, cancer, and other diseases [57].
In summary, the epigenetic gene regulation functions of vitamin C encompass:
The regulation of DNA demethylation as an essential cofactor for TET dioxygenases;
The regulation of histone demethylation as an essential cofactor for JmjC domain-containing histone demethylases;
The role of interface between the genome and environment;
The critical role in maintaining the epigenome, especially at early embryonic stages;
The contribution to different disease in the case of deficiency, which causes reduction of the catalytic activity of TET dioxygenases and JmjC domain-containing histone demethylases [58].
According to some authors, vitamin C causes widespread, consistent, and remarkably specific DNA demethylation of 1847 genes in human embryonic stem cells (hESCs), including important stem cell genes, with a clear bias toward demethylation at CpG island boundaries [59].
Other epigenetically relevant effects of vitamin C include:
The development of dopamine neuron differentiation in fetal midbrain [60], the induction of pluripotent state in mouse embryonic stem cells [61, 62];
The enhancement of the demethylating activity of 5-azacytidine, and induction of cytotoxicity [63, 64];
The inhibition of the malignant phenotype on melanoma cells in vitro, by partially reestablishing the global content of 5-hydroxymethylcytosine (5-hmC) and the consequent alteration in the transcriptome [65];
The upregulation of several microRNA (miRNA) involved in tumor suppression and drug resistance, the most prominent of which correlates with increased overall survival of breast cancer or nasopharyngeal carcinoma [66];
The inhibition of the proliferation, migration, and epithelial-mesenchymal-transition (EMT) of lens epithelial cells by destabilizing HIF-1α [67].
Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress, and vitamin C supplementation improves a number of different immunologic functions, including, among others: antimicrobial and natural killer (NK) activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Furthermore, by maintaining the cellular redox integrity, vitamin C protects the cells of the immune system against ROS [68, 69]. Immunocompetent cells such as lymphocytes, neutrophils, and monocytes have vitamin C levels 10-–100-fold higher than the plasma, and accumulate it against a concentration gradient (Figure 6) [70].
As a cofactor for TET dioxygenases, vitamin C participates in the conversion of 5-mC to 5-hmC, and further 5fC and 5caC, thus modulating DNA demethylation. Legend to figure: 5C = cytosine, 5-mC = 5-methylcytosine, 5-hmC = 5-hydroxymethylcytosine, 5fC = 5-formylcytosine, 5caC = 5-carboxylcytosine, BER = base excision repair, DNMT1 = DNA methyltransferase-1, DHAA = dehydroascorbic acid, Vit. C = vitamin C.
A decrease in the intracellular content of vitamin C may result in locally increased apoptosis of immune cells and immunosuppression [71].
Vitamin C is essential for immunoglobulin synthesis [72] and active phagocytosis [73] enhances the production of interferon [74] and suppresses the production of interleukin-18 (IL-18), a key regulator in malignant skin tumors, including melanomas, squamous cells carcinomas, and a number of other tumors [75].
The concept that the immune system can help fighting cancer has deep roots. In 1909, the German scientist Paul Ehrlich proposed that the incidence of cancer would be much higher, were it not for the action of our immune system in recognizing and eliminating tumor cells [76].
Half a century later, two scientists, Lewis Thomas and Frank Macfarlane Burnet, took Paul Ehrlich’s original idea a step further and proposed the model of “immune surveillance,” according to which the cells of the immune system actively patrol the body looking for cancerous cells and eliminate them as they arise. This idea became a grounding principle of the new field of cancer immunology that took shape beginning in the 1950s [77].
More recently, the relationship between cancer and the host immune system has become clear with the introduction of the concept of “immune editing,” a three-phase process leading cancer cells to escape the control of the immune system, with consequent cancer progression [78].
Therefore, since no doubts exist, nowadays, about the role of the immune system in controlling cancer development, progression and spread, natural substances such as vitamin C, whose action spreads over a wide range of effectors of both the innate and adaptive immunity, represent a new promising therapeutic tool against cancer.
Much of the “booster” action of vitamin C on the immune system depends on its antioxidant nature. Indeed, vitamin C downregulates ROS-dependent expression of pro-inflammatory interleukin genes, via inhibition of transcription of NF-κB (nuclear factor kappa-light chain-enhancer of activated B cells), which, in turn, regulates the expression of pro-inflammatory cytokines, such as IL-1 and tumor necrosis factor-alpha (TNFα) [79]. Recent evidence shows that vitamin C enhances antioxidant defenses of T-cells [80] and increases T-cell responsiveness to antigens, thus suggesting that it has a definite role in regulating immune function [81].
Confirm of the role of vitamin C in regulating the immune system function come from studies showing that increased vitamin C concentrations inhibit antigen-induced, withdrawal-induced, steroid-induced, and spontaneous T-cell apoptosis [82], fas-induced apoptosis of monocytes [83], and increased cytotoxic activity of natural killer cells in humans [84]. All these data indicate that it can modulate the immune system by inhibiting T-cell apoptosis signaling pathways [85]. Similar results apply to monocyte-derived dendritic cells (DCs) [86].
As mentioned in the “historical background,” more than four decades ago, Pauling attributed to vitamin C the role of a “booster” of the immune system. This was his main argument against the negative results reported by the Mayo Clinic scientists, since they should not have included, in their clinical trials, cancer patients previously treated with chemotherapy, because chemotherapy destroys immunocompetent cells and severely impairs the individual immune response to cancer.
The Mayo Clinic scientists apparently did not understand this argument and, in reply to the legendary scientist wrote “… Any contention that previous chemotherapy prevented our patients from achieving the extraordinary survival increase claimed by Drs. Cameron and Pauling must be considered highly speculative at best. Our patients were entered into the study only when they were well past any acute immune-suppressive effects of previous therapy” [87].
The evidence, today, indicates that a healthy immune system is necessary to control the malignant disease and that immune suppression associated with cancer and cancer chemotherapy contributes to its progression [88]. Therefore, in agreement with Pauling and the current evidence, it is likely to assume that since cancer chemotherapy produces long-lasting deleterious effects on the immune system [89, 90], patients previously treated with cytotoxic chemotherapy should not expect positive outcomes from the treatment with vitamin C as a “booster” of the immune system.
William McCormick first proposed, about 6 decades ago, the hypothesis that cancer could be due to a defect in the metabolism of collagen [91]. Given the fundamental role of vitamin C, in the synthesis of collagen [92], the scientist concluded that a deficient intake of vitamin C (as in full blown or chronic subclinical scurvy) could determine cancer by disrupting the synthesis of collagen, thus creating a local permissive environment for cancer to grow and spread to other organs and tissues (Figure 7) [93].
The “nutrient mix” used is a mixture of vitamin C, L-lysine, L-proline, and epigallocatechin gallate (EGCG). Cancer cells can destroy enzymatically the collagen matrix (A) between the two chambers of the vial, and spread over the second chamber. When the nutrient mix is added (B), cancer cells are no longer able to destroy the collagen matrix and therefore they remain confined to the superior chamber (see Refs. [99, 100]).
As we have seen in the previous sections, vitamin C is required for collagen synthesis by acting as a cofactor for nonheme iron α-ketoglutarate-dependent dioxygenases such as prolyl-4-hydroxylase. It stimulates all types of collagen synthesis by donating electrons required for hydroxylation reactions of proline and lysine in procollagen, normally performed by specific hydroxylating enzymes.
In recent years, the role of basement membrane (BM) in the dynamic regulation of cell behavior and cell-signaling pathways has clearly emerged. The BM defines the tumor microenvironment and provides significant host-derived regulatory signals during progression of tumor growth and metastasis. The major component of basement membrane is type IV collagen, and recent studies indicate that in cancer progression there is a disruption of the normal assembly and organization of the basement membrane [94].
These studies support the notion that the loss of collagen type IV chains may provide a permissive microenvironment for cancer invasiveness, as hypothesized by McCormick, more than 5 decades ago [95].
Metastatic spread is a crucial event in the evolution of cancer, being responsible of the majority of cancer-related deaths. The steps leading to metastatic spread of cancer encompass the detachment of cancer cells from the primary tumor, the disruption of the BM, the invasion of the surrounding stroma, cancer cell entry into and transport through the vascular or lymphatic system to distal sites (liver, lungs, brain, etc.), and extravasation, tumor cell proliferation and angiogenesis at distal sites [96].
A critical event in tumor cell invasion is the degradation of the extracellular matrix (ECM), a complex network of extracellular macromolecules such as collagen, proteoglycans, fibronectin, laminin, and other glycoproteins that act as a barrier to the spread of cancer cells to distal sites by restricting tumor growth and invasion.
Matrix metalloproteinases (MMPs) are calcium-dependent endopeptidases, which require coordination of a zinc ion to mediate catalysis. As implied by their name, MMPs operate on a variety of substrates belonging to the ECM [97], and owing essentially to their vast diversity, MMPs participate in nearly every biological process, involving the remodeling of the ECM, from implantation of an embryo into the uterine wall to tissue necrosis.
A major structural protein for ECM and basement membrane is type IV collagen. Therefore, type IV collagenases MMP-2 (72-kd gelatinase A) and MMP-9 (92-kd gelatinase B), usually overexpressed in malignancy, are the focus of research in this field.
All types of cancer cells form tumors and spread in the body by degrading the ECM by means of various matrix MMPs. The activity of these enzymes correlates with the aggressiveness of tumor growth and invasiveness of the cancer.
In 1992, Pauling and Rath hypothesized that natural compounds such as lysine and vitamin C could inhibit ECM proteolysis and, as such, had the potential to modulate cancer growth and spread [98]. These nutrients would exert their anticancer activity by both inhibiting MMPs and strengthening the connective tissue surrounding the tumor.
Several lines of evidence support an indispensable role for vitamin C in maintaining good-quality collagen. Vitamin C assists the posttranslational modification of collagen by reducing iron in the participating enzymes, lysyl-hydroxylase, and prolyl-hydroxylase. Experimental in vitro data show incubation of cancer cells with a nutrient mixture containing vitamin C, L-lysine, L-proline, and epigallocatechin gallate (EGCG), they are no longer able to invade the collagen matrix [99, 100] and spread at distant sites (Figure 7).
Although the mechanisms through which the nutrient mixture used in these experiments inhibits MMPs deserves further investigation, it is quite clear that the role of vitamin C is to stabilize collagen, and contribute to tumor cell toxicity, through one or more of the mechanisms illustrated in the previous sections.
Experiments on Gulo-knockout (GULO-KO) mice challenged with murine B16FO cancer cells show that vitamin C–supplemented mice developed smaller tumors with more collagen encapsulation and fibrous capsule inter digitation. On the contrary, Gulo-KO mice deprived of ascorbate hosted large tumors with poorly defined borders showed more necrosis and mitosis, [101], thus reinforcing the notion that vitamin C plays a central role in the prevention and control of tumor growth, progression, and metastatic spread.
To further confirm their data, the author showed that vitamin C-supplemented GULO-KO mice injected with B16FO melanoma cells demonstrated a significant reduction (by 71%, p = 0.005) in tumor metastasis compared to GULO-KO mice on the control diet [102].
“Ascorbic acid is a potent detoxicant which counteracts and neutralizes the harmful effects of many poisons in the body. It will combat various inorganic poisons, such as mercury and arsenic, and it neutralizes the bad reactions of many organic poisons, drugs, and bacterial and animal toxins. Ascorbic acid detoxifies carbon monoxide, sulphur dioxide, and carcinogens, so it is the only immediate protection we have against the bad effects of air pollution and smoking” [3].
This sentence defines yet another way through which vitamin C can prevent and fight off cancer, i.e., by neutralizing chemical carcinogens. Whether this effect depends on its antioxidant, anti-inflammatory effect, or yet other mechanisms, it is clear that vitamin C is an essential factor in cancer chemoprevention, and this cancer-preventive capacity is more likely associated with its protective effect against oxidative stress mediated by ROS [103].
Free radicals and other ROS are molecular species capable of independent existence that contains an unpaired electron in an atomic orbital. Free radicals derive either from normal metabolic processes or from external sources, such as exposure to X-rays, ozone, cigarette smoking, air pollutants, and industrial chemicals.
An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage. Antioxidants delay or inhibit cellular damage mainly through their free radical scavenging property.
Given this peculiarity, vitamin C, as noted by Stone, can combat the toxic effects of different organic and inorganic poisons, thus preventing and fighting cancer due to environmental pollutants.
Recently, the US Department of Agriculture and the National Cancer Institute recommend the consumption of a minimum of five servings of fruit and vegetables to prevent cancer, with vitamin C being able to reduce the risk of stomach, mouth, pharynx, esophagus, lung, pancreas, and cervical cancers [104]. Furthermore, both epidemiologic and observational studies based on food intake provide evidence for a strong, protective role of vitamin C against cancer [105, 106].
Different studies show that the vitamin C is capable of preventing nitrosation and interfere with experimentally induced carcinogenesis [107, 108].
Vitamin C administered together with diethylnitrosamine (NDEA) shows an inhibitory effect on the experimental esophageal carcinogenesis in Wistar rats [109]. It also protects against the toxic effects of a number of pesticides/insecticides, including malathion [110], imidacloprid [111], endosulfan [112], dimethoate [113], fenvalerate [114], and many others.
More importantly, vitamin C reduces the toxic effects of different anticancer agents, including cisplatin [115, 116], cyclophasphamide [117], selenium-cisplatin conjugates [118] radiation [119], arsenic [120], doxorubicin [121], alkylating agents [122], and many others.
As shown in the previous section, vitamin C protects normal cells from the oxidative, genotoxic effects of chemotherapeutic agents, but this does not imply that it counteracts the cytotoxic effects of cancer chemotherapy and radiotherapy.
Regarding the clinical use of high doses of vitamin C in combination with standard anticancer chemotherapy, for a long time, and even today, detractors of vitamin C (that are still a multitude, within the scientific community!) warn against the risk that antioxidants (such as vitamin C) may enhance cancer cell proliferation.
The role of micronutrients with antioxidant properties (including vitamin C) as a useful adjunct to conventional chemotherapy and /or radiotherapy has been controversial, essentially because they could protect cancer cells from the deleterious effects of free radicals generated by the therapy, thereby preventing cancer cell death.
After an exhaustive review of the literature, encompassing more than 44 scientific articles on the effectiveness of vitamin C alone, or with other vitamins, with chemotherapy, the authors concluded that: “… antioxidants [including vitamin C] do not protect cancer cells against free radical and growth-inhibitory effects of standard therapy. On the contrary, they enhance its growth-inhibitory effects on tumour cells, but protect normal cells against its adverse effects” [123]. This literature review suggests that the use of vitamin C alone with chemotherapy results in increased survival, enhancement of chemotherapy, inhibition of tumor growth, decrease in the overall toxicity, modulation of genotoxicity linked to chemotherapy, distinct potentiating effect of chemotherapy, improved quality of life, and a whole series of other positive effects on the outcome of treated patients.
Recent evidence suggests that vitamin C can efficiently
aid low-dose methotrexate (MTX) in inducing cell death in Hep3B cells [124],
synergize arsenic trioxide in acute promyelocytic leukemia [26],
improve chemosensitivity of ovarian cancer, reducing, at the same time, the toxicity of chemotherapy [125],
sensitize tumor cells toward cytostatic drugs [126], and
improve the quality of life of patients undergoing chemo/radiotherapy [127, 128].
In a position paper published in the Journal of the American College of Nutrition in 2001, the authors highlight that “… none of the published data on the effect of antioxidants in combination with radiation or chemotherapeutic agents on tumour cells supports this hypothesis” [129]. As the authors observe, normal and tumor cells differ in their responses to antioxidants; low-dose and high-dose antioxidants differ in their effect on tumor cells, some actions of antioxidants on tumor cells are unrelated to scavenging of free radicals, and antioxidants have profound effects on the regulation of gene expression in tumor cells.
As we have seen, the expectations generated from in vitro and animal studies on vitamin C still wait for the confirmation of clinical studies. The discrepancy between in vitro and in vivo results is due to several factors presented in the next.
Among the many mystifying (and sometimes pseudoscientific) data regarding the anticancer effects of vitamin C, the most blatant is surely the one concerning the dose used. While it is clear that therm “high” designates doses of vitamin C (generally administered by intravenous injection) leading to plasma concentrations in the order of millimoles (from one to several), current “institutional” clinical trials pass off as “high” doses of vitamin C of 1000 mg (1 g)! This is the case of a number of clinical trials, among which we could mention:
A phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases [130],
A clinical experience on the combination of arsenic trioxide and ascorbic acid in patients with refractory metastatic colorectal carcinoma [131],
A phase I study on combination of decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia [132], and many others. Clinical trials designed as the ones reported above are of no value in verifying the role of high doses of vitamin C in the treatment of cancer, since 1000 mg of the nutrient, even if administered in vein, is not a high (“pharmacologic”) dose.
If we assume that one of the main mechanisms through which vitamin C in pharmacologic doses is toxic to cancer cells is the production of H2O2, then oxygen becomes a fundamental part of the cytotoxic activity of vitamin C against cancer. Solid tumors often contain areas subjected to acute or chronic hypoxia. Although severe or prolonged hypoxia is deleterious, adaptation to a hypoxic microenvironment, allows cancer cells to survive and proliferate in a hostile milieu. More importantly, since cell culture experiments are usually performed in an oxygen-rich environment, while solid tumors usually show a very low content of oxygen, this difference in oxygen content may explain the different outcome in vitamin C cancer cell killing in vitro, compared to what happens in vivo [133]. Overcoming cancer hypoxia may therefore represent one of the main ways to improve the anticancer activity of high doses of vitamin C in clinical settings, as commonly realized with either hyperbaric oxygen (HBO) or ozonated autohemotherapy.
Sodium ascorbate, rather than ascorbic acid, may be the preferred preparation for intravenous injection. Ascorbic acid produces a very acidic solution, when dissolved in water or saline solution, and, as such, unsuitable for intravenous injection. Therefore, in order to obtain a neutral solution, it is necessary to buffer it with either sodium bicarbonate or sodium hydroxide. However, adding a buffer may represent a major problem, in terms of stability of the solution, and therefore the sodium salt of vitamin C, which produces a pH of around 7.0, is clearly preferable.
According to some author, a constant “flow” of vitamin C in the blood works as if the body would produce the nutrient on its own (the “dynamic flow” hypothesis) [134]. The slow, constant infusion of vitamin C is the best option to maintain a stable plasma level of the nutrient, by intravenous injection [135] even though this approach is not common in the treatment of cancer patients with intravenous high doses of the nutrient. In fact, the great majority of the cancer clinical trials performed so far with intravenous vitamin C use the infusion of vitamin C on alternate days, withdrawing the treatment during the weekend. With this treatment modality, systemic conditioning (the accelerated metabolism or disposal of ascorbic acid) may occur after prolonged supplementation of high doses of vitamin C. Thus, if vitamin C supplementation were to cease abruptly, the accelerated disposal of the nutrient may create a deficiency state (“rebound scurvy”), and this may represent a serious inconvenience, when treating cancer patients. This is why, since Klenner’s experience with multiple administration routes, it may turn out to be useful to combine both intravenous and oral administration of large doses of vitamin C [7].
John Ely first proposed the glucose-ascorbate antagonism (GAA) theory in the 1970s [136]. According to this theory, the chemical structure of vitamin C and glucose is very similar and therefore they compete for the same transport system to enter the cells. As a consequence, both vitamin C and its oxidized form, DHAA, transported into different cell types (including adipocytes, erythrocytes, granulosa cells, neutrophils, osteoblasts, and smooth muscle cells), are inhibited by high blood glucose. Although in vivo studies are missing, investigations on diabetic patients have confirmed the theory. Therefore, given the inverse relationship between glucose and vitamin C blood levels, maintaining blood glucose levels within the normal range may greatly enhance the anticancer effect of vitamin C.
As a necessary premise to an evaluation of the anticancer properties of vitamin C, a realistic look at the state of the art on cancer chemotherapy can be helpful. The “war on cancer,” officially declared by President Richard Nixon, with the National Cancer Act, in 1971, has been largely considered a failure, by the experts [137, 138], because of the following:
The major improvements in survival rates mainly concern cancers of children and young adults, which account for 1.3% of all known cancers, and this has a little impact on the overall picture. Therefore, in most cases and for most forms of cancer, the war (the “war” metaphor) has been lost [139, 140].
Targeted therapies (the “magic bullet” metaphor) are not curative because cancer usually adapts itself, becoming resistant to every new “weapon” used [141].
Since the overwhelming majority of cancer is due to environmental, particularly lifestyle, factors, prevention, rather than cure, should be the foremost aim [142].
The industry continues to be developed and the institutional organisms approve new cancer drugs, based on marginal improvements in survival at an unsustainably high financial cost [143].
Furthermore, cancer chemotherapy has an inherent toxicity, which, in many instances, encompasses, among others, nausea, vomiting, mucositis, hair loss, bone marrow toxicity, cardiac, neurologic, and renal toxicity, and, in the long term, sterility and secondary malignancy.
Finally, both early and recent reports demonstrate that cancer chemotherapy can be either ineffective/useless [144, 145] or definitely harmful [146, 147].
Compared to the current chemotherapeutic agents, vitamin C in high (“pharmacologic”) concentration has the following advantages:
It is a natural compound that is usually produced by the vast majority of plants and animals, but not (no longer!) by humans. As any other natural product, it is neither patentable nor commercially exploitable.
Both tissues and plasma of cancer/leukemia patients show reduced levels of this nutrient and therefore the routine administration of adequate amounts of vitamin C to these patients is not only warranted, but highly desirable.
High concentrations of vitamin C within tumor cells are associated with extended disease-free survival, while low concentrations are associated with aggressive tumor phenotype.
It has no relevant side effects, with the exception of a slight diarrhea, a “guiding symptom” that indicates that the body “saturation” with the nutrient (“bowel tolerance”). To control the mild diarrhea that follows the body saturation threshold, it is sufficient to reduce or fractionate the doses, but in clinical practice, it is useful to maximize the effects of vitamin C, when assumed by mouth. Given the almost total absence of side effects, undue and sometimes laughable attempts to warn against its use have come, from time to time, from detractors of vitamin C, dealing with the possibility that several grams per day could lead to oxalate stone formation. In this regard, it will suffice to mention the European Food Safety Authority (EFSA) report n. EFSA-Q-2003-018, which, on this matter, clearly affirms: “No significant relationships were found in an analysis of data from 5214 men and 5785 women between serum vitamin C concentrations and the prevalence of kidney stones” [148]. Moreover, the hyperoxaluria associated with the use of high-dose vitamin C is primarily due to a laboratory artifact, resulting from the conversion of vitamin C to oxalate ex vivo (i.e., after it has left the body, while it is in the collection bottle) [149]. The only contraindication to the treatment with high doses of intravenous vitamin C is the deficiency of glucose-6-phosphate dehydrogenase (G6-P-D), a rare genetic disorder in which a number of different drugs are usually contraindicated.
It is inexpensive.
Beyond all these advantages, vitamin C in high doses is clearly cytotoxic for a large number of human tumor cell lines. At plasma concentrations achieved by intravenous administration, vitamin C induces death in 75% of 48 cancer cell lines tested in vitro [150], but has no toxic effect on human peripheral white blood cells, fibroblasts, or epithelial cells. This represents the realization of the dream of the “magic bullet,” even though the “scientific community” seems to continue to ignore it!
Regarding the anticancer efficacy of vitamin C in vivo, although the results of the first clinical trials have been rather disappointing, an unbiased analysis of the data currently available reveals an excellent safety profile, a clear-cut improvement of the quality of life [127], and a potentially important antitumor activity even though further, well-designed, controlled studies are strongly required.
Almost 50 years after the discovery of the anticancer properties of vitamin C, scientists are still looking for a rationale for the use of this nutrient in the treatment of cancer. However, as we have seen, this rationale not only exists, but it is also evidence-based, well-founded, complex, and variegated, given the many extraordinary benefits of vitamin C for human health. Therefore, faced with such an overwhelming evidence in favor of the efficacy of vitamin C against cancer, the question may become “why mega doses of vitamin C have not yet entered the routine clinical treatment of cancer?”
As sad as it may appear, the many advantages of vitamin C as an anticancer agent represent likewise limitations to its use in clinical practice. In fact, vitamin C is a natural compound, and this implies that no pharmaceutical company can effectively exploit it for commercial purposes. Drug companies must patent the molecular structure of the active ingredient of their products in order to make a profit. Natural substances, such as vitamin C, cannot undergo any patent submission procedure, because they exist in nature.
Another important issue may be the price: compared to the high costs of cancer drugs, some of which may reach the 30,000 USD for a single dose [151], vitamin C with its price ranging from 20 to 40 USD per kilogram (depending on the country) represents a real outsider within such an expensive market. No pharmaceutical company would ever invest in the clinical development of such an inexpensive product!
Going deeper into this apparent “lack of interest” for vitamin C as an anticancer compound, we can find the outstanding issue of its selectivity of action (the “magic bullet” principle); an aspect that still fascinates the clinical oncologists. As we have seen, contrary to the chemotherapeutic agents, vitamin C kills cancer cells by exploiting a substantial metabolic difference between them and their normal counterpart; a property virtually unknown to the vast majority of the chemotherapeutic agents of common use in clinical practice!
The ethical implications of the above considerations are clear, and we will not discuss them herein. However, there are aspects, in this incomprehensible “indifference” to vitamin C as an anticancer molecule, which go far beyond plausibility and common sense.
One is surely the evidence that vitamin C deficiency is common in patients with advanced cancer, and, at the same time, patients with low plasma concentrations of vitamin C almost invariably show shorter survival, if compared to those with normal/higher concentrations [152]. Should not this evidence alone compel the clinicians to use vitamin C supplementation in cancer patients on a routine basis? A vitamin C deficiency, as we have seen in the first section of this chapter, is most probably in play in the genesis and development of cancer, and traces of this deficiency often remain, unless patients use supplements on their own, in blood and tissues of affected individuals. Is not this data alone sufficient to warrant the routine administration of vitamin C to cancer patients?
The other, not less relevant, aspect is the safety of vitamin C. The LD50 for a mouse (who normally produces its own vitamin C), is more than 3.3 g/kg of body weight, but most probably, even more than that, for mammals not producing their own vitamin, such as humans. This has clearly emerged from clinical studies on intravenous injection of mega doses of the nutrient, which have also showed a definite and unequivocal improvement in the quality of life of the treated patients.
The last aspect, regarding the importance of vitamin C in the treatment of cancer, is the demonstration of the capacity of this nutrient to reduce the side effects and improve the anticancer activity of conventional chemotherapeutic agents, when combined with them [125].
Do we really need more information to introduce high doses of vitamin C in the routine treatment of cancer?
This chapter has been realized, in part, thanks to the financial support of the “Pescara Cell Factory Foundation,” and the “Associazione Italiana dei Genitori dei bambini affetti da Retinoblastoma” (AIGR).
Bariatric individuals not only present with specific medical complications and more prevalent risk factors for cardiovascular disease (CVD) and musculoskeletal (MSK) conditions, this population also has significantly greater potential for functional decline. Graded increase in activities of daily living (ADL) limitation was observed with increasing body weight [1]. Rehabilitation medicine approach to address the needs of a bariatric individual encompasses both ends of the management spectrum: to restore and prevent further deterioration of physical function associated or aggravated with excess body weight; as well as to enhance post-operative results with a sustainable weight management strategy.
\nThe rehabilitation medicine approach to function can be viewed from The International Classification of Functioning, Disability and Health (ICF) concept to better understand the interactive nature of a chronic health condition such as obesity and formulate a rehabilitation plan to address physical, psychological and socio-environmental barriers to bariatric-related disability [2, 3] (\nTable 1\n). Individualisation of care from all disciplines involved in the bariatric population to produce long-term sustainable results can also be deduced by understanding the dynamics of a disease process through this concept. We shall discuss the approaches to a bariatric evaluation, rehabilitation intervention and functional outcome in two parts with special focus on prehabilitation and peri-operative rehabilitation.
\nDomains affected | \nDescriptors | \n
---|---|
Body function | \nEnergy and drive function | \n
Weight maintenance functions | \n|
Activities and participation | \nHandling stress and other psychological demands | \n
Walking | \n|
Moving around | \n|
Looking after one’s health | \n|
Environmental factors | \nProducts of substances for personal consumption | \n
Immediate family | \n
Brief ICF Core set for Obesity [3].
Obesity affects physical, biopsychosocial aspects of an individual’s health and function. The complex nature may require rehabilitation interventions to be carried out in various settings to accommodate for different functional goals and engaging a multidisciplinary rehabilitation team to tap into different expertise to achieve the desired functional milestones. The bariatric individual presents with unique challenges to the treating team in both functional limitations and the approaches that can be employed to address these impairments and prevent further functional deterioration. The ICF highlights the domains that are affected by excessive weight: pain, cutaneous sensation, neuromusculoskeletal issues and movement difficulties as well skin issues due to difficulty in reaching during cleaning and toileting are the most commonly impaired function and complications leading to limitation in general tasks, mobility and poorer quality of life [1]. Concurrent presence of medical comorbidities can add up to tip the individual into compromised functional independence [1]. Common comorbidities related to obesity such as osteoarthritis of the weight bearing joints and cardiopulmonary conditions impacts severely on an individual’s functional reserves. Thus, the goal for bariatric rehabilitation program should include assisting the attainment of optimal weight reduction; to address current and potential medical complications especially metabolic syndrome, CVD and MSK conditions; to address functional limitations resulting from physical disabilities and improve quality of life through improving functional independence, self-confidence and empowering self-management.
\nSevere obesity with multiple comorbidities requires admission to medical facilities structurally adequate to assist in supporting and assisting individuals with excess body mass to transfer and mobilise with the use of bariatric- safe lifting devices, mobility equipment and transfer aids. Ideally these rehabilitation facilities are linked to a bariatric- dedicated medical and surgical specialities [4].
\nThe bariatric patients frequently develop medical complications that may run a protracted course [5]. Common medical complications readily noted at admission include:
Skin excoriations, rashes or ulcers in deep tissue folds with possibility of fungal infections.
Edema or fluid retention and venous congestion that causes feeling of limb heaviness or leading to diaphoresis-fluid leakage that renders the skin sensitive to shear forces, skin tears and infection.
Diabetes and respiratory problems including obesity hypoventilation syndrome or obstructive sleep apnoea.
These complications may indicate specialised nursing care or aids to protect during mobilisation. It may also preclude the use of some rehabilitation modalities i.e. hydrotherapy and priorities needs to be given to address medical conditions that delays resumption of weight bearing or therapeutic standing.
\nHospitalisation-related complications that tend to occur are mainly as a result of prolonged recumbency, also known as deconditioning. While deconditioning is not exclusive to bariatric population, its effects are more pronounced as bariatric individuals face challenges for immediate resumption of upright posture especially those who were admitted acutely for medical complications such as cardiopulmonary emergencies, following falls or exacerbation of musculoskeletal conditions leading to pain on weight bearing. Deconditioning can affect both physical and psychological domains as prolonged bed rest affects nearly all body systems. Specific to bariatric population these complications may entail a prolonged stay and protracted course of recovery:
Cardiovascular system: orthostatic hypotension and reduced exercise tolerance contributed by decreased cardiac output and resting tachycardia affecting sitting up, standing, transfers and physical activity participation.
Pulmonary system: orthostatic pneumonia or atelectasis resulting in hypoxemia and reduced tolerance to physical activity may complicate obesity hypoventilation syndrome or sleep apnoea.
Haematological system: deep venous thrombosis and pulmonary embolism may occur despite no lower limb neurological deficit as abdominal mass may compress on lower limb circulation and altered blood viscosity.
Musculoskeletal system: muscle atrophy causing weakness; leading to longer periods of non-weight bearing and increasing the risk of osteoporosis, joint stiffness and worsening posture. Especially of concern is weakness of extensor muscles needed to assume or assist to an upright position.
Gastrointestinal: constipation from lack of upright posture often complicate prescription diet plans due to the bloating sensation, abdominal discomfort and possibility of spurious diarrhoea complicating personal hygiene due to poor access to the perineal region combined with postural stasis that predisposes to the development of pressure ulcers.
Endocrine: impaired insulin response with hyperglycemia; gastrostasis leading to sensation of nausea and oesophageal reflux symptoms.
The result impacts on a bariatric individual’s functional reserves in terms of muscle power, balance, and coordination, jeopardising functional performance and results in the development of psychological sequelae as a direct result of deconditioning or from the loss of function it entails. Confusion and disorientation are part of the deconditioning constellation seen earlier on the bedrest period which can culminate in clinically significant anxiety and depression once the impact of functional loss sets in as self-care, leisure activities and gainful employment becomes challenging. Reconditioning as a rehabilitation goal will be discussed further in the prehabilitation section. Given the prospect of functional deterioration that can occur at an accelerated rate in the bariatric population due to inherent difficulties in mobilisation, special attention should be given to addressing factors that negate upright sitting and to promote lower limb weight bearing in cases that permit them as soon as possible. These include identifying at risk bariatric individuals with hip and knee replacements, paralysis, amputations, contractures, osteoporosis, respiratory and cardiac conditions, and skin conditions such as pressure ulcers. Availability of bariatric mobility aids such as hoists, tilt tables, chairs or wheelchairs and walking aids greatly assist in preventing the ill effects on deconditioning and translates to better cost-efficiency to prevent such deleterious complications rather than treatment of the aforementioned complications.
\nVarious models of bariatric rehabilitation exists to generally addresses 5 key factors: knowledge to empower action, goal-setting and self-care; beliefs surrounding causes and solutions to obesity; behavioural adaptation focusing on diet and physical activity, psychological coping strategies and adjustments of physical activity to include exercise, current functional capacity and that expected after bariatric surgery. A holistic model such as bio-psycho-social model explained via ICF helps to provide a multi-dimensional framework to evaluate the needs, identify the barriers and provide intervention or solutions to improve independence. Selection of the model to address such an individualistic experience such as function is paramount as the different considerations of the desired rehabilitation goals and outcomes of interest are given priority by different models [6]. The lack of obesity-specific outcome measures to quantify physical impairments and ADL limitations prevents stratification of bariatric individuals based on the magnitude of disability [7]. This is useful to establish as a threshold value for inpatient rehabilitation admission, and serves as an objective severity identification tool that impacts on the decision of appropriate rehabilitation setting and chart progress during rehabilitation. An example of such tool is the Obesity-related Disability Test (TSD.OC) developed by Donini et al. that aims to evaluate pertinent obesity- specific functional dimensions [8]. The main targets for bariatric rehabilitation are the cardiorespiratory, musculoskeletal and multi-systemic effects of deconditioning as described above. Strategies that reduce pain, increases strength and mobility as well as optimise functions can be delivered in various settings depending on the severity of obesity-induced disability. Inpatient rehabilitation facility offers an opportunity for more intensive rehabilitation input and caters well to bariatric clients admitted acutely for MSK or CVD that often runs a prolonged hospital stay and poorer functional recovery if left without rehabilitation input. The goals of inpatient rehabilitation are focused on attaining maximal functional independence for safe home discharge through improvements in strength, balance, and endurance coupled with initiation of CVD risk factor control and body weight reduction through dietary and physical activity prescription. An outpatient program may provide significant functional improvements in clients who can access both the centres and their lodging with appropriate means of transportation between them. This is attained by promoting increased pain-free joint range of motion, increasing muscle strength and cardiopulmonary endurance during functional activities. Concurrent efforts to optimise CVD risk factor and improve lean-to-fat mass ratio are also continued in the outpatient setting through education and individualised counselling on dietary and physical activity plan to maximise functional capacity despite excessive weight. Capodaglio et al. conducted a prospective 4-week inpatient bariatric rehabilitation with orthopaedic conditions consisting of strengthening and aerobic exercises adapted to the patient’s mobility; caloric restriction and nutritional education with psychological counselling [7]. The results exemplified that mild and severely disabled bariatric individuals with orthopaedic comorbidities can significantly experience functional improvements independent of the weight loss sustained; with the higher BMI and younger individuals showing the most functional gains. Similarly, Hanapi et al. employed an approach based on the cardiac rehabilitation model and resources for inpatient bariatric clients with CVD risk factors and orthopaedic comorbidities [9]. Employing adapted physical activity and exercise prescription, dietary modification, provision of psychological and social support, their approach successfully addressed weight, cardiometabolic profile optimisation prior to bariatric surgical intervention and conferring postoperative improvement in mood, dependency level, perceived physical and mental health during the postoperative phase with sustained functional capacity, endurance and quality of life up to 3 months post operatively.
\nAdmission planning for an inpatient rehabilitation stay is crucial to ensure logistic requirements, staffing ratio, bariatric-compliant equipment, administrative support and a mobilisation plan is developed as part of a function-centric rehabilitation plan. By definition, bariatric individuals include individuals whose weight exceeds or appears to exceed the identified safe working loads for equipment, lacks mobility or presents with challenges in manual handling [10, 11]. Moving and handling of bariatric clients can accentuate the risks of musculoskeletal injuries and excessive spinal loading in health care workers. Planning of staff and equipment reduces the risks associated with the care of bariatric patients. Safety of patients and health care workers can be enhanced by developing a movement and handling plan as each bariatric admission often presents with unique issues that require problem solving and an understanding of equipment or patient transfer procedures. Involvement of occupational health and safety representatives as well as risk reduction efforts can minimise unplanned situations that may differ between patients due to individuals’ risks, goals and resources available. Every aspect of patient- HCW interaction should be therapeutic from rehabilitation perspective including communication. Open discussion on equipment use and transfer techniques can lead the way to more serious discussions on dietary habits, adapting lifestyles and long-term functional goals. Education on the importance of physical activity and dietary management to aid weight loss and maintain functional independence helps boost motivation and compliance [9]. Discharge planning should include not just physical preparation of the destination. Consideration should be given to post-rehabilitation functional limitations that may require physical help or adaptive equipment as functional goals attainment may require repeated cycles of rehabilitation. Potential home modifications and long-term plans for adapted physical activity, dietary maintenance, psychological support, surveillance for relapses and complications as well as plans for higher functions such as return to work and driving should be discussed with the patients and their social support.
\nOutpatient bariatric rehabilitation continues the inpatient gains made with focus on long-term prevention of function and weight- gain relapse. The common impairments addressed are osteoarticular pain especially of the lower back and knees as well as joint malalignment. The effects of excessive weight on systemic inflammation, joint compression and premature degenerative disease of the joint can be offset by the role of adapted physical activity which is more pronounced in this setting to maintain compliance to caloric expenditure, CVD prevention and positive psychosocial reinforcement. A combination of both aerobic, resistance and flexibility exercises adapted to individual MSK conditions working on large muscle groups alongside dietary modification has led to improvement in CV biomarkers, fat loss and skeletal muscle gains conferring enhanced functional improvements in programs that include resistance exercises [12, 13]. In comparison to diet modification intervention alone, multimodal exercises program combined with diet interventions conferred lean mass sparing effect [14]. This is also evident in a systematic review of sarcopenic obesity treatment whereby excess fat mass and reduced lean mass impairs physical performance in which weight loss attained through exercise in combination with dietary intervention is the best treatment strategy that improves metabolic consequences of excess fat mass while preserving lean muscle mass and promotes functional recovery [15]. Aerobic exercises for caloric expenditure, reducing joint pain and controlling weight which is a risk factor of osteoarthritis as well as resistance exercise for strengthening of the joint supporting musculature and cartilage health reduces obesity-related joint conditions [16, 17]. As the client returns to the community, psychological support to sustain weight loss motivation and purpose as well as addressing stigma associated with excessive weight is equally important to ensure sustained functional and weight loss gains are maintained. Chronic pain and its effect on gait, psychical activity, participation and quality of life also needs to be addressed.
\nIn conclusion, bariatric rehabilitation addresses common medical comorbidities and obesity related MSK complications through multimodal rehabilitative and allied health interventions, including prescription exercises and diet modification to increase cardiopulmonary endurance and caloric expenditure while minimising fear of movement and joint pain. This in turn leads to progressive body weight reduction and improved comorbidities profile leading to better body composition and physical function capacity.
\nBariatric individuals often present with medical comorbidities arising from obesity-related changes or complications sustained from hospitalisation- related bedrest for acute medical crises. Functional impairments evident pre-operatively should be addressed to improve postoperative results and functional independence. The concept of deconditioning is discussed above- the bariatric individual runs a higher risk of developing deconditioning due to delayed weight bearing or resumption of an upright position. This is often multifactorial: common patient related factors such as sarcopenia, kinesiophobia, osteoarticular joint pain and exertional dyspnoea; logistic issues i.e. lack bariatric-safe equipment or staffs’ lack of ergonomic awareness are among easily amenable factors [18]. Deconditioning impacts the geriatric age group more [19]. Adapted exercises have been successful to prevent multisystem deconditioning from zero-gravity environment or from prolonged bed rest [20, 21]. Hanapi et al. demonstrated a 6-weeks bariatric surgery prehabilitation [9] consisting of patient education and prescription of therapeutic exercises, dietary modification and nutritional-behavioural counselling, the use of technological advancement to facilitate early non-weight bearing aerobic and resistance exercises that had successfully prepared the bariatric patients for the demands of the surgery as well as facilitated early post-operative mobilisation that has been purported to reduce post-surgical morbidity [22, 23]. This model adapted the principles of cardiac rehabilitation in formulating the evaluation, intervention and outcomes including risk-stratifying the bariatric surgery candidates for cardiovascular risk during exercise participation, quantifying exercise capacity for exercise prescription and addressing CVD risk factors that can complicate anaesthetic and post-operative care. Priorities were given to utilising adapted physical activity and early mobilisation to translate cardiorespiratory and musculoskeletal reserve improvements into functional mobility and independence in basic activities of daily living. This model along with other bio-psycho-social approaches have shown positive impact on long term functional capacity, endurance, dietary habits, weight loss and quality of life up between 3 to 12-month post-surgery [24].
\nIn the management of a complex, chronic condition such as obesity a multidisciplinary approach has consistently shown the best outcomes [25]. This approach however must be integrated into individual clinical complexity of each individual bariatric patient. An approach that entail evaluation with the intent to individualise treatment plan utilising multimodal treatment strategies i.e. diet, physical activity and functional rehabilitation, educational therapy, cognitive-behaviour therapy, drug therapy, and bariatric surgery will most likely ensure quality of weight loss, addressing the medical and psychiatric comorbidities together, psychosocial problems and physical disability [26]. Older bariatric patients may face a more challenging rehabilitation course due to age-related changes such as sarcopenia, muscular fatty infiltration which leads to strength reduction and diminishing exercise capacity; as well as external factors such as increased inertia from excessive mass causing imbalance, longer exposure to effects of obesity causing pronounced musculoskeletal degeneration and pain as well as more damage in the peripheral tissues [7]. Sarcopenic obesity in advanced age contributes to more dependence in ADL [27]. Muscular and mobility deterioration in combination contributes to exacerbate physiological changes associated with ageing. Thus, identification of such patients earlier prior to surgery is paramount to ensure successful outcomes following bariatric surgery.
\nThe economics of bariatric rehabilitation can be seen from 2 angles- in respect to functional restoration and from a long-term preventive viewpoint. Bariatric individuals who have undergone rehabilitation have shown functional improvement independent of the amount of weight lost, with more pronounced improvement in function observed in the severely disabled individuals [7]. This translates to earlier weight bearing, resumption of mobility and independence in self-care which in turns minimises the risk post-operative complications. Alongside improvement in muscular strength and lean mass, individuals who have undergone rehabilitation also had controlled CVD risk profiles, joint pain and reduced sedentary time conferring protection to future CVD in this high-risk group. However, to truly understand the cost–benefit effect of bariatric rehabilitation, long term outcomes expressed in multiple domains of function are needed to allow better understanding of the effect of different rehab interventions, optimal intensity and duration to therapeutic effect.
\nCapacity building in an organisation that caters for bariatric rehabilitation is essential to reduce personal risks to patients and staff as well as minimise disruption of bariatric rehabilitation services. This includes developing a bariatric rehabilitation pathway, continuous staff education and training and an audit of the outcomes from the pathway. A bariatric rehabilitation pathway details the appropriate facilities, staff and equipment are available at each stage of the bariatric individuals’ rehabilitation process from admission to outpatient facilities. Although this may incur short term increase in expenditure, the long term return of investment can be quantified through better morbidity and mortality reduction of the bariatric population regardless of conservative or surgical management approach chosen to suit individual medical and functional needs.
\nFormulation of an individually-tailored rehabilitation program based on each bariatric patients’ clinical complexity should be the priority to holistically manage such clients using a multidisciplinary team approach. Multidisciplinary teams offer the best post-operative outcomes [28], addressing quality of weight loss, medical and psychiatric comorbidities, psychosocial problems and physical disability [29]. To ensure a smooth transition from prehabilitation through postoperative rehabilitation, the physical, biopsychosocial model continues to be relevant and emphasis should be placed on preventing surgical-related complications, secondary prevention of CVD, addressing bariatric-related disabilities, psychological and socio-environmental barriers, enhancing physical function through adapted physical activities, education on nutritional management as well as implementation of sustainable weight management strategies.
\nThe post-bariatric surgery management will require coordinated care from a multidisciplinary team of healthcare providers starting from immediate post-op followed by long-term management. The integration of several medical specialties including clinical nutrition, endocrinology, psychiatry [1], rehabilitation medicine, as well as allied health professionals including physiotherapy, occupational therapy, and nursing should be included as part of the core management team. Each team member should provide detailed assessment of impairments, outline prevention strategies and provide solutions for disease management alongside implementation of a functional restoration program. A functional restoration program post-operatively should aim to not only achieve marked weight loss, but also prevention of weight regain, progression of obesity-associated comorbidities, restoration of physical functioning and increase health-related quality of life.
\nA post-op functional restoration program can be broadly grouped into two categories:
\nMedical
Nutritional management
Weight management
Comorbidities
Rehabilitation
Physical activity and exercise training
Psychosocial
The goal of weight loss procedures in general is to either reduce the amount of consumed calories (restrictive) per day or to alter the absorption of the fat (malabsorption) in the food one consumes. For restrictive procedures such as vertical banded gastroplasty (VBG) or laparoscopic adjustable gastric banding (LAGB), that has no malabsorption effect, the volume of food intake will be reduced overall, hence, some nutritional deficiencies may occur. Malabsorptive surgeries such as or biliopancreatic diversion (BPD), gastric sleeve (GS) or Roux-en-Y gastric bypass (RYGB) causes alterations in the intestinal tract and creates challenges in maintaining healthy levels of nutrients including proteins, vitamins and minerals as well as reduction in the absorption of calcium and iron [30].
\nManagement of these potential nutritional deficiencies is therefore paramount for patients undergoing bariatric surgery and strategies should be employed to compensate for food reduction or food intolerance to reduce the risk for clinically important nutritional deficiencies. Signs and symptoms of protein deficiency such as hair loss, fatigue and leg swelling should be monitored. Heber et al. recommended the nutritional management should include: an average of 60 – 120 g of protein daily in all patients to maintain a lean body mass during the weight loss and for the long term to prevent protein malnutrition and its effects, and this is especially important in those treated with malabsorptive procedures to prevent protein malnutrition and its effects [28].
\nLong-term vitamin and mineral supplementation is recommended in all patients undergoing bariatric surgery with those who have had malabsorptive procedures requiring potentially more extensive replacement therapy to prevent nutritional deficiencies [28]. Specific signs and symptoms of common vitamin and mineral deficiencies include bone pain (calcium), fatigue (iron, vitamin B12), brittle nails (zinc), poor wound healing (vitamin E), easy bruising (vitamin K), numbness and tingling in the hands and feet (vitamin B1). Deficiencies in fat-soluble vitamins A, D, E and K is expected therefore, it is essential for patients to take specially formulated vitamins (A, D, E, and K in water-soluble form). B-complex vitamins, iron, and calcium must also be supplemented at higher than daily recommended levels, because of the impact of the gastric bypass procedure on their absorption. Due to the body’s limited ability to a absorb calcium postoperatively and the acidic environment needed for absorption, a citrated form of calcium is recommended and taken in amounts that meet or exceed daily recommended levels [30]. For maximal absorption, elemental calcium supplements should be taken in divided doses not to exceed 500 mg, three times daily [30]. Iron deficiency is also very common after malabsorptive procedures and iron-fortified foods such as leafy greens, legumes, seafood, iron-fortified grains, red meat and poultry should be consumed on a regular basis. Routine laboratory testing of the iron stores postoperatively may be required with iron supplementation either orally or parenterally administered accordingly by the healthcare provider.
\nDumping syndrome may occur as a result of malabsorptive procedures such as RYGB where the food content empties into the small intestine faster than usual. Patients may experience symptoms such as abdominal cramping, nausea and vomiting due to the small intestine being unable to absorb the nutrients from food that have not been fully digested in the stomach. Reactive hypoglycaemia may also occur due to the large surge of insulin after “dumping”. Dietary changes is the mainstay of treatment for dumping syndrome. Avoidance of simple carbohydrates such as white flour and sugar, consumption of more complex carbohydrates such as whole grain and sources of protein such as fish, meat, beans, legumes and soy are recommended. Frequent loose stools is also a potential side-effect of malabsorptive procedures. It is critical that patients stay adequately hydrated to reduce the risk of dehydration. Lack of mobility may also predispose patients with regular soiling of the perineum to skin pathologies including development of pressure areas. Nutritional education is vital to the success of the surgery and prevention of complications. Regular follow-up and periodic monitoring of nutritional deficiencies postoperatively will be required for detection and correction. Lifelong supplementation of daily mineral, multivitamin and micronutrients must be considered.
\nFollowing weight loss surgery, patients may lose weight fairly rapidly at first, and then as time passes the weight loss becomes more gradual. Commonly, weight will stabilise at about 18 months after RYGB [30]. During these 18 months, weight loss can be erratic with alternating periods of significant weight loss followed by a plateau. Other than the loss of fat mass, there are many other factors that may contribute to the fluctuations in weight loss during the initial phase. This includes variations in water weight which is dependent upon the individuals’ hydration status, contents of the gastrointestinal tract, gain of muscle mass, or menstrual cycles [30].
\nSustainable weight loss strategies should include tailored exercise programs with monitoring of the exercise frequency and intensity to boost metabolic rate for a more rapid weight loss. A generic exercise program with lack of progressive targeted goals may lead to weight loss plateaus. Increase in physical activity and strength training will cause slower weight loss as the fat is replaced by muscle mass, which are denser tissues. This should not be perceived as a deterrent, but rather a positive trend that will lead to a leaner frame and stronger body. The recommended nutritional plan should be adhered to diligently to ensure adequate nutrition and muscle mass is maintained. Most weight regain or plateaus in weight loss boils down to eating habits. It is recommended that a patient eat several small meals a day with the ultimate goal of eating a regular diet in smaller amounts. Binge eating, snacking or grazing should be avoided as the extra calories will add up to the weight gain.
\nSeveral anatomic factors may influence weight loss, and this include the size of the gastric pouch which may change over time with the RYGB. As it enlarges over time, it will accommodate larger meals, causing a reduction in weight loss. Anostomotic dilatation between the stomach pouch and the intestine may also occur and this allows quicker emptying of the pouch, reducing its effect on satiety and potential weight loss [30] This is also the underlying reason why one should not drink during meals after gastric bypass as it will result in a more rapid transition of solid food from the gastric pouch, eliminating the effect on satiety resulting in ingestion of larger portions. The resultant change in anatomic structure after malabsorptive procedures such as the RYGB also alters the absorption of food with higher absorption of fats, thus reducing the benefit of the surgery [30]. Eating small meals high in protein may help mitigate this effect.
\nPlateaus and fluctuations in weight loss are to be expected throughout various phases post-surgery. Constant reassurance, providing patient education on the expected outcomes and exploring together the underlying causes of weight plateaus can increase understanding, avoid miscommunication, avert patient depression or frustration with the surgery. A regular exercise regimen and adherence to correct eating behaviour and nutritional intake may lead to greater outcome and a more sustainable long-term weight loss.
\nFrequently, patients undergoing bariatric surgery have associated comorbidities including Type 2 Diabetes Mellitus, cardiovascular disease, lipid abnormalities, fatty liver, degenerative joint disease, hypertension, gastroesophageal reflux disease, and obstructive sleep apnea with considerable impact on disability and quality of life. To reduce the likelihood of weight regain and to ensure that comorbid conditions are adequately managed, all patients should receive careful medical follow-up postoperatively. Monitoring postoperative glycaemic control should consist of achieving glycated HBA1c of 7% or less with fasting blood glucose no greater than 110 mg/dl and postprandial glucose no greater than 180 mg/dl [28]. Lipid abnormalities should be monitored and treated with lipid-lowering therapy that remain above desired goals should be continued. However due to the dramatic reductions in lipid levels, the doses of lipid-lowering drugs should be periodically evaluated [28]. Ideally, a multidisciplinary team should be in place before the operation is performed. The bariatric surgeon should be part of this comprehensive team that provides pre- and postoperative care. The inclusion of other medical specialties in the team including endocrinologists, gastroenterologists and rehabilitation physicians allow a more holistic approach for the treatment of patients with multiple comorbidities and associated impairments and disabilities.
\nSurgery-induced weight loss by itself was associated with a series of beneficial health effects, including increased objectively measured habitual physical activity and cardiorespiratory fitness [29]. Using a cardiac rehabilitation model is effective to cause significant improvement in bariatric individuals’ cardio-metabolic profile [31]. Hanapi et al. demonstrates the application of cardiac rehabilitation principle for post-bariatric surgery patients which include risk stratification through the use of submaximal exercise stress testing to objectively quantify the patient’s cardiovascular capacity for exercise participation, subsequent exercise prescription based on the individuals’ physical impairments and cardiovascular functioning, lifestyle modification to manage cardiovascular risk factors and translating the gains of cardiorespiratory and musculoskeletal fitness into more functional activities [9].
\nPostoperative exercise is imperative and remains the most important factor that can help a patient achieve long-standing and successful weight loss. Exercises can begin as early as day one postoperatively and short term and long term goals should be set early on and revised as activity and exercise capacity increases. The exercise program should incorporate muscle strengthening, physical endurance or aerobic exercises to improve cardiorespiratory fitness, balance training, functional mobility, musculoskeletal reconditioning, joint protection as well activity of daily living (ADL) training, tailored individually within the limit of patients’ cardiovascular capacity.
\nTo sustain weight loss, effective behaviour changes towards increasing energy expenditure through occupational, leisure time and planned physical activity needs to occur alongside dietary management [32]. Physical activity can be incorporated to daily activities which helps with caloric expenditure or decreasing the amount of sitting time or sedentary leisure activities. Education on the importance of physical activities to aid weight loss and maintain functional independence helps boost motivation and compliance. This ultimately affects their level of independence, quality of life and self-efficacy [9].
\nIn addition to loss of fat mass, there are other numerous benefits to exercise. These benefits include prevention of loss of muscle mass when losing weight rapidly after surgery, and improved overall weight loss. Exercise may also reduce a person’s appetite, increases immunity and reduces fatigue which may lead to improved self-confidence, and overall improved sense of well-being.
\nA substantial number of patients experience poor long-term outcomes following bariatric surgery which may be contributed by difficulty in making and sustaining changes in dietary intake and physical activity as well as post-surgery binge eating, which has also been associated with poorer weight outcomes [33]. A thorough preoperative assessment to evaluate patients’ understanding of the disease condition, identifying any misconceptions, assessing readiness and commitment to undergo a radical change in lifestyle and behaviour modification, as well identifying issues that may pose as barriers may be the key to a successful and sustainable weight management postoperatively. Sheets et al. recommend that preoperative assessment should include identifying patients strengths and weaknesses, educating patients thoroughly about postoperative changes including dietary intake and physical activity, coaching on lifestyle change strategies as well as offering specific recommendations to address any areas of concern [34]. The period post bariatric surgery is still a vulnerable time for most individuals as the reality sinks in as adjustment of behaviours and new habits take place. The need for continuous care and screening of psychosocial issues throughout both pre-and postoperative periods cannot be undermined. Screening for aberrant eating behaviours and depressive symptoms should be assessed whilst administering interventions to address emotional and psychological issues, behavioural modification strategies, increase compliance, and provide support [34]. It is the responsibility of each team member to detect or identify the presence of any psychological issues, and administer interventions through early referral to mental health professionals to improve outcomes of these individuals.
\nIntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n1. RETRACTIONS
\\n\\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\\n\\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\\n\\nPublishing of a Retraction Notice will adhere to the following guidelines:
\\n\\n1.2. REMOVALS AND CANCELLATIONS
\\n\\n2. STATEMENTS OF CONCERN
\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"105746",title:"Dr.",name:"A.W.M.M.",middleName:null,surname:"Koopman-van Gemert",slug:"a.w.m.m.-koopman-van-gemert",fullName:"A.W.M.M. Koopman-van Gemert",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105746/images/5803_n.jpg",biography:"Dr. Anna Wilhelmina Margaretha Maria Koopman-van Gemert MD, PhD, became anaesthesiologist-intensivist from the Radboud University Nijmegen (the Netherlands) in 1987. She worked for a couple of years also as a blood bank director in Nijmegen and introduced in the Netherlands the Cell Saver and blood transfusion alternatives. She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n12-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n13-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n14- Abdel Karim M. El Hemaly. 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