Appearances of hepatic steatosis on the main liver imaging modalities
\r\n\tb. The growth of digital environments which can educate and empower as well as exploit and destroy (mobile learning, STEM education, tablets, etc.).
\r\n\tc. Social, racial, class, and gender-based discriminations that restrict the developmental potential and the prosperity perspectives
\r\n\td. Health hazards and illnesses such as the laters COVID-19 pandemic.
\r\n\te. Armed conflicts with casualties and displacements of populations seeking refuge
\r\n\tf. Lack of physical spaces that will support and nourish development and learning, etc.
\r\n\tEducation in the post-modern era strives to address the above issues and develop policies, curricula, methodologies, and strategies to contribute to an environmentally and socially sustainable future. It embraces multiple perspectives and worldviews and seeks to touch on inequalities and discriminations in favor of equity. In this direction, children’s s agency lies at the heart of democratic approaches. Educational processes adopt forms of interactions that actualize learning as “becoming” and place it in a continuum between past, present, and future. This book intends to feature innovative approaches that employ transformative elements (targets, methods, materials, ideas, etc.) and embrace the concept of child development as “becoming” in an ever-changing and challenging world.
\r\n\r\n\tWe invite authors to contribute original research or research review papers that present innovative approaches addressing personal and social transformation. All aspects of early childhood education will be considered, including research methodology for the early years.
",isbn:"978-1-80355-949-0",printIsbn:"978-1-80355-948-3",pdfIsbn:"978-1-80355-950-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"351c41dca5c8c997f15e758f2e035178",bookSignature:"Dr. Maria Ampartzaki and Associate Prof. Michail Kalogiannakis",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11281.jpg",keywords:"Early Childhood Education, Preschool, STEAM, Environmental Sustainability, Social Sciences, Social Sustainability, ICT, Digital Devices, Education for Equity, Gender Issues, Post-modern Epistemology, Social Constructivism",numberOfDownloads:65,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 16th 2021",dateEndSecondStepPublish:"December 14th 2021",dateEndThirdStepPublish:"February 12th 2022",dateEndFourthStepPublish:"May 3rd 2022",dateEndFifthStepPublish:"July 2nd 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"8 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education.",coeditorOneBiosketch:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool\r\nEducation, University of Crete in Greece. He graduated from the Physics Department\r\nof the University of Crete and continued his post-graduate studies at the University\r\nParis-7 and University Paris-5 and received his Ph.D. degree at the University Paris 5.\r\nHis research interests include science education in early childhood, science teaching\r\nand learning, e-learning, the use of ICT in science education, and games simulations.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}}],coeditorOne:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:[{id:"81575",title:"Caring about Early Childhood Education",slug:"caring-about-early-childhood-education",totalDownloads:15,totalCrossrefCites:0,authors:[null]},{id:"80874",title:"Postmodernist Ideas and Their Translation into a Critical Pedagogy for Young Children",slug:"postmodernist-ideas-and-their-translation-into-a-critical-pedagogy-for-young-children",totalDownloads:38,totalCrossrefCites:0,authors:[{id:"338161",title:"Dr.",name:"John",surname:"Wilkinson",slug:"john-wilkinson",fullName:"John Wilkinson"}]},{id:"82431",title:"Next-Generation Science and Engineering Teaching Practices in a Preschool Classroom",slug:"next-generation-science-and-engineering-teaching-practices-in-a-preschool-classroom",totalDownloads:12,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440212",firstName:"Elena",lastName:"Vracaric",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440212/images/20007_n.jpg",email:"elena@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:"6942",title:"Global Social Work",subtitle:"Cutting Edge Issues and Critical Reflections",isOpenForSubmission:!1,hash:"222c8a66edfc7a4a6537af7565bcb3de",slug:"global-social-work-cutting-edge-issues-and-critical-reflections",bookSignature:"Bala Raju Nikku",coverURL:"https://cdn.intechopen.com/books/images_new/6942.jpg",editedByType:"Edited by",editors:[{id:"263576",title:"Dr.",name:"Bala",surname:"Nikku",slug:"bala-nikku",fullName:"Bala Nikku"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6926",title:"Biological Anthropology",subtitle:"Applications and Case Studies",isOpenForSubmission:!1,hash:"5bbb192dffd37a257febf4acfde73bb8",slug:"biological-anthropology-applications-and-case-studies",bookSignature:"Alessio Vovlas",coverURL:"https://cdn.intechopen.com/books/images_new/6926.jpg",editedByType:"Edited by",editors:[{id:"313084",title:"Dr.",name:"Alessio",surname:"Vovlas",slug:"alessio-vovlas",fullName:"Alessio Vovlas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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Alone these agents were associated with overall tumour response rates in the order of 20%.[10] In the last decade newer agents such as Oxaliplatin and Irinotecan have emerged on the market. These agents are not administered alone but normally in combination with a thymidylate synthase inhibitor. These combinations have seen the reported objective response to chemotherapy rise to typical rates of 50%.[11-13]
In parallel with the development of these conventional chemotherapeutics a new class of biological agents, i.e. antibody based therapies, have emerged. These agents are used to tackle specific pathways in tumour growth and development such as angiogenesis (e.g. anti-VEGFA antibody Bevacizumab) or cellular proliferation (e.g. the anti-epidermal growth factor antibodies Cetuximab and Panitumumab). When these agents are added to Oxaliplatin or Irinotecan based chemotherapy a further 10-15% increase in overall tumour response rate can be obtained.[14-17]
This improvement in response rates has led to a resurgence of interest in utilising chemotherapy as a means of down-sizing metastatic disease to enable subsequent surgical resection – so called conversion chemotherapy.[18] This approach was initially described in 1996 in a series of 330 patients with inoperable colorectal liver metastases of whom 53 (16%) were able to undergo a subsequent liver resection with curative intent after receiving systemic chemotherapy. The five year survival for these patients was 40% which compared favourably to patients with operable disease treated with surgery alone during the same period.[19] In 2004 the same group reported the outcome of 1104 patients with initially unresectable colorectal liver metastases who were treated primarily with systemic chemotherapy over an 11 year period from 1988 – 1999. Of this cohort 138 patients had a sufficient response to chemotherapy to permit subsequent curative intent surgery with an overall 5 year survival of 33% being achieved.[20]
In a small phase II trial of 42 patients with inoperable colorectal liver metastases Alberts et al reported that systemic treatment with 5-FU/Oxaliplatin was associated with a tumour response rate of around 60% with 14 patients (33%) having a sufficient response to permit a liver resection with curative intent.[21] Similar results have been reported with a 5-FU/Irinotecan regimen by Nuzzo et al with 15 out of 42 patients (36%) with inoperable disease being able to undergo subsequent surgical treatment.[22] In an attempt to determine the most appropriate regimen for use as conversion chemotherapy the GERCOR trial randomised patients with inoperable metastatic colorectal cancer to receive either 5-FU/Irinotecan until disease progression or unacceptable toxicity and then 5-FU/Oxaliplatin or the reverse sequence (n=113 per arm). Those patients receiving first line Oxaliplatin demonstrated a higher resection rate (n=24; 22%) than those receiving first line Irinotecan (n=10; 9%) and as such this is the approach most commonly applied in UK practice.[23]
More recently studies have been designed to determine the role of the biological agents in conversion therapy. In the phase II uncontrolled BOXER trial 46 patients with inoperable colorectal liver metastases were treated with Capecitabine/Oxaliplatin in combination with Bevacizumab. 35 of these patients experienced an objective tumour response with 18 (40%) able to undergo a liver resection with curative intent. In addition 5 patients (11%) experienced a complete radiological response to systemic therapy.[24] The CRYSTAL trial randomised patients with inoperable metastatic disease to Irinotecan/5-FU either alone or in combination with Cetuximab and found that the addition of Cetuxmiab was more likely to result in patients undergoing subsequent R0 liver resection with curative intent (Odds Ratio 3.02; p=0.002).[17] It is important to note that the response to Cetuximab is primarily determined by KRAS mutation status. In the Crystal trial there was no evidence of benefit in patients with mutant KRAS who received Cetuximab as compared to those who received 5-FU/Irinotecan alone.[25]
For those patients who receive successful conversion chemotherapy and are subsequently considered for liver resection with curative intent it is important to be aware of what the likely long term outcome will be. Adam et al. reported a series of 184 patients with initially inoperable disease who underwent hepatectomy after systemic therapy. In these patients a 5 year overall survival rate of 33% was obtained although it is important to note that a significant proportion of patients in this study underwent 2 or more surgical procedures, often interspersed with further chemotherapy, before long lasting disease control was obtained.[26]
Whilst the role of conversion chemotherapy is widely accepted in the HPB community more recently the question has been asked about what role systemic therapy may play in the management of patients presenting with operable disease from the outset i.e. true neoadjuvant chemotherapy. The EPOC trial was a multicentre randomised controlled trial which allocated such patients to receive either surgery alone or 6 cycles of 5-FU/Oxaliplatin prior to surgery followed by a further 6 cycles of therapy after surgery (n=182 per arm). Of those patients randomised just over 80% of patients in both arms underwent a curative intent liver resection. When the results of this study were analysed on an intention to treat basis there was a non-significant trend to improved 3 year overall survival in the chemotherapy arm (35.4% vs. 28.1%; p=0.058) although statistical significance was only achieved when the analysis was limited to only those who underwent resection (42.4% vs. 33.2%; p=0.025).[27] The difficulty in interpretation of the EPOC trial is that it is impossible to know whether the benefits of peri-operative chemotherapy were primarily a result of the neoadjuvant or adjuvant treatment or if both are required. This important question remains, at present, unanswered.
At present most authors would agree that there is insufficient evidence to consider all patients with operable disease candidates for systemic therapy prior to surgery although it may play a role in those with poor prognostic features such as multiple tumour deposits, a large tumour size or extra-hepatic disease.[28, 29] What is clear however is that an ever increasing number of patients are presenting for surgical resection on the background of multiple cycles of chemotherapy.[30] As experience of managing this patient cohort has increased there has been a growing recognition that the use of chemotherapy can be associated with a toxic injury to the liver parenchyma.[31] The nature of this liver injury and its implication for the surgical approach to these patients will form the subject of the remainder of this chapter.
The presence of fatty change within the liver is increasingly prevalent in the general adult population where it is commonly associated with the presence of obesity and insulin resistance (i.e. the metabolic syndrome). Fatty liver disease represents a spectrum of changes within the liver ranging from simple steatosis through to steatohepatitis and in extreme cases cirrhosis.[32] Steatohepatitis differs from simple steatosis in that significant inflammatory infiltrates are present in the liver commonly in association with ballooning degeneration of hepatocytes.[33]
The link between chemotherapy use and fatty liver disease was first reported in the literature in 1998. In a series of 21 patients with colorectal liver metastases treated with systemic 5-FU Peppercorn et al. reported that 48% (n=10) of patients had developed radiological evidence of steatosis on follow-up imaging.[34] In a later series Pawlik et al. reported the histological findings in the liver parenchyma of 334 patients who had undergone resection of colorectal liver metastases, 153 of whom had received pre-operative chemotherapy. In this study steatosis ≥ 30% (i.e. steatosis affecting more than 30% of hepatocytes) was present in 18.4% of patients who received pre-operative chemotherapy as compared to only 3.4% of patients who were chemotherapy naive (p=0.004). In particular the authors observed that steatosis was most strongly associated with Irinotecan based chemotherapy (27.3% of patients; p<0.001) than 5-FU monotherapy (14.9%; p=0.03) and lastly Oxaliplatin based chemotherapy (9.6%; p=0.04) suggesting that the nature of the chemotherapy regimen may be important in determining liver toxicity.[35]
In contrast however a separate series of 406 patients who underwent resection of colorectal liver metastases failed to demonstrate any association between the administration of pre-operative chemotherapy and the subsequent development of steatosis ≥ 30%. In those receiving Irinotecan based chemotherapy (n=94) there was however a dramatic increase in the incidence of steatohepatitis as compared to those patients who were chemotherapy naive (20.2% vs. 4.4%; p=0.001), a finding which was in contrast to the smaller study described above.[35, 36]
To more accurately determine the nature of the association between chemotherapy use and the development of fatty change within the liver our group undertook a systematic review and meta-analysis of the published literature. In this analysis it was not possible to demonstrate any association with chemotherapy use overall (Relative Risk 1.25; 95% confidence interval 0.99 – 1.57; p=0.15) or Oxaliplatin based chemotherapy (Relative Risk 0.98; 95% confidence interval 0.59 – 1.63; p=0.95) and the development of steatosis ≥ 30%. In the case of Irinotecan based chemotherapy there was a strong trend to an increased risk of steatosis > 30% (Relative Risk 2.51; 95% Confidence Interval 0.79 – 7.90; p=0.12) which was not statistically significant as a consequence of the heterogeneity within the included studies. In contrast there was a strong association between Irinotecan based chemotherapy and steatohepatitis (Relative Risk 3.45; 95% Confidence Interval 1.12 – 10.62; p=0.03) which was not demonstrated with other regimens.[37]
Sinusoidal obstruction syndrome (SOS; previously known as hepatic veno-occlusive disease) represents a microvascular injury to the liver characterised by the histological findings of dilatation of the hepatic sinusoids and associated atrophy of the surrounding hepatocytes. In more advanced SOS these changes are accompanied by the development of regenerative nodules within the liver and ultimately peri-sinusoidal liver fibrosis.[38] Historically SOS was described as a condition occurring after ingestion of pyrrolizidine alkaloids, a group of compounds found in plants used in traditional African herbal remedies.[39, 40] Furthermore SOS has been reported to occur in up to 50% of patients receiving myeloablative chemotherapy prior to bone marrow transplantation.[41, 42]
In a seminal paper in 2004 Rubbia-Brandt published a report of histological changes in the liver parenchyma of 153 patients who had undergone resection of colorectal liver metastases. In this study it was reported that 44 out of 87 patients treated with pre-operative chemotherapy had histological features of SOS, the majority of whom had received treatment with Oxaliplatin based regimens.[38] Similar results were reported by Vauthey et al who demonstrated a significantly increased incidence of SOS in patients receiving Oxaliplatin based chemotherapy as compared to those who were chemotherapy naive (18.9% vs. 1.9%; p<0.001) where as no such association was demonstrated with other chemotherapy regimens.[36] In our systematic review of the published literature we demonstrated a strong association between Oxaliplatin based chemotherapy and SOS (Relative Risk 2.78; 95% Confidence Interval 1.35 – 5.69; p=0.0007) which again was not replicated in patients receiving alternative chemotherapy regimens.[37] The typical appearances of an Oxaliplatin injured liver, as encountered at laparotomy, are shown in Figure 1.
The classical appearance of the Oxaliplatin injured liver with SOS – commonly described as a “blue liver”
It is therefore clear from this discussion that the nature of liver injury following administration of chemotherapy to patients with colorectal liver metastases is dependent on the nature of the regimen administered. Irinotecan based regimens are primarily associated with the development of hepatic steatosis/steatohepatitis whereas Oxaliplatin based regimens are associated with the development of SOS. The assessment of the severity of this liver injury and its implications for the surgical management of these patients forms the discussion in the remainder of this chapter.
Post hepatectomy liver failure (PHLF) is a feared complication of major liver resection and was recently defined as “a postoperatively acquired deterioration in the ability of the liver to maintain its synthetic, excretory and detoxifying functions”[43] whose presence is associated with a dramatic increase in the risk of post-operative mortality.[44, 45]
A key risk factor for the development of PHLF is the presence of background liver disease or injury. Belghiti et al reported, in a series of 747 patients undergoing liver resection, that the presence of either cirrhosis or steatosis affecting more than 30% of hepatocytes (n=253) was associated with a post-operative mortality of 9.5% as compared to only 1% in those with a normal liver parenchyma.[46] In a series of 406 patients undergoing resection of colorectal liver metastases Vauthey et al reported that those patients with steatohepatitis (n=34) experienced an increase in both 90 day mortality (14.7% vs. 1.6% p = 0.001) and post hepatectomy liver failure (5.8% vs. 0.8%; p=0.01).[36] The findings from these case series have been supported by a meta-analysis of the published literature which demonstrated that the presence of hepatic steatosis > 30% was associated with an increased risk of peri-operative complications (risk ratio 2.01; p<0.0001) and mortality (risk ratio 2.79; p=0.02).[47] Similarly the presence of SOS has been associated with an increased incidence of PHLF in a series of 51 patients undergoing resection of CRLM, 38 of whom had histologically proven SOS (68% vs. 23%; p=0.004)[48]
The other factor that is pivotal in determining the risk of PHLF is the volume of liver which will remain following surgery, commonly referred to as the future liver remnant or FLR, which can often be estimated pre-operatively by CT volumetry.[49] In 2003 Shoup et al reported a series of 126 patients who had undergone a liver resection to treat colorectal liver metastases. In those patients with a FLR of ≤ 25% (n=20) 90% developed PHLF as compared to 19% of those with an FLR > 25%. Logistic regression analysis demonstrated that the presence of an FLR<25% tripled the risk of PHLF (Odds Ratio 3.09; p<0.0001). Similarly in a study of 119 patients with a normal liver parenchyma undergoing major liver resection (i.e. resection of 3 or more Couinaud segments) the median FLR in the 7 patients who developed PHLF was 29.6% as compared to 42.5% in those who did not (p=0.009).[50] As a consequence of this evidence the minimum safe FLR in patients with an otherwise normal liver undergoing resection of CRLM is 25%.[51]
In those patients presenting for surgery on the background of multiple cycles of pre-operative chemotherapy it is pivotal, particularly when an extensive liver resection is planned, to minimise the risk of PHLF. When significant parenchymal injury is present it may be necessary for the FLR to be as high as 40% and this may have a significant impact on the surgical strategy employed.[52] Careful pre-operative assessment of the liver is therefore essential in these patients and the techniques which can be employed for doing this are discussed in more detail below.
Identifying those patients at risk of steatohepatitis following Irinotecan based chemotherapy is particularly difficult not least because a significant proportion of patients in the background community will have a fatty liver as a consequence of either the metabolic syndrome, other underlying liver disease or lifestyle. This is reflected in the study of Ryan et al. which analysed histological changes in the liver of 334 patients undergoing resection of colorectal metastases. Only 8 patients in this study had histologically defined steatohepatitis the presence of which, on multivariate analysis, was found to be independently associated with a BMI > 30kg/m2 but not the use of chemotherapy.[53] The study of Vauthey et al. reported that, in 94 patients treated with Irinotecan, the incidence of steatohepatitis was 12.1% in those with a BMI of < 25kg/m2 but 24.6% in those with a BMI of ≥ 25kg/m2. This study did not however undertake a multivariate analysis to identify independent risk factors associated with the presence of steatohepatitis.[36] It has been proposed that elevated serum transaminases may be of use in determining simple steatosis from steatohepatitis in patients with non-alcoholic fatty liver disease but it is not know whether this observation also holds true in those with chemotherapy associated steatohepatitis.[54-56]
Whilst one might intuitively expect that there would be a direct correlation between the number of cycles of chemotherapy received and the presence of liver injury this relationship is in fact less than clear cut. In the study of Vauthey et al. which reported the presence of liver injury in 406 patients undergoing resection of colorectal metastases there was no association between the number of cycles of chemotherapy administered and the incidence of steatohepatitis or SOS.[36] On the other hand Kishi et al., in a series of 219 patients who were treated pre-operatively with Oxaliplatin based chemotherapy, reported that SOS was present more frequently in those who received 9 or more cycles of chemotherapy than those who did not (42% vs. 26%; p=0.017).[57] Similarly the study of Aloia et al. reported that the incidence of SOS in those receiving greater than 12 cycles of chemotherapy was 50% as compared to 25% in those receiving 6-12 cycles and 10% in those who received less than 6 cycles (p=0.01).[58] Several studies have undertaken multivariate analysis to identify independent risk factors associated with the development of chemotherapy induced liver injury. Nakano et al demonstrated that the presence of SOS was independently associated with receiving 6 or more cycles of Oxaliplatin based chemotherapy (Relative Risk 3.2; p=0.048).[59] In contrast however 3 other studies have failed to demonstrate any such independent association between the number of cycles of Oxaliplatin administered and the development of SOS.[48, 60, 61] This raises the question of whether other variables, such as the presence of underlying liver disease, also make a significant contribution to the development of chemotherapy induced liver injury.
Some authors have suggested that tumour related factors may play a role in determining the development of SOS. On a univariate analysis of 78 patients treated with pre-operative Oxaliplatin based chemotherapy Soubrane et al. reported that those with SOS tended to have a larger tumour size (7.8cm vs. 5.2cm; p = 0.004) although this was not identified as an independent risk factor on multivariate analysis.[48] Tamandl et al. were able to confirm this observation in a separate study and on this occasion they were able to demonstrate that a tumour size > 5cm was independently associated with the development of SOS on multivariate analysis (Hazard Ratio 4.42; p = 0.012).[61] This clinical data is supported by experimental data from our group which suggests that the presence of tumour within the liver of mice treated with Oxaliplatin based chemotherapy accelerates changes in gene expression associated with the development of SOS.[62]
The role of various haematological and biochemical parameters to predict the presence of SOS has also been explored in several studies. Soubrane et al. reported on univariate analysis that an elevated AST (p=0.0009), ALT (p=0.02) and a low platelet count (p<0.0001) were all suggestive of the presence of SOS. On multivariate analysis they demonstrated that a high AST to platelet count ratio (APRI score) was an independent predictor for the presence of SOS (Odds Ratio 5; p<0.005).[48] Similarly a multivariate analysis from Nakano et al. demonstrated an independent association between an elevated AST and the presence of SOS (Relative Risk 3.86; p=0.044). [59] Tamandl et al. reported that on multivariate analysis on multivariate analysis an elevated alkaline phosphatase or γGT was an independent predictor of SOS (Hazard Ratio 4; p=0.038) although this was not true for AST or ALT.[61]
Whilst none of these studies have demonstrated a single factor that is reliably able to predict the presence of chemotherapy induced liver injury it is possible to begin to develop a picture of the patient characteristics which may lead to a raised index of suspicion and prompt a more thorough assessment of the liver parenchyma prior to surgery.
The volume of data on the radiological assessment of fatty liver disease is vast and this is a reflection of the high incidence of non-alcoholic fatty liver disease in the general population. The consequence of this is that the appearances of fatty liver disease on each of the 3 main imaging modalities of the liver have been well described and is summarised in Table 1. It should be pointed out that on CT scanning hepatic steatosis is best detected on unenhanced images which are often not performed routinely in most imaging protocols in order to minimise patient radiation exposure.[63] A recent systematic review and meta-analysis of the published literature concluded that MRI represented the most accurate method for determining the extent of hepatic steatosis with a reported sensitivity of 97.4% and specificity of 76.1% for the detection of steatosis >30%.[64]
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Ultrasound | \n\t\t\tIntracellular fat accumulation leads to an increase in liver echogenicity [63] | \n\t\t
Computed Tomography | \n\t\t\tSteatosis leads to a decrease in attenuation of the liver parenchyma [63, 65] | \n\t\t
Magnetic Resonance Imaging | \n\t\t\tA loss of liver signal intensity occurs on T1 weighted gradient echo (GRE) opposed images[63, 65] | \n\t\t
Appearances of hepatic steatosis on the main liver imaging modalities
Several studies have attempted to identify the utility of pre-operative cross sectional imaging to identify hepatic steatosis specifically in patients undergoing liver resection. The first of these was published in 2008 by Cho et al. who conducted a retrospective analysis of 131 patients undergoing partial hepatectomy over a 4 year period who had one of either a non-contrast CT scan (n=26), contrast enhanced CT scan (n=74) or a gradient opposed MRI (n=32) with a median interval between imaging and surgery of 17 Days. The ability of these imaging modalities to predict histologically defined steatosis > 30% was determined. The authors demonstrated that of the two CT methods studied only non-contrast CT was of any utility in determining the presence of hepatic steatosis with a high degree of specificity (100%) but had low sensitivity (33%) with a corresponding positive predictive value (PPV) of 100% and negative predictive value (NPV) of 83%. In contrast MRI fared much better in excluding the presence of hepatic steatosis with an NPV of 94% but a PPV of only 44% with a sensitivity of 88% and specificity of 63%. The conclusion of this study was that cross-sectional imaging alone was not consistently able to determine the presence of hepatic steatosis and was therefore of limited utility for this purpose.[66]
In 2009 O’Rourke et al. reported a prospective study of n=37 patients undergoing resection of colorectal liver metastases who received pre-operative liver specific MRI. Again this study demonstrated a much better performance for MRI in determining the presence of hepatic steatosis > 30% with a PPV of 100%, NPV of 87% a sensitivity of 63% and a specificity of 100%.[67] A subsequent retrospective study by Marsman et al compared the ability of non-contrast enhanced CT (n=32) and MRI (n=36) to detect the presence of histologically defined steatosis > 33% in patients undergoing resection of colorectal liver metastases after receiving pre-operative chemotherapy. In this study MRI by far out performed CT in terms of sensitivity (78% vs. 70%), specificity (100% vs. 86.4%); PPV (100% vs. 70%) and NPV (93.1% vs. 86.4%) suggesting that this is the imaging modality of choice.[68]
On the basis of the currently available evidence it appears that MRI is the imaging modality of choice to assess the extent of hepatic steatosis in patients with colorectal liver metastases prior to surgery. It must be highlighted that cross-sectional imaging is not able to differentiate between simple steatosis and steatohepatitis which can only be achieved with histological assessment of the liver. Furthermore a ‘normal’ imaging study does not exclude the presence of hepatic steatosis and in those cases where there is a high level of clinical suspicion a further evaluation of the liver must be undertaken.
The role of cross-sectional imaging in detecting the presence of SOS is much less clear cut as compared to hepatic steatosis. It has been proposed that the development of splenomegaly on post-chemotherapy imaging may serve as a surrogate marker for the presence of SOS. Overman et al conducted a study in patients who received either 5-FU/Oxaliplatin (n=96) or 5-FU alone (n=40) as adjuvant therapy following resection of a colonic primary and compared spleen size on pre-operative imaging to that 6 weeks after the final cycle of chemotherapy. They demonstrated that the median increase in spleen size was 22% for those patients receiving 5-FU/Oxaliplatin whereas there was no increase in size in those receiving 5-FU alone (p<0.001). The authors went on to look at a subgroup of patients (n=63) who underwent a liver resection after 5-FU/Oxaliplatin and demonstrated, on multivariate analysis, that a greater than 50% increase in spleen size following chemotherapy was independently able to predict the presence of SOS (Odds Ratio 2.34; p=0.02) with a sensitivity of 43%, and specificity of 90%.[60]
Several authors have explored the utility of various MRI protocols to predict the presence of SOS. Ward et al. reported a study of 60 patients with colorectal liver metastases who underwent superparamagnetic iron oxide (SPIO) enhanced MRI prior to liver resection. Following SPIO administration SOS is characterised by reticular hyperintensity on T2*-gradient response echo weighted MRI images the presence of which the authors graded on a scale of 0 – 3 (summarised in Table 2) with a score of 2 or greater indicating the presence of SOS. Using this technique 24 of the 60 patients were thought to have SOS on the basis of MRI the presence of which was subsequently confirmed histologically in 20 patients. Of the 36 patients thought not to have SOS on the basis of MRI 3 were subsequently found to have histological features of SOS. This means that SPIO enhanced MRI, in this study, had a sensitivity of 87%, specificity of 89%, PPV of 83% and NPV of 92% for the presence of SOS.[69] In contrast to these findings however O’Rourke et al. in their study of 37 patients found that SPIO enhanced MRI had a high specificity (100%) and PPV (100%) for the presence of severe SOS but a low sensitivity (11%) with a NPV of 78% suggesting that this technique may fail to identify a significant proportion of patients with SOS.[67]
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
0 | \n\t\t\tAbsent | \n\t\t
1 | \n\t\t\tFine reticulations on a minority of sections | \n\t\t
2 | \n\t\t\tDiffuse reticulations or localised coalescent areas of high signal | \n\t\t
3 | \n\t\t\tDiffuse reticulations present on all sections or densely coalescent areas of high signal on multiple sections | \n\t\t
Grading of reticular hyperintensity on SPIO enhanced MRI to determine the presence of SOS[69]
Shin et al. explored the ability of Gadoxetic acid disodium (EOB-MRI; Primavist®) enhanced MRI to detect the presence of SOS prior to resection of colorectal metastases. On EOB-MRI the presence of SOS appears as reticular hypointensity which the authors graded on a scale of 1-5 with a score of 4 (probably present) or 5 (definitely present) being considered diagnostic of SOS. Of the 42 patients included in this study all 12 MRI identified cases of SOS had the diagnosis confirmed histologically and of the 30 MRI negative cases 4 had histological evidence of SOS. This resulted in a sensitivity of 75%, specificity of 100%, PPV of 100% and a NPV of 87%. The images in this study were independently reviewed by a radiological resident with a good level of agreement (weighted kappa 0.765) suggesting that this technique is subject to minimal interobserver variability.[70]
The small number of patients in these studies make it difficult to recommend the routine use of any of these MRI protocols for the sole purpose of detecting pre-operative SOS. The presence of splenomegaly on pre-operative imaging, particularly in patients who have received multiple cycles of Oxaliplatin based chemotherapy, should raise suspicion about the presence of SOS and prompt a thorough assessment of the liver parenchyma if extended resection is to be performed.
A variety of techniques have been described which aim to quantitatively assess the functional reserve of the liver and thereby provide a means to determine the minimum safe FLR that is required to avoid the risk of PHLF. Perhaps the most widely described of these techniques is the Indocyanine Green (ICG) retention test. Following injection ICG is transported in the systemic circulation bound to albumin and does not leave the serum until it reaches the liver where it is taken up by hepatocytes. These hepatocytes then clear ICG by excreting the compound into the biliary system in an ATP dependent manner. ICG does not enter the portal circulation nor is it metabolised by hepatocytes prior to its excretion and therefore the clearance of ICG provides a direct measure of hepatocyte function.[71]
Typically the retention of ICG at 15 minutes is measured in a serum sample (ICGR-15) and this value is used as a measure of hepatic functional reserve with a value of <10% being considered normal. Based on their experience of using this test in a series of 1429 patients Imamura et al. described the maximum extent of liver resection they thought could be safely performed according to the ICGR-15 value (see Table 3).[72] Others however view this ICGR-15 value as too conservative and state that a cut off of <14% should be used to identify those patients in whom it is safe to perform major liver resection.[73] The use of ICG retention as a pre-operative assessment of liver function is however predominantly limited to Asia where the majority of liver resections are performed for hepatocellular carcinoma and therefore the data regarding the validity of this test in patients with colorectal liver metastases is limited.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
<10% | \n\t\t\tRight/Left Trisectionectomy | \n\t\t
10 – 19% | \n\t\t\tLeft hepatectomy / Right sectorectomy | \n\t\t
20 – 29% | \n\t\t\tSegmentectomy | \n\t\t
≥ 30% | \n\t\t\tLimited non-anatomical resection | \n\t\t
Typical safe liver resection volumes as recommended by Imamura et al based on ICGR-15 values[72]
Nakano et al reported the outcome of 36 patients who underwent major hepatectomy (>3 Couinaud segments) 20 of whom had histologically proven SOS and 16 who had a normal liver parenchyma. The presence of SOS in these patients was independently associated with an ICGR-15 of >10%. It is of note that these patients experienced an increased risk of peri-operative complications (40% vs. 6.3%; p=0.026) and a longer mean hospital stay (17 days vs. 11 days; p = 0.006).[59] Experimental studies have also suggested that ICGR-15 may be a useful measure of hepatocyte function in the context of hepatic steatosis.[74] In a series of 101 patients undergoing liver resection for colorectal metastases Klinger et al reported that the use of preoperative chemotherapy (n=83; all regimens) was associated with a longer ICGR-15 (7.3% vs. 3.5%; p = 0.005). Similarly those who had received pre-operative chemotherapy were more likely to have an ICGR-15 ≥ 10% (27.7% vs. 0%; p=0.011) and this was associated with an increased rate of post-operative complications (39.1% vs. 12.8%; p=0.005). No attempt was made in this study to correlate ICGR-15 values with histological changes within the liver parenchyma.[75]
The LiMAx test has recently been described as an alternative means of assessing the hepatic functional reserve. This test measures the cytochrome P450 mediated metabolism of 13C labelled methacetin into acetaminophen and 13CO2 which is exhaled. The test measures changes in the ratio of exhaled 13CO2 : 12CO2 over a 60 minute period – the greater the 13CO2 excretion the greater the functional reserve of the liver.[76] The authors have demonstrated that low post-operative LiMAx values (<80µg/kg/h) are correlated with an unacceptable risk of post-operative morbidity. On the basis of this they have proposed an algorithm to determine the safety of liver surgery based upon pre-operative measurement of the LiMAx to calculate the likely post-operative LiMAx using CT volumetric calculations of the FLR. This strategy has not however been proven in an independent prospective cohort and therefore cannot currently be recommended for routine clinical use.[77]
A final technique for assessing the functional reserve of the liver is hepatobiliary scintigraphy using 99mTc-mebrofenin. Following injection 99mTc-mebrofenin is taken up by hepatocytes and excreted directly into the biliary system without prior intracellular metabolism in a similar manner to ICG. The hepatic uptake and excretion of 99mTc-mebrofenin is determined using images obtained with a gamma camera and from this it is possible to determine the total liver uptake, corrected for body surface area, as a %/min/m2 of the total injected dose (referred to as the total liver function or TL-F). In addition the FLR uptake function (FLR-F) can be calculated as a function of the TL-F based on uptake in the calculated.[78]
De Graaf et al. reported a series 55 patients judged to be at high risk of post-operative complications following liver resection assessed with 99mTc-mebrofenin scintigraphy prior to liver resection. They demonstrated that TL-F was significantly reduced in those patients with background parenchymal disease (7.4 vs. 8.5 %/min/m2; p=0.007). In addition the FLR-F was significantly lower in those patients who developed PHLF as compared to those who did not (2.2 vs. 4.3%/min/m2; p=0.001).[79] Whilst this technology needs further evaluation in prospective studies it is likely that the emerging ability to perform single photon emission computed tomography (SPECT) thereby enabling quantification of tracer compound activity in combination with standard CT will lead to renewed interest in the technique.
At present none of these technologies have been adequately characterised in patients with colorectal metastases undergoing liver resection. Whilst they undoubtedly have potential merit in identifying those patients with an impaired hepatocyte mass it is not known whether the information they add is superior to that obtained standard clinical and radiological assessment. This must be established before the routine integration of these technologies into the assessment of this cohort of patients can be recommended.
When either clinical suspicion or pre-operative imaging suggest the presence of a chemotherapy induced injury to the liver it may no longer be possible to resect all metastatic disease whilst maintaining an adequate FLR to avoid the risk of liver failure. In this situation two key surgical strategies have been described to reduce the risk of surgery i.e. pre-operative portal vein embolisation and two-stage hepatectomy and these are discussed in more detail below.
Portal vein embolisation (PVE) is a particularly useful technique in patients who have disease which is technically resectable in a single operation but where so doing would lead to a compromised FLR. As early as 1920 Rous and Larimore observed that if they ligated a single branch of the portal vein in a rabbit there was atrophy of the ipsilateral lobe and hypertrophy of the contralateral lobe.[80] As a clinical technique PVE was initially described by Kinoshita et al. in 1986 as a means of limiting the extension of tumour thrombus in patients with hepatocellular carcinoma.[81] Subsequently in 1990 Makuuchi et al. demonstrated the safety and efficacy of this technique as a means of increasing the FLR in a series of 14 patients undergoing resection of hilar cholangiocarcinoma.[82] In a prospective study Farges et al. performed CT volumetry on patients undergoing pre-operative PVE and demonstrated that in those patients with no underlying parenchymal disease the typical increase in FLR was 16% whereas in those with chronic liver disease the typical increase in FLR was 9%.[83]
In 2010 Wicherts et al. reported a retrospective series of 67 patients who underwent liver resection for colorectal metastases after pre-operative PVE with a cohort of 297 patients who did not receive PVE. The authors observed that those patients treated with pre-operative PVE demonstrated a significantly higher complication rate (55.5% vs. 41.1%; p = 0.035) although there was no difference in surgical mortality between groups. Whilst this difference in morbidity is striking it is difficult to interpret since whilst all patients in the study underwent a major hepatectomy (≥3 Couinaud segments) 54% of those in the PVE group underwent a right trisectionectomy as compared to only 28% in the control group. What was striking in this study however was that 32 of the patients treated with PVE did not proceed to surgery and amongst these patients there were no 3 year survivors as compared to a 3 year survival rate of 44% in those who did undergo surgery.[84]
A similarly designed study by Pamecha et al. compared the outcome of 36 patients treated with pre-operative PVE with 65 patients who did not receive PVE all of whom had a diagnosis of colorectal metastases. Of the 36 patients treated with PVE 12 did not progress to surgery and had a median survival of 14 months as compared to 42 months in those who did progress to surgery (p<0.0001). Again there was a tendency to higher morbidity in the PVE group (36% vs. 20%) but in a similar manner to the study of Wicherts et al. more of these patients had undergone a right trisectionectomy (22% vs. 11%).[85]
The most important finding in both of these series is that nearly a third of all patients selected to undergo pre-operative portal vein embolisation do not undergo subsequent surgery and this is primarily a consequence of disease progression.[84, 85] It is likely that the most important factor driving this disease progression is the compensatory increase in arterial blood flow which occurs in the embolised lobe.[86] The blood supply of colorectal metastases is predominantly derived from the hepatic artery[87] and it is probable that the increase in arterial flow results in increased oxygen and nutrient supply to the tumour. In addition following PVE there is an increase in the hepatic production of a wide variety of cytokines, growth factors and other humoral factors that mediate liver regeneration and it may be that these also contribute to the progression of metastatic disease.[88, 89]
In summary PVE is a potentially useful technique for increasing the FLR in patients in whom this is likely to be compromised there is a significant risk that the procedure will result in disease progression rendering the patient inoperable and therefore must not be embarked upon lightly.
For a proportion of patients presenting with bilobar disease it is not possible to clear the entire tumour burden by an extended resection alone (e.g. right trisectionectomy) but rather it is necessary to combine an anatomical resection (e.g. or the right lobe) with multiple metastectomies from the contralateral lobe potentially resulting in an insufficient FLR, particularly in patients with a background liver injury (Figure 2). In such circumstances a PVE alone would not be appropriate because of the significant risk of tumour progression in the FLR and therefore a two stage resection should be considered. In the scenario described above this would typically consist of an initial operation to clear the left liver of tumour using multiple metastectomies followed several weeks later by a right hepatectomy. If it was felt at the time of the primary operation that the hypertrophy induced by surgery alone would not leave an adequate FLR for the second operation then it may be desirable to perform either intra-operative ligation of the right portal vein or post-operative percutaneous portal vein embolisation.[90] In this situation it is the authors preference to perform the latter procedure thereby avoiding unnecessary dissection of the hilum prior to right hepatectomy.
Wicherts et al. reported the outcomes of 59 patients considered to be inoperable using a single stage procedure who were selected for a two stage approach. All of these patients underwent a primary surgical procedure which in the majority of cases consisted of a minor hepatectomy (<3 Couinaud segments resected) the aim of which was to clear the left liver of tumour. Subsequently 42 patients underwent a second procedure which was typically a major hepatic resection (≥3 Couinaud segments) and typically this took place 3 months after the initial surgical procedure. It is of note that 17 patients selected for this approach did not undergo a second procedure primarily as a consequence of disease progression. The overall 5 year survival in this series was 31% when analysed on an intention to treat basis and this did not differ, in a statistically significantly manner, from patients undergoing a single stage hepatectomy over the same period in the authors unit.[91]
More recently Narita et al. reported the outcome of 79 patients treated using a two stage approach. After the initial surgical procedure 75 of these patients were considered appropriate to proceed to the second operation although the majority (92%) were thought to require portal vein embolisation to facilitate this. Of that cohort of patients 61 (78% of the original cohort) eventually underwent a successful second operation. The main reasons for patients not proceeding to a second procedure were tumour progression in 10 cases and insufficient regeneration of the FLR in a further 5 cases. It is of note that almost 1:6 of the patients who underwent a second surgical procedure were found to have new disease in the previously cleared FLR although this was dealt with at the time of surgery in all cases. In those patients who underwent a successful two stage resection the overall 5 year survival was 32%. Of the 61 patients who were treated successfully by a two stage approach 11 went on to have a subsequent resection of lung metastases although this had no effect on overall survival when compared to the 50 patients who did not.[92]
Typical MRI scan of patient with bilobar disease who would be considered suitable for a two staged approach to liver resection. With this distribution of disease a one stage approach would not leave an adequate FLR.
In a similar manner to PVE alone a two stage hepatectomy is a major undertaking and before embarking on this both surgeon and patient should be aware that there is a significant risk of not being able to complete the planned course of treatment. Despite this it does provide an opportunity to achieve a meaningful long term survival in selected patients with advanced disease.
Whilst the primary focus of this chapter is on the effects of chemotherapy associated liver injury on the surgical management of patients with colorectal liver metastases it would not be complete without some mention of the emerging evidence that this injury may have an effect on long term disease specific outcomes. Tamandl et al. have suggested that the presence of the histological features of SOS within the resected liver of patients with colorectal liver metastases may have a negative impact on long term disease specific survival. In particular patients with SOS demonstrated a significantly poorer 3 year progression free survival (6.7% vs. 22.7%; p=0.006) a finding which was upheld on multivariate analysis (Hazard Ratio 2.20; p=0.006). Specifically patients with SOS demonstrated a higher rate of intra-hepatic recurrence following surgery (66.7% vs. 30.5%; p=0.003) and not surprisingly this was associated with an increased risk of early all cause mortality on multivariate analysis (Hazard Ratio 2.90; p<0.001).[61]
A major criticism of the study of Tamandl et al. is that it includes only small numbers of patients (n=20 with SOS) and therefore it is difficult to draw definitive conclusions.[61] None the less a recent paper by Vreuls et al. has reported that the development of SOS may be associated with a poorer tumour response to Oxaliplatin based chemotherapy which the authors propose may be a consequence of tissue hypoperfusion leading to diminished leading to impaired delivery of chemotherapy to the tumour.[93] An alternative explanation may be that SOS is associated with increased expression of the chemokine CCL20 within the liver which is known to act as a chemo-attractant for colorectal cancer cells.[94] At the same time as this is occurring within the liver Oxaliplatin chemotherapy also results in increased expression of the CCL20 receptor CCR6 within colorectal liver metastases thereby increasing the migration and proliferation of tumour cells in response to CCL20.[95, 96] It may therefore be that the presence of SOS leads to the establishment of an autocrine signalling loop which favours the further growth and development of colorectal liver metastases.[97]
This emerging evidence is clearly a cause for concern and, if proven to be true, would add further impetus to the drive to develop strategies for the prevention of liver injury in patients being treated with systemic chemotherapy.
Advances in chemotherapy over the last decade or so have revolutionised the care for patients with colorectal liver metastases with the end result that patients who historically would have been considered inoperable are now able to undergo potentially curative surgical resection. The pay off for this advance has been the development of a chemotherapy associated injury to the liver the nature of which is determined the specific regimens used.
There is no specific test that is able to reliably detect the presence of an injured liver parenchyma and ultimately surgeons must maintain a high index of suspicion for its presence particularly in patients who have received multiple cycles of chemotherapy over a prolonged period of time. When a liver injury is present it is important that the surgical approach is considered carefully and makes allowances for the possibility of an impaired FLR with a subsequent risk of post operative liver failure. In those situations where there is a high risk of an insufficient FLR it may be appropriate to utilise techniques such as PVE or two stage hepatectomy although there is a risk with both these techniques of treatment failure as a consequence of disease progression.
In the nervous system, astrocytes are isotypes of neuroglia, also identified as astrocytic cells. They are Star-shaped; their countless progressions enclose synopses prepared by nerve cells. A particular astrocytic cell can simultaneously act together with the human being by two billion synapses. These specialized glial cells are more numerous than neurons by above fivefold. They closely tile the central nervous system (CNS) and apply for multiple important diverse roles in the energetic CNS. Astrocytes react to all methods of CNS offences through a procedure stated as reactive astrogliosis, which has developed a pathological mark of CNS fundamental abrasions. Two main subtypes of astrocytes are classified based on their structural and anatomical position. Those names are protoplasmic astrocytes and fibrous astrocytes. Protoplasmic astrocytes seem to spread equally in the interior of cortical grey matter, while the fibrous astrocytes are structured with white matter regions [1]. Astrocytes of the brain and spinal cord are very different in morphology and function. Brain cells (astrocytes) are accountable for the homeostasis of ions and neurotransmitters in the synaptic cleft, native metabolic sustenance, and relief of sensitive oxygen species. Pathology of many nervous disorders containing neuropsychiatric and neurodegenerative syndromes is well-defined by loss of homeostatic role. Astrocytes play a significant role in the homeostasis of the central nervous system (CNS). Brain cells or astrocytes are extremely diverse cells that regulate the network, emergence and function, and homeostasis. Since it’s involved in protective astrogliosis, it’s become an essential component of neuropathology. Most neuropathology astroglial cells are impacted by degenerative alterations that inhibit their functional and neuroprotective capacities, allowing the pathology to proceed [2]. Astrocytes play an important role in data handling, and communicative mechanism proficiencies of brain circuits are unknown. Around all research studying the correlation among astrocyte cells’ structure and function concentrates on its influences on nervous system activity and flexibility under functional and syndrome conditions. At synapses, a collective subject important to these outcomes is that astrocytes analyse, respond to, and control glutamate release and post-synaptic activity.
Removal and postponement of PAPs in reaction to glutamate improve post-synaptic responses, inhibit trans-synaptic activation, and prevent additional glutamate proclamation. Still, astrocyte operational flexibility exchange is not recognized upon declaration of other GABA, dopamine, somatostatin, serotonin, acetylcholine, etc. (neurotransmitters) [3]. The appearance of glial fibrillary acid protein (GFAP) has become a typical indicator for immunohistochemically astrocytic cells [4]. Research on transgenic mice showed that the appearance of GFAP isn’t necessary for the usual form and role of the furthermost astrocytic cell in the energetic, nervous system of transgenic mice. Still, it’s essential to develop reactive astrogliosis and glial scar development. Over and above, concerning the procedure of GFAP as an astrocyte indication, it’s compulsory to pay attention that GFAP expression isn’t limited to protoplasmic and fibrous astrocytes. In the interior of the nervous system, GFAP is too expressed by numerous cells that can be reflected as part of prolonged astroglial cells. On the outer side of the nervous system, GFAP is articulated extensively in countless nerves via a range of cell forms Figures 1–4 [5].
Astrogliosis and GFAP articulation in astrocytes.
Astroglial asthenia/atrophy and astrogliosis in neuropathology.
Hypoxia and HIF-1α stabilization in brain.
Role of hypoxia in activation of inflammatory pathway.
Astrocytes tile the whole CNS in a touching, non-covering, organized, and efficient way. Comparative individual astrocyte areas show up liable to exist in white matter. However, this has not yet been as broadly written about. Astrocytes are giant, intricate, and different from astrocytes in rodents. Astrocytes show controlled proliferation in intracellular calcium absorption [Ca++], which signifies a method of astrocyte excitability. An enormous suggestion is now obtainable that these delimited proliferations in astrocyte [Ca++] remain of purposeful importance in astrocyte and astrocyte-neuron intercellular communication. The advice is that calcium signalling permits astrocytes to show a direct role in synaptic transmission. It’s worth noting that astrocytes do communicate with one another via gap junctions generated by connexins. Gap junctional partnering of astrocytes into multicellular systems may contribute to normal function and CNS disorders. The suggestion is that calcium signalling permits astrocytes to show a natural interest in synaptic transmission.
ASTROCYTIC cells are central homeostatic and protective cells of the nerves, and every kind of astrocyte plays an integral part in neuropathological changes. Hence, the decline in nerve cells or astrocytes causes a disease-permissive landscape and triggers nerve cell malfunction, nerve cell death, and nerve cell deficiency. Glia cells are essential for sustaining nerve function, and nerves survive bodily procedures and pathology [6]. Most essential findings concerning astrocyte’s functional significance depend on the dead animal model research. It’s given a durable but incomplete base for a complete astrocyte role in physiopathology [7]. They are categorized into three kinds that are reactive astrogliosis, Astro-degeneration with astroglial atrophy, and pathological remodelling and loss of function of astrocytes. Altogether these pathological feedbacks proceed together. It’s categorized on the base of neuroanatomical and severity. According to neuroanatomical, astrocytes are further distributed into isomorphic and isomorphic astrogliosis [8]. The isomorphic astrogliosis conserves astroglial defensive areas that are changeable.
In contrast, anisomorphic astrogliosis continues through the destruction of the defensive regions, cell relocation and territorial overlap, development of astroglial palisades, and eventually scar formation. While in severity, astrogliosis is categorized into slight to adequate astrogliosis, severe diffuse astrogliosis and severe astrogliosis by dense scar development [9]. Astroglial atrophy is mainly noticeable in major psychiatric illnesses. For example, schizophrenia, a primary depressing condition, Wernicke–Korsakoff encephalopathy, and addictive disorders decrease the storing concentration of astrocytic cells. The conclusion is furthermost particularly accompanied by glutamate-glutamine shuttle and glutamate homeostasis; both are impaired in these conditions [10]. It promotes several leukodystrophies, especially Alexander disease, megalocephalic leukoencephalopathy with subcortical lumps or disappearing white matter disease, in which the astrocyte-pathy pledges destruction of the white matter [11]. It also describes mesial temporal lobe epilepsy, in which astrocytes obtain abnormal cell structure, decreases gap junction coupling, and decrease Kir4.1 channel expression; these alterations weaken K+ homeostasis, contributing to seizure start [12].
Reactive astrogliosis and glial scar realization are noticeable structures of CNS trauma and are progressively involved by playing significant parts in the decisive prolonged medical result. Glial formation of scar and severe reactive astrogliosis at the location of the neurons trauma are glowing familiar to inhibit axonal regeneration and are extensively observed as harmful to medical results. Contagions of the CNS triggered by microbes, parasites, fungi, and viruses are categorized into inflammation of meninges, active tissues of the brain, or (pus-filled pocket of infected material in your brain) cerebral abscess. Not all germs can attack the nervous system. Somewhat, merely confirmed neurotropic parasites, fungi, bacteria, and viruses can enter obsessed by the cerebral and vertebral column. Utmost of the microbe are efficiently stopped by the cerebral obstacles [13].
The SAE (Sepsis-associated encephalopathy) explicitly uses a scientific disorder linked through the common cerebral disorders that progresses in sepsis to the lack of core contagion of the neural tissue. In the cerebral parenchyma, sepsis is frequently linked with the production of inflammations and tiny inflammation directly related to the SAE. Particularly in the initial phases, the disease associated with structural infection remains frequently linked through ‘sickness behaviour’ [14].
Dense metals are a source of extreme cephalic disorder with intellectual deficiencies, mainly targeting neuroglia. Heavy metals that are manganese, lead, aluminium or mercury primarily gather into an astrocytic cell by diverse plasma lemma transporters. Overall, it’s also a down-regulating astroglial expression of glutamate transporters, reducing glutamate permission and activating excitotoxicity [15]. Aluminium toxic encephalopathy is demonstrated via mental losses, communication variations, seizures, and flapping wrist shake (asterixis) [16]. It disturbs the cerebrum due to liver encephalopathy, which is described by mental and developmental damage signs including misperception, amnesia, bad temper, and alterations in perception, such as fatigue and sleepiness. Cerebral swelling, unconsciousness, and death also occur in the severity of Hyperammonemia. In stroke, a blood vessel ruptures that restricts blood supply to the brain or parts of the brain due to a systemic decrease of vascular occlusion in blood supply, all-cause disruptions in blood flow. This is known as brain ischemia. As a result, cerebral ischemia could be either focal or global, the latter of which can lead to a stroke. In stroke, astrocytes serve as both neurotoxic and neuroprotective agents, complicating and diverse astrgliopathology [17]. In cases of Congenital Glutamine Deficiency with Glutamine, Synthetase Mutations newborns expire in a while after delivery. The prominent pathophysiological contrivance is related to the weakened capacity of astrocytes to yield glutamine, which disturbs excitatory and inhibitory conduction; furthermore, lacking glutamine synthetase cannot accurately decontaminate ammonium. Pyruvate carboxylase is principally articulated in neuroglia. Pyruvate carboxylase deficit is an autosomal recessive disease linked to a diminished metabolic rate. The warning sign comprises delay of cerebral growth, persistent seizures, and increased plasma acidity.
Aceruloplasminemia is a congenital condition of iron metabolism due to the deficiency of ceruloplasmin action. Most important abrasions describe this disorder as neuroglia, which disturbs their structure and consequences in the presence of frothy spheroid forms at the vascular end feet. Aceruloplasminemia is also linked with brain demise and the exterior of iron deposition [18].
Alexander disease is an exceptional, long-lasting, and ordinarily neurodegenerative severe condition. Its consequences on or after a dominant gain-of-function mutation of the gene encoding GFAP. It is sub-categorized into Type I and types II [19]. Autism Spectrum Disorders (ASD) are a few medically introverted conditions connected to cerebral inadequacies. Astrocytes are accountable for neuroprotection and detoxifying harmful bodies like receptive oxygen species. The principle procedure of ASDs is undoubtedly associated with brain network mutation and abnormal neurotransmission during the undeveloped turn of events [20]. In Down syndrome, the thickness of astrocytes is fundamentally diminished in the cortex with diminished capacity to uphold synaptogenesis and neuronal development appropriately. Astroglial asthenia, loss of homeostatic capacities, atrophy, and perhaps pathogenic remodelling are all related to schizophrenia, although reactive alterations are not. Epilepsy, mood disorders, and addictive disorders are linked with astrogliopathology [12].
Astrocyte is the essential part of the blood–brain barrier (BBB) that can be damaged by traumatic brain injury (TRI) or ischemia. Astrocytes provide the morphological and physiological link between neural networks and cerebral circulation. Astrocytes have the power to adjust blood flow to the brain to keep the brain parenchyma’s PCO2 and PO2 steady [21]. The formation of ATP in the brainstem through local astrocytes aids respiration and counters hypoxia-induced respiratory network depression. Hypoxia-induced alterations in brain inflammation, neuroprotection, and blood–brain barrier permeability against ischemic injury appear to be mediated by astrocytes. Astrocytes play a critical function in neuronal function in everyday situations and pathological conditions when the supply of oxygen to the brain is disrupted [22].
The telomerase reverse transcriptase (TERT) gene is linked to cell injury and stress resistance. After hypoxia-ischemia, protein and TERT mRNA were increased in neurons after a few days but moved to astrocytes [23]. TERT overexpression decreased astrocyte multiplication by upregulating the cell-cycle regulatory protein p15. While neurons were cultured with precondition medium from astrocytes with TERT inhibition contrasted to neurotrophin-3 expression, TERT overexpression in astrocytes decreased, resulting in higher death [24]. In TERT-overexpressing brains with hypoxia-ischemia, neuronal damage and Ki67-positive astrocytes were also suppressed [25].
Matrix metalloproteinase (MMP)-9 is an endo-peptidase that plays a crucial role in Blood–Brain Barrier proteolysis post-trauma and leads to cell death with persistent convulsions [26]. Activation of mitogen-activated protein kinases (MAPKs) in astrocytes can be caused by thrombin, oxidative stress, tissue plasminogen activator, or tumour necrosis factor- α and includes stimulation of MMP-9. In astrocytes, albumin causes a rise in MMP-9 synthesis, which requires ROS formation and motivation of the MAPK pathway [27]. These results add albumin to signalling molecules that activate MMP-9 in astrocytes alongside thrombin. These findings connect albumin to MMP-9-mediated cellular mechanisms such as intracerebral haemorrhage, neuronal damage, dendritic remodelling, and epileptogenesis [28].
Stroke and Traumatic Brain Injury (TBI) are frequently linked with hypoxia, which causes glial initiation. Glial cells, particularly astrocytes, play an essential part in stress prevention and the homeostasis of the CNS by offering structural and metabolic stability [29]. Hypoxia can cause astrocyte homeostasis to be disrupted, resulting in cell enlargement. Wnt pathway suppression was the most substantially disrupted signalling pathway in the mechanism of hypothermia-induced responses in human astrocytes after oxidative stress activation and hypoxia [30]. Global suppression of Wnt signalling can be troublesome because of its essential role in controlling critical mechanisms associated with the functional regulation of immune and stem cells and its effect on post-mitotic neuronal and glial cells [31].
Molecular oxygen (O2) is required for most organisms on the planet because it supports intracellular biogenesis and is utilized by several metabolic activities. As a result, low oxygen level (hypoxia) is a crucial stress factor that usually disrupts aerobic species’ lives and is a common feature of pathologic conditions such as cardiovascular abnormalities, inflammation, wounds, bacterial infection, and cancer [32]. Since it is required throughout breathing, oxygen is essential in life. In oxidative phosphorylation, O2 acts as the ultimate electron acceptor, raising the possibility of reactive oxygen species formation (ROS). ROS interact with biological macromolecules, changing their metabolic or physical characteristics and causing cell death or malfunction [33].
To sustain a wide range of cellular functions to secure life, organism cells require sufficient oxygen. The oxygen concentration in the body and localized tissues fall (hypoxia) whenever the need for oxygen increases, resulting in a physiological crisis that compromises physiological processes and survivability. Organisms have formed an effective and quick oxygen sensing system called (hypoxia-inducible factors (
Arterial and central chemoreceptors detect changes in the oxygen content in the external environment. The brainstem’s medulla, beneath the respiratory centres, contains central chemoreceptors. The carotid and aortic bodies include arterial chemoreceptors [35]. The stimulation of arterial chemoreceptors promotes neurotransmission and alters the function of neprilysin (NEP), a neutral endopeptidase that changes the biological response to hypoxia by hydrolytic component P [36]. Neuroendocrine cells in neuroepithelial bodies also govern oxygen sensing by imposing chemosensitivity, critical for oxygen sensing in the early stages of life. These exciting chemoreceptors enhance sympathetic nervous activity (SNA) and the systemic and arterial pulmonary blood flow to receive enough oxygen. Therefore, in organism cells, the expression of many adapted genes is activated to improve the oxygen supply and enable anaerobic ATP production. Hypoxia-inducible factors regulate these hypoxic responses (
There is a difference between sustained and intermittent hypoxia. Mitochondrial respiration utilizes more than 90% oxygen in humans during every day physiological situations [38]. The remaining (10%) oxygen is used to degrade
A transcription factor that binds to specific nuclear cofactors and transactivates several genes, causing a range of adaptive responses in response to low oxygen levels in the body, is called Hypoxia Inducible Factor
The brain is the most vulnerable organ to hypoxia, resulting in coma, convulsions, cognitive impairment, other neurological impairments, and brain death if left untreated [44]. Cardiac arrest, asphyxia, or systemic metabolic abnormalities affecting the blood’s oxygen content, systemic hypoxia, severe anaemia, and systemic hypotension can lead to hypoxic brain damage [45]. Hypoxia-induced autophagy is linked to the HIF-1 signalling pathway. According to studies, hypoxic preconditioning protection is lost in HIF-1α knockout mice exposed to neonatal hypoxia/ischemia [46]. HIF1α hydroxylation is prevented by blockage of prolyl- and asparaginyl-hydroxylases in hypoxic environments. Prolyl-hydroxylase inhibitors reduce HIF1α breakdown, resulting in fast
PI3K (Phosphatidylinositol 3-kinase) and Akt (protein kinase B) signalling pathway is related to hypoxia-ischemia injury as it increases the phosphorylation of downstream molecules such as apoptosis-related family members, transcription factors, mammalian target of rapamycin (mTOR), and glycogen synthase kinase-3. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that inhibits the PI3K/Akt pathway by hydrolysing PIP-3 to PIP-2 and preventing downstream p-Akt. PI3K and its downstream effector. Akt is a member of a well-studied family of signal transduction enzymes that regulate cellular activation, inflammation, and apoptosis [49].
Chemokines and cytokines are low-molecular-weight proteins produced mostly by lymphocytes and macrophages. As neurotransmitters and hormones, they mediate intracellular and extracellular interactions in an autocrine, endocrine, and paracrine manner. They regulate various biological activities, including local and systemic anti- and pro-inflammation, chemotaxis, metabolism, cellular proliferation, and tissue repair, by adhering to certain cell surface receptors [50].
cAMP-mediated signalling pathways might be changed in the presence of HIF1A, causing inflammatory-like processes to worsen. Only in the presence of Ni-induced hypoxia-inducible factor 1 (
Astrocytes have a crucial role in maintaining the normal oxygen levels in the brain. If the PO2 goes less than 17MMHg, astrocytes robust the Calcium ions into the brain; they act as the source of ATP in the hypoxic state of the brain. Astrocytes also have the potential to sense an increase in PCO2 levels too [21]. This chemosensation helps the cells to provide the astroglial networks with ATPS that help spread Ca + 2 activation and excitation. It also increases breathing to maintain homeostasis. It suggests that ATP released helps to keep living in the face of the hypoxia-evoked depression of the respiratory network [55].
In the previous century, it has also become clear that astrocytes can protect neurons under hypoxia conditions. The potential process is similar to “hypoxic preconditioning,” in which a temporary interval of moderate hypoxia protects neurons from subsequent ischemia episodes that are generally fatal [56]. Mild hypoxia synthesizes several protective astrocytic factors that help neurons survive. Hypoxia increases the production of specific proteins, such as connexin 43, which may promote ATP/adenosine transit towards the interstitial space [57]. Astrocytes release erythropoietin in reaction to hypoxia, which has a significant neuroprotective impact. The erythropoietin expression in astrocytes is increased once hypoxia-inducible factors are activated. HIF-1α and HIF-2α are two transcription factors. [58]. In an adult brain, astrocytes can alter and monitor synaptic functionality. It was believed that synaptic plasticity is solely based on neurons, but in recent research, it has been found that the glial network and astrocytes alter synaptic transmissions [59]. The activation of metabotropic receptors modulates synaptic alterations by astrocytes. It helps release glutamate, gliotransmitter ATP, and D-serine, which act on neurons [60]. As per Astrocyte-induced pathogenesis, astrocytes can cause adenosine accumulation that affects glial cells and cause sleep deprivation and cognitive impairment [61]. Experimental investigations have found that the astrocytes sense synaptic activity with the help of astrocytic calcium. Astrocytes elevate their Ca + levels to sense neural activity with the help of the Gq-coupled protein pathway [62].
Astrocytes play a significant role in the homeostasis of the central nervous system. Astrocytic cells are central homeostatic and protective cells of the nerves. The decline in nerve cells or astrocytes causes a disease-permissive landscape and triggers nerve cell malfunction, nerve cell death, and nerve cell deficiency. Astroglial atrophy is mainly noticeable in major psychiatric illnesses. Severe reactive astrogliosis and glial scar formation at the location of the neurons trauma are glowing familiar to inhibit axonal regeneration. More research into the processes of Astrocytes protection, particularly the substances they produce, will give crucial insights into how to protect the Blood–Brain Barrier throughout trauma and neurological condition.
Moreover, its expression timing in astrocytes is essential to determine the influence of hypoxia-induced signalling on stroke volume. Furthermore, in addition to the impacts of hypoxia-signalling in astrocytes on neuron viability, it seems necessary to consider how such alterations will affect astrocyte viability. We must fully comprehend how to lessen the harm caused by stroke if we can better define the various consequences of hypoxia signalling in astrocytes.
The research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
The authors have declared no competing interests.
The study does not require any ethical approval.
No data was generated in the current study.
Authors are listed below with their open access chapters linked via author name:
",metaTitle:"IntechOpen authors on the Global Highly Cited Researchers 2018 list",metaDescription:null,metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"New for 2018 (alphabetically by surname).
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
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\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
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\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
\n\nYiqi Luo 2016-18
\n\nJoachim Maier 2014-18
\n\nAndrea Natale 2017, 2018
\n\nAlberto Mantovani 2014-18
\n\nMarjan Mernik 2017, 2018
\n\nSandra Orchard 2014, 2016-18
\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"49246",doi:"10.5772/61300",title:"Chitosan as a Biomaterial — Structure, Properties, and Electrospun Nanofibers",slug:"chitosan-as-a-biomaterial-structure-properties-and-electrospun-nanofibers",totalDownloads:4727,totalCrossrefCites:27,totalDimensionsCites:63,abstract:"Chitosan is a polysaccharide derived from chitin; chitin is the second most abundant polysaccharide in the world, after cellulose. Chitosan is biocompatible, biodegradable and non-toxic, so that it can be usedin medicalapplications such as antimicrobial and wound healing biomaterials. It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]},{id:"70919",doi:"10.5772/intechopen.90891",title:"Antimicrobial Effect of Titanium Dioxide Nanoparticles",slug:"antimicrobial-effect-of-titanium-dioxide-nanoparticles",totalDownloads:1817,totalCrossrefCites:21,totalDimensionsCites:47,abstract:"The widespread use of antibiotics has led to the emergence of multidrug-resistant bacterial strains, and therefore a current concern for food safety and human health. The interest for new antimicrobial substances has been focused toward metal oxide nanoparticles. Specifically, titanium dioxide (TiO2) has been considered as an attractive antimicrobial compound due to its photocatalytic nature and because it is a chemically stable, non-toxic, inexpensive, and Generally Recognized as Safe (GRAS) substance. Several studies have revealed this metal oxide demonstrates excellent antifungal and antibacterial properties against a broad range of both Gram-positive and Gram-negative bacteria. These properties were significantly improved by titanium dioxide nanoparticles (TiO2 NPs) synthesis. In this chapter, latest developments on routes of synthesis of TiO2 NPs and antimicrobial activity of these nanostructures are presented. Furthermore, TiO2 NPs favor the inactivation of microorganisms due to their strong oxidizing power by free radical generation, such as hydroxyl and superoxide anion radicals, showing reductions growth against several microorganisms, such as Escherichia coli and Staphylococcus aureus. Understanding the main mechanisms of antimicrobial action of these nanoparticles was the second main purpose of this chapter.",book:{id:"9521",slug:"antimicrobial-resistance-a-one-health-perspective",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A One Health Perspective"},signatures:"Carol López de Dicastillo, Matias Guerrero Correa, Fernanda B. Martínez, Camilo Streitt and Maria José Galotto",authors:[{id:"244902",title:"Dr.",name:"Carol",middleName:null,surname:"Lopez De Dicastillo",slug:"carol-lopez-de-dicastillo",fullName:"Carol Lopez De Dicastillo"},{id:"315494",title:"Mr.",name:"Matias",middleName:null,surname:"Guerrero Correa",slug:"matias-guerrero-correa",fullName:"Matias Guerrero Correa"},{id:"315495",title:"Ms.",name:"Fernanda",middleName:null,surname:"B. Martínez",slug:"fernanda-b.-martinez",fullName:"Fernanda B. Martínez"},{id:"315496",title:"Mr.",name:"Camilo",middleName:null,surname:"Zuñiga",slug:"camilo-zuniga",fullName:"Camilo Zuñiga"},{id:"315497",title:"Dr.",name:"Maria José",middleName:null,surname:"Galotto",slug:"maria-jose-galotto",fullName:"Maria José Galotto"}]},{id:"65613",doi:"10.5772/intechopen.84411",title:"The Methods for Detection of Biofilm and Screening Antibiofilm Activity of Agents",slug:"the-methods-for-detection-of-biofilm-and-screening-antibiofilm-activity-of-agents",totalDownloads:9283,totalCrossrefCites:15,totalDimensionsCites:26,abstract:"Biofilm producer microorganisms cause nosocomial and recurrent infections. Biofilm that is a sticky exopolysaccharide is the main virulence factor causing biofilm-related infections. Biofilm formation begins with attachment of bacteria to biotic surface such as host cell or abiotic surface such as prosthetic devices. After attachment, aggregation of bacteria is started by cell-cell adhesion. Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"63397",doi:"10.5772/intechopen.80624",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2486,totalCrossrefCites:12,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. 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After attachment, aggregation of bacteria is started by cell-cell adhesion. Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"62553",title:"Antibiotic Use in Poultry Production and Its Effects on Bacterial Resistance",slug:"antibiotic-use-in-poultry-production-and-its-effects-on-bacterial-resistance",totalDownloads:7327,totalCrossrefCites:43,totalDimensionsCites:92,abstract:"A surge in the development and spread of antibiotic resistance has become a major cause for concern. Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"65914",title:"Introductory Chapter: The Action Mechanisms of Antibiotics and Antibiotic Resistance",slug:"introductory-chapter-the-action-mechanisms-of-antibiotics-and-antibiotic-resistance",totalDownloads:4428,totalCrossrefCites:6,totalDimensionsCites:10,abstract:null,book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu, Nesrin Gareayaghi and Bekir S. Kocazeybek",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"},{id:"248288",title:"Prof.",name:"Bekir",middleName:null,surname:"Kocazeybek",slug:"bekir-kocazeybek",fullName:"Bekir Kocazeybek"},{id:"406463",title:"Dr.",name:"Nesrin",middleName:null,surname:"Gareayaghi",slug:"nesrin-gareayaghi",fullName:"Nesrin Gareayaghi"}]},{id:"63397",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2486,totalCrossrefCites:12,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. Álvarez-Cisneros and Edith Ponce-Alquicira",authors:[{id:"256345",title:"Dr.",name:"Yenizey Merit",middleName:null,surname:"Alvarez Cisneros",slug:"yenizey-merit-alvarez-cisneros",fullName:"Yenizey Merit Alvarez Cisneros"},{id:"256347",title:"Dr.",name:"Edith",middleName:null,surname:"Ponce-Alquicira",slug:"edith-ponce-alquicira",fullName:"Edith Ponce-Alquicira"}]},{id:"49246",title:"Chitosan as a Biomaterial — Structure, Properties, and Electrospun Nanofibers",slug:"chitosan-as-a-biomaterial-structure-properties-and-electrospun-nanofibers",totalDownloads:4726,totalCrossrefCites:27,totalDimensionsCites:63,abstract:"Chitosan is a polysaccharide derived from chitin; chitin is the second most abundant polysaccharide in the world, after cellulose. Chitosan is biocompatible, biodegradable and non-toxic, so that it can be usedin medicalapplications such as antimicrobial and wound healing biomaterials. It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]}],onlineFirstChaptersFilter:{topicId:"897",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81704",title:"Quorum Sensing Inhibition Based Drugs to Conquer Antimicrobial Resistance",slug:"quorum-sensing-inhibition-based-drugs-to-conquer-antimicrobial-resistance",totalDownloads:22,totalDimensionsCites:0,doi:"10.5772/intechopen.104125",abstract:"Quorum sensing is the cell to cell communication mechanism in microorganism through signalling molecules. Regulation of virulence factor, sporulation, proteolytic enzymes production, biofilm formation, auto-inducers, cell population density are key physiological process mediated through quorum-sensing (QS) signalling. Elevation of innate immune system and antibiotic tolerance of pathogens is highly increased with perspective of quorum-sensing (QS) activity. Development of novel drugs is highly attractive scenario against cell-cell communication of microbes. Design of synthetic drugs and natural compounds against QS signal molecules is vital combat system to attenuate microbial pathogenicity. Quorum sensing inhibitors (QSIs), quorum quenchers (QQs), efflux pump inhibitors (EPIs) act against multi-drug resistance strains (MDR) and other pathogenic microbes through regulation of auto-inducers and signal molecule with perceptive to growth arrest both in-vitro and in-vivo. QQs, QSIs and EPIs compounds has been validated with various animal models for high selection pressure on therapeutics arsenal against microbe’s growth inhibition. Promising QSI are phytochemicals and secondary metabolites includes polyacetylenes, alkaloids, polyphenols, terpenoids, quinones.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Kothandapani Sundar, Ramachandira Prabu and Gopal Jayalakshmi"},{id:"82372",title:"Unlocking the Potential of Ghost Probiotics in Combating Antimicrobial Resistance",slug:"unlocking-the-potential-of-ghost-probiotics-in-combating-antimicrobial-resistance",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.104126",abstract:"Antimicrobial resistance is a global concern that requires immediate attention. Major causes of development of antimicrobial resistance in microbial cells are overuse of antimicrobials along the food chain especially in livestock, in preventing infections as well as misuse of antimicrobials by patients. Probiotics could be a viable alternative to antibiotics in the fight against antimicrobial resistance. Probiotic strains can act as a complement to antimicrobial therapy, improving antimicrobial function and enhancing immunity. However, there are safety concerns regarding the extensive use of live microbial cells especially in immunocompromised individuals; these include microbial translocation, inhibition of other beneficial microorganisms and development of antimicrobial resistance, among other concerns. Inevitably, ghost probiotics have become the favored alternative as they eliminate the safety and shelf-life problems associated with use of probiotics. Ghost probiotics are non-viable microbial cells (intact or broken) or metabolic products from microorganisms, which when administered in adequate amounts have biologic activity in the host and confer health benefits. Ghost probiotics exert biological effects similar to probiotics. However, the major drawback of using ghost probiotics is that the mechanism of action of these is currently unknown, hence more research is required and regulatory instruments are needed to assure the safety of consumers.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Abigarl Ndudzo, Sakhile Ndlovu, Nesisa Nyathi and Angela Sibanda Makuvise"},{id:"82178",title:"Managing Antimicrobial Resistance beyond the Hospital Antimicrobial Stewardship: The Role of One Health",slug:"managing-antimicrobial-resistance-beyond-the-hospital-antimicrobial-stewardship-the-role-of-one-heal",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.104170",abstract:"Infections caused by micro-organisms affect the health of people and animals, causing morbidity and mortality, with Asia and Africa as the epicenters. Some of the infectious diseases are emerging and re-emerging in nature. Examples include viral hepatitis, Lassa fever, Ebola, yellow fever, tuberculosis, covid-19, measles, and malaria, among others. Antimicrobials have been playing an important role in the treatment of infections by these microbes. However, there has been a development of resistance to these antimicrobials as a result of many drivers. This write-up used secondary data to explore the management of antimicrobial resistance (AMR) beyond the hospital antimicrobial resistance steward using the one health concept. The findings showed AMR to be a transboundary, multifaceted ecosystem problem affecting both the developed and developing countries. It is also one of the top ten global public health threats facing mankind. Globally, AMR will cost over US$100 trillion in output loss by 2050, about 700,000 deaths a year, and 4,150,000 deaths in Africa by 2050. About 2.4 million people could die in high-income countries between 2015 and 2050 without a sustained effort to contain AMR. The drivers of AMR are beyond the hospital and hospital AMR stewardship. Therefore, the need for one health concept to manage it.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Istifanus Anekoson Joshua, Mathew Bobai and Clement Sokfa Woje"},{id:"81918",title:"Machine Learning for Antimicrobial Resistance Research and Drug Development",slug:"machine-learning-for-antimicrobial-resistance-research-and-drug-development",totalDownloads:53,totalDimensionsCites:0,doi:"10.5772/intechopen.104841",abstract:"Machine learning is a subfield of artificial intelligence which combines sophisticated algorithms and data to develop predictive models with minimal human interference. This chapter focuses on research that trains machine learning models to study antimicrobial resistance and to discover antimicrobial drugs. An emphasis is placed on applying machine learning models to detect drug resistance among bacterial and fungal pathogens. The role of machine learning in antibacterial and antifungal drug discovery and design is explored. Finally, the challenges and prospects of applying machine learning to advance basic research on and treatment of antimicrobial resistance are discussed. Overall, machine learning promises to advance antimicrobial resistance research and to facilitate the development of antibacterial and antifungal drugs.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Shamanth A. Shankarnarayan, Joshua D. Guthrie and Daniel A. Charlebois"},{id:"81891",title:"Alternatives to Antibiotics in Semen Extenders Used in Artificial Insemination",slug:"alternatives-to-antibiotics-in-semen-extenders-used-in-artificial-insemination",totalDownloads:29,totalDimensionsCites:0,doi:"10.5772/intechopen.104226",abstract:"Antimicrobial resistance is a serious global threat requiring a widespread response. Both veterinarians and medical doctors should restrict antibiotic usage to therapeutic use only, after determining the sensitivity of the causal organism. However, the addition of antibiotics to semen extenders for animal artificial insemination represents a hidden, non-therapeutic use of antimicrobial substances. Artificial insemination for livestock breeding is a huge global enterprise with hundreds of million sperm doses prepared annually. However, reporting of antimicrobial resistance in semen is increasing. This review discusses the consequences of bacteria in semen samples, as well as the effect of antimicrobial substances in semen extenders on bacteria in the environment and even on personnel. Alternatives to antibiotics have been reported in the scientific literature and are reviewed here. The most promising of these, removal of the majority of bacteria by colloid centrifugation, is considered in detail, especially results from an artificial insemination study in pigs. In conclusion, colloid centrifugation is a practical method of physically removing bacteria from semen, which does not induce antibiotic resistance. Sperm quality in stored semen samples may be improved at the same time.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Jane M. Morrell, Pongpreecha Malaluang, Aleksandar Cojkic and Ingrid Hansson"},{id:"81699",title:"Efflux Pumps among Urinary E. coli and K. pneumoniae Local Isolates in Hilla City, Iraq",slug:"efflux-pumps-among-urinary-e-coli-and-k-pneumoniae-local-isolates-in-hilla-city-iraq",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.104408",abstract:"Urinary tract infections (UTI) are the most common bacterial infections affecting humans. Escherichia coli and Klebsiella pneumoniae were common enterobacteria engaged with community-acquired UTIs. Efflux pumps were vital resistance mechanisms for antibiotics, especially among enterobacteria. Overexpression of an efflux system, which results in a decrease in antibiotic accumulation, is an effective mechanism for drug resistance. The ATP-binding cassette (ABC) transporters, small multidrug resistance (SMR), and multidrug and toxic compound extrusion (MATE) families, the major facilitator superfamily (MFS), and the resistance-nodulation- cell division (RND) family are the five superfamilies of efflux systems linked to drug resistance. This chapter highlights the results of studying the prevalence of efflux pump genes among local isolates of E. coli and K. pneumoniae in Hilla City, Iraq. class RND AcrAB-TolC, AcrAD-TolC, and AcrFE-TolC genes detected by conventional PCR of E. coli and K. pneumoniae respectively. The result revealed approximately all studied efflux transporter were found in both E. coli and K. pneumoniae in different percentages. Biofilm formation were observed in 50(100%) of K. pneumoniae and 49(98%) of E. coli isolates were biofilm former and follow: 30(60%), 20(40%) were weak, 12(24%), 22(44%) were moderate and 7(14%) and 8(16%) were Strong biofilm former for E. coli and K. pneumoniae, respectively.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Hussein Al-Dahmoshi, Sahar A. Ali and Noor Al-Khafaji"}],onlineFirstChaptersTotal:13},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"July 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:14,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"306970",title:"Mr.",name:"Amin",middleName:null,surname:"Tamadon",slug:"amin-tamadon",fullName:"Amin Tamadon",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002oHR5wQAG/Profile_Picture_1623910304139",institutionString:null,institution:{name:"Bushehr University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",institutionURL:null,country:{name:"Spain"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",institutionString:null,institution:{name:"Alexandria University",institutionURL:null,country:{name:"Egypt"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",institutionString:"Kafkas University",institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"186048",title:"Prof.",name:"Ines",middleName:null,surname:"Drenjančević",slug:"ines-drenjancevic",fullName:"Ines Drenjančević",profilePictureURL:"https://mts.intechopen.com/storage/users/186048/images/5818_n.jpg",institutionString:null,institution:{name:"University of Osijek",institutionURL:null,country:{name:"Croatia"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"79615",title:"Dr.",name:"Robson",middleName:null,surname:"Faria",slug:"robson-faria",fullName:"Robson Faria",profilePictureURL:"https://mts.intechopen.com/storage/users/79615/images/system/79615.png",institutionString:null,institution:{name:"Oswaldo Cruz Foundation",institutionURL:null,country:{name:"Brazil"}}},{id:"84459",title:"Prof.",name:"Valerie",middleName:null,surname:"Chappe",slug:"valerie-chappe",fullName:"Valerie Chappe",profilePictureURL:"https://mts.intechopen.com/storage/users/84459/images/system/84459.jpg",institutionString:null,institution:{name:"Dalhousie University",institutionURL:null,country:{name:"Canada"}}}]},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. 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