\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8634",leadTitle:null,fullTitle:"Veterinary Medicine and Pharmaceuticals",title:"Veterinary Medicine and Pharmaceuticals",subtitle:null,reviewType:"peer-reviewed",abstract:"Veterinary pharmaceuticals provide animals with the requisite, complete animal health care. The availability of safe and good quality medicines in the right amounts is needed in achieving optimum animal health care. The economic benefits of animal food products cannot be under-estimated. Veterinary pharmaceuticals are needed to meet the ever-growing demand of animal protein for the human population. However, their routine and unguarded use play significant roles in many public health issues, such as antimicrobial resistance. The practices, knowledge, and awareness needed on the use and application of veterinary pharmaceuticals amongst farmers, animal health professionals, microbiologists, and policy makers remain key in ensuring a safe and healthy food chain for all. In the field of veterinary medicine, canine practice is a challenge to veterinarians. In recent years, newer diagnostic methods and therapeutic protocols have been published on a regular basis. Along with the existing knowledge of important canine diseases like ascites, duodenal disorders, pericardial effusions, and canine mastitis, this book is supplemented with all the latest information. Discussion of duodenal disorders in dogs, including IBD and SIBO, is an important topic in day-to-day practice. Ascites and mastitis in dogs are also important topics and are discussed in this book. Each topic carries practical points for the diagnosis and management of important diseases of dogs. Hence, this book will be very useful for canine practitioners.",isbn:"978-1-78985-440-4",printIsbn:"978-1-78985-439-8",pdfIsbn:"978-1-83880-062-8",doi:"10.5772/intechopen.79335",price:119,priceEur:129,priceUsd:155,slug:"veterinary-medicine-and-pharmaceuticals",numberOfPages:194,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"db391e7122c6eb34af53134b5cd50027",bookSignature:"Samuel Oppong Bekoe, Mani Saravanan, Reimmel Kwame Adosraku and P K Ramkumar",publishedDate:"March 11th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8634.jpg",numberOfDownloads:13259,numberOfWosCitations:4,numberOfCrossrefCitations:31,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:57,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:92,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 11th 2018",dateEndSecondStepPublish:"September 6th 2018",dateEndThirdStepPublish:"November 5th 2018",dateEndFourthStepPublish:"January 24th 2019",dateEndFifthStepPublish:"March 25th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"186990",title:"Dr.",name:"Samuel Oppong",middleName:null,surname:"Bekoe",slug:"samuel-oppong-bekoe",fullName:"Samuel Oppong Bekoe",profilePictureURL:"https://mts.intechopen.com/storage/users/186990/images/system/186990.png",biography:"I have been a Lecturer (since 2005), and am currently a Senior Lecturer (since 2016) with the Department of Pharmaceutical Chemistry, KNUST, Ghana. My research activities involve the quality assessment of pharmaceuticals, the monitoring and evaluation of antimicrobial resistance, the Safe Water for Good Health project, the development of analytical methods for the determination of pharmaceuticals in various matrices with the use of liquid chromatography with a range of detectors (MS, UV, etc.) and extraction procedures such as the solid phase extraction. I have been involved in the training and supervision of both undergraduate and postgraduate students. I have co-authored a number of publications from these research activities.",institutionString:"Kwame Nkrumah University of Science and Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:{id:"201185",title:"Dr.",name:"Mani",middleName:null,surname:"Saravanan",slug:"mani-saravanan",fullName:"Mani Saravanan",profilePictureURL:"https://mts.intechopen.com/storage/users/201185/images/system/201185.jpeg",biography:"Dr. Mani Saravanan, B.V.Sc., M.V.Sc., Ph.D., is working as Assistant Professor in Veterinary Clinical Complex with the specialization in Veterinary Medicine. He is working on canine internal medicine especially on liver and intestinal disorders. Dr. Saravanan has completed his Ph.D research work on Biodynamic measures to evaluate ascites and its catalytic therapy in dogs. He has expertise in gastrointestinal endoscopy and abdominal ultrasound.",institutionString:"Tamil Nadu Veterinary and Animal Sciences University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Tamil Nadu Veterinary and Animal Sciences University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"261471",title:"Dr.",name:"Reimmel Kwame",middleName:null,surname:"Adosraku",slug:"reimmel-kwame-adosraku",fullName:"Reimmel Kwame Adosraku",profilePictureURL:"https://mts.intechopen.com/storage/users/261471/images/12224_n.jpg",biography:"Reimmel Kwame Adosraku obtained his Bachelor of Pharmacy Degree from the Kwame Nkrumah University of Science and Technology (KNUST) in 1980 and the Master’s in 1984. On completion of his programme he joined the faculty as a Lecturer that same year.In 1994, Prof. Adosraku was awarded a PhD Degree in Pharmaceutical Chemistry at the University of London School of Pharmacy, Brunswick Square, London, UK.\n\nHis work in academia has been extensive, with institutions both home and abroad. He has served as Head of the Department of Pharmaceutical Chemistry at the Faculty of Pharmacy for four terms. He serves on a number of Boards including Faculty of Science Board, Faculty of Pharmacy and the College of Health Sciences Board. Prof. Adosraku was a member of the Committee that assessed application for accreditation of Pharmacy School for two Universities in the country.\nOn the International front, he is an External Examiner in the Department of Pharmaceutical Chemistry, University of Sierra Leone, Freetown, Sierra Leone and a Member of the West African Health Organization (WAHO) Expert Committee evaluating Drug Quality Control Laboratories in West African countries (2010 – 2011). He offers professional consultancy services to various organizations in Ghana and abroad including BioResources International, USA and Ghana Standards Board. He also has several technical publications to his credit. Currently, he is an Associate Professor in Pharmaceutical Chemistry at KNUST.",institutionString:"Kwame Nkrumah University of Science and Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"261443",title:"Dr.",name:"P K",middleName:null,surname:"Ramkumar",slug:"p-k-ramkumar",fullName:"P K Ramkumar",profilePictureURL:"https://mts.intechopen.com/storage/users/261443/images/system/261443.jpeg",biography:"Dr. P.K.Ramkumar, B.V.Sc., M.V.Sc., is working as Assistant Professor in Veterinary Clinical Complex with the specialization in Veterinary Medicine. He is working on canine gastro enterology. Dr. Ramkumar has completed his M.V.Sc. research work on infectious agents causing enteritis. He has expertise in Electrocardiography and abdominal ultrasound.",institutionString:"Tamil Nadu Veterinary and Animal Sciences University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1193",title:"Animal Pharmacology",slug:"animal-pharmacology"}],chapters:[{id:"70025",title:"Prologue: Veterinary Pharmaceuticals",doi:"10.5772/intechopen.89902",slug:"prologue-veterinary-pharmaceuticals",totalDownloads:483,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Samuel Oppong Bekoe",downloadPdfUrl:"/chapter/pdf-download/70025",previewPdfUrl:"/chapter/pdf-preview/70025",authors:[{id:"186990",title:"Dr.",name:"Samuel Oppong",surname:"Bekoe",slug:"samuel-oppong-bekoe",fullName:"Samuel Oppong Bekoe"}],corrections:null},{id:"63964",title:"Antimicrobial Usage and Resistance in Dairy Cattle Production",doi:"10.5772/intechopen.81365",slug:"antimicrobial-usage-and-resistance-in-dairy-cattle-production",totalDownloads:1022,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:1,abstract:"Antimicrobial resistance (AMR) has been a public health threat globally, with millions of lives lost due to AMR infections each year. The cases of AMR continue to escalate and cause devastating effect to both humans and animals. AMR contributes to high morbidity and mortality of the livestock, which results in staggering economic losses to the livestock producers. The main factor for AMR to arise in this industry is mainly due to the eagerness of livestock producers to meet high demand by using antimicrobials to promote animal growth and disease prevention. From a public health perspective, AMR in dairy cattle can also jeopardize human population due to the potential dissemination of AMR pathogens to humans via consumption of infected dairy products or direct contact with infected dairy cattle. At the current rate of unrestricted antimicrobial usage, AMR will be expedited and soon we will run out of effective treatment for even the simplest infection. World Health Organization (WHO) has issued a set of guidelines for the use of medically important antimicrobials on animals to mitigate the adverse consequences of AMR on human. Thus, this chapter will explain antimicrobial usage in dairy cattle production and the recent approaches and challenges on AMR.",signatures:"Enli Loo, Kok Song Lai and Rozaihan Mansor",downloadPdfUrl:"/chapter/pdf-download/63964",previewPdfUrl:"/chapter/pdf-preview/63964",authors:[{id:"221544",title:"Dr.",name:"Kok-Song",surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai"},{id:"240934",title:"Dr.",name:"Rozaihan",surname:"Mansor",slug:"rozaihan-mansor",fullName:"Rozaihan Mansor"},{id:"264957",title:"Mr.",name:"Loo",surname:"Enli",slug:"loo-enli",fullName:"Loo Enli"}],corrections:null},{id:"64854",title:"Importance of Socio-Economic and Institutional Factors in the Use of Veterinary Services by the Smallholder Dairy Farmers in Punjab",doi:"10.5772/intechopen.82310",slug:"importance-of-socio-economic-and-institutional-factors-in-the-use-of-veterinary-services-by-the-smal",totalDownloads:575,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The study has shown the importance of identifying factors that determined the likelihood of using veterinary services in Punjab. Secondary data were used for analysis with the sample size of 1137 dairy households. Estimates of factors influencing the use of veterinary services are reasonably consistent with the farmer decision to use it. The proportional relationship between veterinary services available within the village and use of veterinary services revealed that, distance of veterinary service availability positively influenced the farmer decision to use the veterinary services. There was a positive relationship between herd size and use of veterinary services. More educated farmers are in a better position to use the veterinary services. The principal source of income from agricultural activities was positively influenced by the likelihood to use veterinary services in study area. The model from empirical point of view is very important to predict whether household will be using the veterinary services or not after incorporating the value of the explanatory variables.",signatures:"Shiv Raj Singh, Kamal Kumar Datta and Supern Singh Shekhawat",downloadPdfUrl:"/chapter/pdf-download/64854",previewPdfUrl:"/chapter/pdf-preview/64854",authors:[{id:"260621",title:"Dr.",name:"Shiv Raj Singh",surname:"Rathore",slug:"shiv-raj-singh-rathore",fullName:"Shiv Raj Singh Rathore"},{id:"260625",title:"Dr.",name:"K.K.",surname:"Datta",slug:"k.k.-datta",fullName:"K.K. Datta"},{id:"260627",title:"Dr.",name:"S.S.",surname:"Shekhawat",slug:"s.s.-shekhawat",fullName:"S.S. Shekhawat"}],corrections:null},{id:"66512",title:"Veterinary Pharmaceuticals and Antimicrobial Resistance in Developing Countries",doi:"10.5772/intechopen.84888",slug:"veterinary-pharmaceuticals-and-antimicrobial-resistance-in-developing-countries",totalDownloads:1570,totalCrossrefCites:10,totalDimensionsCites:18,hasAltmetrics:0,abstract:"Veterinary pharmaceuticals include a wide range of anti-infectives and additives in the use for animal health, nutrition, reproduction, and productivity. Antimicrobials are among the most extensively used drugs in developing countries largely due to large population of livestock and the burden of infectious diseases. The introduction of penicillin in 1943 and other antibiotics thereafter provided remedies for many infections in humans and animals, reducing mortality and productivity losses. Since then, a repertoire of antibiotics and antimicrobials has been introduced as chemotherapeutics and/or prophylaxis. This success notwithstanding, many pathogens of consequences are no longer susceptible owing to emergence of antimicrobial-resistant (AMR) microorganisms. This has made treatment of infectious diseases less effective. Beside spontaneous emergence of mutant microorganisms, scientists are wary of AMR caused by intensive use of antibiotics in humans and animals, sometimes in subtherapeutic doses as preventive medicine. In developing countries, environmental exposure and persistent use of antibiotics in food animals may leave residues in the food chain. The consequences include development of AMR. In this chapter, we reviewed antimicrobial use in veterinary medicine and sequela in the emergence of AMR and described the imperative of antimicrobial stewardship in veterinary practice to combat AMR in developing countries.",signatures:"Meseko Clement, Makanju Olabisi, Ehizibolo David and Muraina Issa",downloadPdfUrl:"/chapter/pdf-download/66512",previewPdfUrl:"/chapter/pdf-preview/66512",authors:[{id:"93517",title:"Dr.",name:"Clement",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko"}],corrections:null},{id:"65176",title:"Veterinary Drug Residues in Meat and Meat Products: Occurrence, Detection and Implications",doi:"10.5772/intechopen.83616",slug:"veterinary-drug-residues-in-meat-and-meat-products-occurrence-detection-and-implications",totalDownloads:2975,totalCrossrefCites:9,totalDimensionsCites:19,hasAltmetrics:1,abstract:"Application of veterinary drugs in livestock production is inevitable as they are essential for treatment of diseases, prevention of diseases, modification of physiological functions, improvement of growth and productivity as well as for ensuring food safety. However, recent reports have revealed that the use of veterinary drugs in large amounts and consistently could result in deposition of antimicrobial residues in muscle and organs of animal. Consumption of these residues in animal products may pose health risk to consumers including development of antibiotic resistance bacteria, allergy, reproductive disorder and hypersensitivity reaction. It is in line with this that this chapter seeks to examine the cause, occurrence, mode of detection, health implication and possible solution to veterinary drugs residues in meat and meat products.",signatures:"Andrew Bamidele Falowo and Oluwakamisi Festus Akimoladun",downloadPdfUrl:"/chapter/pdf-download/65176",previewPdfUrl:"/chapter/pdf-preview/65176",authors:[{id:"271285",title:"Dr.",name:"Andrew",surname:"Falowo",slug:"andrew-falowo",fullName:"Andrew Falowo"},{id:"288263",title:"Mr.",name:"Oluwakamisi Festus",surname:"Akimoladun",slug:"oluwakamisi-festus-akimoladun",fullName:"Oluwakamisi Festus Akimoladun"}],corrections:null},{id:"67293",title:"Foot-and-Mouth Disease Virus (FMDV) and Its Treatment with Plant Extracts",doi:"10.5772/intechopen.84938",slug:"foot-and-mouth-disease-virus-fmdv-and-its-treatment-with-plant-extracts",totalDownloads:1064,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Foot-and-mouth disease (FMD) is a contagious viral infection which is caused by foot-and-mouth disease virus (FMDV). The disease appears in cloven-footed animals. Symptoms of the disease are abrupt manifestation of sores on the mouth, nose, feet, etc. Nowadays the control and treatment of FMDVare becoming a worldwide economic problem and challenge for the society. Currently, there is no particular treatment available for FMDV, as well as the limitations and disadvantages in the use of vaccines divert the focus of researchers toward natural sources like plant extracts which possess potential antiviral activity. Various researches documented in the literature demonstrated various plant extracts with antiviral potency against FMDV. In the current chapter, we discussed about FMDV and its possible treatment with plant extracts.",signatures:"Ishrat Younus, Sidra Maqbool, Sarah Jameel Khan, Humera Sarwar, Shagufta Nesar, Rida Fatima, Sidra Siddique and Moona Baig",downloadPdfUrl:"/chapter/pdf-download/67293",previewPdfUrl:"/chapter/pdf-preview/67293",authors:[{id:"243372",title:"Dr.",name:"Ishart",surname:"Younus",slug:"ishart-younus",fullName:"Ishart Younus"}],corrections:null},{id:"68546",title:"Prologue on DISEASES OF DOGS - for Practioners",doi:"10.5772/intechopen.88479",slug:"prologue-on-diseases-of-dogs-for-practioners",totalDownloads:460,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Mani Saravanan",downloadPdfUrl:"/chapter/pdf-download/68546",previewPdfUrl:"/chapter/pdf-preview/68546",authors:[{id:"201185",title:"Dr.",name:"Mani",surname:"Saravanan",slug:"mani-saravanan",fullName:"Mani Saravanan"}],corrections:null},{id:"67372",title:"An Update on Canine Duodenal Disorders",doi:"10.5772/intechopen.86049",slug:"an-update-on-canine-duodenal-disorders",totalDownloads:768,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Duodenal disorders are difficult to identify clinically because of the non-specific symptoms. They may or may not be identifiable through routine radiographic, ultrasonographic, or laboratory evaluation methods, because many diseases of duodenum primarily involve the mucosal surface. Duodenal ulcers, inflammatory bowel disease (IBD), and small intestinal bacterial overgrowth (SIBO) are the duodenal disorders. Duodenoscopy is an efficient way of identifying the abnormalities of mucosal irregularities, distortion, ulceration, neoplasia, and inflammation, and it is also useful for obtaining mucosal biopsy and duodenal juice for routine histopathological and bacteriological studies. This paper will provide more detail about the advanced diagnostic methods and therapeutic measures for various duodenal disorders.",signatures:"Mani Saravanan",downloadPdfUrl:"/chapter/pdf-download/67372",previewPdfUrl:"/chapter/pdf-preview/67372",authors:[{id:"201185",title:"Dr.",name:"Mani",surname:"Saravanan",slug:"mani-saravanan",fullName:"Mani Saravanan"}],corrections:null},{id:"69693",title:"Overview of Canine Babesiosis",doi:"10.5772/intechopen.82243",slug:"overview-of-canine-babesiosis",totalDownloads:1368,totalCrossrefCites:5,totalDimensionsCites:10,hasAltmetrics:1,abstract:"Canine babesiosis is a tick-borne, protozoal, haemoparasitic disease that can cause varying degrees of haemolytic anaemia, splenomegaly, thrombocytopenia and fever. There are two hosts for the transmission of Babesia spp., viz. invertebrate (tick) and vertebrate host. Dogs are one among the many targets of Babesia spp., causing canine babesiosis, and now there are clinical evidences of possible vertical transmission too. Dogs of all ages can be affected with Babesia spp., but young puppies are more commonly affected. Considering advanced diagnostic techniques, for an early and specific detection of acute infections, an AgELISA that is potentially translatable to a rapid diagnostic test design is reported. Different molecular techniques used for identification and differentiation of the various species of Babesia are semi-nested PCR, reverse line blotting and PCR-restriction fragment length polymorphism analysis. Treatment consists of three components: treatment with antiprotozoal agents to eliminate the parasite, blood transfusions to treat severe anaemia and supportive care for the complications and metabolic derangements. Blood lactate concentrations can serve as a prognostic indicator in severe or complicated canine babesiosis. For prevention apart from conventional measures, vaccines against Babesia species such as B. gibsoni are currently being developed.",signatures:"Poonam Vishwakarma and M.K. Nandini",downloadPdfUrl:"/chapter/pdf-download/69693",previewPdfUrl:"/chapter/pdf-preview/69693",authors:[{id:"267230",title:"Dr.",name:"Poonam",surname:"Vishwakarma",slug:"poonam-vishwakarma",fullName:"Poonam Vishwakarma"},{id:"267243",title:"Dr.",name:"Nandini",surname:"M. K",slug:"nandini-m.-k",fullName:"Nandini M. K"}],corrections:null},{id:"66978",title:"Review on Ascites in Pets",doi:"10.5772/intechopen.84767",slug:"review-on-ascites-in-pets",totalDownloads:1224,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Ascites is one of the major complications seen in various disease conditions in pets. Ascites is characterised by distension of the abdomen with accumulation of fluid of various colours and consistencies depending on the cause. The most common causes of ascites in pets include but not limited to the following health conditions: hypoproteinaemia, left-sided heart failure, congestive heart failure, cirrhosis, hepatic diseases, renal diseases, ancylostomosis and bacterial infection such as tuberculosis. Pathogenesis of ascites often emanate from portal hypertension, cirrhosis, hepatorenal syndrome, etc. Oftentimes the diagnosis of ascites could be cumbersome considering the myriad of diseases implicated in the condition. Standard diagnostic procedures include the following: physical examination, clinical examination, ultrasonography, computed tomography, serum ascites albumin gradient (SAAG), biochemical analysis such as triglyceride, urea and creatinine concentration, total protein, etc. Novel diagnostic procedures with possible clinical relevance include the following: leucocyte esterase reagent strip, platelet indices, tumour markers, etc. Diagnosis is made through standard diagnostic procedure, while special cases of idiopathic origin are detected through diagnostic laparotomy. Novel diagnostic procedures such as platelet indices, leucocyte esterase reagent strip and tumour markers would aid in easy diagnosis of ascites. Treatment of ascites is dependent on identification of the cause of ascites.",signatures:"Rosemary Ijeoma Ogechi Nwoha",downloadPdfUrl:"/chapter/pdf-download/66978",previewPdfUrl:"/chapter/pdf-preview/66978",authors:[{id:"269467",title:"Dr.",name:"Rosemary",surname:"Nwoha",slug:"rosemary-nwoha",fullName:"Rosemary Nwoha"}],corrections:null},{id:"69431",title:"Pericardial Effusion in Dogs",doi:"10.5772/intechopen.89051",slug:"pericardial-effusion-in-dogs",totalDownloads:845,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pericardial disease in dogs is relatively uncommon, but its presence may be life-threatening. It is an incidental finding or manifestation of a systemic or cardiac disease. The spectrum of pericardial effusions ranges from mild asymptomatic effusions to cardiac tamponade. Pericardial effusion in dogs has an overall prevalence of 0.43% in general and occurs in approximately 7–10% of the dogs with clinical signs of cardiac disease. More commonly seen in dogs, the clinical signs of pericardial disease can be easily overlooked or mistaken for those of other disease processes. In patients with life-threatening pericardial effusion, which has led to cardiac tamponade, it is important to rapidly identify and treat the elevated intrapericardial pressure. Management is guided by the haemodynamic impact, size, presence of inflammation (i.e. pericarditis), associated medical conditions, and the aetiology whenever possible. In this chapter, pericardial effusion in dogs is emphasized.",signatures:"Gurram Sreeramamurthy Haritha",downloadPdfUrl:"/chapter/pdf-download/69431",previewPdfUrl:"/chapter/pdf-preview/69431",authors:[{id:"285823",title:"Dr.",name:"Haritha",surname:"Yadav",slug:"haritha-yadav",fullName:"Haritha Yadav"}],corrections:null},{id:"67004",title:"How Reliable Are Laboratory Test When Diagnosing Bitch Mastitis?",doi:"10.5772/intechopen.86151",slug:"how-reliable-are-laboratory-test-when-diagnosing-bitch-mastitis-",totalDownloads:908,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Canine mastitis represents a major threat for both pups and nursing bitch. If left untreated, it can complicate with neonatal death, sepsis, and mastitis gangrenosa; for this reason quick and accurate diagnosis and treatment initiation are crucial health restoration. Even though mastitis is considered to be an emergency, most of the time it is overlooked. Henceforth, clinicians should be aware of the clinical importance of mastitis and that laboratory assays such as milk pH, cytology, and biochemistry (milk and serum) are of high utility. Furthermore, milk microbiology and susceptibility tests are still important since they bring additional information about the pathogenesis and the treatment possibilities.",signatures:"Iosif Vasiu, Roman Dąbrowski, Flaviu Alexandru Tăbăran, Raul Alexandru Pop, Flore Chirilă, Gheorghe Florinel Brudaşcă, Asta Tvarijonaviciute and Nicodim Iosif Fiţ",downloadPdfUrl:"/chapter/pdf-download/67004",previewPdfUrl:"/chapter/pdf-preview/67004",authors:[{id:"38782",title:"Dr.",name:"Roman",surname:"Dąbrowski",slug:"roman-dabrowski",fullName:"Roman Dąbrowski"},{id:"286303",title:"Ph.D.",name:"Iosif",surname:"Vasiu",slug:"iosif-vasiu",fullName:"Iosif Vasiu"},{id:"294897",title:"Prof.",name:"Flavius Alexandru",surname:"Tăbăran",slug:"flavius-alexandru-tabaran",fullName:"Flavius Alexandru Tăbăran"},{id:"294898",title:"Prof.",name:"Raul Alexandru",surname:"Pop",slug:"raul-alexandru-pop",fullName:"Raul Alexandru Pop"},{id:"294899",title:"Prof.",name:"Flore",surname:"Chirilă",slug:"flore-chirila",fullName:"Flore Chirilă"},{id:"294900",title:"Prof.",name:"Gheorghe Florinel",surname:"Brudaşcă",slug:"gheorghe-florinel-brudasca",fullName:"Gheorghe Florinel Brudaşcă"},{id:"294901",title:"Dr.",name:"Asta",surname:"Tvarijonaviciute",slug:"asta-tvarijonaviciute",fullName:"Asta Tvarijonaviciute"},{id:"294902",title:"Prof.",name:"Nicodim Iosif",surname:"Fiţ",slug:"nicodim-iosif-fit",fullName:"Nicodim Iosif Fiţ"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"761",title:"Pain Management",subtitle:"Current Issues and Opinions",isOpenForSubmission:!1,hash:"0ae9f6b167596d2cdb07492d2ec14134",slug:"pain-management-current-issues-and-opinions",bookSignature:"Gabor B. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"79243",slug:"corrigendum-to-hypoxia-angiogenesis-and-atherogenesis",title:"Corrigendum to: Hypoxia, Angiogenesis and Atherogenesis",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/79243.pdf\r\n",downloadPdfUrl:"/chapter/pdf-download/79243",previewPdfUrl:"/chapter/pdf-preview/79243",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/79243",risUrl:"/chapter/ris/79243",chapter:{id:"53523",slug:"hypoxia-angiogenesis-and-atherogenesis",signatures:"Lamia Heikal and Gordon Ferns",dateSubmitted:"September 6th 2016",dateReviewed:"November 3rd 2016",datePrePublished:null,datePublished:"April 5th 2017",book:{id:"5682",title:"Physiologic and Pathologic Angiogenesis",subtitle:"Signaling Mechanisms and Targeted Therapy",fullTitle:"Physiologic and Pathologic Angiogenesis - 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\r\n\tThis book is intended for professionals dealing with diagnostics and treatment of infertility and aims to provide comprehensive information on the current state of assisted reproductive technologies and their directions of development.
\r\n\tAssisted Reproductive Technologies (ART) is a key technology for treating infertility, which occurs in 10-15% of the general population in reproductive age. This has been one of the most tumultuously developing interdisciplinary technologies in medicine in recent decades. Thanks to in vitro methods, more than 5 million children were born in the whole world. For 40 years, the success rates of this treatment have increased many times, respectively in the first years from less than 10% to more than 50% in present days (in some groups of patients). The reason for this rapid increase is the introduction of new drugs and stimulation protocols, improvement of embryo culture media, and the use of new types of laboratory equipment that improve the conditions for embryo development. Last but not least, the introduction of modern genetic methods, as well as new gamete and tissue freezing techniques, has improved the methods' diagnostic and therapeutic capabilities.
Cystic fibrosis (CF) is the most common life-threatening genetic disease in North America and Europe. The birth prevalence of CF is estimated to be one in 3500–4500, with 200–300 new cases each year in Europe. The typical form of CF is diagnosed during early childhood and is characterized by recurrent pulmonary infections, pancreatic insufficiency, and elevated chloride concentrations in sweat. CF is a multi-organ disorder, however infections often occur in the lungs accompanied with severe inflammation and tissue destruction [1]. CF is directly caused by mutations in the
The previous commonly accepted hypothesis for CF pathology is the excessive secretion of thick mucus that remains in the lungs and is accompanied by impaired mucociliary clearance. This viscous mucus layer predisposes CF patients to chronic pulmonary infections. An intriguing speculation arose from the specificity of organisms that tend to infect CF patients. We hypothesized that the susceptibility of CF patients to these infectious agents is due to weak autophagic activity since most of the organisms that tend to cause chronic infection in CF are controlled by autophagy in healthy cells [4–6]. Autophagy is a highly regulated biological process that provides energy during periods of stress and starvation [7] and is typically induced upon glucose or amino acid starvation. Autophagy clears pathogens, inflammatory molecules, and dysfunctional protein aggregates within macrophages. Autophagy proceeds through sequential steps that begin with the formation of the phagophore or isolation membrane at a pre-autophagosomal structure (discussed in chapter of this book) [8]. The nascent autophagic membrane elongates to form a double-membrane autophagosomes that captures regions of cytoplasm, damaged mitochondria, or aggregated proteins. Upon maturation, the autophagosome containing the isolated cargo then fuses with the lysosome to form a single membrane compartment called the autolysosome. The autophagosomal cargo is then degraded in this compartment by lysosomal acid hydrolases and other degradative enzymes. The resulting degradation products including free amino acids, fatty acids, and nucleotides are released to the cytoplasm by the action of lysosomal permeases, where they may be reutilized for anabolic pathways [9, 10]. However, this process is impaired in CF patients and CF mice, as their macrophages and epithelial cells exhibit limited autophagic activity. The mechanisms linking a malfunctioning ion channel to the defective autophagy remains unclear.
\nUntil recently, it was believed that the production of thick mucus and the impairment of mucociliary clearance was the main underlying culprit, allowing the persistence of specific infections in the CF lung. The idea of the existence of an innate immune deficiency disorder in CF was not examined until lately. The discovery that the innate immune functions of macrophages and neutrophils are disrupted in CF was a turning point in the CF field and in understanding the pathobiology of CF. Several years were consumed to provide what is now undisputable data confirming that CF should be considered an innate immune disorder.
\nIn this chapter, we describe and discuss the recent findings in the field, which demonstrate that CF is a newly recognized innate immune deficiency disorder. We will discuss several reports demonstrating that macrophage functions are disrupted in CF contributing to the pathobiology of the disease. This chapter, encompassing recent data in CF, suggests that targeting autophagy may be exploited as a novel strategy for treatment of CF.
\nThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is an integral membrane glycoprotein that functions as a cAMP-activated and phosphorylation-regulated Cl channel at the apical membrane of epithelial cells. CFTR is a member of the ATP-binding cassette transporter superfamily. It is a multi-domain glycoprotein whose biosynthesis, maturation, and functions involve multi-level posttranslational modifications and complex folding processes to reach its native, tertiary conformation. The topology of CFTR includes two transmembrane-spanning domains, two nucleotide-binding domains, and a regulatory domain, which is a unique feature among ATP-binding cassette transporters (Figure 1) [11]. The newly synthesized CFTR emerges out of the ribosome and is targeted through the signal recognition particle to the ER membrane translocon [12, 13]. The CFTR polypeptide chain emerges into the ER lumen, and its glycosylated helping stabilize the protein. CFTR follows the secretory pathway through the Golgi in order to reach the plasma membrane [14]. The recycling of internalized CFTR channels is important for maintaining a functional pool of CFTR at the plasma membrane.
\nOnly 20–40% of the nascent chains achieve folded conformation, whereas the remaining molecules are targeted for degradation by endoplasmic reticulum, lysosomes, or autophagy. A large number of mutations impair processing of CFTR. Growing knowledge of CFTR biosynthesis has enabled understanding of the cellular basis of CF and has brought to light various potential targets for novel and promising therapies [15]. The most common mutation leading to CF is deletion of phenylalanine at position 508 (F508del) and is present in over 70% of the CF alleles [2, 3]. As mutant CFTR is targeted for degradation by the proteasome, the formation of protein aggregates occurs, hence provoking an unfolded protein response (UPR) [16]. Other common mutations such as the G551D exhibit defective CFTR function, however it does not aggregate or elicit a UPR. Comparing the phenotypes and immune functions of the F508del and G551D mutants will discern if defective bacterial clearance and uncontrolled inflammation are due to defective channel function, UPR, or both.
\nHyper-inflammation and failure to clear infection is recognized as a leading cause of lung tissue destruction in CF [17] that can be explained, at least in part, by incompetent autophagy machinery in cells with a dysfunctional CFTR channel [18]. Bronchoalveolar lavages from CF patients contain high levels of the pro-inflammatory cytokine interleukin (IL)-1β [1, 19–26]. IL-1β is primarily expressed as a precursor inactive molecule that is later cleaved by caspase-1 to yield active 17-kDa IL-1β [27]. The biological activities of IL-1β include promoting inflammatory responses and leukocyte infiltration. Autophagy directly regulates the level of pro-IL-1β in response to lipopolysaccharide (LPS) and infections [28, 29]. Interestingly, stimulation of autophagy by rapamycin dramatically reduced signs of inflammation in the murine CF lung [30, 31].
\nAutophagy process is impaired in CF cells preventing bacterial clearance.
Several reports demonstrated multiple malfunctions in adaptive and innate immune responses in CF. Lack of functional CFTR in CD3+ lymphocytes leads to aberrant cytokine secretion and hyper-inflammatory adaptive immune responses [32] while producing high levels of IL-1β [1, 19]. Naive cystic fibrosis T cells are intrinsically predisposed to differentiate toward a Th17 phenotype [33]. Therefore, CF is a multifaceted immune deficiency disease.
\nRab (Ras-related proteins in brain) proteins are key regulators of both vesicular transport and trafficking of proteins [34]. Several Rab GTPases have been implicated in the regulation of the intracellular transport and the plasma membrane delivery of CFTR. The trafficking of CFTR from the plasma membrane to early endosomes is controlled by RAB5 [35, 36]. RAB7 regulates the movement of CFTR away from the recycling pathway and into late endosomes and also from late endosomes to lysosomes for degradation [37]. RAB9, however, can move CFTR away from lysosomal degradation by mediating its transport from late endosomes back to the trans-Golgi, from which CFTR may reenter the secretory pathway leading to plasma membrane insertion [37].
\nGrowing knowledge of CFTR biosynthesis has enabled understanding of the cellular basis of CF and has brought to light various potential targets for novel and promising therapies [15]. Although some
The major molecular regulator of autophagy in response to starvation or energy depletion include the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 by starvation or rapamycin results in the activation of autophagy and the start of autophagosome formation. The capacity of autophagy to clear intracellular pathogens such as bacteria, viruses, and parasites is collectively referred to as xenophagy [5], whereas the selective autophagic degradation of mitochondria is denoted as mitophagy and that of protein aggregates is termed aggrephagy. But how do autophagosomes find their targets? The modification of targets by ubiquitination represents a signal for selection of substrates to the autophagy pathway.
\nMammalian cells ubiquitinate bacteria that erroneously enter the cytosol or their containing vacuole and target them for destruction by autophagy. Adaptors, including p62/SQSTM1 [42], optineurin (OPTN) [43], NBR1 (neighbor of BRCA1 gene 1) [44–46], and NDP52 (nuclear dot protein 52 kDa) [47], mediate “eat-me” functions by promoting autophagic sequestration of cargo. The adaptor molecule p62 is a ubiquitously expressed cellular protein and its quantity is critical for cell viability [48]. p62 has multiple protein-protein interaction domains, including the ubiquitin-associated domain for binding of ubiquitinated cargo and a LC3 interaction region for binding Atg8/LC3 [49]. p62 plays a role in amino acid sensing and the oxidative Stress response, in addition to its function as an autophagy receptor for ubiquitinated cargos [50]. Most p62 protein in the healthy cell is distributed in the cytoplasm. In response to various stressors though, it is translocated to autophagy substrates such as protein aggregates, damaged mitochondria, and intracellular bacteria [42]. Then, through its LC3-binding domain, p62 engages autophagosomes.
\nAutophagy is responsible for the degradation of p62. Therefore, impairment of autophagy is usually accompanied by massive accumulation of p62 followed by the formation of aggregate structures positive for p62 and ubiquitin [50]. This accrual is a defining characteristic of impaired autophagy. Aggregation occurs due to both the predilection for self-oligomerization and the ubiquitin-binding capabilities of p62 [51]. Notably, p62 accumulates in CF macrophages and promotes the sequestration of mutant CFTR (Figure 1). These aggregates, in turn, consume important autophagosome-needed proteins, such as BECN1 and LC3 [30, 31]. Recent reports demonstrate that the adapter protein NDP52 directly binds to ubiquitinated bacteria and facilitates the assembly of an autophagic membrane that surrounds these invaders [47]. Interestingly, NDP52 can also bind ubiquitinated bacteria-containing vacuole when p62 is drastically reduced [30, 31]. Optineurin can mediate the removal of protein aggregates through an ubiquitin-independent mechanism. In addition, this protein can induce autophagy upon overexpression or mutation [43]. NBR1 and p62 cooperate in the sequestration of misfolded and ubiquitinated proteins in p62 bodies and are both required for their degradation by autophagy. Recently, NBR1 was found to be necessary and sufficient for pexophagy [44–46]. Whether NBR1, optineurin, and NDP52 play important roles in CF-associated autophagy is still unknown.
\nCFTR is an anion channel permeable to chloride and bicarbonate [2, 52]. Upon activation, CFTR transports chloride following its electrochemical gradient. In the lung, CFTR is expressed at the apical membrane of bronchial cells where it regulates chloride transport and fluid homeostasis [53]. The absence of functional CFTR in the lung results in abnormal surface hydration and decreased airway surface fluid. Thus, mutations in the CFTR protein results in the accumulation of thick mucus at the surface of epithelial cells, leading to impairment of pathogen clearance and dysregulated inflammatory responses that in turn results in chronic infection and inflammation [54]. In addition, epithelial cells expressing mutant CFTR exhibit weak autophagy activity.
\nMacrophages are central innate immune cells that engulf invaders within a vacuole and target them to fuse with the lysosome for degradation. Therefore, lysosomes contribute to antimicrobial capacities by fusing with the pathogen-containing, intracellular vacuole [55]. Lysosomes are acidic compartments filled with various acid hydrolases, NADPH oxidases, and oxygen radicals that degrade and break down proteins, lipids, and polysaccharides.
\nThe lung disease seen in CF was accordingly suggested to result in part from lysosomal dysfunction [56], yet the exact location and function of CFTR in macrophages are still debatable. A report showed impaired bacterial killing due to impaired function of antibacterial proteins at low pH in a CF pig model [57]. Another study demonstrated that acidification requires anion transport through CFTR [58]. More recently, defective lysosomal acidification was also invoked as the mechanism underlying CF lysosome malfunction [59]. Others failed to confirm the involvement of CFTR in acidification [60, 61]. Both these reports are plausible. When macrophages are infected with autophagosome-resident organisms such as
Polymorphonuclear neutrophils (PMNs, neutrophils) are responsible for the earliest innate immune response to infection and most of their antimicrobial activity against ingested microbes is confined within phagosomes. However, exuberant neutrophil activation can culminate in extracellular release of oxidants and granule contents that leads to local damage to healthy tissue. Neutrophils function to kill microbes through compartmentalization by use of membrane-bound phagosomes, where toxic oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) are generated [62]. The azurophilic granule protein myeloperoxidase (MPO) catalyzes the oxidation of Cl− to form HOCl. Neutrophils predominate in the CF patient’s lung and is a major contributor to the inflammation and destruction of the lung [63]. Yet, despite a successful inflammatory response, neutrophils fail to eradicate invading microbes in the CF lung [64]. CFTR dysfunction results in impaired intraphagosomal HOCl production and neutrophil-mediated microbial killing. Notably, the
In the CF lung, there is overproduction of the neutrophil chemotactic cytokine interleukin 8 (IL-8). This leads to excessive infiltration of neutrophils [67]. Lung infections cause significant morbidity and mortality in patients with CF, even in the presence of neutrophil infiltration into infected lungs. Thus, disturbance in innate neutrophil function in CF includes excessive recruitment [65], hyper-production of oxidants, and increased release of degradative enzymes [64]. Thus, it is evident that CF is indeed an innate immune disorder involving several malfunctioning immune cells.
\nSeveral autophagy proteins are scarcely expressed in CF cells, yet the underlying mechanism is undefined [30, 31]. This strongly suggests the presence of an epigenic regulation that targets autophagy mRNA in cells bearing mutant F508del-CFTR. Considering the strong implications of microRNAs (miRs) in autophagy [28, 29, 68–70] and given the increasing evidence showing reduced expression of essential autophagy proteins in CF cells, we performed an
In airway epithelial cells, absence of functional CFTR increases oxidative stress and transglutaminase 2 (TGM2), a calcium-dependent enzyme that creates intra- or intermolecular covalent bonds between proteins. TGM2-mediated cross-linking causes sequestration of BECN1 and its accumulation in histone deacetylase-6 (HDAC6), p62, and ubiquitin-containing cytoplasmic aggresomes. BECN1 sequestration in aggresomes results in the dislodgement of class III PtdIns3K complexes from the endoplasmic reticulum, thereby inhibiting autophagy [30, 81]. In addition, the sequestration of BECN1 within F508-CFTR protein aggregates deprives the cell for an essential factor needed for autophagosome formation.
\nHigh levels of p62 promote the aggregation of mutant F508del-CFTR sequestering several autophagy molecules such as BECN1. This p62 buildup could be due to reduced recycling in CF macrophages as a consequence of compromised autophagosome formation and maturation. Notably, p62 downregulation disassembles mutant CFTR and autophagy factors, thus improving autophagy activity and allowing the maturation and trafficking of CFTR to the cell surface in epithelial cells and bacterial clearance in macrophages [30, 31]. Similarly, genetic manipulation or autophagy stimulatory proteostasis regulators such as cystamine restore BECN1 availability and detangle SQSTM1/p62, which partially rescues F508del CFTR function in airway epithelial cells and reduces lung inflammation [82].
\nThere is evidence for autophagy dysregulation in a variety of disease states, including cancer, neurodegenerative diseases, chronic granulomatous diseases, infectious diseases, and autoimmune disorders [83–85]. For this reason, therapeutic modulation of autophagy is of great interest. Autophagy has emerged as a central component of the innate and adaptive immune responses where it plays roles in direct and indirect killing of intracellular and extracellular pathogens, the generation of bactericidal peptides, and antigen presentation [29]. Functions of autophagy that are compromised in CF include bacterial clearance, degradation of protein aggregates, and the elimination of dysfunctional mitochondria. Thus, the restoration of autophagy will have positive therapeutic effects in CF.
\nPatients with CF are susceptible to Nontypeable
In healthy cells,
\n
NTM strains infect between 5 and 22% of CF patients and are a growing concern among CF populations due to their increasing prevalence and multi-drug resistance. Infection is often associated with poor clinical outcomes [99]. Although autophagy contributes to clearance of
NTHi chronically colonizes the airways of CF patients at a very young age. Recent reports suggest that autophagy may be actively subverted by NTHi by an unknown mechanism.
\nOn the other hand, following phagocytosis, the degradation of
\n
Many of the opportunistic bacteria that infect the CF lung have employed mechanisms to target phagolysosomal maturation and/or autophagy, suggesting that these are major barriers that need to be overcome. Activation of autophagy through rapamycin treatment has shown efficacy in promoting clearance of certain bacteria
Rapamycin was developed as an antifungal agent but its use was abandoned due to the potent immunosuppressive and antiproliferative properties. Recently, it was found that rapamycin inhibits mTOR and therefore induces autophagy [105]. Rapamycin promotes clearance of the CF-associated pathogens
Among the most common autophagy-stimulating compounds were the antipsychotic drugs bromperidol, metergoline, thioridazine, and chlorpromazine. However, the psychoactive nature of these compounds and their potentially life-threatening side effects limit their utility, but nevertheless provide a strong theoretical basis for future drug development [109, 110].
\nMetformin is a drug that activates AMPK and therefore stimulates autophagy via TORC1-dependent and TORC-1-independent methods [111, 112]. Metformin probably has many other mechanisms of action that cannot be explained by the induction of autophagy. Metformin and resveratrol activate SIRT1 that in turn activates autophagy [113, 114].
\nCertain anticancer drugs have also been found to stimulate autophagy. For example, Perifosine inhibits mTOR signaling through a different mechanism than classical mTOR inhibitors such as rapamycin [115], whereas Tamoxifen, an antagonist of the estrogen receptor, is known to induce autophagy [116]. Tamoxifen stimulates autophagy by increasing the intracellular level of ceramide, which inhibits mTOR activation and/or stimulates expression of Atg genes.
\nThe second generation of selective histamine H1-receptor antagonist astemizole is a potent inducer of autophagy at biologically achievable concentrations [117]. Astemizole exhibits antifungal activity and antimalarial properties making it attractive option for CF patients even though the mechanism by which it activates autophagy is still unclear [117, 118]. Safety and drug interaction profiles of astemizole are well characterized. However, due to the availability of superior next-generation histamine receptor agonists, it is not commonly used in Europe or North America.
\nThe potential application of the TGM2 inhibitor cystamine in CF patients has recently been reviewed. Cystamine restores normal autophagy in CFTR-deficient cells and mouse models. Cystamine also restores normal trafficking of the F508del-CFTR and stabilizes the expression of the protein at the plasma membrane of airway epithelial cells [100]. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and epigallocatechin gallate (EGCG) restored the levels of the autophagy molecules BECN1 and p62 and improved CFTR function from nasal epithelial cells
There is now strong evidence that immune cells, such as macrophages and neutrophils, are intrinsically impaired in CF. We therefore, recommend that CF be added to the list of innate immune disorders. In fact, autophagy, an intracellular degradation process that contributes to bacterial clearance, protein degradation, and cell survival, is defective in CF. Therefore, we propose that altered autophagy in CF contributes to chronic lung infection and inflammation. The CF field is in desperate need for an approach to correct autophagy in CF patients. The autophagy-correcting agents should ameliorate the marginally positive effects of correctors (therapies that correct the trafficking defect of F508del CFTR) and activators (compounds that activate the F508del CFTR that reaches the cell membrane) typically used in CF. Thus, the development of safe novel autophagy stimulating agents will improve the clinical outcome of CF and promote the clearance of infectious agents.
\nCardiac arrest is the leading cause of ischemic and hypoxic encephalopathy, as the brain is the organ that receives blood from the heart at 25% of all the blood that leaves the heart. Regardless of the underlying cause, patients with cardiac arrest often experience neurological complications, both short-term and long-term. Therefore, neurological monitoring is essential and essential in cardiac arrest patients for proper care and accurate prognosis [1].
The prognostication after cardiac arrest consists of (1) neurological examination, (2) neurophysiologic evaluation, (3) neuro-radiologic evaluation, (4) biochemical markers.
The algorithm for prognostication in post-cardiac arrest (PCAS) patients with restoring spontaneous circulation (ROSC) invented by the American Academy of Neurology in 2006 (as shown in Figure 1) has become a landmark guideline [2]. The primary purpose of the algorithm is to determine the poor outcomes for withdrawal of life-sustaining treatment, although most of the PCAS patients fall into indeterminate outcomes. However, due to improved outcomes with targeted temperature management (TTM), clinical and surrogate makers in the algorithm need to be interpreted more carefully in patients treated with TTM [1, 3]. The recent resuscitation guidelines updated the algorithm using multimodal evaluation (as shown in Figure 2) to ensure better accuracy in determining the prognosis in post-cardiac arrest patients treated with TTM [4]. The predicting tool for prognostication in post-cardiac arrest patients is available [5]. In contrast, the prognostication in coma patients outside post-cardiac arrest is much less established [6]. In general, for patients who remain coma for more than four weeks, the chance to achieve a meaningful recovery is low.
The algorithm for prognostication in post-cardiac arrest (PCAS) patients with restoring spontaneous circulation (ROSC) was invented by the American Academy of Neurology in 2006.
The algorithm for prognostication in post-cardiac arrest (PCAS) patients with restoring spontaneous circulation (ROSC) was invented by the American Heart Association in 2020.
The neurological examination remains essential for prognostication in PCAS patients, which indicates the degree of hypoxic-ischemic brain injury. Therefore, physicians usually use the overall neurological signs to predict the outcomes after ROSC. The optimal time to predict the outcomes with neurological examination is three days after ROSC in PCAS patients not treated with TTM [2]. In contrast, the neurological examination should get delayed until five days after ROSC or three days after normothermia in PCAS patients treated with TTM [7].
The initial purpose of the Glasgow Coma Scale (GCS) was to measure the level of consciousness in traumatic brain injuries; however, it is also helpful for predicting outcomes in PCAS [8]. Serial improvement of GCS in PCAS patients is usually associated with good outcomes [9]. Therefore, predicting tools for outcomes in PCAS usually included the GCS [10]. The GCS motor scores less than three at three days after ROSC in PCAS patients not treated with TTM strongly predict poor outcomes (false positive rate 0–3%) [2]. On the other hand, in PCAS patients treated with TTM, the GCS motor scores less than three at three days after normothermia or five days after ROSC may not always predict poor outcomes (false positive rate 19%) [11, 12]. The GCS motor scores more than three before initiation of TTM strongly predict good outcomes [13].
Intact pupillary light reflex (PLR) indicates proper midbrain function. The absence of PLR three days after ROSC in PCAS patients not treated with TTM strongly predicts poor outcomes (false positive rate 0–3%) [2]. On the other hand, in PCAS patients treated with TTM, the absence of PLR at three days after normothermia or five days after ROSC remains predictive for poor outcomes with a 2.1% false-positive rate [11, 14]. Thus, early absent PLR after ROSC before initiation of TTM may not always predict poor outcomes [15]. Abnormal Neurological Pupil index and PLR quantitative measurements by pupillometry early after ROSC increase accuracy for the predictor of poor outcomes [16, 17].
The corneal reflex indicates the degree of intactness of the pathway from the ophthalmic branch of the fifth cranial nerve through the pons to the seventh cranial nerve and facial muscles [18]. Gently touching the cornea with a thin wisp of sterile cotton will aggravate, leading to involuntary closure of the ipsilateral eye, as well as the closing of the other eye (consensual response). Therefore, the accuracy of the technique is crucial for declaring the corneal reflex present or absent [19]. The absence of bilateral corneal reflex three days after ROSC in PCAS patients not treated with TTM strongly predicts poor outcomes (false positive rate 0–3%) [2]. On the other hand, in PCAS patients treated with TTM, the absence of bilateral corneal reflex at three days after normothermia or five days after ROSC remains predictive for poor outcomes with a 2.2% false-positive rate [11].
The intact reaction of oculocephalic reflexes (Doll’s eye movement) consists of the deviation of both ocular globes towards the opposite direction of cephalic turning. A fully conscious patient does not have oculocephalic reflex due to voluntary suppression. Once an unconscious PCAS patient does not express these symptoms, a lesion must be located at either the afferent or efferent arm of the reflex loop. The afferent arm includes the labyrinthine complex, vestibular nerve (CN VIII), and neck proprioceptors. The efferent arm includes the oculomotor nerve (CN III), trochlear (CN IV), and abducens nerve (CN VI), and their responsible muscles. If the connective pathways between the afferent and efferent arms in the pons and medulla become interrupted in unconscious PCAS patients, the doll’s eyes reflex will also be absent. Physicians usually use the lack of oculocephalic reflex together with the absence of other brainstem reflexes to indicate poor outcomes for withdrawal of life support in PCAS patients [20].
Irrigating one tympanic membrane with cold water or saline introduces ipsilateral deviation of both eyes with contralateral fast phase nystagmus lasting for one to two minutes. While switching to hot water produces the opposite reaction: contralateral deviation, with ipsilateral fast phase nystagmus. Bilateral irrigating with cold water or saline gives rise to a downward deviation with upward nystagmus. In contrast, bilateral irrigating with hot water or saline, the opposite reaction occurs. Patients with inflammations and traumatic lesions within the outer and middle ear are contra-indicated to get the vestibulo-ocular reflex test. The absence of any or abnormal responses indicates brainstem dysfunction [21]. The absence of vestibulo-ocular reflex at more than 24 h after ROSC in PCAS patients not treated with TTM usually predicts poor outcomes with a false positive rate of 14% [22].
Myoclonic movement disorders occurred after hypoxic-ischemic brain injury in PCAS patients entitles post-hypoxic myoclonus. The post-hypoxic myoclonus is divided into the malignant, the so-called Myoclonus Status Epilepticus (MSE), and the benign, the so-called Lance Adam Syndrome (LAS), subtypes. MSE indicates more severe hypoxic-ischemic brain damage than LAS. Clinical features of the post-anoxic myoclonus alone are difficult to discriminate between MSE and LAS. The electrophysiologic studies help enhance the accuracy of the post-anoxic myoclonus diagnosis [23]. The early presence of MSE within 24 h after ROSC in PCAS patients not treated with TTM predicts poor outcomes (false positive rate 0–8.8%) [2]. However, an increasing number of studies report good outcomes in PCAS patients with initial MSE treated with TTM [24, 25]. Therefore, the early presence of post-anoxic myoclonus should not discourage the use of TTM in PCAS patients [25].
Somatosensory evoked potentials (SSEPs) consist of electronic waves that result from the stimulation of neural structures along the somatosensory tracks. The stimulation sites typically performed for prognostic SSEPs studies are the median nerve at the wrist. The measurement sites are the N20 wave at the contralateral parietal cortex, as shown in Figure 3 [26]. The artifacts and low amplitude of the N20 wave are the limitations of SSEP interpretation [27]. The absence of N20 wave within three days after ROSC in PCAS patients not treated with TTM strongly predicts poor outcomes (false positive rate 0–3.7%) [2]. An increasing number of cases reported initial absence but the later presence of N20 wave and good outcomes in PCAS patients treated with TTM [28, 29]. Series of SSEPs with the absence of N20 wave until six days after ROSC provide better accuracy for poor outcomes in PCAS patients treated with TTM [30]. Visual Evoked Potentials may be as valuable as SSEPs for outcomes predictor in PCAS patients [31].
The somatosensory evoked potential (SSEP).
EEG has been used together with other prognostic tools for the outcomes predictor in PCAS patients for more than five decades. EEG patterns, which can be found in PCAS patients, include iso-electric, low voltage (less than 20 milli-volts), burst suppression, epileptiform, continuous activity with frequency less than eight Hertz, and continuous activity with frequency less than eight frequency more than or equal to eight Hertz [32]. The first three patterns are considered malignant EEG and predict poor outcomes in PCAS patients [33]. However, malignant EEG alone may not accurately predict poor outcomes (false positive rate
CT-brain is convenient to obtain early in PCAS patients, and the results are not disturbed by any treatment during resuscitation. CT-brain is beneficial to help determine some neurological causes of cardiac arrests, such as an intracranial hemorrhage. However, CT-brain is not sensitive enough to detect the early phase of hypoxic-ischemic brain injury. The apparent abnormalities such as diffuse cerebral edema with effacement of the basal cisterns and sulci, loss of cortical gray-white differentiation, bilateral hypodensities involving the deep gray nuclei or the arterial border zones (as shown in Figure 4), take a few days or weeks to show up in CT-brain [36]. The measurement of gray-white matter ratio (GWR) by the Hounsfield units is helpful to detect the unvisualized early cerebral edema from hypoxic-ischemic brain injury in CT-brain. Many previous studies have shown that if the GWR is low in the CT-brain, it indicates an initial sign of severe hypoxic-ischemic brain injury and a PCAS patient’s likelihood of death [37]. The area of the brain used for GWR calculation is varied among studies [38]. In general, the average GWR of less than 1.14 is highly predictive for poor outcomes with 100% specificity and 100% positive predictive value [39].
CT-Brain in a patient with severe hypoxic/ischemic brain injury: diffuse cerebral edema with effacement of the gyri and sulci (A), loss of cortical gray-white differentiation, bilateral hypodensities involving the deep gray nuclei (B).
CT-brain without contrast in PCAS patients with profound brain swelling from severe hypoxic-ischemic insults may mimic subarachnoid hemorrhage [40], as shown in Figure 5. Pseudo-subarachnoid hemorrhage was postulated to define this phenomenon [41]. The transposition of edematous brain tissue into the subarachnoid space, transposition of cerebrospinal fluid, and distension of superficial pial veins should be the mechanisms of this appearance CT-brain [42]. Hyperdensity area suspected blood at Sylvian fissure is usually less than 35 Hounsfield unit in pseudo-subarachnoid hemorrhage, but more than 50 Hounsfield unit in actual subarachnoid hemorrhage [43, 44, 45].
Pseudo-subarachnoid hemorrhage (A, arrows) in CT-brain without contrast from PCAS patients with profound brain swelling (B) from severe hypoxic-ischemic insults.
MRI-brain is more sensitive than CT-brain for detection of early hypoxic-ischemic brain injury. However, MRI-brain is not as convenient as CT-brain to obtain early in PCAS patients [46]. Diffusion-Weighted Imaging (DWI) sequences of MRI-brain are the most sensitive for cytotoxic injury from hypoxic-ischemic brain insults [47]. Restricted water molecules within ischemic brain tissue cause DWI restriction leading to hypersignal intensity appearance (Figure 6) [48]. DWI restriction threshold of 650 x 10−6 mm2/s in more than 9 percent of brain volume determines poor outcomes [49]. Diffusion Tensor Imaging (DTI) plays a significant role in white matter tractography with a similar principle of intercellular water diffusion in DWI [50]. Fractional anisotropy, a DTI parameter, is a quantitative measurement for white matter abnormality [51]. Quantitative whole-brain white matter fractional anisotropy measured by DTI between days seven and 28 after cardiac arrest can predict long-term neurological outcomes [52, 53]. The fluid-attenuated inversion recovery (FLAIR) sequences of MRI-brain can also detect cytotoxic injury from hypoxic-ischemic brain insults [54]. The appearance of hypoxic-ischemic brain injury detected by FLAIR adds up the specificity to DWI in predicting unfavorable outcomes [55].
Imaging of a PCAS patient on five days after ROSC: CT-brain (A) showed no hypodensity lesion, DWI (B) showed hyperintensity in deep nuclei corresponded with hypointensity in Apparent Diffusion Coefficient sequences (C).
Several previous studies have shown that many chemicals are secreted from the brain into the bloodstream and cerebrospinal fluid (CSF) following hypoxic-ischemic brain insults, including neuron-specific enolase (NSE), S100B protein, Tau, neurofilament light chain, and glial fibrillary acidic protein.
NSE is an isoenzyme of the glycolytic pathway found in neurons. Hypoxic–ischemic brain injuries anaerobically upregulate glycolysis, producing and releasing NSE from damaged neurons into the bloodstream [56]. Blood NSE levels were correlated with the severity of hypoxic–ischemic brain injury [57]. Serum NSE is the most useful biochemical marker for cardiac arrest prognostication [2, 4]. In PCAS patients not treated with TTM, serum NSE more than 33 μg/L between 24 and 72 h after ROSC predicts poor outcome (false positive rate 0–3%) [2]. The predictive value for poor outcome (false positive rate 0%) becomes more specific when using the cutoff level at more than 80 μg/L [57]. The cutoff level of serum NSE for poor outcome prediction became inconclusive, ranging from 33 to 120 μg/L in PCAS patients treated with TTM [4]. Serial serum NSE at 24, 48, and 72 h after ROSC was proposed to improve outcome prediction accuracy in PCAS patients treated with TTM [58, 59].
Other biochemical markers rather than NSE have limited data to use for prognostication in PCAS patients. S100B, a glial-derived protein, more than 0.2 μg/L in serum within 72 h after ROSC may predict poor outcomes [60]. Serial serum S100B at 24, 48, and 72 h after ROSC did not add any predictive accuracy to serial serum NSE [61]. The accuracy of serial serum Tau, a neuron-derived protein, at 24, 48, and 72 h after ROSC is comparable with serial serum NSE for predicting poor outcomes [62]. However, the role of serum Tau fragments, Tau-A and Tau-C, in cardiac arrest prognostication remains uncertain [63]. Serial plasma neurofilament light chain at 24, 48, and 72 h after ROSC with the respective cutoff value of 127, 263, and 344 pg/ml is predictive for poor outcomes [64]. The specificity of serial plasma neurofilament light chain for poor outcome prediction is comparable with other standard methods used in the guidelines [65]. Glial fibrillary acidic protein, another glial-derived protein, is released into the bloodstream only in the presence of pathologic conditions and is more specific to acute brain damage than NSE or S100B [66]. Elevated serum glial fibrillary acidic protein more than 0.8 μg/L at 48 h after ROSC predicts poor outcomes [67].
Intracranial pressure (ICP) monitoring is rarely applied in PCAS patients. The reliable ICP monitoring techniques, including intraventricular catheter and intracerebral transducer, are solely invasive. Non-invasive techniques using transcranial Doppler, optic nerve sheet diameter ultrasound, and jugular venous pulse pressure are available but have low accuracy [68]. The benefit of ICP monitoring in treatment or prognostication in PCAS patients is uncertain [69]. Persistent elevated ICP above 20 mmHg is usually associated with poor outcomes in PCAS patients [70].
Sinus bradycardia during TTM treatment reflects intact autonomic response and predicts good outcomes in PCAS patients [71, 72]. The difference in heart rate during the hypothermic maintenance and normothermic phase of TTM also reflects the intact autonomic response to temperature change and predicts good outcomes [73]. Heart rate variability (HRV) is a conventional method for autonomic function assessment [74]. HRV is feasible to apply in PCAS patients [75]. However, the role of HRV in cardiac arrest prognostication remains uncertain.
The role of aging in PCAS prognostication remains controversial [76]. Advanced age should not be the indication for withdrawal of care in PCAS patients. Also, the role of the pulse index contour cardiac output monitoring system in PCAS prognostication and treatment remains controversial [77].
It is essential to determine PCAS patients with poor outcomes for the decision of care withdrawal. There are several methods of prognostication after the cardiac arrest that should be combined to assist in proper prediction. A multimodal approach using Neurological examination, Neurophysiologic evaluation, Neuro-radiologic evaluation, and Biochemical markers is recommended to provide the most accuracy for poor outcome prediction. Most of the data used in prognostication studies derive from the out-of-hospital cardiac arrest subgroup. However, the data can be applied to other subgroups of cardiac arrest. Even though a multimodal approach has been used, the prognosis of most PCAS patients still falls into indeterminate outcomes.
This work is supported by the center of excellence in stroke from Thammasat University.
The authors declare no conflict of interest.
post-cardiac arrest syndrome return of spontaneous circulation out-of-hospital cardiac arrest in-hospital cardiac arrest targeted temperature management American Academy of Neurology somatosensory evoked potential electroencephalography neuron specific enolase transcranial Doppler Glasgow Coma Scale pupillary light reflex myoclonus status epilepticus Lance Adam Syndrome gray-white matter ratio diffusion-weighted imaging diffusion tensor imaging fluid-attenuated inversion recovery cerebrospinal fluid intracranial pressure.
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Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11405,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. 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