**3.4 Optical coherence tomography**

Anterior eye segment imaging with 830 nm optical coherence tomography (AS OCT) was first demonstrated and published in 1994. Changing the light wavelength from 830 nm to 1310 nm allowed the direct transcleral anterior eye segment structures including trabecular-iris angle visualization in 2000. OCT provides in vivo anterior eye segment imaging with the axial resolution from 18 μm with time domain OCT (TD OCT) to 5 μm with spectral domain OCT (SD OCT) and to 5 μm with ultra high resolution spectral domain OCT. OCT is proven to provide reliable anterior eye segment morphology and morphometry results with high reproducibility and repeatability. Application of OCT in herpetic keratitis patients include: assisting in diagnosis of patients at active stage and assessing the scars in patients qualified for laser or surgical interventions. Active keratitis could be characterized

*Recent Advances in the Diagnosis and Management of Herpetic Keratitis DOI: http://dx.doi.org/10.5772/intechopen.96898*

#### **Figure 6.**

*Representative images of the confocal microscopy scans revealing significant features characteristic for HSV keratitis. (A) Epithelial, healed dendritic ulcer with noticeable fibrotic borders (arrows). (B) Multiple infiltration of small dendritic structures as the level of the epithelium. Clusters of inflammation cells (arrows). (C) Multiple infiltration of pronounced dendritic cells forming a lattice pattern (arrows) at the level of the basal epithelial cells. (D) Marked fibrosis at the level of the Bowman layer (arrow) with inflammation cells infiltration (stars). (E) Excessive fibrosis and inflammation cells infiltration forming clusters at the level of the Bowman layer (arrows). Dendritic structures visible (star). (F) Anterior stromal keratocytes activation with accompanying haze (arrow). (G) Stromal infiltration and haze accompanied by multiple crystalline structures due to the lipid degeneration (stars). (H) Multiple endothelial opacities. Examples marked with stars.*

by the presence of the ulceration, stromal edema and inflammatory hyperreflective infiltrates. Corneas with inactive keratitis are characterized by stromal scarring and thinning, and epithelial remodeling [17–22]. Characteristic OCT features are presented in the **Figure 7**.

#### **3.5 Laboratory testing**

There are several laboratory techniques, which may help in the diagnostic process. Clinical samples for the analysis may be obtained through collection of tears, corneal epithelial cells, and conjunctival cells. Tear samples are usually obtained using Schirmer test. Epithelial or conjunctival cells may be collected through corneal scrapings, corneal impression membranes (CIM) or using conjunctival or corneal swab. The less invasive the technique the lesser probability of obtaining a clinically detectable material.

The isolation of the HSV from the cornea and performing a viral culture remains a conventional, gold standard technique, however the main disadvantages of this methods are low sensitivity and a time consuming process. Giemsa staining of the epithelial corneal cells may visualize multinucleated giant cells, resulting from coalescence of HSV infected epithelial cells and intranuclear HSV inclusions. Immunofluorescence assay (IFA) is one of the modern techniques developed to diagnose HSV keratitis. The principle of the method is to introduce antibodies, that bind to HSV antigens specifically to gain fluorescence based immunological detection of HSV-1 antigen through color visualization under microscopy. Disadvantages of the method include: required subjective interpretation by an experienced technician and the risk of obtaining false positives results due to cross-reactivity between other microorganisms.

#### **Figure 7.**

*Representative images of the anterior segment swept source optical coherence scans revealing significant features characteristic for HSV corneal scars. (A) Slit lamp photograph of the central post herpetic keratitis scar. (B) High resolution scan. Hyperreflective tissue within corneal stroma with irregular borders (arrows). (C) Pachymetry map. Marked paracentral corneal thinning to 398* μ*m. (D) Slit lamp photograph of the central post herpetic keratitis scar. (E) High resolution scan. Hyperreflective tissue within corneal stroma with irregular borders. Note the relatively smooth corneal surface and epithelial compensation over the irregular corneal stroma (arrows). (F) Pachymetry map. Marked irregular, paracentral corneal thinning to 382* μ*m.*

Advanced diagnostic techniques include: Polymerase Chain Reaction (PCR) conventional PCR, reverse transcriptase PCR (RT-PCR), real-time PCR (qPCR) and multiplex PCR. qPCR overcomes the disadvantages of conventional PCR by acquiring more rapid and sensitive results. Guda SJM. et al. assessed sensitivity and specificity of the conventional and real-time PCR compared to IFA performed on corneal scrapings. The sensitivity and specificity of conventional PCR was 100% and 76.9% and 100% and 28.2% of qPCR respectively. Satpathy et al. assessed and concluded, that specificity and positive predictive value (PPV) of PCR was higher in tear (90.6% and 37.5%). compared to cornea scrapings (71.3% and 30.3%). Moreover, Akbarian A. et al. reported, that conventional PCR with added internal amplification control (IAC) had higher sensitivity (100%) vs. culture method (66.66%), while the specificity was 100% for both diagnostic methods.

Also novel methods, such as multiplex dot hybridization (MDH) assay, immunochromatographic assay (ICGA, AmpliVue) or Infected cell protein 0 (ICP0) detection in tears are either tested or incorporated into a clinical practice. AmpliVue is a commercially available immunochromatographic assay, office-based diagnostic test characterized by a 64.7% positive detection rate. Sensitivity and specificity of AmpliVue was assessed as 84% and 100% respectively, based on true positives from culture and PCR combined. The MDH assay is a rapid technique, that involves a series of oligonucleotide probes specific for HSV genes. Compared to the real-time PCR, the MDH assay is characterized by very high values of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.3%, 100%, 100% and 98.4%, respectively. The infected cell protein 0 (ICP0) is an acute phase protein during HSV infection and plays a significant role in the virus gene expression activation. ICP0 could be potentially defected in tears of affected subjects [23–28].


**Jimlea Nadezhda Mendoza** is from the Philippines, daughter of a fisherman and public-school teacher. She works at Ca' Foscari University of Venice, is passionate about exploring the local ecological knowledge of fishers and about contributing to building bridges between academia and local communities through storytelling, conveying the acquired oral histories about the freshwater resources to a wider audience. Jimlea loves to eat fish all day long.

**Juliana Merçon** was born and raised in Brazil but has lived for the past 12 years in Mexico. She studied psychology, philosophy, and education, before exploring the field of agroecology. Collaborating towards social and environmental justice is at the heart of her (academic) life. For Juliana, transdisciplinarity and participatory action research are not only epistemological approaches as they also entail ways of being and deeply connecting with people, places, and time. Her eight-year-old daughter Michelle is her main source of fun, learning, and inspiration.

**Esther Meyer** was born in Fürth, and has a background in philosophy, economics, and sustainability sciences. She is committed to supporting transdisciplinary change agents and those who move at the institutional boundaries of education by teaching, knowledge systematization, consultation, creating networks, and methodological accompaniment. As a lifelong learner, Esther completed training in organizational development and consultancy. As a passionate dancer, she has recently started going to football stadiums to watch fan choreographies.

**Joost Meyer** discovered his scientific focus through his work at the forest lab *Waldlabor* in Cologne. With a team of young scientists, he founded the *Willowprint* project, where he and his colleagues seek for sustainable biogenic materials for 3D printing. In addition to his work for science and teaching, Joost uses sculptural means to explore the meaning of the natural environment in human perception. He enjoys the Scandinavian summer in Denmark's North Jytland, swimming in the rain.

**Stefanie Meyer** has been leading the Case Study Office at Leuphana University in Lüneburg since 2019. She is responsible for the coordination and further development of the structural and content-related conception of case studies in the areas of transdisciplinary research and teaching in bachelor and master programs at the School of Sustainability.

**Ewald Mittelstädt** has been a founder since his youth. Later he studied business management, slavistics, political science, and public law in Münster as well as Economics in Krakow. At TU Dortmund, he worked in teacher education and did research on chaos theory. Following postdoctoral positions in Freiburg and Kiel, Ewald now teaches and conducts research at South Westphalia University of Applied Sciences in Iserlohn. Ewald is interested in contemporary and street art and feels dedicated to the maxim: Life is as colorful as you dare to paint it.

**Manon Mostert-van der Sar** is director of Stadslab Rotterdam, the fab lab of Rotterdam University of Applied Sciences, and author of *Hey Teacher, Find Your Inner Designer*. Manon is a maker and designer of education. She trains teachers, coaches instructors, designs cross-institute modules, and developed a didactic compass, but still loves to teach students. At home Manon is a real maker, rebuilding her own farmhouse. She is not afraid of bricklaying, sawing, milling, and all kinds of carpentry.

**Daniel Münderlein** is a trained landscape architect. His research focuses on the perception and further development of urban landscapes and the integration of productive open-space systems. Special attention is paid to the interrelationships between landscape, health, and well-being as well as the development of innovative methods for visual communication in spatial planning. Daniel loves taking pictures of urban landscapes and plays the electric guitar louder than the neighbors would like.

**Olena Mykolenko** works as a lecturer and researcher in the field of entrepreneurship at Karasin University in Kharkiv. She is currently doing her post-doctoral research on humane entrepreneurship with a special focus on leadership and sustainability. Olena is also involved in a European research project on sustainability thinking and entrepreneurship. She likes theater, and – despite challenging circumstances – she regularly visits it in her city together with her lovely daughter.

**Oliver Parodi**, philosopher, cultural scientist, and civil engineer, is head of the Karlsruhe Transformation Center for Sustainability and Cultural Change at the KIT Institute for Technology Assessment and Systems Analysis. As an expert in transformative sustainability research, he was the initiator and has been director of the real-world lab *Quartier Zukunf t – Labor Stadt* since 2012. A matter close to his heart is personal sustainability in research and teaching – but in private, he is still far away from achieving it.

**BinBin J. Pearce** is an assistant professor for policy analysis and design at TU Delft's Faculty of Technology, Policy and Management. Her transdisciplinary research interests include public participation processes and policy design for the energy transition, collaborative decision making for sustainable development, joint problem-framing processes, and developing curriculum based on integrated systems and design thinking.

**Daniela Peukert** has a background in product design and sustainability sciences and holds the professorship of design for sustainability transformation at Tomorrow University of Applied Sciences in Berlin. In her research, she explores prototyping practices and material metaphors to foster integration and knowledge co-production within transdisciplinary processes and works towards a more-than-humancentered-design approach. Daniela enjoys being outdoors on boards and bikes.

**Jonas Pfister** came to philosophy through conversations during adolescence, stayed with it because of a guy who talked about the philosophy of Paul Grice – a topic which eventually became one of his main areas of research. He taught for several years at the universities of Berne, Lucerne, and others, and is now teaching at the University of Innsbruck. He is the author of introductions to philosophy, to philosophical methodology, and to critical thinking – all in German. He hopes to write more.

**Thorsten Philipp** studied Romance languages, art history, and political science in Munich, Aix-en-Provence, Vienna, and Brescia. As an advisor to the presidium at TU Berlin, his mission is to promote transdisciplinary learning. A lecturer with a non-disciplinary agenda at various universities, such as the University of Freiburg, Thorsten explores pop music as a sounding board for sustainability communication. Background music by Dat Adam, Monolink, PNL, Tommy Guerrero, and Nils Petter Molvær accompanied him while working on this handbook.

**Roland Postma** is a geographer, storyteller, and professional video-maker. He has been researcher, director, and editor-in-chief of a number of leading programs for Dutch National Television for children and series about science and nature. He also gives on-location and online training courses to students, and public and private organizations. Roland's emphasis is on telling stories with content that matter: Stories that captivate the viewers in such a way that they are willing to listen to the message.

**Monique Potts** is a learner, thinker, teacher, mother, and healer whose research focuses on understanding resilience and experiential learning for young people in the context of uncertain futures and climate disruption. Her background is in public media, education, and digital media. Living on Gadigal land of the Eora Nation in the inner west of Sydney, Monique has a long and checkered work background, including dressing up as a koala to collect money for wildlife, being a clown, and fire-eating.

**Susanne Pratt** is a transdisciplinary artist, educator, and researcher working at the intersection of foresight, environmental change, and transdisciplinary learning. Her recent research focuses on participatory arts-led means of reimagining practices of care, multi-species relations, and regenerative futures. She grew up on a kiwifruit orchard in Aotearoa and currently lives and works in Australia on unceded Gadigal Land.

**Baiba Prūse** is research associate at Vrije Universiteit Amsterdam, where her work involves discussions regarding public engagement in research, food systems, and local ecological knowledge aspects. She is also a coach for the course on interdisciplinary community service learning and is eagerly following the student knowledge exchange on the course topics. Collaboration is the motto of Baiba's approach to life and this process is directly ref lected in her work. Part of her contribution to this book received funding from the European Research Council under the EU Horizon 2020 research and innovation program.

**Sanjeet Raj Pandey** is a skilled full-stack software developer and graduate in computer science. As a research associate in the service-centric networking at TU Berlin, he teaches in the field of web-technology and his research is focused on Web3 for privacy in digital systems. Sanjeet is the head of software engineering in the sustainability education startup *PROSUMIO* and a core member of the *Sustainable Handprint* project lab at TU Berlin. Sanjeet loves to use fast carsharing with his friends.

**Eliana Rodrigues** is a dedicated researcher in the areas of Ethnobotany and Ethnopharmacology at the Federal University of São Paulo. She coordinates the activities of the Center for Ethnobotanical and Ethnopharmacological Studies. Eliana has dedicated her studies to the area of traditional use and management of medical plants, from the perspective of participatory ethnobotanism. She loves making mosaics on the walls of her house.

**Katie Ross** is curious about ways to facilitate change towards more beautiful, equitable futures. As a transdisciplinary writer and facilitator at *Soils for Life*, and an adjunct fellow at the University of Technology Sydney, she integrates transformative learning processes into collaborative transdisciplinary action learning. One of the best perks in Katie's role is meeting incredible farmers and experiencing their delicious food, grown in living soils, brimming with the nutrients we need.

**Sara Roversi** is an author, entrepreneur, public speaker, and activist. She has been a serial entrepreneur since 2003, formulating multiple for-profit and not-forprofit ventures. In 2010, Sara shifted her focus onto sustainable food systems to increase awareness and understanding through education, research projects, and innovation challenges. She loves connecting and working with people and organizations on food systems transformation and radical change.

**Alexander Ruser** is professor of Sociology and Director of the Centre for Digital Transformation at the University of Agder in Kristiansand. His research focuses on the social role of expertise and the impact of scientific knowledge on environmental discourses and climate politics. Alex owns too many guitars and always keeps an emergency half-acoustic in his office.

**Olivia Rütti-Joy** is a senior researcher at the Université de Fribourg and the research assistant of the rector at the St. Gallen University of Teacher Education. Building on her background in Media Studies, English Literature, and English language teaching, she now pursues research in foreign language teaching and learning, applied linguistics, language testing, educational assessment, and teacher education. If she's not behind her screen, Olivia is most likely somewhere in the mountains.

**Lyda Patricia Sabogal-Paz** is an associate professor at São Carlos School of Engineering, University of São Paulo. Her research is centered on selection, design, and assessment of drinking water treatment for small and medium-sized communities. She has a strong record on water research with a focus on technology assessment and economic evaluation. Brazilian and United Kingdom research councils have been financing her research. Lyda enjoys traveling and discovering new cultures.

**Jennifer Schluer** is an assistant professor for Teaching English to Speakers of Other Languages and Advanced Academic English at Chemnitz University of Technology. As an applied linguist and teacher educator, she specializes in digital teaching and digital feedback methods as well as in language awareness, multilingualism, and culture learning. Jennifer can be a cat or cow and a dog or dolphin, but has never turned into a camel or crow on her yoga mat so far.

**Marco Schmitt** is a sociologist with a strong background in network research and theory working at the Chair of Sociology of Technology and Organization at RWTH Aachen University. He has worked in a variety of transformation and innovation projects involving public administration, industry, politics, research, and civil interest groups. For Marco, transdisciplinary thinking is the most striking success factor in enabling change, but so hard to achieve.

**Stephan Schmidt-Wulf fen** is senior professor for Art Theory at the Free University Bozen-Bolzano. As the head of the Academy of Fine Arts Vienna – among others – for many years he developed university programs in art and design. His research focuses on artistic practice and its history since the early 20th century.

**Tobias Schmohl** is passionate about the transformative potential of learning. He believes that by fostering critical thinking we can empower individuals to make positive impact on the world around them. Tobias has spent years exploring the intersection of higher education and education research to better understand how to create meaningful learning experiences. His children's love for inquiry-based projects, exploring their passions, inspired him to pursue progressive and avant-garde teaching and learning methods.

**Erika Solimeo** is an environmental legal specialist. She focused her earlier career on global water policy and the human right to water, which evolved toward an analysis of marine conservation and ocean ecosystems. At the Future Food Institute in Rome, she directly followed topics such as nutrition, climate change, earth regeneration, Mediterranean diet, water safety, and security. Erika has always been known in the family as Don Chiscotte for having a soft spot for the hard causes.

**Alexander Sonntag** works as a research assistant at the Living Labs Incubator of the Human Technology Center at RWTH Aachen University. He is currently participating in the project *TRANSFER* in which he is observing mechanisms of knowledge transfer in Living Labs. Alexander Sonntag studies Governance of Technology and Innovation at RWTH Aachen University.

**Anja Steglich** is a landscape architect and consultant for urban transformation and transfer. She has many years of experience in transformative research and transdisciplinary teaching. Anja coordinates the development of TU Berlin's *Stadt-Manufaktur*, a platform and center for Living Labs in the Executive Board of the TU of Berlin. Her work focuses on urban transformation, water-sensitive design strategies, and productive infrastructure development. Anja develops stage designs and learns from dance.

**Sadaf Taimur** is a researcher exploring how to create effective learning processes and environments for sustainability that lead to individual and organizational transformation. She has researched transformative learning approaches to improve pedagogies in Higher Education for Sustainability at the University of Tokyo. In addition, Sadaf is interested in reading non-fiction and exploring different perspectives and cultures.

**Wing-Shing Tang**'s research interests focus on experimenting mainstream urban thinkers with socio-historical processes and patterns of urban development in Hong Kong, mainland China, and India, and, concomitantly, formulating new ontology, epistemology, and methodology for this cause. Teaching high-school students on the spatial dialectics of injustice had been experimented with in Hong Kong by taking them around urban communities on local tours.

**Ewald Terhart** is professor Emeritus in the Institute of Educational Science at the University of Münster. His academic fields are research on teaching and general didactics, as well as teacher professionalism and teacher education. He serves on the editorial boards of several academic journals in these research areas. Due to his expertise in teacher education, he has been a member or chair of several commissions on the evaluation and reform of teacher education in Germany and other European countries.

**Axel Timpe** is a landscape architect and research and teaching associate at RWTH Aachen University's Institute of Landscape Architecture. He is coordinating *H2020 IA proGIreg*, the transdisciplinary green infrastructure research project *CoProGrün*, and had a coordinating role in *COST Action Urban Agriculture Europe*. Axel's research focus is on green infrastructure, nature-based solutions, and urban agriculture and their co-production with local stakeholders. In addition to design studio teaching, Axel developed the edX MOOC *Nature-Based Urban Regeneration.*

**Peter Troxler** is a research professor at Rotterdam University of Applied Sciences. He studies how digital technologies enable new ways of designing and manufacturing and challenge and inf luence incumbent practices in industry and education. Peter has worked internationally in the energy industry, as a design consultant, and in higher education. He enjoys photographing weird inner-city moments and sharing them with the world.

**Valentin Unger** is a senior researcher at St. Gallen University of Teacher Education. His research interests stem from his dual role as a teacher and researcher. Valentin's research focuses on the empirical study of educational learning processes, especially in language subjects, research on the teaching profession, and research on the impact of crises on education. Besides his very cool research job, he has an even cooler hobby: classical music.

**Karen van den Berg** is professor of Art Theory and Curating at Zeppelin University in Friedrichshafen, and head of the university's arts program. Research and fellowships have taken her to international universities and research institutions, including the Chinati Foundation in Marfa, IKKM Bauhaus University in Weimar, and the Department of Comparative Literature at Stanford University. Karen's research focuses on art, politics, and activism; artistic episteme and studio practice.

**Laura Verbrugge** is an environmental scientist aiming to improve collaborations across disciplines and especially between the natural and social sciences. She developed educational material about invasive alien species for Dutch (vocational) schools and coordinated communication and monitoring campaigns between government and stakeholder organizations. Currently, Laura works as a grant writer at Aalto University.

**Matteo Vignoli** is building the future through research, education, and business all centered on the application of design thinking experimenting with the world-renowned *Reggio Approach* in higher education. He is associate professor at Università di Bologna, teaches in several master programs and business schools, and works on innovation projects with global organizations. According to Matteo, involving the client and future user during co-design sessions is the secret sauce of the world's most visionary companies.

**Ulli Vilsmaier** grew up in the Austrian Alps and has a background in Geography. She conducts and studies inter- and transdisciplinary research and higher education. Her work is based on a responsive logic and emphasizes complementarities between different ways of knowing, acting, and being. Ulli accompanies teams of researchers and educators in transforming research and higher education towards inter- and transdisciplinarity. While her professional life allows her to travel and learn with colleagues from different world regions, she loves to spend her spare time mountaineering in the Alps.

**Maximilian Voigt** works for the Open Knowledge Foundation Germany on the topics of Open Education and Open Hardware. He is focused on the potential of open technologies and infrastructures for the circular society. Maximilian is a board member of the Association of Open Workshops – the German umbrella organization of makerspaces – and studied engineering, journalism, and the philosophy of technology. When he is not writing, he sings in a choir, repairs things, or sails the Baltic Sea.

**Johannes Vollbehr** is an experienced carpenter and purpose entrepreneur. At TU Berlin, he studies vocational education, being a scholar in the professional talents program of the German Federal Ministry of Education and Research. Johannes works as head of business development for the sustainability education startup *PROSUMIO*. In 2020, he initiated and facilitated the project lab *Sustainable Handprints* together with his colleagues at TU Berlin. Johannes loves to ride his bike on Berlin's roads, being part of the critical mass.

**Hildrun Walter** is a researcher at the University of Graz with her research interests in science communication at the interface to science education. She is particularly dedicated to evaluating communication programs in order to assess their potential to evoke emotions and foster scientific interest. She is concerned with the ref lection of open science practices and participatory approaches in research. Like a herb lady, she loves to spice up the vegetables from the garden in colorful dishes.

**Christine Wamsler** is professor at Lund University Centre for Sustainability Studies and Director of the Contemplative Sustainable Futures Program. She is an internationally renowned expert in sustainable development and associated (material and cognitive) transformation processes, with 25 years of experience, both in theory and practice. Christine has led many international projects and published more than 200 papers and book chapters on these issues. She draws inspiration from nature and her two children, who help her daily take better care of spiders, f lowers, and the world at large.

**Hendrik Weiner** researches urban transformation and co-design processes and develops concepts and projects for the collaborative development of urban spaces. He organizes transdisciplinary working and teaching settings to connect practice and theory, students with citizens, universities with cities. He teaches at the Brandenburg University of Technology Cottbus-Senftenberg and at the Otto-von-Guericke-University Magdeburg and runs the office *raumdialog*. Hendrik enjoys bicycle tours with his two children.

**Annika Weiser** is coordinating the sustainability-focused responsibility module for all first-year students at Leuphana University Lüneburg. With a background in transdisciplinary sustainability research, she has long been working – and teaching – in various transdisciplinary research projects such as *Lüneburg 2030+*. She invests large parts of her spare time in trying to grow, with varying success, the best pimientos de padrón north of the Alps.

**Christina West**, a geographer, philosopher, and artist, founded the *Energy Academy* in DELTA, an experimental real-world lab of the energy transition, for the University of Applied Sciences Darmstadt. She is Chairwoman of Urban Innovation-Rethinking City. At Heidelberg University, she headed two real-world labs, was interim professor for the Didactics of Geography at Koblenz-Landau University, and visiting scholar at EUAP Hong Kong Baptist University. Her favorite mode is exploring the world while dancing.

**Ulrike Weyland** is a professor in the Institute of Educational Science at the University of Münster. Her research focuses on teacher professionalism and teacher education, competence modeling and measurement, career orientation, and digitization, with a special focus on vocational education in the health care professions and their educational personnel. She serves on the editorial boards of academic journals in these research areas. In addition, she has served on various commissions as an expert on issues related to the design of internships in teacher education.

**Mary Whalen** was the managing director of EPIZ – Center for Global Education in Berlin until 2019. Presently, her work focuses on international dialog forums on the implementation of Global Education, fostering a critical discussion of Global Citizenship Education in European civil society, and biographical approaches to feminist civic education. She divides her time between the magical Wet Tropics in Queensland and the pulsating diversity of the city of Berlin.

**Claudia Wiepcke** studied economics, Slavic studies, and politics at the University of Münster, where she also received her doctorate. She worked as a research assistant at TU Dortmund and has been professor of Business and Economic Education since 2008. Claudia researches and teaches at the University of Education in Karlsruhe. She is interested in art and creates content about art and museums.

**Johannes Wildt** studied Psychology, Pedagogy and Sociology. Since 1970 he has worked as a professional educationalist and academic developer at different universities, mainly at TU Dortmund, heading its Center for Teaching and Learning. Johannes put his main emphasis on innovative learning concepts like project-oriented studies and transformative learning, participatory curriculum development, learner-centered further education, and consulting. He likes to dance at a lot of weddings.

**Tyson Yunkaporta** is an academic, an arts critic, and a researcher who is a member of the Apalech Clan in far north Queensland. His work focuses on applying Indigenous methods of inquiry to resolve complex issues and explore global crises. He carves traditional tools and weapons and also works as a senior lecturer in Indigenous Knowledges at Deakin University in Melbourne.

#### 422 Handbook Transdisciplinary Learning

**Eike Zimpelmann**'s research is mainly focused on the fields of vocational teacher education and the subjective perception teachers develop regarding their academic disciplines and their work. Further, he is interested in vocational didactics, education policy, and education for sustainable development. Eike is passionate about understanding how people construct their reality. Probably, that's why he likes spending his time with roleplaying games where he can try out behaving like other people.

 Handbuch Transdisziplinäre Didaktik

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 Andreas Germershausen, Wilfried Kruse Ausbildung statt Ausgrenzung Wie interkulturelle Öffnung und Diversity-Orientierung in Berlins Öffentlichem Dienst und in Landesbetrieben gelingen können

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 Andreas de Bruin Mindfulness and Meditation at University 10 Years of the Munich Model

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# Pädagogik

 Andreas de Bruin Achtsamkeit und Meditation im Hochschulkontext 10 Jahre Münchner Modell

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 Holger Angenent, Jörg Petri, Tatiana Zimenkova (Hg.) Hochschulen in der Pandemie Impulse für eine nachhaltige Entwicklung von Studium und Lehre

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 Ivana Pilic, Anne Wiederhold-Daryanavard (eds.) Art Practices in the Migration Society Transcultural Strategies in Action at Brunnenpassage in Vienna

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**1. Introduction**

Structural materials for nuclear fusion applications will have to withstand a very hard environment in the future reactor. Very energetic neutrons which will produce displacement cascades, transmutation into light atoms, nuclear activation and nuclear heating will be produced during operation. These neutron reactions, along with stresses produced by the reactor weight itself, and cyclic loads due to thermal and electromagnetic stresses draw a very harsh panorama for these materials [1–4].

Neutrons from nuclear fusion reaction induce elastic and inelastic nuclear reactions. The very first atoms from the matrix displaced by the incident neutron are denominated Primary Knock-on Atoms (PKA) spectrum, and this PKA spectrum is generated by both elastic and inelastic reactions. Generally speaking, depending on the isotope considered, the larger contribution to the total displacement is due to the elastic reactions (90%). However, atoms initially displaced for their lattice site

by neutrons (PKA spectrum) will induce elastic reactions, which produce additional displacement damage (displacement cascades) because they eventually will produce large collision cascades, since the secondary atom impacted by the PKA has enough energy to move a third one and so on.

Therefore, this PKA spectrum will be responsible to deposit the displacement damage in the material. On the other hand, if the neutron produced an inelastic reaction, an induced transmutation by neutron collision will be produced, generating light atoms as helium and hydrogen until hundreds of atomic parts per million (appm) in the whole life service of the reactor along with PKAs depending on the energy deposited [5].

Regarding helium atoms, one of the main issues in terms of structural material degradation is the nucleation and growth of He bubbles at grain boundaries which would produce a reduction of service lifetime. This degradation comes due to helium atoms produced by transmutation reaction of Fe; around 4 MeV of neutron energy may produce the following reaction generating alpha particles 56Fe (n.a) 53Cr [6]. It is well known that the combination between helium atoms and vacancies is very energetically favorable, so it will form eventually He bubbles. For that reason a deeper understanding of the effect of those bubbles in the evolution of microstructure and further degradation of mechanical properties are critical. However, several parameters have to be controlled and studied to determine properly the evolution of He bubbles during irradiation such as temperature, He production rate, displacement rate, and dose (accumulation of He).

Candidate materials for being used as structural materials are reduced activation ferritic martensitic (RAFM) steels, since they show a high resistance to irradiation damage, higher thermal conductivity, good corrosion resistance, and good liquid metal compatibility than austenitic steels. Several studies have shown that grain boundaries or phase boundaries may also act as sinks for radiation-induced point defects and the cluster formed during irradiation [7].

On the other hand, collision cascades known as accumulation of atoms displaced will form a complex form of Frenkel pair defects such as interstitial clusters which may turn into large dislocation loops or vacancy-type voids. Those irradiationinduced defects act as barriers to the dislocation movement, so they produce a significant hardening and hence a ductility reduction.

Neutron irradiation is not the most used technique to irradiate materials since the nuclear activation of the specimens makes necessary to have available hot cells to characterize the samples. On the other hand, nowadays there is no facility to emulate neutron fusion environment; for that reason ion beam irradiations are used to emulate neutron irradiation, of course, having into consideration the main differences such as shallow depth of irradiated material, elevated dose rate, and, clearly, not transmutation.

Current neutron sources with an energy spectrum typical of fusion reactions (14 MeV neutrons) are far from the fluence expected in a fusion reactor, and they are only useful for a few cases involving functional materials not exposed to high radiation doses [8, 9]. Therefore, a common approximation to test fusion materials consists of using ion irradiation to emulate the effects of neutron irradiation [10]. Ion irradiation can yield higher damage rates generating negligible activation levels in the irradiated samples at a reduced cost than other approximations to the problem like fission reactor irradiations. These elevated dose rates are very interesting to obtain samples submitted to an accelerated damage aging that would take several years to be achieved by fission irradiation. It is necessary to consider, however, that these accelerated tests may be driven by aging mechanisms very different from the real processes taking place under the low damage rate produced by real fusion conditions.

**17**

evolution.

**2. Accelerator description**

*Ion Beam Experiments to Emulate Nuclear Fusion Environment on Structural Materials…*

thicknesses in order to achieve different mitigations of the beam energy [11].

As stated before, to date, most of the studies on these structural materials have been focused on material behavior as a function of different parameters as irradiation dose, particle energy, and irradiation temperature, among others [12]. However, nextstep fusion devices, such as the International Thermonuclear Experimental Reactor (ITER) [13] and demonstration power plant (DEMO) [2, 14, 15], are magnetically confined devices, and the performance of the materials under reactor conditions when high magnetic fields are present is still unexplored. Besides, theoretical predictions suggest that magnetism can be a non-negligible factor in defining the defect properties induced by He irradiation or in determining the atomic distribution in FeCr alloys [16, 17]. Material microstructural properties can be modified by defect propagation due to irradiation. It is considered that such propagation may be affected by external magnetic fields, as recently pointed in Ref. [18]. For this reason, more detailed experimental knowledge of structural materials is sought, in particular with regard to mobility and clustering, as well as helium and hydrogen accumulation in reactor conditions. Thus, expanded experimental knowledge of structural material response to irradiation

In this chapter, the development of a new sample holder located at a vacuum chamber of standard (STD) irradiation line at CMAM is presented. Preliminary results have been obtained in this system for a series of FeCr alloy (10–15% Cr),

field produced by a permanent magnet (0.5 T) at STD irradiation line at CMAM. As sometimes, experiments are costly even with ion beams and are not always available; modeling is one of the key tools to predict long-term defect evolution. However, irradiation damage predictive simulation is still under development and needs many experimental results as inputs to validate their simulations. So, sometimes, irradiation experiments are headed not only to study the degradation of complex microstructure materials such as RAFM candidates but to obtain results of irradiating very simple and pure such as very high pure iron, iron chromium model alloys in order to study the effect of certain alloying elements on irradiation defects

Electrostatic accelerators over the world present a variety of shapes and sizes and can be classified attending to different factors. The fundamental features that characterize a DC accelerator are mainly three: the type of particle that can accelerate, the beam current and the maximum kinetic energy achievable. These defining

In this section, we describe the fundamentals of a 5 MV Tandetron delivered by high-voltage engineering (HVE) for ion beam analysis (IBA) and ion beam modification of materials (IBMM) at operation in CMAM in the Universidad Autónoma de Madrid (Spain) [19]. In **Figure 1** it is possible to observe (a) plan view of the

parameters determine the subsequent research field of application.

ions under the effect of the magnetic

Another important difference that must be considered is the low ion penetration in the material (typically several microns for heavy ion energy in the range of 1–20 MeV) compared to the tenths of centimeters that a neutron can travel before interacting with a material nucleus. Since the particle accelerators have a fixed energy, a selective filter or energy degrader system is required to obtain an almost uniform spectrum of beam energies to allow a particle implantation in the most controlled possible way. The thickness of the filter determines the final energy of the beam, so to obtain a certain energy spectrum, it has been thought of a multifilter revolver-type system, consisting of a design in the form of a rotating daisy, with peripheral aluminum foils of different

*DOI: http://dx.doi.org/10.5772/intechopen.87054*

under magnetic fields has become critical.

alloy specimens irradiated with 1 MeV Fe+

### *Ion Beam Experiments to Emulate Nuclear Fusion Environment on Structural Materials… DOI: http://dx.doi.org/10.5772/intechopen.87054*

Another important difference that must be considered is the low ion penetration in the material (typically several microns for heavy ion energy in the range of 1–20 MeV) compared to the tenths of centimeters that a neutron can travel before interacting with a material nucleus. Since the particle accelerators have a fixed energy, a selective filter or energy degrader system is required to obtain an almost uniform spectrum of beam energies to allow a particle implantation in the most controlled possible way. The thickness of the filter determines the final energy of the beam, so to obtain a certain energy spectrum, it has been thought of a multifilter revolver-type system, consisting of a design in the form of a rotating daisy, with peripheral aluminum foils of different thicknesses in order to achieve different mitigations of the beam energy [11].

As stated before, to date, most of the studies on these structural materials have been focused on material behavior as a function of different parameters as irradiation dose, particle energy, and irradiation temperature, among others [12]. However, nextstep fusion devices, such as the International Thermonuclear Experimental Reactor (ITER) [13] and demonstration power plant (DEMO) [2, 14, 15], are magnetically confined devices, and the performance of the materials under reactor conditions when high magnetic fields are present is still unexplored. Besides, theoretical predictions suggest that magnetism can be a non-negligible factor in defining the defect properties induced by He irradiation or in determining the atomic distribution in FeCr alloys [16, 17]. Material microstructural properties can be modified by defect propagation due to irradiation. It is considered that such propagation may be affected by external magnetic fields, as recently pointed in Ref. [18]. For this reason, more detailed experimental knowledge of structural materials is sought, in particular with regard to mobility and clustering, as well as helium and hydrogen accumulation in reactor conditions. Thus, expanded experimental knowledge of structural material response to irradiation under magnetic fields has become critical.

In this chapter, the development of a new sample holder located at a vacuum chamber of standard (STD) irradiation line at CMAM is presented. Preliminary results have been obtained in this system for a series of FeCr alloy (10–15% Cr), alloy specimens irradiated with 1 MeV Fe+ ions under the effect of the magnetic field produced by a permanent magnet (0.5 T) at STD irradiation line at CMAM.

As sometimes, experiments are costly even with ion beams and are not always available; modeling is one of the key tools to predict long-term defect evolution. However, irradiation damage predictive simulation is still under development and needs many experimental results as inputs to validate their simulations. So, sometimes, irradiation experiments are headed not only to study the degradation of complex microstructure materials such as RAFM candidates but to obtain results of irradiating very simple and pure such as very high pure iron, iron chromium model alloys in order to study the effect of certain alloying elements on irradiation defects evolution.

Electrostatic accelerators over the world present a variety of shapes and sizes and can be classified attending to different factors. The fundamental features that characterize a DC accelerator are mainly three: the type of particle that can accelerate, the beam current and the maximum kinetic energy achievable. These defining parameters determine the subsequent research field of application.


*4.2. Geomorphological Setting of the Coroglio-Trentaremi Sea Cliff*

Geomorphological analysis has been addressed to the recognition of the predisposing factors that may cause landslides and cliff retreat, and the results are reported in the geomorphological map of Figure 6. The study area is characterized by high sea cliffs that are prone to retreat because of both their stratigraphical setting (alternation of poorly cemented pyroclastics and tuffs) and the occurrence of a dense net of sub-vertical fractures in the tuffaceous deposits.

**Figure 6.** Geomorphological map of the Coroglio-Trentaremi area.

The geomorphological map of Figure 6 highlights the diffuse presence of landslides, which have also been reported on Google Earth 3D view (Figure 7), where they have been classified according to the type of movement and the type of material involved. Moreover, flow-like landslides (yellow dots in Figure 7) affect the sectors of the Coroglio-Trentaremi sea cliff where post-NYT pyroclastics outcrop and with slope angle between 45◦ and 70◦, whereas rock-falls (red dots in Figure 7) occur in the NYT with slope angle between 70◦ and 90◦. We also mapped in Figure 7 the caves at the base of the sea cliff, which are mainly due to anthropic activities for the NYT extraction. The collected data clearly suggest

that the main factors influencing the types of landslide are lithology and slope degree (Figure 8). Flow-like landslides remain confined to the upper part of the cliff, where soft unconsolidated deposits rest on top of the NYT formation. The presence of hard/soft rock-types contacts along the sea cliff may also increase the possibility of detachment of rock falls because of selective erosion. Also, the presence of caves (both natural and artificial) plays a crucial role in the evolution of the sea cliff by identifying sectors more prone to instability because of the presence of vacuums that may enhance sea erosion at the base of the cliffs.

**Figure 7.** (**A**) Google Earth 3D views of the Coroglio-Trentaremi coastal sector. (**B**) Detail of the Coroglio sea cliff. (**C**) Detail of the Trentaremi sea cliff.

**Figure 8.** Main predisposing factors controlling cliff stability along the Posillipo promontory. Geological cross-sections are modified from Figure 5. Vertical lines in the NYT indicate sub-vertical fractures affecting this unit.

In Figure 9 we show some photos of the sea cliff that allow us to appreciate the size of the landslide bodies, which are up to some hundreds of cubic meters. Landslide bodies of different ages may also be appreciated because of the lack of vegetation, which testify for the high frequency of rock falls along this sea cliff. The tuffaceous deposits of the NYT are also locally affected by a very dense fractures network that shapes the sea cliff profile. Fractures are in many cases open, thus suggesting the possible occurrence of a landslide event in the near future (Figure 10).


*3.7. External Influencers of Resilience*

External influencers of resilience refer to the individuals who influenced them growing up and, in adult situations, those who nurtured their self-respect and the strength to confront disrespectful situations without allowing such situations to harm their professional advancement. More than half (58%) of the participants stated that the significant people who influenced them were women. These included their mothers, grandmothers, aunts, and/or women in the workplace. The remaining women (42%) indicated that the significant people in their life who influenced them were male. These included fathers, grandfathers, other male relatives, and men in the workplace.

## *3.8. Internal Forces Influencing Success*

Internal forces refer to motivational forces that are inherent to the self or the task. For the participants whose motivators were less conscious, the analysis suggested that they were primarily related to people they knew and circumstances that occurred early in their lives. These associations served as an unseen force that kept the participants motivated to persist in pursuit of their goals when faced with disrespect.

These early influences in their personal lives informed their perception of gender roles and gender expectations. For example, one participant's father was a strong influence because he essentially believed that women should not be molded to be a certain type, even though she grew up in a country where women were expected to play the role of homemaker. Another participant grew up in a small town in the South, and her grandfather taught her how to drive when she was six years old and not tall enough to see over the steering wheel. That experience became a reminder later in life when she found herself in difficult circumstances and was unable to see how a successful outcome was possible. For example, she married at a young age, divorced, and was left to raise a child as a single parent by the time she was 18 years old.

One participant did not remember consciously setting goals, yet she recalled two circumstances that stood out in her memory as an adult. The first was when she was a young girl. The women in her family either worked as grocery store clerks or as housekeepers cleaning other people's homes, except for one aunt who made a big impression on her. Growing up in the Midwest she remembers her aunt's company flying her to the East Coast for meetings during a time when few women worked in organizations beyond clerical workers. She had opportunities to visit her aunt and admired the lifestyle that she attained professionally.

The second circumstance was learning how to challenge herself and take risks, a skill that proved valuable as an adult. Because both of her parents worked, she and her brother were without adult supervision when they returned home from school, often referred to as latchkey kids. She was the oldest and therefore in charge. Her brother and his friends did not allow her to play with them. The boys would mainly play softball and girls could not play. Jeanie said this was her earliest remembrance of disrespect. She found ways to entertain and challenge herself by taking risks without any awareness of putting herself in danger. These experiences helped her develop characteristics and take risks that helped her succeed professionally.


**1. Introduction to menopause**

Menopause is a normal physiological and natural event. The WHO defined menopause as permanent cessation of menstruation due to loss of ovarian follicular activities at the end of reproductive life. Menopause before the age of 40 years is considered as premature menopause or premature ovarian insufficiency.

The average age of menopause is 51 years, which is influenced by both genetic and environmental factors. Due to increased life expectancy of women, postmenopausal years cover more than one third of the total female life span.

Though natural events of estrogen deficiency of menopause herald a variety of potential problems that can affect the quality of life, specific concerns include subjective symptoms such as vasomotor instability, i.e., hot flushes, psychological and psychomotor disorders, menstrual irregularities, vaginal dryness, genitourinary dysfunction, and osteoporosis which have implications for longterm health [1–6].

So doctors and menopausal women both are interested in and deserve an understanding of the symptoms and the basis for therapeutic recommendation aimed at relieving symptoms and reducing subsequent health risks.


**2. Methods**

### *2.1. Literature Review*

Starting from several recent reviews of oil palm in Indonesia, we used a 'snowball' method to identify more recent papers citing these sources and followed up on the citation network thus established to document a synthetic view on the various sub-topics.

#### *2.2. Maps*

For a more detailed analysis of the different forest designations within the forest zone and for the time frames of expansion within the forest zone, we compiled data for Jambi, a province in Sumatra around the Equator, and West-Kalimantan. The two provinces were selected to represent the two islands where oil palm is major (Sumatra and Kalimantan) while they had different historical settings on traditional land use of agroforest and its dynamics. Availability of the data also determined the choice of the two provinces. We traced the development of oil palm and agroforestry areas in the 2000–2020 period in each of the Forest-zone categories and sought the trajectories of changes and observed interlinks between oil palm, forest and agroforestry. Where the data were available, we incorporated the other major agroforestry tree-crops; otherwise, we utilized the common class of 'mixed agricultural tree-crops' mapped in most datasets. The following dataset was utilized for the analyses (Table 1).

### *2.3. Public Consultation*

In a webinar in September 2020, attended by 374 participants, the issue of overlap between Indonesian forest estate and oil palm was highlighted and a number of the basic data presented; the questions and discussions formed the start of this manuscript. Specific aspects discussed are listed in Appendix A at the end of this manuscript.

#### **3. Indonesian Context**

### *3.1. Forest Legality*

While efforts to agree on a forestry law during the Colonial period stranded [36], the postindependence (1945) constitution clarified that all the country's resources were for the benefit of the Indonesian people—with subsequent debate on the degree to which the Government of Indonesia has to respect prior claims of customary communities ('Masyarakat Hukum Adat') [37]. The Basic Agrarian Law of 1960 that recognizes colonial period documents as a basis for valid rights to land and the Forestry Law of 1967 was considered to be complementary but had gaps between them [38]. The 1999 revision of the

Forestry Law specified that state ownership claims within the designated 'forest zone' ('Kawasan Hutan') required completion of a gazettement procedure (verifying that there are no valid pre-existing claims), which has been very slow to implement [39], leaving doubts on the legality of government forestry policies that treat the Forest-zone as government-owned.

The total area of forest-zone lands in Indonesia (63% of total land area) is subdivided by primary function, as 'Production Forest' (68.8 M ha; 36.1% of the country), 'Protection Forest' (29.7 M ha; 15.6% of the country) and 'Conservation Areas' (22.1 M ha; 1.6% of the country) [40]. Logging is only allowed in the production forests, with further restrictions in part of the zone, and conversion to monocultural plantations for the pulp and paper industry in other parts. Although logging-based economic interests prevail in this zone, the production forests still have a recognized role in biodiversity conservation, carbon storage and maintenance of watershed functions. Most of the Protection Forest (the Indonesian term could also indicate '(watershed) protecting' forests) are on mineral soils and have been defined through a scoring system emphasizing slope and similar criteria for soil and water protection. For peatland areas, there are separate criteria for determining a Protection Function ('Fungsi Lindung') indication, based on peat depth and the peatland moratorium policy [41]. The total area of Protection Function in Indonesia's peatlands is 12.3 M ha [42].

Building on the specific example of the damar agroforests in Krui (West Lampung, Sumatra) where government ownership claims to forest-like vegetation could not be substantiated [43,44], it was realized that 'agroforests', of various specific histories and intensities of management, were included in the Forest-zone, either with Production or Protection Forest designations, but also claimed by local communities as existing before the Forestry law was formalized [45]. Since then, a government commitment to 'community-based forest management' and 'village forests' has allowed some conflict zones to be resolved, but much remains to be done [46,47]. Meanwhile, calls to redefine the Indonesian forest estate and get the boundaries of its Forestry Regulatory Framework and Agrarian rules right [12,48–51] were largely unheeded. Global interest in and country-level expectations of, new financing mechanisms through Reducing Emissions from Deforestation and (forest) Degradation (REDD+) created a new dynamic where issues of 'forest legality' obtained new relevance [52,53]. Indonesia's challenge to balance the new global environmental agenda on forest conservation, with the existing development deficits is part of a wider global pattern [54].

#### *3.2. Complexity of Frontier Situation*

In Southeast Asia's long engagement with global markets, cocoa, coffee, fast-growing trees, oil palm, rubber and shrimp have all had periods of rapid expansion or 'booms' when the region proved to be a low-cost producer in which land, labor, know-how, and market access could be rapidly mobilized [55]. The 'land grab' literature tries to answer key questions on who seeks to exercise control over land to grow export-oriented crops under boom conditions, how would-be producers navigate regulatory powers and market forces to gain control over land, and how booms differentially affect areas with secure and insecure land control relations.

Since the 19th century, commodities such as rubber [56], coffee [57] and cocoa [58] have boomed in specific parts of Indonesia, creating new 'forest frontier' conditions, involving local people, attracting investors to come in, but also stimulating people from other location to move in, spontaneously and/or in government-sponsored transmigration [59]. The relationships between spontaneous migrants, large-scale plantation companies, local communities and various branches of government have become complex in many locations [60–63]. Due to its location, boom crop production is closely associated with the issue of deforestation and environmental degradation [64].

Indigenous people and local communities (jointly described here as IP/LC) in forest frontier areas have had a long tradition of a 'dual economy' [65] where food security continued to depend on swiddening, while cash-crop agroforestry (rubber, coffee, resin trees and now oil palm) provided a financial basis for their livelihoods [66]. Where the terms of trade were sufficiently favorable, staple food production could be 'outsourced' [67]. Accordingly, most of the oil palm grown by IP/LC, just not to say smallholders, has not been a direct cause of deforestation as they developed in a village environment of orchards, old rubber groves and swidden fallows. Smallholders also tend to use fertilizer sparingly, as they are unable to access subsidized fertilizer supplies that are monopolized by larger plantations [68].

While global policies and markets are often held responsible for accelerated deforestation in the tropics [69], local knowledge is generally assumed to lead to overall positive outcomes in matters of conservation [70,71]. Even in matters of primary forest conversion, local communities are usually presented as the best managers to reconcile conservation and development [69]. Increased attention for forest protection in the context of REDD+ may have increased pressure on converting agroforests outside the forest zone to become oil palm monocultures [72].

The Indonesian forest frontier is home to approximately 26 thousand villages (often defined as 'forest villages') and more than 37 M peoples, with some 18% still struggling to escape from poverty based on the national standard [73]. Most of the forest villages are also not formally registered yet, as nationally only 30% of villages are already registered, mostly in Java. They have no clear and defined boundary and are dominated by state forest land, with formal restrictions to use for crops to generate food or income. In such landscapes, boom crop production, such as oil palm, has taken place. Expansion of agriculture into the forest area, often following onto a logging phase that brought people and road access (however poor) into the forest zone, is considered because of these complexities, that for decades have remained unresolved.

#### *3.3. Total Oil Palm Area*

According to the most recent official figure, the oil palm area in Indonesia was 14.7 M ha in 2019 [74]. Several organizations have also mapped oil palm areas for different objectives and with a range of methods (Table 2). Bahktiar et al. [75] claimed a substantially larger area (16.8 M ha), by including areas cleared for oil palm but without stands recognizable by remote sensing yet. The lowest recent estimate was 11,530,000 ha [33], in a study that only included fully-developed stands. Time-series data of oil palm for Borneo were analyzed for forest loss or deforestation [76] and biodiversity impacts [77]. The breakdowns of oil palm areas varied, with one study differentiating 'industrial' and 'smallholder' oil palm [33], while another study [75] focused on oil palm areas within forest zone lands. Condro et al. [28] mapped major commodities including coffee and cacao, and obtained area estimates close to the data from the Ministry of Agriculture. Across Indonesia, the largest oil palm areas are in Sumatra and the second largest in Kalimantan, covering respectively 6.4 M ha and 4.9 M ha in 2018 [74], while another study [75] mentioned 10.5 M ha and 5.7 M ha, respectively, for these two islands. Oil palm is expanding in W and SE Sulawesi, and in Papua, but current areas remain relatively small.

The distribution of oil palm in Indonesia is uneven and strongly related to climatic conditions. In North Sumatra (Figure 2A), the province with the most even rainfall distribution and virtually

no dry season oil palm can reach up to 50% of the area at district (Kabupaten) level; elsewhere in lowland Sumatra and the southern half of Kalimantan it can reach up to 30% of the area, but in most of Indonesia, oil palm forms less than 10% of the landscape or is virtually absent. For Indonesia as a whole oil palm covers about 8% of the total land area. The fraction of oil palm under smallholder ownership (see below for the distinctions within this category) is approaching 50% for Sumatra, but half of that in most of Kalimantan (Figure 2B). The recent expansion of oil palm, indicated by relatively young stands, is evident outside of the areas that already have a large oil palm fraction (Figure 2C).

**Figure 2.** Maps on 2017 oil palm distribution at the district level in Indonesia, highlighting Jambi and West Kalimantan provinces; (**A**) Area fraction under oil palm; (**B**) Share of oil palm cultivated by smallholders; (**C**) Share of oil palm that does not yield yet as it is too young (usually less than three years old); Sources: Own maps, oil palm data from [79]; district boundary and area data from [80].

Several authors have quantified oil palm development within the forest zone in Indonesia [76,78]. Estimates vary from 2.5 [76] to 3.4 M ha [75]. This implies that 15–20% of Indonesian oil palms grow within the designated forest zone. The dataset of [75] allows some further exploration of the geographical patterns of Indonesia's Forest-zone oil palm (FZ-OP). The relative share in Indonesia's FZ-OP at the province level does not match shares in total oil palm production. With 31.5% of

Indonesian oil palm, the two provinces of Riau + C Kalimantan have 66.8% of its FZ-OP (Riau 20.7% OP, 42.1% of FZ-OP; C. Kalimantan 10.9% of OP and 24.7% of FZ-OP). With 41.2% of Indonesian OP, the rest of Sumatra has 24.0% of its FZ-OP; with 23.7% of Indonesian OP, the rest of Kalimantan has 7.7% of its FZ-OP and with 3.6% of Indonesian OP, Eastern Indonesia + Java have 1.4% of its FZ-OP. Across Indonesia, 2.96% of FZ-OP is designated as conservation area, 4.71% as (watershed) protection forest, 15.15% as production forest with restrictions, 45.4% as regular production forest, and 34.8% as production forest indicated for conversion. The total area of FZ-OP is 2.88 times the amount of production forest indicated as 'conversion forest' (planned, legal deforestation).

For further exploration of that pattern as well as to showcase the development of oil palm gardens as part of agroforestry pathways, we focused on two provinces, one each in Sumatra (Jambi ranked #7 in oil palm production and #5 in FZ-OP) and Kalimantan (W. Kalimantan, ranked #3 in oil palm production and #6 in FZ-OP). Both are outside the historical oil palm core area in N. Sumatra, but they were part of the expansion since the 1990s; the district-level presence of oil palm within these provinces varies from 0–30%. The two provinces have harmonized their Kawasan Hutan areas with the provincial planning (RTRWP) with ministerial decrees that legalized the status of 'Forest-zone lands.' Therefore, issues of agroforest and oil palm practices in these two provinces are not burdened by different interpretations of forest legality between the central government (MoEF) and the provincial governments.

#### **4. Oil Palm in the Forest Zones of West Kalimantan and Jambi**

#### *4.1. Data by Province and Forest Category*

The total area of Forest-zone lands, encompassing all Conservation Areas (National Park and forest reserves), Protection Forest and all Production Forest status (HP, HPT, HPK) in West Kalimantan is 8.1 M ha or 56% of the province area, while for Jambi it is 2 M ha or 43% of the province.

For West Kalimantan, agroforest area occupied 38% of all Production Forest status and 16% of Protection Forest areas [31], while according to [32], agroforest covered <10% (Table 3). Some of the agroforests in [32] are mapped by [31] as disturbed forest, and that was the main differentiating factor of forest and agroforest areas in the two maps. Major commodities of oil palm and rubber are negligible in West Kalimantan's Forest-zone lands, the highest being oil palm in Production Forest areas (4%) mapped by [28].

**Table 3.** Areas of agroforest and major tree crops in West Kalimantan and Jambi in 2018–2019.

<sup>+</sup> processed/reclassified for this paper, # utilized for further analyses, \* percentage lower than 1% of the respective forest-zone land category.

In Jambi, agroforest occupied 19% of the land with Production Forest status, and <10% for Protection Forest and Conservation Areas [31] (Table 3). Rubber and oil palm monocultures were <10% in all Forest-zone land categories in Jambi [28,33]. A breakdown of FZ-OP by elevation and forest category (Figure A1) shows most are below 100 m above sea level.

Taking the total amount of palm oil produced in each of the provinces as point of references, the likely source areas differ between the two provinces, and according to three data sources specified in Table 4, with 6–17% derived from the forest zone. Within the forest zone, the fractions derived from production forest are highest (even after correction for the total area), followed by protection forest and conservation areas.

**Table 4.** Likely source area of palm oil produced in West Kalimantan and Jambi according to three spatial data sources, expressed as %, assuming homogenous productivity per unit land.

*4.2. Data by Time Period—Land Cover Changes Involving Agroforest and Smallholder Oil Palm*

Agroforest in West Kalimantan was mostly as rubber gardens and *tembawang* (Dayak traditional land-use system) having been practiced for generations [81,82]. Inside the Forest-zone lands in West Kalimantan, the majority (76%) of 300,000 ha agroforest areas in 2019 was already agroforest in 2000, and only 11% was forest (Figure 3)

**Figure 3.** Land cover trajectory (2000) of 2019 agroforest in each Forest-zone class in West Kalimantan (analyzed from [31,32]).

The development of independent smallholder oil palm was closely linked to the conversions of the locally managed agroforest areas due to the lucrative oil palm market in the vicinity of the villages and the decreasing popularity of rubber due to its volatile price [82]. That trend is observed in the land cover trajectory of independent smallholder areas in West Kalimantan, i.e., 57% of which was agroforest in 2000 and 54% in 2009 (Figure 4). Only 13% and 6% of independent oil palm was a forest in 2000 and in 2009, respectively.

**Figure 4.** Land cover trajectories (2000 and 2009) of 2019 independent smallholder oil palm in each Forest-zone class in West Kalimantan (based on [31,33]).

For Jambi, agroforest was originally developed by local communities with rubber as the major crop introduced in the beginning of the 1900s during the Dutch period [56,82,83]. It dominated private lands (APL), but its growth reached the areas designated as Forest-zone lands. The 2018 agroforest in Jambi's Forest-zone lands was equally agroforest (44%) and forest (44%) in 2000 (Figure 5), proving the historical presence of this locally managed land use in state's lands.

**Figure 5.** Past land cover types of agroforest in Forest-zone lands in Jambi (analyzed from [31]).

Expectations of high profitability of conversion to oil palm attracted many agroforest rubber farmers in Jambi, also signifying the changes from food sufficiency to cash-cropping [84], in addition to the volatile price mentioned earlier. Independent smallholder oil palm in Jambi's Forest-zone lands was 39% agroforest and 15% plantations in 2009, while in 2000 it was 11% agroforest and 21% plantations (Figure 6). These demonstrate the development of independent smallholder oil palm in Forest zone lands involving agroforest and plantations, mostly rubber. Growth of oil palm also reached degraded areas, shown by 15% shrubs in 2000 and 34% in 2009 (Figure 6), which included peatlands in the lowland areas [85,86].

**Figure 6.** Land cover trajectories (2000 and 2009) of 2019 independent smallholder oil palm in each Forest-zone class in Jambi (based on [31,33]).

Agroforest that has long been managed by local communities has evolved in Forest-zone lands, with the highest proportions and areas in Production Forest status (Figures 4 and 6). With the long history, this land use had faced unresolved forest zone issues since before the 1999 Forestry Law (see Section 3.1) until now, under the *Kawasan Hutan* officiated in 2014 for the two provinces. Since the past decade, oil palm has emerged to become part of the dynamics of this local farming, including in Forest-zone lands. The data show that these dynamics mostly occupied the Production Forest status (Table 3), the class allocated to support various production functions. Looking at the 'predecessor' cash-crop of rubber as part of the ever-evolving mixed-crop agroforest land use [56,81,82], independent oil palm might grow similarly, spatially and or temporally, as part of community-based production functions in land with Production Forest status.


*3.2. Na Atom and O Atom Adsorption*

The adsorption behaviors of Sodium atom on both Mo (110) and Mo-Re (110) surfaces are investigated firstly. In the current calculations, the adsorption energy for the Na atom adsorbed on the Mo (110) or Mo-Re (110) surfaces is defined as:

$$E\_{\rm ads} = E\_{(Mo/Mo-Rc)-Na} - E\_{(Mo/Mo-Rc)slab} - E\_{Na} \tag{2}$$

Here *E*(*Mo*/*Mo*−*Re*)−*Na* is the total energy of the adsorbate–substrate system, *E*(*Mo*/*Mo*−*Re*)*slab* is the total energy of the clean Mo/Mo-Re surface, and *ENa* is the average energy of BCC Na. A negative *Eads* value indicates the attractive interaction between the adsorbate and the substrate. The more negative adsorption energy implies the stronger attractive interaction between the adsorbate and the substrate.

Figure 2 shows the Initial states and final states of Na adsorption Mo (110) and Mo-Re (110) surfaces. The adsorption energies and structural parameters of Na on Mo or Mo-Re (110) surfaces are given in Table 2. For the Mo (110) surface, the hollow site is the energetically most favored for Na adsorption and the corresponding energy is −0.51 eV. The Bridge site is second preferred for Na adsorption with the adsorption energy of −0.44 eV. The Top site is a stable one for Na adsorption, but the adsorption energy is only −0.35 eV. For Mo-Re (110) surface, all un-equivalent Top, Hollow and Bridge sites are considered for Na adsorption. For each type of adsorption site, only the initial and final sites with the lowest energy are collected and shown in Figure 2 and Table 2. Compared with the pristine Mo (110) surface, Mo-Re (110) surface provides stronger affinity to the Na atom. It is worth noting that the Na atom initially placed at the Bridge site moves towards the Re atom after the structure optimization, as can be seen in Figure 2f, and this configuration delivers the lowest adsorption energy of −0.60 eV. The adsorption energies of Na adsorption on the Top site and Hollow site of Mo-Re (110) surface are −0.43 eV and −0.56 eV, respectively. The average vertical distance between adsorbed Na atom and the top layer (*dNa*−*sur*) is also listed in Table 2. It is interesting to found that the Na adsorption energy is proportional to *dNa*−*sur f* (Figure 3). A shorter distance between the Na atom and the top layer indicates a stronger attractive interaction. Both energetical and geometric parameters indicate that the Re atom can strengthen the attractive interaction between Na and the Mo surface. The electronic structure is analyzed for understanding the effect of Re atom on Na adsorption. On the Mo (110) surface, the Na atom only interacts with Mo atoms in the upmost layer, as shown in Figure 4a. The Re atom can significantly affect the charge redistribution induced a by Na adsorption. As shown in Figure 4b, electrons from the Mo settled in the second atomic layer migrate to the first layer, resulting to great electron accumulation. In this case, the columbic attraction between the Na atom and the substrate is enhanced and lead to a lower adsorption energy.

**Figure 2.** Initial and final configurations of Na adsorption on Mo (110) and Mo-Re (110) surfaces. Snaps (**a**–**c**) show Na atoms initially placed at Top site, Hollow site and Bridge site of Mo (110) surface. Snaps (**d**–**f**) show Na atoms initially placed at Top site, Hollow site and Bridge site of Mo-Re (110) surface. Blue and green spheres represent Mo atoms in the first layer and the second layer. Yellow and purple spheres represent Re atoms and Na atoms, respectively.

**Table 2.** Adsorption energy of Na on Mo (110) and Mo-Re (110) surfaces. *Eads* is the adsorption energy, and *dNa*−*sur f* is the vertical distance between the adsorbate and the top layer of the slab model.

**Figure 3.** Na adsorption energy as the function of the average distance between the Na atom and the top layer of the substrate.

**Figure 4.** Difference charge density of Na adsorption at the hollow site of (**a**) Mo (110) surface and (**b**) Mo-Re (110) surface. The red isosurface represent the electron accumulation region, while the green isosurface represent the electron depletion region. The Re atom is located in the center of Mo (110) surface, as shown in Figure 1c.

The adsorption energies of O on Mo and Mo-Re (110) surfaces are also investigated in the present study (Table 3). The adsorption energy for the O atom adsorbed on the Mo/Mo-Re (110) surfaces is defined as

$$E\_{\rm ads} = E\_{\rm (Mo/Mo-Rc)-O} - E\_{\rm (Mo/Mo-Rc)slab} - \frac{1}{2}E\_{O\_2} \tag{3}$$

where *E*(*Mo*/*Mo*−*Re*)−*O* is the total energy of the adsorbate–substrate system, *E*(*Mo*/*Mo*−*Re*)*slab* is the total energy of clean Mo/Mo-Re surfaces, and *EO*2 is the energy of an isolated O2 molecule. The adsorption energy of a single O atom on the surface is always calculated to characterize the oxygen-substrate interactions for refractory materials, and the energy of an O atom is usually referenced to the half of the O2 molecule [35–37].

**Table 3.** Adsorption energy of O on Mo/Mo-Re (110) surface.

As listed in Table 3, The Hollow site is energetically preferred for O adsorption on the Mo (110) surface with the adsorption energy of −4.09 eV. It is worth noting that the O atom initially placed at the Bridge site will spontaneously move to the Hollow site after the structure optimization as shown in Figure 5c. The O atom can also be stabilized at the Top site, but the adsorption energy is only −2.80 eV. As with Na on Mo (110) surface, the shorter vertical distance between O atom and the substrate (*dO*−*sur f*) leads to a lower (more negative) adsorption energy. For the Mo-Re (110) surface, the Hollow site is also the most favored for O adsorption and the corresponding adsorption energy is −4.14 eV, which is even 0.05 lower than the adsorption energy of O at the Hollow site of Mo (110) surface. It is worth mentioning that all un-equivalent Hollow sites around the Re atoms are checked, and Figure 5 as well as Table 3 demonstrates configurations with the lowest energy. As with the pristine Mo (110) surface, the O atom initially placed at the Bridge site of the Mo-Re (110) surface will move to the Hollow site after the structure relaxation. In addition, the O atom can be stabilized at the Top site with a much higher adsorption energy of −2.82 eV. As with Na adsorption, the Re atom in the surface can also strengthen the attractive interaction between the adsorbed O atom and the Mo-based substrate.

**Figure 5.** Initial and final configurations of O adsorption on Mo (110) and Mo-Re (110) surfaces. Scheme 110. surface. Snaps (**a**–**c**) show O atoms initially placed at Top site, Hollow site and Bridge site of Mo (110) surface, while snaps (**d**–**f**) show O atoms initially placed at Top site, Hollow site and Bridge site of Mo-Re (110) surface. Blue and green spheres represent Mo atoms in the first layer and the second layer. Yellow and red spheres represent Re atoms and O atoms, respectively.

#### *3.3. Impact of O on Na Adsorption and Diffusion*

O is the key impurity in liquid metal for the high-temperature heat pipe. The impact of pre-adsorbed O on Na adsorption behavior is also investigated. The configurations of pre-adsorbed O atom are adopted from Figure 6b,e. The adsorption energy for the Na on surface with a pre-adsorbed O is defined as

$$E\_{\rm ads} = E\_{\rm (Mo-O/Mo-Rc-O)-Na} - E\_{\rm (Mo-O/Mo-Rc-O)slab} - E\_{\rm Na} \tag{4}$$

where *E*(*Mo*−*O*/*Mo*−*Re*−*O*)−*Na* is the total energy of the adsorbate–substrate system, *E*(*Mo*−*O*/*Mo*−*Re*−*O*)*slab* is the total energy of Mo or Mo-Re surface with a pre-adsorbed O atom, and *ENa* is the energy of an Na atom in the BCC structure. In Equation (4), the subscript Mo-O represents the Mo (110) surface with a pre-adsorbed O atom and Mo-Re-O represent the Mo-Re (110) surface with a pre-adsorbed O atom.

All un-equivalent sites are considered and only the configurations with the lowest energies are shown in Figure 6. Adsorption energies and geometric parameters are given in Table 4. It is found that Na atoms initially placed at Top and Bridge sites move to Hollow sites after the optimization. The former one occupied the Hollow site which is 6.02 Å away from the pre-adsorbed O atom, and latter one occupied the Hollow site which is only 2.35 Å away from the O atom. However, these two final configurations lead to the same adsorption energy of 0.52 eV. For the Na atom initially placed at the Hollow site, the adsorption energy is −0.53 eV with *dNa*−*O* = 2.36 Å. It can be inferred that the O atom does not affect the adsorption behavior of the Na atom.

**Figure 6.** The initial and final configurations of Na atom adsorption on Mo-O (110) and Mo-Re-O (110) surface. Snaps (**a**–**c**) show Na atoms initially placed at Top site, Hollow site and Bridge site of Mo-O (110) surface, while snaps (**d**–**f**) show Na atoms initially placed at Top site, Hollow site and Bridge site of Mo-Re-O (110) surface. Blue and green spheres represent Mo atoms in the first layer and the second layer. Yellow, purple and red spheres represent Re atoms, Na atoms and O atoms, respectively.

**Table 4.** Na adsorption energy on different surface models.

For the Mo-Re (110) surface with a pre-adsorbed O, Na initially placed at the top site will spontaneously move to a Hollow site which is close to the O atom (*dNa*−*O* = 2.37 Å) as shown in Figure 6d. However, it should be noticed that the Na atom at the Hollow site which is closer to a Re atom has lowest adsorption energy of −0.61 eV in Figure 6e. The adsorption energy of Na at the Bridge site is −0.57 eV, which is also closer to the Re atom in Figure 6f and has a lower adsorption energy than the Na atom shown in Figure 6d. For the Na adsorption on the clean Mo-Re (110) surface, the adsorption energies of the Hollow site and Bridge site are −0.56 eV and −0.60 eV. As with the Mo (110) surface, pre-adsorbed O on the Mo-Re (110) surface cannot affect the Na adsorption behavior significantly.

Figure 7 show the energy barrier of Na migration from one most stable site to its first-nearest most stable site is also calculated in this work using CI-NEB method. Our theoretical results show that the diffusion barrier of Na on Mo (110) surface is 0.037 eV, while it is 0.063 eV on the Mo-Re (110) surface. It can be inferred that the Re atom can slower down the Na diffusion kinetics on the Mo surface. The impact of pre-adsorbed O on the Na diffusion is also investigated. For the Mo (110) surface, the pre-adsorbed O atom can increase the diffusion barrier to 0.087; for the Mo-Re (110) surface, the pre-adsorbed O can significantly increase the Na diffusion barrier to 0.221 eV. Therefore, it can be inferred

that both the existence of O impurity and Re alloy atoms can block the Na diffusion on the Mo surface.

**Figure 7.** Calculated diffusion energy profiles for a Na atom diffusion on different surfaces: (**a**) Na diffusion on pure Mo (110) surface; (**b**) Na diffusion on Mo-Re (110) surface; (**c**) Na diffusion on Mo (110) surface with an adsorbed O atom; (**d**) Na diffusion on Mo-Re (110) surface with an adsorbed O atom.


**2. Physiology of human feeding**

The gastrointestinal tract processes ingested food via a complex series of actions in specific organs.

sensation that the stomach feels heavy. Some reports have suggested that delayed gastric

Diet in the Etiology and Management of Functional Dyspepsia

http://dx.doi.org/10.5772/57138

97

Visceral hypersensitivity is also an important factor contributing to the feeling of dyspepsia. When a balloon is distended in the stomach of an FD patient, the threshold at which pain is perceived is significantly lower in FD patients compared to normal controls [11]. Such gastric

Different nutrients and food items may modulate gastrointestinal motor and sensory func‐ tions, and so provoke gastrointestinal symptoms. The three basic nutritional components (carbohydrates, proteins and lipids) can contribute to disturbed gastrointestinal function. The individual nutritional components impact gastric emptying and the sensation of fullness differently. 1. Lipids (fat) and proteins exert a negative ("braking") effect on gastric motility. Fat releases enteric hormones (such as CCK) that increase pyloric sphincter tone and delay

Proteins alter gastric motility, leading to a feeling of fullness and this provides satiety. 3.

Carbohydrates and some food chemicals (like salicylates and amines) give rise to an osmotic effect with increased luminal volume. This can result in a sensation of fullness particularly in

In addition to the individual nutrients, the caloric content, the physical form, and the ingested volume of food affect the sensation of satiety and fullness. High meal viscosity has a greater effect on the sense of satiety, whereas high caloric foods delay gastric emptying. [12,13].

Dietary nutrients influence gastrointestinal function and seem to be related to symptom generation. Thus, it seems logical that disturbances of gastrointestinal motor and sensory functions can lead to generation of gastrointestinal symptoms after food ingestion. However, usually mixtures of food items are eaten, creating difficulties when attempting to pinpoint the individual responsible factor and limiting advice in terms of dietary restrictions in patients with dyspepsia. Dietary measures are classically prescribed in the management of patients

**5. Role of meals in the generation of symptoms in functional dyspepsia**

Epidemiologic studies, both in the USA and Europe, have shown that 50 to 80% of subjects with functional dyspepsia indicate that their symptoms are meal-related [5]. Meal ingestion is associated with diverse changes in the environment of the gastrointestinal lumen, the gastro‐ intestinal function and potential physiopathological mechanisms. The two most cited causes of pathology are delayed gastric emptying and visceral hypersensitivity. After ingestion of a

with motility disorders, although they have not been systematically studied.

hypersensitivity relates to symptoms of postprandial pain, belching and weight loss.

emptying may be seen in up to 40% of FD patients [10].

**4. Nutrients and gastrointestinal function**

gastric emptying. 2.

patients with visceral hypersensitivity.

The esophagus propels food into the stomach though a relaxed lower esophageal sphincter that subsequently contracts to prevent gastroesophageal reflux. The functions of the proximal and distal stomach differ remarkably. Initially, the proximal stomach relaxes, providing a reservoir function. The distal stomach regulates the gastric emptying of solids by grinding and sieving the contents until the particles are small enough to pass the pylorus. The small intestine also regulates the gastric emptying rate through a feedback mechanism mediated by vagal nerves, and by physiological changes, such as gastric relaxation and the release of gastroin‐ testinal hormones [3].

The overall process of digestion is coordinated by interactions between the gut and brain. Hunger is the sensation that leads us to seek and consume food, whereas satiety notifies us when to stop feeding.

Food intake is influenced by several types of gastrointestinal signals. These signals, when elicited by receptors in the stomach, provide information to the brain via the vagus nerve [6]. The stomach functions as a food reservoir; its capacity limits food intake. The gastric distention associated with ingestion of food activates tension mechanoreceptors and this generates a feeling of satiety. Pyloric chemoreceptors have an important role in regulating gastric motility, a fixed energy load being emptied into the duodenum at a constant rate regardless of meal composition. Conversely, gastrointestinal peptides, secreted by the stomach and small intestine with meals, primarily exert short–term effects on food intake. The gut peptides that reduce meal size are cholecystokinin (CCK), glucagon, glucagon – like peptide 1, amylin, somatostatin, peptide YY and bombesin. In contrast, ghrelin appears to have the opposite effect, stimulating enhanced food intake [3].


**10. Hypoxic growth**

*In vivo M. tuberculosis* experiences low oxygen tension that may be encountered in the cen‐ ters of granulomas as previously described. Studies have shown that tuberculous granulo‐ mas are hypoxic in a variety of animal models including rabbits, guinea pigs, and nonhuman primates (Via et al, 2008). The response to low oxygen tension is biphasic. There is an initial response that predominates and is controlled by the two component system DosS/DosT-DosR (Table 1.). This two component system upregulates genes that are known to be part of the "dormancy regulon". DosR is the transcriptional regulator, and Dos T and DosS are the sensor kinases that respond to low oxygen tension as well as nitric oxide (Park et al, 2003; Kumar et al, 2007). *hspX* ( *acr*, *Rv2031c)* is upregulated by low oxygen, is regulated by DosR, and has chaperonin activity that may aid in refolding proteins which are damaged by low oxygen tension (Vasudeva-Rao and McDonough, 2008; Florczyk et al, 2003). It is known that this protein is expressed *in vivo* as latently infected individuals pos‐ sess T-cells that are reactive to the HspX protein (Geluk et al, 2007). Interestingly one half of the genes in the DosR regulon return to their baseline level after 24 hours. After this ini‐ tial 24 hour period other regulators play a role in hypoxic responses such as sigE and sigC (Table 1.). An enduring hypoxic response begins after the initial response, and this may be important for *M. tuberculosis* to enter and stay in a dormant state (Rustad et al, 2008).

#### **11. Toxin-antitoxin systems**

Interestingly there are many toxin-antitoxin systems within the *M. tuberculosis* genome. These systems seem to provide a mechanism by which bacteria can alter growth rate rapidly, potentially in response to environmental stressors. The toxin is not a protein secreted and targeted against the human host, but targeted against mycobacterial cellular components. The toxin is a stable protein which may be complexed with an antitoxin forming a toxin-antitoxin pair. The antitoxin is relatively unstable and environmental stressors can inactivate it causing release of a free toxin. The toxin is then available to interact with cellular components, and may function to cleave mRNA thus inhibiting subsequent translation and rapidly halting growth of the bacterium. As static bacteria are more resistant to environmental stressors and antibiotics, this system may allow *M. tuberculosis* to survive in the face of external stressors. *M. tuberculosis* possesses 88 toxin-antitoxin systems and four of these have been shown to be activated by phagocytosis of bacilli, by macrophages, or hypoxia (Table 1.). It appears that the toxin in these systems acts by cleaving mRNA (Rapage et al, 2009).

**Table 1.** Mycobacterial responses to in vivo stressors and conditions.


**<IP_ADDRESS> Central venous catheters**

CVCs have become critically important as medical and supportive management of various diseases and have greatly improved quality of life. They bear two serious complications: thrombotic occlusion and CVC-associated DVT as well as systemic infections. CVCs seem to be the most important risk factor for DVT. The range of reported CVC-related DVT ranges from 1% to nearly 70%, reflecting the problem of different definitions, diagnostic methods and alertness.(Mitchell et al, 2003; Male et al, 2003) However, the estimated contribution of CVCs to all thromboembolic events in newborns is as high as 90% and over 50% in older children.(Parasuraman & Goldhaber, 2006) There are only a few controlled studies on the prevalence of CVC-related DVT and infection rate as well as the efficacy of antithrombotic measures to prevent catheter occlusion and infection.

#### **<IP_ADDRESS> Childhood cancer**

TE is a well known complication in adult patients with cancer. With the exception of acute lymphoblastic leukemia (ALL), the knowledge about TE in childhood cancer is still limited. ALL has the highest rate of TE in childhood that is not necessarily related to the use of a CVC. In contrast, brain tumors have a rather low incidence of thrombosis with or without CVC.(Tabori et al, 2006) An overall estimation looks at a risk of up to 16%.

Venous Thromboembolism in Neonates, Children and

**<IP_ADDRESS> Other acquired prothrombotic conditions**

events may occur.

risk factors.

**3.4 Therapy and prophylaxis**

initial treatment dose

initial prophylactic dose

after injection

**Recommendations**

LMWH (Grade 1B).

\* 1 mg Enoxaparin = 110 anti-FXa units

Patients with Chronic Renal Disease – Special Considerations 57

heparin (UFH) for venous thrombosis. HIT-associated TE is mainly venous but arterial

Perinatal asphyxia, systemic infections/sepsis/DIC, congenital heart disease (CHD) and hypovolemia are the main risk factors in neonates, the latter particularly prone to arterial events in association with CHD and/or arterial catheters frequentlyused in an intensive care setting.47 There are additional factors in older children: trauma, major surgery, immobilization, estrogen containing contraceptives in adolescent girls, corticosteroid therapy, nephrotic syndrome, hemolytic uremic syndrome, inflammatory bowel disease, and rheumatic and other chronic disorders. To date, it remains an individual decision if and which antithrombotic prophylaxis should be offered considering additional and individual

Irrespective of an underlying disease, every thromboembolic manifestation should be treated, aiming at the complete recanalization of the occluded vessel and stopping the thrombotic process. In the vast majority of cases thrombosis will resolve under heparin given for 5–14 days. Other therapy options with a higher risk such as thrombolytic therapy or surgical embolectomy should be limited for patients with extensive thrombosis and/or threatened organ function. As LMWH show considerable advantages over UFH for therapeutic as well as prophylactic purposes, the following recommendations are in favor of LMWH. Yet evidence shows no difference in the antithrombotic efficacy. For detailed

**UFH i.v. Neonates < 5kg Children > 5kg Target aPTT at 4h**

**LMWH s.c. Neonates < 5kg Children > 5kg Target anti-FXa at 4 h**

For UFH: aPTT 4 hours after loading dose and 4 hours after each dosage adjustment, at least once daily; keep AT level within normal range; daily blood count (platelets!). For LMWH: anti-FX activity 4 hours

In children with thrombosis, we recommend anticoagulant therapy with either UFH or

maintenance 25–30 U/kg/h 20 U/kg/h 60–85 sec.

Enoxaparin\* 1 x 2.0 mg/kg/d 1 x 1.5 mg/kg/d 0.4–0.8 U/mL Dalteparin 1 x 200 U/kg/d 1 x 150 U/kg/d 0.4–0.8 U/mL Reviparin 2 x 150 U/kg/d 2 x 100 U/kg/d 0.5–1.0 U/mL

Enoxaparin\* 1 x 1.5 mg/kg/d 1 x 1.0 mg/kg/d < 0.4 U/mL Dalteparin 1 x 100 U/kg/d 1 x 50 U/kg/d < 0.4 U/mL Reviparin 2 x 50 U/kg/d 2 x 30 U/kg/d < 0.5 U/mL

Table 4. Recommended dosing of UFH and LMWH in neonates and children.

In children with VTE (CVL and non-CVL related): first TE for children:

recommendations refer to **Table 4** and reference (Monagle et al, 2004).

loading dose 1 x 75 U/kg/10 min 1 x 75 U/kg/10 min

TE in cancer is the result of complex interactions of a variety of factors such as the malignancy itself, chemotherapy and its side effects including infections or dehydration, CVCs, the unbalanced hemostatic system with predominant hypercoagulability as well as possible hereditary thrombophilia. The impact of the different types of childhood malignancy on the hemostatic system is still not well understood. Most reports are regarding ALL and show the highest risk for TE under ALL/non-Hodgkin lymphoma (NHL) treatment is during induction and re-induction therapy that contains L-asparaginase, the most common site being the upper deep venous system and the cerebral veins.