Genetics and environments risk factors for ADHD clinical features.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5356",leadTitle:null,fullTitle:"Air Quality - Measurement and Modeling",title:"Air Quality",subtitle:"Measurement and Modeling",reviewType:"peer-reviewed",abstract:"Addressing the matter of air quality in a collection of focused scientific topic chapters is timely as a contribution to the international discussion and challenges of global warming and climate change. This book engages with the debate by considering some of the social, public health, economic and scientific issues that relate to the contribution made by airborne pollutants to the observable trending variances in weather, climate and atmospheric conditions. From a wide range of submissions for inclusion in the book, there are seven carefully selected chapters that individually relate to air sampling and analysis: the monitoring, measurement and modelling of air quality. The authors come from a range of academic and scientific disciplines, and each is internationally credited in his/her field. This book will appeal to scholars, to students and generally to those interested in the following contemporary thought in the matter of environment pollution, air quality and the issues of climate and atmosphere the world is facing today.",isbn:"978-953-51-2765-9",printIsbn:"978-953-51-2764-2",pdfIsbn:"978-953-51-4137-2",doi:"10.5772/62563",price:119,priceEur:129,priceUsd:155,slug:"air-quality-measurement-and-modeling",numberOfPages:196,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"4a7d0d06a1f8d925fcfa9d8b79858729",bookSignature:"Philip Sallis",publishedDate:"December 14th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5356.jpg",numberOfDownloads:16455,numberOfWosCitations:21,numberOfCrossrefCitations:18,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:31,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:70,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 14th 2016",dateEndSecondStepPublish:"April 4th 2016",dateEndThirdStepPublish:"July 9th 2016",dateEndFourthStepPublish:"October 7th 2016",dateEndFifthStepPublish:"November 6th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8,9",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"10893",title:"Prof.",name:"Philip John",middleName:null,surname:"Sallis",slug:"philip-john-sallis",fullName:"Philip John Sallis",profilePictureURL:"https://mts.intechopen.com/storage/users/10893/images/5060_n.jpg",biography:"Dr. Philip Sallis is a Professor in Computer Science at the Auckland University of Technology in New Zealand. His research over the past 10 years has predominantly been in the field of GeoComputation with a focus on instrumentation and measurement, particularly in the context of agrometeorological applications of wireless sensor networks for data acquisition and subsequent dynamical systems modelling of micro-climates. In recent years, this work has extended to other areas of environmental sensor applications such as autonomous vehicles, pest control and sensory assistance for children with learning disabilities. With an academic career spanning more than 40 years, he has held university positions in England, Australia and New Zealand, including the senior roles as Head of School, Dean and Deputy Vice Chancellor. He is currently a Pro-Vice Chancellor assisting in the academic leadership of the Auckland University of Technology.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Auckland University of Technology",institutionURL:null,country:{name:"New Zealand"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"865",title:"Air Pollution",slug:"environmental-pollution-air-pollution"}],chapters:[{id:"52850",title:"A Mathematical Approach to Enhance the Performance of Air Pollution Models",doi:"10.5772/64758",slug:"a-mathematical-approach-to-enhance-the-performance-of-air-pollution-models",totalDownloads:1596,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The main objective of this chapter is to introduce a mathematical method for enhancing the correctness of the output results of air pollution dispersion models via the calibration of input background concentrations. For developing this method, an air pollution model was set up in ADMS‐Roads for a study area in the City of Nottingham in the UK. The method was applied iteratively to the input background concentrations, which effectively reduced the error between calculated and monitored air pollution concentrations on both the annual mean and hourly levels. The inclusion of the traffic flow profiles of the modeled road network reduced further the error between the hourly, but not the annual mean, calculated and monitored concentrations. The application of the calibration approach to the model in ADMS‐Roads was compared to the use of grid air pollution sources for the same model in ADMS‐Urban. In terms of the accuracy of the model results, the calibration approach was better than using grid sources on the annual mean level and was much better on the hourly level. Compared to the use of grid sources in ADMS‐Urban, the use of the calibration approach in either ADMS‐Roads or ADMS‐Urban can significantly reduce the air pollution model runtime.",signatures:"El-Said Mamdouh Mahmoud Zahran",downloadPdfUrl:"/chapter/pdf-download/52850",previewPdfUrl:"/chapter/pdf-preview/52850",authors:[{id:"187987",title:"Dr.",name:"El-Said",surname:"Zahran",slug:"el-said-zahran",fullName:"El-Said Zahran"}],corrections:null},{id:"52206",title:"Particulate Matter Sampling Techniques and Data Modelling Methods",doi:"10.5772/65054",slug:"particulate-matter-sampling-techniques-and-data-modelling-methods",totalDownloads:3504,totalCrossrefCites:6,totalDimensionsCites:14,hasAltmetrics:0,abstract:"Particulate matter with 10 μm or less in diameter (PM10) is known to have adverse effects on human health and the environment. For countries committed to reducing PM10 emissions, it is essential to have models that accurately estimate and predict PM10 concentrations for reporting and monitoring purposes. In this chapter, a broad overview of recent empirical statistical and machine learning techniques for modelling PM10 is presented. This includes the instrumentation used to measure particulate matter, data preprocessing, the selection of explanatory variables and modelling methods. Key features of some PM10 prediction models developed in the last 10 years are described, and current work modelling and predicting PM10 trends in New Zealand—a remote country of islands in the South Pacific Ocean—are examined. In conclusion, the issues and challenges faced when modelling PM10 are discussed and suggestions for future avenues of investigation, which could improve the precision of PM10 prediction and estimation models are presented.",signatures:"Jacqueline Whalley and Sara Zandi",downloadPdfUrl:"/chapter/pdf-download/52206",previewPdfUrl:"/chapter/pdf-preview/52206",authors:[{id:"188593",title:"Associate Prof.",name:"Jacqueline",surname:"Whalley",slug:"jacqueline-whalley",fullName:"Jacqueline Whalley"},{id:"188594",title:"Ms.",name:"Sara",surname:"Zandi",slug:"sara-zandi",fullName:"Sara Zandi"}],corrections:null},{id:"52560",title:"Economics and Air Pollution",doi:"10.5772/65256",slug:"economics-and-air-pollution",totalDownloads:3685,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This chapter discusses the relationship between economics and air pollution: first, it presents the main characteristics of the economic growth-environmental pressure debate and introduces the concept of environmental Kuznets curve hypothesis (EKC). As an example of the EKC, the estimated relationship between CO2 emissions and economic growth, using a cross-sectional sample of 152 countries, is reported. Second, the chapter discusses air pollution as a result of a market failure and introduces the main theoretical causes of ambient degradation, acknowledging air pollution externalities as a common problem that leads to overexploitation in the absence of well-defined property rights for the atmosphere. Third, the main instruments for pollution control, including traditional regulation based on standards and the more flexible incentive-based regulation, are presented. Finally, the chapter reviews the main features of cost and benefits related to air pollution emissions.",signatures:"Fernando Carriazo",downloadPdfUrl:"/chapter/pdf-download/52560",previewPdfUrl:"/chapter/pdf-preview/52560",authors:[{id:"186900",title:"Dr.",name:"Fernando",surname:"Carriazo",slug:"fernando-carriazo",fullName:"Fernando Carriazo"}],corrections:null},{id:"53329",title:"Atmospheric Pollution and Microecology of Respiratory Tract",doi:"10.5772/66039",slug:"atmospheric-pollution-and-microecology-of-respiratory-tract",totalDownloads:1495,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter elaborates the source and ingredients of atmospheric pollutants, the microecology of respiratory tract in animals and humans and the effect of atmospheric pollution on it and thus clarifies the relationship between air pollution and microecology of the respiratory tract based on the experiments.",signatures:"Chunling Xiao, Xinming Li, Jia Xu and Mingyue Ma",downloadPdfUrl:"/chapter/pdf-download/53329",previewPdfUrl:"/chapter/pdf-preview/53329",authors:[{id:"186486",title:"Prof.",name:"Chunling",surname:"Xiao",slug:"chunling-xiao",fullName:"Chunling Xiao"}],corrections:null},{id:"52290",title:"The Air Quality Influences of Vehicular Traffic Emissions",doi:"10.5772/64692",slug:"the-air-quality-influences-of-vehicular-traffic-emissions",totalDownloads:1718,totalCrossrefCites:4,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The number of automobiles has been steadily increasing in cities as a consequence of rapid urbanization and economic growth. It has been widely reported that vehicular emissions are strongly correlated with the level of urban air pollution. The major primary air pollutants that are linked to direct emissions from on‐road vehicles include soot (black carbon), carbon monoxide (CO), and nitric oxide (NO). Human exposure to these air pollutants is of health concern. Therefore, it is important to investigate air pollutants of traffic origin (e.g., BC, CO, and NO) in ambient air at different locations of cities and to assess the effects of vehicles on the urban air quality. With this goal in mind, we carried a systematic study in Singapore (the fourth most densely populated country in the world) with concurrent measurements of BC, NO, and CO in ambient air at four different locations having variations in traffic flows and meteorology. We then assessed the relationship between traffic flows and prevailing levels of the three air pollutants, and studied the association of these air pollutants among each other and with diverse meteorological conditions. The major outcomes of the study are discussed.",signatures:"Sailesh N. Behera and Rajasekhar Balasubramanian",downloadPdfUrl:"/chapter/pdf-download/52290",previewPdfUrl:"/chapter/pdf-preview/52290",authors:[{id:"93412",title:"Dr.",name:"Sailesh",surname:"Behera",slug:"sailesh-behera",fullName:"Sailesh Behera"},{id:"162402",title:"Prof.",name:"Rajasekhar",surname:"Balasubramanian",slug:"rajasekhar-balasubramanian",fullName:"Rajasekhar Balasubramanian"}],corrections:null},{id:"52269",title:"Air Pollution Monitoring: A Case Study from Romania",doi:"10.5772/64919",slug:"air-pollution-monitoring-a-case-study-from-romania",totalDownloads:2522,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"The first section of this chapter provides an up‐to‐date general view of air pollution/air quality topic. It indicates main pollutants and their sources and impacts and presents and discusses current air quality standards and air quality indexes worldwide; how datasets are acquired, gathered and analyzed and how the measurements are then interpreted are also presented. Recent works containing updated and detailed technical discussions for each issue addressed and additional web resources are mentioned. The great importance of air pollution monitoring is emphasized. Second, in the international context of incomplete information on air pollution in East Europe, the chapter includes a section presenting an assessment of air pollution at some sites in Romania together with its evolution from the beginning of the monitoring up to present. Availability of PM10, PM2.5, NOx, SO2 and CO concentrations is site and pollutant dependent and varies from 3 to 9 years. Investigation of temporal and spatial variation of pollutant levels, as well as of PM10 and PM2.5 relationships with the measured gaseous air pollutants and with meteorological variables, includes correlation and linear regression analysis and temporal‐trend analysis; coefficient of divergence was calculated to check up on the air pollution inter‐sites’ differences and pollutant seasonal variation intra‐site.",signatures:"Gabriela Iorga",downloadPdfUrl:"/chapter/pdf-download/52269",previewPdfUrl:"/chapter/pdf-preview/52269",authors:[{id:"187615",title:"Dr.",name:"Gabriela",surname:"Iorga",slug:"gabriela-iorga",fullName:"Gabriela Iorga"}],corrections:null},{id:"52865",title:"Air Pollution Mapping with Bio‐Indicators in Urban Areas",doi:"10.5772/65299",slug:"air-pollution-mapping-with-bio-indicators-in-urban-areas",totalDownloads:1936,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Our study consists of the assessment and the mapping of the atmospheric pollution, which concerns the region of Tiaret city, by using the lichens as bioindicators. In our zone, we did a survey on 25 domains by using Kirschbaum and Wirth 1997 method. This method has enabled to define five classes according to the calculated air quality index (AQI). The dominant class was the one that contained a high pollution degree, which is reflected through the spatial distribution of the lichen species. 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Traditional pathology concentrates on the morphological manifestations of disease. Molecular pathology, in addition, integrates tools of molecular biology to: isolate and identify the causative agents in infectious disease, understand the role of differential gene expression in disease etiology, provide more accurate means of disease diagnosis and provide more individualized approaches to therapy.
Molecular pathology is a branch of the biomedical sciences which focuses on the progress, development, and evolution of diseases on the molecular level. It can be applied practically to patients in addition to being utilized in biomedical research to learn more about specific diseases, ranging from cancer to genetic conditions. Usually, molecular pathology is treated as a subset of the field of pathology, but it also involves genetics, immunology, and many other aspects of the medical field, and people can approach it from a number of perspectives.
A molecular pathologist can conduct a variety of tests to learn about the fundamental components of a cell, including the array of amino acids which makes up cellular DNA. In addition to performing amino acid sequencing, people in this field also look at samples of cellular tissue, and they perform a variety of tests to learn more about the progress of disease in specific patients and in general.
To understand the causes and molecular basis of the development of disease, with particular reference to cancer, and to apply this knowledge to improving disease prevention, detection, diagnosis and treatment. Improving the outlook for cancer patients can only come from an understanding of molecular and cell biology. There has been a dramatic increase in knowledge of the molecular genetics of cancers over the last few years and already we have reached the point where this can be translated into clinical application.
Many diseases are caused by inherited gene mutations, for example, cystic fibrosis, muscular dystrophy and lysosomal storage diseases. Other gene alterations confer a greater susceptibility to disease – for example, cancer or heart disease.
One common use for a molecular pathologist is in the study of specimens taken from cancer patients. The pathologist can test the specimen to determine where the cancer originated, and to look for biomarkers which could indicate susceptibility to specific cancer treatments. For example, a breast cancer which is estrogen sensitive will be treated differently than a breast cancer which is not. Using molecular pathology, an oncologist can develop a treatment approach which is tailored to the patient.
Key techniques used in molecular pathology to identify relationships between gene alterations and disease include cell isolation and cell culture. Immunohistochemistry is not considered a molecular technique but it is based on the antigen-antibody affinity, it has emerged as a powerful investigative tool that can provide supplemental information to the routine morphological assessment of tissues. The antibody is usually linked to other molecules to aid visualization [(fluorophore, reporter enzyme, etc), FISH (A cytogenetic method of detecting and localizing specific DNA sequences on chromosomes)] and laboratory molecular biology techniques (identification of gene mutations, expression profiling, protein analysis, blotting, microarrays).
It is thought that the development of malignant disease progresses through defined stages such as hyperplasia, dysplasia, carcinoma in situ, primary carcinoma, invasive carcinoma and metastases, each of which may be linked to mutations and alterations in the expression of subsets of genes. Laser microdissection is useful for isolating particular cells, or populations of cells, from tissue (frozen sections, fixed sections and in cell culture monolayers) for genetic analysis allowing direct comparison of nucleic acid from cells in different stages of disease progression.
Automated Cellular Imaging System (ACISR III), an example of an image acquisition and image analysis instrument.
The impact of gene alterations on protein function and disease can be investigated using a variety of imaging techniques (Figs.1 and 2). Of particular importance is the imaging of protein-protein interactions using time-lapse imaging, TIRF microscopy and confocal fluorescence microscopy techniques such as 3-D rendering, FRET/BRET. These enable spatial and temporal analysis of dynamic events involving, for example, receptor interactions and other signaling events (Fig.3).
Nikon\'s powerful fully-automated confocal imaging system, capable of capturing high-quality confocal images of cells and molecular events.
Another important role of the immune system (Fig.4) is to identify and eliminate tumors. The
The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells [4, 7]. Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal [8] NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors [9].Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system [5].
Clearly, some tumors evade the immune system and go on to become cancers [10]. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells [8]. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes [11]. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells [10].
Paradoxically, macrophages can promote tumor growth [12] when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.
The immune system protects the body from potentially harmful substances. The inflammatory response (inflammation) is part of innate immunity. It occurs when tissues are injured by bacteria, trauma, toxins, heat or any other cause.
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions.
A genetic disorder may or may not be a heritable disorder. Some genetic disorders are passed down from the parents\' genes, but others are always or almost always caused by new mutations or changes to the DNA. In other cases, the same disease, such as some forms of cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and by non-genetic causes in still other people.
Nucleic acid–based testing is becoming a crucial diagnostic tool not only in the setting of inherited genetic disease (e.g., cystic fibrosis and hemochromatosis) but also in a wide variety of hemato-oncologic, solid neoplastic and infectious conditions. Molecular diagnostics provides the necessary underpinnings for any successful application of gene therapy or biologic response modifiers. It offers a great tool for assessing therapy response and detecting minimal residual disease. Currently, it is estimated that more than 5% of all laboratory testing is based on DNA or RNA analysis.
Microdissection can be performed in a variety of ways, all of which have different advantages and disadvantages. These methods range from the simple and inexpensive manual methods to laser-capture microdissection (LCM) methods that require expensive and complex equipment. These methods are reviewed here, with particular emphasis on manual microdissection, which can be performed easily with common equipment in the pathology laboratory (Fig. 5).
One of the major benefits of microdissection is the production of relatively pure samples of morphologically confirmed cellular populations [13]. This relative purity may be essential for assessing a genetic change or for quantification of genetic changes. For example, in assessing possible loss of heterozygosity of tumor suppressor genes, normal contaminating cells will artifactually equalize the allelic balance, and it may appear that the tumor cells contain normal DNA. In molecular identity testing for tissue floaters (tissue carryover artifacts), microdissection is essential for separating the fragments of the suspected floater from the rest of the tissue sample [14, 15]. When examining expression of some gene targets in tumor cells at the mRNA level, results may be confounded by the expression found in normal contaminating stromal and lymphoid cells. In some diseases it may be important to measure events in rare single neoplastic cells [16-18]. Perhaps the most notable example is in Hodgkin lymphoma, where molecular experiments require detailed microdissection to isolate the Reed-Sternberg cells from the surrounding lymphoid infiltrates.
This method "microdissection", can be performed easily with common equipment in the pathology laboratory.
The polymerase chain reaction (PCR) is a laboratory technique for "amplifying" a specific DNA sequence (Fig.6). PCR is extremely efficient and sensitive; it can make millions or billions of copies of any specific sequence of DNA, even when the sequence is in a complex mixture. Because of this power, researchers can use it to amplify sequences even if they only have a minute amount of DNA. A single hair root, or a microscopic blood stain left at a crime scene, for example, contains ample DNA for PCR.
PCR is based on the way cells replicate their DNA. During DNA replication, the two strands of each DNA molecule separate, and DNA polymerase, an enzyme, assembles nucleotides to form two new partner strands for each of the original strands. The original strands serve as templates for the new strands. The new strands are assembled such that each nucleotide in the new strand is determined by the corresponding nucleotide in the template strand. The nucleotides adenine (A) and thymine (T) always lie opposite each other, as do cytosine (C) and guanine (G). Because of this base-pairing specificity, each newly synthesized partner strand has the same sequence as the original partner strand, and replication produces two identical copies of the original double-stranded DNA molecule.
In PCR, a DNA sequence that a researcher wants to amplify, called the "target" sequence, undergoes about thirty rounds of replication in a small reaction tube. During each replication cycle, the number of molecules of the target sequence doubles, because the products and templates of one round of replication all become the templates for the next round. After n rounds of replication, 2n copies of the target sequence are theoretically produced. After thirty cycles, PCR can produce 230 or more than ten billion copies of a single target DNA sequence. This is called a polymerase chain reaction because DNA polymerase catalyzes a chain reaction of replication.
PCR is used to enlarge a few pieces of DNA which would create thousands to millions of copies of that one sample of DNA.
Gel electrophoresis uses a gel as an anticonvective medium and or sieving medium during electrophoresis, the movement of a charged particle in an electrical field. Gels suppress the thermal convection caused by application of the electric field, and can also act as a sieving medium, retarding the passage of molecules; gels can also simply serve to maintain the finished separation, so that a post electrophoresis stain can be applied [21].DNA Gel electrophoresis is usually performed for analytical purposes, often after amplification of DNA via PCR, but may be used as a preparative technique prior to use of other methods such as mass spectrometry (Fig.7), RFLP, PCR, cloning, DNA sequencing, or Southern blotting [22] for further characterization.
Mass spectrometry
In a specialized molecular biology laboratory, researchers can make a sequence of nucleotide bases that is complementary to a target sequence that occurs naturally in a cell (in a gene, for example). When this complementary sequence is exposed to the cell, it will bind with that naturally occuring target DNA or RNA in that cell, thus forming what is known as a hybrid. The complementary sequence thus can be used as a "probe" for cellular RNA or DNA.
Thus, the term "hybridization" refers to the chemical reaction between the probe and the DNA or RNA to be detected. If hybridization is performed on actual tissue sections, cells, or isolated chromosomes in order to detect the site where the DNA or RNA is located, it is said to be done "
Application of the Probe for DNA or RNA to Tissues or Cells:
When
A process by which the sequence of nucleotides along a strand of DNA is determined. Originally a difficult process to carry out, DNA sequencing can now be done routinely by machines. The completion of the Human Genome Project in 2000 produced the largest DNA sequence ever assembled. To carry out the sequencing of the human genome, scientists cut the DNA up into short fragments, sequenced these fragments simultaneously, and then assembled the entire genome by using sophisticated computer techniques to match the fragments to each other.
Gene expression profiling using DNA microarrays holds great promise for the future of molecular diagnostics. This technology allows, in one assay, for simultaneous assessment of the expression rate of thousands of genes in a particular sample. The 2 types of DNA microarrays that are widely used are cDNA microarrays and oligonucleotide/ DNA chips.
A lung primary tumor, for example, has a different fingerprint than an ovarian or colonic primary. This feature can be exploited in the setting of tumors of unknown primary, in which DNA microarrays have been shown to predict the correct primary site with an amazing accuracy rate of 99%.
In cDNA microarrays, DNA sequences complementary to a library of mRNA from thousands of genes are mechanically placed on a single glass slide. The immobilized cDNA sequences serve as anchoring probes to which mRNA extracted from the tested sample will specifically attach during hybridization. If the tested mRNA is first tagged with a fluorescent dye, the intensity of fluorescence at each anchoring probe location will be proportional to the amount of mRNA (degree of expression) of the gene at that location. A microarray reader displays the intensity of fluorescence at each cDNA location as a colored dot per gene location on a grid.
The applications of these technologies are limitless. By analyzing and comparing hundreds of tumor samples, databases of gene expression ‘‘fingerprints’’ are being built and specific patterns of expression linked to both prognosis and outcome of therapy.11–16 Patterns of gene expression in tumors are also linked to the primary site of origin (Fig.8).
The term
Proteomic analysis of nipple aspirate fluids using 2-dimensional gel electrophoresis. Spots in the bottom panel (enlarged from the top panel) indicate proteins expressed solely by nipple aspirate fluids from breasts containing tumor and not by the contralateral control breast. Copyright 2002 American Cancer Society. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. [
These technology uses matrix-assisted lasers desorption and time-of-flight analysis to allow fully automated separation of even minute amounts of protein components. The assay exploits variations in mass and electric charge of different protein components in a given sample (e.g., serum). It is the variation in time of flight—based on the mass/charge ratio of each peptide—that allows for separation of the different protein components. With the aid of computer analyses, results are displayed as peaks representing the different peptide components of a given sample. By characterizing proteomic ‘‘fingerprints’’ associated with a particular type of tumor, it is possible to identify an unknown sample that matches a previously defined fingerprint. This can be done on the basis of the ‘‘peaks’’ pattern without knowing which protein each peak represents. Appropriate integration of genomic and proteomic data is crucial to elucidate protein functions as they relate to pathogenesis. This integration will help highlight potential pathogenically important epigenetic deviations at the protein level.18 Integration of genomics and proteomics will no doubt facilitate discovery of novel drug target proteins and biomarkers of diseases.
Molecular diagnostics can be widely defined as the measurement of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, or other metabolites to detect certain genotypes, mutations, or biochemical changes that may be associated with certain states of health or disease, main applications of molecular genetic testing … [28]. The emergence of molecular diagnostics is due to advances in biology that have resulted in an understanding of the mechanisms of normal and disease processes at the molecular level. Prior to this understanding, many disease states were diagnosed from morphologic observations.
The first widely used molecular tests were for infectious diseases, such as for hepatitis B and C or human papillomavirus (HPV), and this continues to be the largest molecular diagnostics market. Certain other fields, such as molecular tests for oncology, inherited conditions, cardiovascular disease, neurological disorders, and forensic testing, are rapidly growing areas of interest. Additionally, molecular diagnostics can be used to monitor a patient’s response to a particular drug treatment.
Many different biological techniques fall under the “molecular diagnostics” umbrella. One of the most common techniques is the polymerase chain reaction (PCR), a method of producing large amounts of specifically defined DNA or RNA fragments that can then be used for multiple purposes, including pathogen identification and detection of aberrant gene expression associated with certain diseases. PCR fragments may also be sequenced to detect gene mutations connected to certain disease states, such as the detection of mutations in the BRCA1 and BRCA2 genes that are often associated with an increased risk of hereditary breast cancer and ovarian cancer.
Examples of main genetic testing….. [29].
Allogeneic, HLA-matched hematopoietic stem cell transplantation (BMT) related or non-related donor. Donor and recipient specific DNA fragment patterns are utilized to distinguish the origins of each cell population.
Applied Biosystems AmpFLSTR Profiler Plus Kit utilizes short tandem repeat (STR) polymorphic DNA markers to distinguish patient and donor cells. Fluorescent multiplex polymerase chain reaction (PCR) is used to amplify the markers.
DNA isolated from the WCB’s (lymphoid or myeloid cells) of the patient and donor is characterized with 10 polymorphic DNA markers prior to the bone marrow transplantation. The patterns are compared and one marker is selected to distinguish donor and patient as uniquely different from one another.
This will be subsequently used to assess the status of donor cell engraftment. In related family members one or more of these markers may demonstrate high incidence of non-identity in the BMT setting. The alleles range in size and heterozygosity.
In the general population, only identical twins have identical DNA profiles at all of these STR loci.When more than one of the ten STR markers has an informative (not identical) pattern between patient and donor, the one that demonstrates the most clearly distinguished differences in size or mobility is selected to follow engraftment status post-transplant. Amelogenin distinguishes X and Y chromosomes and may be used when the patient and donor are not of the same gender. Enriched subpopulations of hematopoietic cells (E.g. T lymphocytes and myeloid cells) may also be assayed
BRCA Ashkenazi Jewish Mutations
BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.
A woman\'s risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.
Genetic tests are available to check for BRCA1 and BRCA2 mutations (Fig.10). A blood sample is required for these tests, and genetic counseling is recommended before and after the tests. If a harmful BRCA1 or BRCA2 mutation is found, several options are available to help a person manage their cancer risk.
Several methods are available to test for
A blood sample is needed for these tests. The blood is drawn in a laboratory, doctor\'s office, hospital, or clinic and then sent to a laboratory that specializes in the tests. It usually takes several weeks or longer to get the test results. Individuals who decide to get tested should check with their health care provider to find out when their test results might be available.
Genetic tests are to check for BRCA1 and BRCA2 mutations
Cystic Fibrosis Mutation Analysis
Cystic fibrosis (CF) occurs at increased frequency in Caucasians and individuals of Ashkenazi Jewish descent, but can occur in any ethnic group (Fig.11). It is a disorder of mucus production, primarily affecting the pulmonary, gastrointestinal and reproductive systems. Although there is some variability of clinical expression, most individuals with CF require lifelong medical care and experience reduced life expectancy.
DNA Fingerprinting
The process begins with a sample of an individual\'s DNA (typically called a "reference sample"). The most desirable method of collecting a reference sample is the use of a buccal swab, as this reduces the possibility of contamination. When this is not available (e.g. because a court order may be needed and not obtainable) other methods may need to be used to collect a sample of blood, saliva, semen, or other appropriate fluid or tissue from personal items (e.g. toothbrush, razor, etc.) or from stored samples (e.g. banked sperm or biopsy tissue). Samples obtained from blood relatives (biological relative) can provide an indication of an individual\'s profile, as could human remains which had been previously profiled.
Cystic fibrosis (CF)
A reference sample is then analyzed to create the individual\'s DNA profile using one of a number of techniques, discussed below. The DNA profile is then compared against another sample to determine whether there is a genetic match.
Another technique, AmpFLP, or amplified fragment length polymorphism was also put into practice during the early 1990s. This technique was also faster than RFLP analysis and used PCR to amplify DNA samples. It relied on variable number tandem repeat (VNTR) polymorphisms to distinguish various alleles, which were separated on a polyacrylamide gel using an allelic ladder (as opposed to a molecular weight ladder). Bands could be visualized by silver staining the gel. One popular locus for fingerprinting was the D1S80 locus. As with all PCR based methods, highly degraded DNA or very small amounts of DNA may cause allelic dropout (causing a mistake in thinking a heterozygote is a homozygote) or other stochastic effects. In addition, because the analysis is done on a gel, very high number repeats may bunch together at the top of the gel, making it difficult to resolve. AmpFLP analysis can be highly automated, and allows for easy creation of phylogenetic trees based on comparing individual samples of DNA. Due to its relatively low cost and ease of set-up and operation, AmpFLP remains popular in lower income countries.
Factor V Mutation Analysis
Factor V Leiden (F5) point mutation G1691A (Formerly FVL) (Fig.12).
Specimen Requirements [Peripheral blood--1 lavender-top (EDTA) tube. Invert several times to mix blood].
Factor V Leiden (F5) point mutation G1691A (Formerly FVL)
Familial Mediterranean Fever Mutation
The MEFV gene (Fig.13) provides instructions for making a protein called pyrin (also known as marenostrin). Although pyrin\'s function is not fully understood, it likely assists in keeping the inflammation process under control. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops the inflammatory response to prevent damage to its own cells and tissues.
Pyrin is produced in certain white blood cells (neutrophils, eosinophils, and monocytes) that play a role in inflammation and in fighting infection. Pyrin may direct the migration of white blood cells to sites of inflammation and stop or slow the inflammatory response when it is no longer needed. Pyrin also interacts with other molecules involved in fighting infection and in the inflammatory response. Research indicates that pyrin helps regulate inflammation by interacting with the cytoskeleton, the structural framework that helps to define the shape, size, and movement of a cell.
Familial Mediterranean Fever Mutation &
Fragile X Mutation Analysis
Fragile X syndrome (FXS), Martin–Bell syndrome, or Escalante\'s syndrome (more commonly used in South American countries,Fig.14), is a genetic syndrome that is the most common known single-gene cause of autism and the most common inherited cause of mental retardation among boys. It results in a spectrum of intellectual disability ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and larger testes (macroorchidism), behavioral characteristics such as stereotypical movements (e.g. hand-flapping), and social anxiety.
Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the
This molecular test detects the DNA expansion observed in approximately 99% of Fragile X Syndrome carriers or affected individuals. Normal individuals have between about 6 and 50 FMR1 CGG repeats. The FMR1 CGG repeats tend to undergo expansion when repeat numbers exceed about 50. Premutation carrier females and normal transmitting males have between about 50 and 200 repeats. Affected males typically have many more than 200 repeats. Females with an X chromosome having greater than 200 FMR1 CGG repeats may or may not be affected depending on X chromosome inactivation patterns. FMR1 CGG repeats of about 50 to 200 show a dynamic instability directly related to their length, to the sex of the transmitting individual, and to subtle DNA sequence variation within the repeat itself. Premutation alleles tend to be unstable when transmitted by females and stable when transmitted by males (stability in males may be a consequence of selection against expanded FMR1 CGG alleles during spermatogenesis). Repeats greater than about 90-100 repeats have nearly a 100% risk of expansion into the affected range when transmitted by a female. The FMR1 CGG repeat demonstrates significant somatic instability when repeat sizes enter the premutation range. Premutation and larger sized CGG repeats determined from peripheral blood DNA may not reflect FMR1 CGG repeat sizes in other tissues.
Friedreich\'s Ataxia Mutation Analysis
A) The lower cervical cord (C6) is atrophic, and the myelin of the posterior column shows marked pallor (Klüver-Barrera stains originally×6.0). (B) Numerous axonal spheroids immunostained by antineurofilament antibody, SMI-31 (brown, arrow head) and corpora amylacea by antibiquitin antibody (purple, arrow) in the posterior column nucleus (originally×514). (C) The gracile fasciculi of the upper cervical cord (C3, left) and lower lumbar cord (L2, right) (toluidine blue stain×514), show decreased axon density and thin myelin. These changes are more marked in C3 than those in L2. (D) Lower medulla (Holzer stain originally×4.4). Marked gliosis is present in the gracile and cuneate nuclei. (E) The dorsal root ganglion of right C7 (periodic acid-Shiff originally×210). Ganglion cells are well preserved and Nageotte\'s nodules are very rare. (F) Cerebellar hemisphere (haematoxylin and eosin originally×64). There is focal loss of Purkinje cells. Purkinje cells have almost disappeared in the upper folium, but are relatively preserved in the lower folium (arrow). (G) Retina (haematoxylin and eosin originally×257). The outer segment layer of photoreceptor cells has disappeared (asterisk) and the outer nuclear layer is not obvious. The inner layers of the retina are thin and atrophic (arrow). Journal of Neurology, Neurosurgery & Psychiatryjnnp.bmj.com-
The ataxia of Friedreich\'s ataxia results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses).
The condition is named after the German physician Nikolaus Friedreich, who first described it in the 1860s [30].
Hereditary Hemochromatosis
Hemochromatosis gene (HFE) testing is a blood test used to check for hereditary hemochromatosis, an inherited disorder that causes the body to absorb too much iron. The iron then builds up in the blood, liver, heart, pancreas, joints, skin, and other organs (Fig.16).
In its early stages, hemochromatosis can cause joint and belly pain, weakness, lack of energy, and weight loss. It can also cause scarring of the liver (cirrhosis), darkening of the skin, diabetes, infertility, heart failure, irregular heartbeats (arrhythmia), and arthritis. But many people do not have symptoms in the early stages.
Perls’ Prussian blue staining of liver sections from HFE+/+ and HFE−/− mice fed control diet (
In men, hereditary hemochromatosis is usually found between the ages of 40 and 60. In women, it is not usually found until after menopause because, until that time, women regularly lose blood and iron during their monthly periods. Genetic testing for hemochromatosis involves a simple blood test. DNA from the blood is extracted and the HFE gene is tested for two specific mutations in the gene known to cause the disease in most people. There are two laboratory techniques typically used to detect the two mutations: allele-specific oligonucleotide hybridization (ASO) and restriction fragment length polymorphism (RFLP) analyses. Both of these tests are designed to detect whether a specific mutation is present or absent in a DNA sample. These tests will also determine if an individual is a carrier of either mutation. The two mutations typically tested for are most commonly called C282Y and H63D. The mutations are named based on their location within the HFE gene and the change that they cause in the gene\'s instructions. The two mutations differ in how frequently they are found in the population, and in how severe your hemochromatosis is if you have them. There are other rare mutations that may predispose individuals towards abnormal iron storage. However they are not yet part of most laboratories testing panels for hemochromatosis.
Huntington Disease
Huntington\'s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems (Fig.17). It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, and indeed the disease used to be called Huntington\'s chorea.
Because HD follows an autosomal dominant pattern of inheritance, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the
Huntington\'s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. Neuron with inclusion (stained orange) caused by HD, image width 250 µm.
A pre-symptomatic test is a life-changing event and a very personal decision [33]. The main reason given for choosing testing for HD is to aid in career and family decisions [33]. Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment.[\n\t\t\t\t\t\t38] A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result [33]. Irrespective of the result, stress levels have been found to be lower two years after being tested, but the risk of suicide is increased after a positive test result [33]. Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected [12]. Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual\'s siblings will be at risk of inheriting it. Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.[39] Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxias [38]. Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer\'s disease and breast cancer [34].
B-Cell Gene Rearrangement
The B- and T-cell rearrangement test [35] can detect a monoclonal population of B- and T-cells, strongly indicative of neoplasia. This is accomplished through the use of DNA probes. The presence of a unique band on the Southern blot (Fig.18) signifies a monoclonal gene rearrangement, which can make or confirm a diagnosis of a lymphoproliferative disorder and classify the lineage as B- or T-cell. T-cell neoplasms generally behave more aggressively than B-cell neoplasms, which can have important implications for prognosis and therapy. The unique gene rearrangement "signature" can be followed during and after therapy to document remission or recurrence. The most commonly examined samples are from the blood, bone marrow, and lymph nodes, but any tissue or fluid suspected of harboring a lymphoid neoplasm can be examined.
B-Lymphocyte Immunoglobulin; Heavy Chain Gene Rearrangement. Detection of monoclonal B-cell populations in B-lymph proliferative disorders.
This test is indicated for the accurate differentiation of malignant vs. benign lymphoproliferative disorders and for establishing T tumor cell lineage. Clonal proliferations of T lymphocytes can be detected by the identification of specific DNA rearrangements in the T-cell gamma chain antigen receptor gene. The majority of lymphocytic leukemias and non-Hodgkin\'s lymphomas arise from a clonal proliferation of a single lymphoid cell that has become aberrant. T cells normally differentiate from stem (precursor) cells in a highly specific and sequential manner. The malignant transformation may take place at any stage in the maturation process and when it occurs, the resulting malignant clone bears the characteristics of the originally transformed cell and is called monoclonal. Some of the early events in the maturation process of lymphoid cells involve specific nucleic acid rearrangements within the gamma chain antigen receptor gene in T-cells.
In this image, hundredfold magnification of a single sperm precursor cell shows the chromosomes – in green – and the places where these chromosomes are most likely to break apart and re-form, called genetic recombination hotspots – in red. Genetic rearrangements at these hotspots have the potential to shuffle maternal and paternal chromosomes, the end results of which ensure that the genetic information in every sperm cell is unique. Source: Fatima Smagulova, Ph.D., USU, and Kevin Brick, Ph.D., NIDDK, NIH.
This test is indicated for the accurate differentiation of malignant vs. benign lymphoproliferative disorders and for establishing B tumor cell lineage. Clonal proliferations of B-lymphocytes can be detected by the identification of specific DNA rearrangements in the immunoglobulin gene. The majority of lymphocytic leukemias and non-Hodgkin\'s lymphomas arise from a clonal proliferation of a single lymphoid cell that has become aberrant. B cells normally differentiate from stem (precursor) cells in a highly specific and sequential manner. The malignant transformation may take place at any stage in the maturation process and when it occurs the resulting malignant clone bears the characteristics of the originally transformed cell and is called monoclonal. Some of the early events in the maturation process of lymphoid cells involve specific nucleic acid rearrangements within the immunoglobulin genes in B cells. To detect B cell gene rearrangements using PCR, primers are constructed to amplify the DNA between the conserved framework (FR) and joining (J) regions. These conserved regions lie on either side of an area within the V-J region where programmed genetic rearrangements occur during maturation. In the germline configuration found in somatic cells, these areas are widely separated (by more than 70KB) making PCR amplification across the area impossible. The sequence alteration brought about by gene rearrangement brings these regions into close proximity, making the area of amplifiable length. Each B cell has a single productive V-J rearrangement that is unique in both length and sequence. The template-free incorporation of nucleotides (N-regions) between the spliced V, D, and J gene segments also adds uniqueness to the PCR product. Therefore, when this region is amplified using DNA primers that flank this region, a clonal population of cells yields one or two prominent amplified products (amplicons) within the expected size ranges. Two products are produced in cases when the initial rearrangement was non-productive and was followed by rearrangement of the other homologous chromosome. In contrast, DNA from a normal or polyclonal population produces a bell-shaped curve (or Gaussian distribution) of amplicon products that reflects the heterogeneous population of V-J region rearrangements. Specimen: Whole blood, bone marrow or tissue(10 mL blood; 4 mL bone marrow; 0.2 g or more of tissue)
BCL-2 Gene Rearrangement
Gene Rearrangement
BCR-ABL Gene Rearrangement
Translocation
BRAF Gene Mutation Detection
BRAF is downstream of KRAS in a signaling pathway involved in cell cycling. Both KRAS and BRAF are prone to mutations in sporadic colorectal carcinomas (CRC).
This assay is capable of detecting the V600E mutation in exon 15 of BRAF. The much rarer V600A or V600G mutations would also be detectable. Detection includes PCR amplification and a single-base extension reaction that generates allele-specific fluorescently labeled probes, detectable by capillary electrophoresis.
Several studies have demonstrated that mutations in KRAS lead to constitutive activation of this pathway, which may lead to cancer progression, and this activation results in a failure to respond to anti-EGFR therapy. Recent published results indicate that mutations in the KRAS gene are present in approximately 40% of patients with metastatic colorectal adenocarcinoma, and the presence of a K-ras mutation isassociated with resistance to cetuximab and panitumumab. BRAF mutations are responsible for an additional 12-15% of patients who fail to respond to anti-EGFR treatment. This finding suggests that testing for the BRAF V600E mutation can compliment KRAS mutation analysis and may be as important as KRAS testing for treatment decisions.
c-kit Mutation Detection for Systemic Mastocytosis
Nucleotide substitutions at and adjacent to codon 816 in the catalytic domain of c-kit are common in SM. Detection of a codon 816 c-kit mutation is included as a minor diagnostic criterion in the WHO’s diagnostic criteria for SM. Determining mutational status of the c-kit gene also has pharmacogenetic implications in patients considered for investigational mast cell cytoreductive therapies and targeted small-molecule tyrosine kinase inhibitors Sequencing analysis. Polymerase Chain Reaction (PCR) is performed for DNA amplification. Primers are designed specifically for exon 17 of the c-kit gene. PCR products are sequenced and analyzed on the ABI 3130xl Genetic Analyzer.
JAK2 Mutation Analysis
The
Structural analysis of JAK2V617F kinase domain mutations. (
Bone marrow morphology demonstrating both dysplastic and proliferative features in a
KRAS Gene Mutation Detection
Mutations in the KRAS oncogene are highly prevalent in human tumors, and they most commonly occur in codons 12, 13, and 61. K-ras mutations have been detected in pancreatic, colorectal, lung, endometrial, gallbladder, and thyroid cancer at variable frequency. Accumulating evidence indicates that these mutations may play a role in prognosis and drug response. Specifically, recent published results indicate that mutations in the KRAS gene are present in approximately 40% of patients with metastatic colorectal adenocarcinoma, and the presence of a K-ras mutation is associated with resistance to cetuximab and panitumumab.
The ViennaLab K-ras StripAssay kit will detect 10 KRAS gene mutations in codons 12 and 13: G12V, G12D, G12L, G12S, G12A, G12I, G12C, G12R, G13C and G13D.
Microsatellite Instability
Microsatellites are typically co-dominant. They are used as molecular markers in genetics, for kinship, population and other studies. They can also be used to study gene duplication or deletion. Microsatellites are also known to be causative agents in human disease, especially neurodegenerative disorders and cancer.
In cells with mutations in DNA repair genes, however, some of these sequences accumulate errors and become longer or shorter. The appearance of abnormally long or short microsatellites in an individual\'s DNA is referred to as microsatellite instability.
Muir Torre syndrome [MTS] is a rare autosomal dominant inherited genodermatosis with malignant potential. It consists of at least one sebaceous gland tumor such as sebaceous adenoma, epithelioma, or carcinoma, with at least one visceral malignancy [40].
Components of Muir-Torre Syndrome. a). Sebaceous adenoma (100X) b). Colonic mucinous adenocarcinoma (100X).
Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer-prone families. The most common clinical syndromes associated with these mutations include familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). The former is associated with mutations of the APC gene, and the latter with mutations of MLH1, MSH2, MSH6, and PMS2 genes [41]. These inherited syndromes are estimated to account for only 2% to 6% of colorectal cancer cases overall. Turcot syndrome is a clinically defined, inherited syndrome associated with both colorectal cancer and a primary brain tumor.
PMLRAR Alpha t(15;17) Translocation
AMLs (Acute Myeloid Leukemias,Fig.23) [42] are characterized with chromosomal translocations resulting in the formation of fusion proteins. Understanding PML (Acute Promyelocytic Leukemia Inducer) function has become an area of intense research because of its involvement in the pathogenesis of APL (Acute Promyelocytic Leukemia), a distinct subtype of Myeloid Leukemia. In the vast majority of APL case studies, the PML gene (on Chromosome-15) fuses to the RAR-Alpha gene (Retinoic Acid Receptor-Alpha) (on Chromosome-17) as a consequence of reciprocal and balanced chromosomal translocations. In the t(15;17) chromosomal translocation, which is specific for APL, PML is found in a reciprocal translocation with the RAR-Alpha resulting in the formation of PML-RAR-Alpha and RAR-Alpha-PML fusion proteins. In a normal cell Vitamin-A (all-
In this assay, extracted RNA is subjected to 2 separate quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) procedures to detect the 2 types of PML/RARA fusion transcripts (long and short isoforms). An additional amplification for the abl gene is performed as a control for sample RNA quality and as a reference for relative quantification. The results are reported as positive or negative; the ratio of target (PML/RARA) to control (ABL) mRNA is reported for positive specimens. The isoform (short or long) is also reported. If available, a previously stored sample will be tested alongside the current specimen to assess quantitative changes with time (trend). The analytical sensitivity of this test is 1 tumor cell in 100,000 normal cells.
In APL cells due to t(15;17) chromosomal translocation the fusion protein PML-RAR-Alpha retains both DBD and LBD of RAR-Alpha, compete with normal RAR-Alpha for ligand binding and inhibits its transcriptional function through aberrant recruitment of HDACs (Histone Deacetylases). Recruitment of HDACs to PML also leads to inhibition of p53 activity and Sumolation. HDACs therefore, represent an ideal candidate for blocking the action of the fusion proteins. PML-RAR-Alpha and RAR-Alpha-PML fusion protein expression disrupts formation of NBs and paralyzes Tumor Suppression, Cellular Senescence, Mature PML degradation and normal Cell Growth and Survival. Co-expression of RAR-Alpha-PML with PML-RAR-Alpha thus results in an increase of Leukemia incidence and makes a cell more prone to pathogen invasions. All-trans-Retinoic Acid is a standard therapy for the management of APL. However, 13-
Under normal conditions PML is a potential Tumor Suppressor and is involved in Cellular Senescence, a process that controls Oncogenic Signaling leading to normal Cell Growth and Survival. PML is the organizer of nuclear matrix domains, NBs (Nuclear Bodies), with a proposed role in Apoptosis control. PML being a member of the RBCC (RING-B-Box-Coiled-Coil) Protein Family, contains three Zinc Finger-Like domains (a RING Finger and two B-Boxes) and a Coiled-Coil Dimerization domain. PML organizes NBs by targeting proteins such as Sp100 (Nuclear Antigen-Sp100), p53, Rb (Retinoblastoma) or Daxx onto these domains. These domains are also known as PODs (PML Oncogenic Domain/Promyelocytic Oncogenic Domains). PML levels increase during both Ras-induced Senescence, leading to a dramatic increase in the size and number of PODs. Survival factors/Ras signaling induce Cellular Senescence by up-regulating PML gene expression though MAPK (Mitogen-Activated Protein Kinase) activation. PML is covalently modified and conjugated to SUMO1 (Small Ubiquitin Related Modifier-1). This enables PML to form NBs and enhances their interaction with other proteins. A specific dephosphorylation event triggered by As2O3 (Arsenic Trioxide) targets PML to the nuclear matrix to form Primary PML bodies. Sumolation then induces the maturation to Secondary PML bodies. In mature PML-NBs (or Secondary PML bodies), PML forms the outer shell and many proteins (Sp100, Rb, p53, Daxx, etc) are found within its electron clear core. DNA damage induced activation of p53-dependent Apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP (CREB-Binding Protein). This acetylation of p53 is reversed by Sirt (Sirtuin (Silent Mating Type Information Regulation-2 Homolog)) releasing p53 into p53 Pathway. PML associates with Daxx-mediated Apoptosis induced by Fas/FasL (Fas Ligand) and TNF (Tumor Necrosis Factor)/TNFR (Tumor Necrosis Factor Receptor) and regulates the transcriptional repressor activity of Daxx. PML acts with Rb and p53 to promote Ras-induced Senescence. PML-Sp100 NBs act against viral invasions. Mature PML-NBs are finally degraded by the 11S Proteasome Complex.
Immunohistochemistry Stains
Immunohistochemistry is not considered a molecular technique but it is based on the antigen-antibody affinity, it has emerged as a powerful investigative tool that can provide supplemental information to the routine morphological assessment of tissues. The use of immunohistochemistry to study cellular markers that define specific phenotypes has provided important diagnostic, prognostic, and predictive information relative to disease status and biology. The application of antibodies to the molecular study of tissue pathology (Fig.24) has required adaptation and refinement of immunohistochemical techniques, particularly for use in fixed tissues. In contrast to solution-based immunoassays that detect relatively abundant native proteins, in fixed tissues the preservation of antigen is variable and unpredictable. Thus, the history of immunohistochemistry has been a constant effort to improve sensitivity for detection of rare surviving antigenic targets with the ultimate goal of integrating tissue-based analysis with proteomic information.
Immunohistochemistry Staining Stages.
Nanotechnology in clinical laboratory diagnostics
Nanotechnologies enable diagnosis at the single-cell and molecule levels, and some can be incorporated in current molecular diagnostic methods, such as biochips. Nanoparticles, such as gold nanoparticles and quantum dots, are the most widely used, but various other nanotechnological devices for manipulation at the nanoscale as well as nanobiosensors are also promising for potential clinical applications, main applications of nanotechnology [43].
Nanotechnologies will extend the limits of current molecular diagnostics and enable point-of-care diagnostics, integration of diagnostics with therapeutics, and development of personalized medicine. Although the potential diagnostic applications are unlimited, the most important current applications are foreseen in the areas of biomarker discovery, cancer diagnosis, and detection of infectious microorganisms. Safety studies are needed for in vivo use. Because of its close interrelationships with other technologies, nanobiotechnology in clinical diagnosis will play an important role in the development of nanomedicine in the future.
The attention deficit hyperactivity disorder (ADHD) is a neurobiological condition, which starts in childhood and youth phase, derived of genetics and external factors, that features an attention, hyperactivity, and impulsivity deficit excess [1]. It hits worldwide an average of 6–10% of children and 2.5–4% of adults [1, 2]. It also causes emotional self-regulation problems, executive impairment, and space and motor disorganization and may cause language problems in 30–40% of the cases [3].
The language problem in ADHD could be expressed in any age, in different intensity levels, that could bring negative effects in all daily activities and learning process, which depends on the right language acquisition during the child’s development. Among the most common comorbidities in ADHD, the abnormalities in language result in greater unsatisfactory evolution and many problems in verbal and nonverbal abilities, and even more in academic life, as a result of losses in reading and writing appropriation [4].
Thus, it is essential to understand the facts that interrelate ADHD with the cognitive and language development process, or particularly where and how ADHD neurobiological dysfunctions affect the dynamic of the neural network responsible for the receptive, integrative, and expressive language structure in different child neurodevelopment levels.
ADHD leads to emotional and cognitive self-regulation problems, which affect the executive attention and operational memory in the performance of discretionary, routine, and habitual activities. Tasks with no immediate reward which are, at the same time, necessary, priority, and essential for the development of basic abilities and general learning, adding the capacity of self-engage for whole process conclusions [5].
The cause of this disorder is still unknown but is generated by the interaction between genetic and environmental factors (Table 1) and by similar epigenetics mechanisms in neuropsychiatry diseases, and they are caused by polygenic inheritances of irregular transmission and are influenced by the environmental and gender predispositions. In the case of ADHD, the predominance is male, in the ratio of 4:1 [6]. So even without a specific cause, these abovementioned data in conjunction with epidemiological evidence provide to the specialists and international consensus a safe outline to the genetic and environmental risk factors for ADHD development (Table 1) [7]. The knowledge about these factors contributes for the clinical surveillance during early childhood in order to observe the possibility of the appearance of the first symptoms, adolescence, and adulthood.
Genetic factors | Environment factors |
---|---|
High heritability (76%) | Prematurity |
Association between twins (80%) | Low birth weight |
Carrier parents (85%) | Perinatal complications |
Average prevalence in countries (5.2%) | Maternal smoking |
Associated with genetic syndromes | Unstable and needy environments |
Associated with 20 genetic mutation | Drug use during pregnancy |
Genetics and environments risk factors for ADHD clinical features.
The symptoms and cognitive-behavioral changes of ADHD are the results of abnormalities in several neuronal connections, both cortical and subcortical, which can lead to functional impairments in one or more brain regions at the same time. The most affected and described connections mainly involve the anterior cingulate gyrus, prefrontal cortex, amygdala, striatum, and ventral integumentary area, that is, both voluntary and involuntary regions of attention that regulate the intensity and support of the attentional focus [8]. These regions are interconnected by the action of dopaminergic and noradrenergic neurotransmitters, and their deficits also contribute to lowering the attentional functional of ADHD. Added to them are the maturational delays that can gradually occur in these connections during the first years of life and which are observed in many research-based evidences in the functional neuroimaging of the brains of children with ADHD when compared to typical children. The pace of neuronal and connective maturation is slower, erratic, diffuse, or delimited and can emerge clinically at different times in the life cycle, from early childhood to late adolescence [8, 9].
Neuroimaging exams, much more developed today because of the technological advances associated with neuroscientific research, such as functional magnetic resonance imaging (fMRI), are able to analyze the maturational dissonance present in groups with ADHD from a comparative perspective with case controls. There are also brain morphometry, cortical thickness index, diffusion images (tractography), surface measurements of brain areas, gyration index, and geodetic mapping. These methods have shown that ADHD leads to microstructural changes and modifies the proportions between the functional regions of the brain [10, 11].
Thus, the various changes present in ADHD can be summarized as dismaturationals, connectives and productive, and abnormal bioavailability of neurotransmitters in the cortical (top-bottom) and subcortical (bottom-up) networks.
If we have a different and inefficient brain to process information, the next question would be: In what and how would it be different? In what functional aspects? What neuropsychological deficits are predominantly present in ADHD?
As there are still no specific biological markers, the description and clinical definition of ADHD is based on the
ADHD DSM-5 criteria. Source: Refs. [
ADHD can lead to three major functional deficits: (1) executive attention deficit, (2) operational memory problems, and (3) self-engagement in sequential tasks without reward [13].
The ADHD patient has a deficit in these three abilities and, therefore, the presentation of its clinical condition and functional difficulties are predominantly concentrated in executive functions, problems in working memory (verbal and nonverbal), difficulties in executive attention, and insufficient surveillance to fulfill correctly activities without immediate attractiveness or pleasure. Even though these characteristics are well defined, there is still no single endophenotypic pattern for ADHD or a neuropsychological profile. However, this evidence is sufficient to better understand the diagnostic approach in clinical suspicion, which evaluation methods to request, and in interdisciplinary evaluations, how to understand the deficits and discrepancies present in each of them and to associate with the main complaints of the child and the child’s school.
Thus, in the neuropsychological evaluation, we have to use the instruments that can measure selective and sustained attention, executive functions, verbal and nonverbal working memory, reaction time, and cognitive flexibility. Furthermore, correlate these assessed skills with the behavior of the assessed person during the exam, their reactions, avoidances, profile of behavioral responses to failure and test prolongation, etc. The description of these behaviors should be part of the feedback for the specialized team and will be useful for the conclusions.
After it all, and the language? The child’s learning, from a young age, in the early years, depends on several factors and, neurobiologically, in his first contact with the world, he needs his sensory and perceptual functions. Vision, hearing, touch, etc. and its perceptual centers in the brain added to the qualitative perceptual functions as well, such as attention and memory, to correctly absorb and fix the selected stimuli in the brain. Language, in this context, results from its innate abilities (presence of a network and integral structure for the language) and the internalization of the “languages” perceived around it. Little is known yet whether ADHD affects more innate or acquired language, but in several comparative studies associating both conditions, it appears that ADHD influences the appearance of language disorders (LDs) much more than the opposite [14, 15]. There are sufficient data demonstrating that, in groups of children with LD, there are proportionally fewer children with ADHD than when evaluating groups of ADHD seeking to verify the presence of LD [16].
The adequate construction and the full development of language structuring processes in childhood depend heavily on attentional, executive, and working memory processes. The union of all these factors in the construction of language can be understood by several psychological theories and theoretical constructs, but it is well summarized in the
The skills that make up the buffer are executive attention, working memory, and phonological awareness (Figure 2). Among the three, the first two are functions specifically associated with ADHD. In ADHD, both are deficient, unstable, and functionally oscillating and end up negatively influencing the development of speech and language in the early years of life, which are skills that depend on phonological awareness and therefore affect the cognitive processes of language.
Interrelation among executive attention, working memory, and phonological awareness to building reading and writing.
In this context, it seems that the selective and sustained attentional deficit would be the main center of disfunction. Attention selectively focuses on one aspect of information and excludes the other. The child who is learning the language from an early age must be able to selectively focus on relevant linguistic information and naturally ignore irrelevant information. He/she must sustain this focus to form an association between an object and a label in the word learning process. When the input source of the language or object changes, the child must also be able to draw attention away to avoid losing relevant information. As language develops, he/she must be able to attend linguistic sequences and social routines for the development of grammatical and pragmatic skills. If he/she cannot do this, whether due to attention deficits or early language problems, the process of language acquisition and consolidation will be fragmented and deficient.
There are also other factors that associate ADHD with language from a genetic and developmental point of view. Children with ADHD may have, in up to 40% of cases, speech development delays because it can affect the perception of sounds during the speech of his peers and caregivers, generate joint problems, and increase chance of stuttering; and by forming phonemes and syllable junction, it is possible to observe a greater slowness in syllabic awareness in these patients [19]. This means the disorder affects attention, motor control (inhibitory and rhythm), and working memory, eventually leading the referred gaps in the evolution of the articulatory and phonological organization.
Another factor described would be the presence of mutations and other genetic abnormalities between both conditions, which would lead to the transmission of their deficits present in the parent(s) to their children. And, finally, the separated association of both conditions that were generated in the same child without one being incidental to the other, but both sharing dysfunctions in specific areas in their interaction, participating in reading and writing language-related functions and language structure [20].
Several publications and researches show language alterations in ADHD patients [21]. There is still a need for greater research about the genetic or environmental factors involved. Some evidence describing genes that appear to be at the interface of both conditions already exists, such as FOX2 and CNTNAP2 [22]. But they still lack models that really demonstrate the solid link between them, what kind of comorbidity is included, and what genetic relationships exist (and, specifically, with which genes or mutations). For now, the most common studies are based on relative risk measures (RRs) and odds ratio (OR), and in these, they observe risks of two to six times greater language problems in ADHD groups when compared to controls [19].
ADHD can affect four axes of language in childhood and adolescence: (1) delays in speech acquisition and language structuring (mainly articulatory, phonological, lexical, and morphosyntactical but also, in a second plane, pragmatical); (2) hearing processing disorders; (3) abnormalities in speech (speech, voice, and fluency); and (4) deficits in the linguistic processes involved in the appropriation of reading and writing and math learning (Table 2).
Axes affected in speech therapy | ADHD effects |
---|---|
Delays in acquiring speech and language during development | Delay in speech acquisition, articulatory errors, memory deficit, and phonological manipulation, problems with rhythm and self-control to speak |
Disorders in auditory processing | Deficits in integration, temporality, and association of sounds |
Abnormalities in speech | A deficit in pragmatic language and in the perception of prosody during the speech, disrespect to the shifts of conversation, loss of significant moments to understand the intention of the speech, disorganization in the sequence of who will speak, frequent forgetfulness, and long-winded speech |
Deficits in the language of reading and writing | Slowness in literacy, delayed processing and spelling engine, poverty in the interpretation and production of texts, spatial trouble remembering quotes and locations in terms of text, and little memorization of facts, concepts, rules that make up the reading and writing |
Four axes of language in childhood and adolescence affected for ADHD.
In research conducted with 76 children with ADHD and an average age of 11 years old, Bruce e cols. (2006) observed that more than half of them were accompanied by a speech therapist and the rest did not receive any intervention. The results showed that most children had problems in pragmatic language, language comprehension with greater receptive communication deficits and delays, and learning gaps in reading and writing. In this same work, cognitive tests were carried out and the evidence showed that the pragmatic losses were due to the inattention and impulsive behavior of ADHD [23]. There are at least seven ADHD symptoms present in the
Besides, the existence of speech delay, articulatory problems, and stutter are relatively frequent in ADHD. Researches show that 25–40% of the cases suffer from such alterations and that indicates possible harm in complex acquisition with aging until it becomes predisposed comorbidity with dyslexia [24]. Many children with ADHD need speech therapy in their early ages of life, and a great part of them keep the therapy until the beginning of school and literacy years, but demonstrations show that with early intervention, the prognostic can get much better [25]. Pieces of evidence show larger deficits in the phonological and articulatory abilities, semantic structure, vocabulary repertoire, reading comprehension, and pragmatic process during dialogs and discursive abilities [26, 27].
The hearing processing is a set of specific and nonspecific skills associated with the set of skills necessary for an adequate perception, integration, and interpretation of what is heard in the most diverse environments. ADHD, due to its characteristics, especially affects the nonspecific skills necessary for auditory processing: the integrative, temporal, and organizational aspects of auditory discrimination. Almost 50% of cases of auditory processing disorders have comorbid symptoms of ADHD and their treatment requires intervention in both for good results to occur [28, 29].
Regarding discursive skills, several changes are observed in people with ADHD. Problems in sustained attention, impulsiveness to conclude and accelerate the discursive times and attentional lack of control, and seeming not to hear the interlocutor make these patients have greater difficulty in applying the right words and expressions at the right time and with plausible intentionality. Through it away occurs both to listening and delivering speeches and, especially, in the consistent persistence of the records heard, they show sudden and erratic self-distractions, little perception for moments of exclamations and tangential comments, hum and make strange noises during the process, enters with new topics decontextualized, and have little sensitivity to perceive commotions during the speech [2]. These difficulties can lead to great losses in the classroom, in lectures, in the coordination of speeches during a comment, and in the correct and strict understanding of a dialog or a recommendation or even “scolding” or warnings from your parents or caregivers. Perhaps, this explains why these patients tend to repeat the same mistakes or do not understand small insinuations or messages contained in the speeches that they hear and receive severe and repeated criticisms in social relations for this.
The significant problems and deficits observed in the processes of learning to read and write and, even later, in the literacy phase and in the already consolidated phase of the acquisition of these skills in these patients are varied and numerous—and today well described—in the scientific literature. People with ADHD have delays and gaps in the process of acquiring and appropriating basic skills for learning to read and write in up to 30–40% of cases. We see little memorization of graphic and phonemic symbols, difficulty in joining letters, and graphophonemic decoding. They usually forget much of what they saw or heard in class and can evolve greater irregularity so that they will acquire the proper fluency and automatic word recognition, sentences negatively affecting the ability to interpret, assimilate statements, and produce texts coherently. They may have more difficulty in organizing the words and phrases sequentially and “lose themselves” in the cohesion of the set of information they write in addition to often not being able to remember all the significant details to clarify an argument in writing.
Not being able to remember orthographic rules or perceive prosodic circumstances in the text to properly apply punctuation or paragraphs are constant in ADHD and can damage the semantic-pragmatic nexus. The longer and subliminal the writings, the greater the difficulties in textual praxis and the subsequent errors. Not to mention the problems of graphomotor coordination generated by the problems of rhythm, persistence, and inhibiting self-control of manual writing mobility, which in addition to deteriorating handwriting, leads to early tiredness, pain in the limb, and aversion/displeasure toward writing. They do not even take care of their writing tools because they lose, break, and play more with them in their hands. By making use of them at the time of class, they confusingly drop, destroy, and barely manage to stay at your desk during the class period. Furthermore, as they usually strain to perform in a less productive/in-depth manner than their colleagues, their text ends elementary, without details, abbreviated, saving words and, even so, they think what they have done is great and “enough”; but, actually, it had resulted in an insufficient work that is poorly done and that had to be corrected. Persistent, recurring delays lead to a progressive inadequate acquisition of skills and many of these young people progress to learning disorders [19].
All of this evidence can help to understand why ADHD patients act socially more with their hands (by actions) than with their eyes and mouth (by structuring words and arguments) and then being less assertive, wordy, and emotionally loosely organized in social interaction. Not to mention the significant losses in school performance, poor interpretation of statements, and low self-esteem for academic processes. The risk of school failures and dropouts is four times higher in these patients and reduces the chance of completing and receiving a university degree by up to eight times [30, 31].
Finally, the knowledge about these changes by health and education professionals is very important because the effects on the global development of the child’s language will lead to a negative, progressive impact in all related areas. The severe appearance of gaps in school learning, in the understanding of verbal and nonverbal processes of social communication, and the emotional and affective relationships that depend on language skills can lead to subjective problems in the patient and in family dynamics with different impacts throughout his life.
In the face of all the observations and the aforementioned evidence, the hearing care professional should be prepared to evaluate these children. Delays in speech and language acquisition should always suggest the possibility of ADHD as well as the presence of quantitative and qualitative deficits in BP, speech skills, and reading and writing, depending on the chronological age. However, studies and publications on ADHD and aspects related to language around the world still lack, except on the area of reading, which is the only one with more robust studies [32].
There is still no protocol or consensual or systematic recommendations on how the speech therapist can act in this area. However, there are articles and publications that can help this professional to create a basic protocol to better direct their work and to assist in a complementary, more refined, and objective way for the interdisciplinary team in order to better conclude the diagnosis and more broadly direct future strategies’ therapeutic [32, 33].
Even so, some recommendations can help, right now, to improve the procedures of speech therapy assessment in ADHD:
Knowing deeply the signs and symptoms of ADHD.
Knowing how to correlate the neurobiology and neuropsychology of ADHD with speech therapy assessment.
Track in the child’s neurodevelopment early signs of ADHD and possible effects of ADHD on the child’s speech and language.
Knowing more clinically the signs of impaired reading and writing that may be associated with language problems or ADHD.
Interpreting the BP test while considering the nonspecific factors that may be negatively influencing the results.
Seeking consensus, new publications, and speech therapy forums or congresses that will systematize instruments to be used in the assessment of these children (instruments in speech therapy, even a foreign language, can help a lot) (Table 3) [21].
Test name | Age | Domains evaluated |
---|---|---|
Clinical evaluation of language fundamentals—4 | 5–21 years | Formulation of sentences, the definition of words, and their classes and semantics |
Test of language development primary | 4–9 years | Semantics and grammar, reception and expression, and general language skills |
Communication abilities diagnostic test | 3–9 years | Varied tests for syntax, semantics, and pragmatics during stories, games, and conversations |
Language processing test 3: Elementary | 5–11 years | Association tasks, categorization, similarities/differences, and multiple meanings and attributes |
Children’s communication checklist-2 | 4–16 years | Evaluates verbal and nonverbal social communication |
Assessment of comprehension and expression | 6–11 years | Understanding sentences, inferences, nonliteral language, and use of narratives |
Test of language competence | 5–18 years | Ambiguous sentences, comprehension, inferences, and figurative language |
Test of pragmatic language | 8–18 years | Pragmatic language |
Test of attention, executive, and language functions | Under 5 years | Translated available tests, validated in neuropsychology and speech therapy |
Instruments in speech therapy for language assessment in ADHD.
Knowing the aspects of ADHD related to the development, structuring and school management of language is essential for undertaking an adequate assessment of these patients during and after the diagnostic process. During, in order to decisively contribute to speech therapy data in the confirmation of a further condition without definitive biomarkers. After, in order to delineate with the results the treatment needs that may involve the speech therapist, who has the role of intensively intervening in deficits that are not within the competence of the school or family but should be corrected by the specialist in order to provide a more favorable and persevering school performance.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. Physiology research may be linked to development, aging, environment, regular and pathological processes, adaptation and evolution, exercise, or several other factors affecting, or involved with, animal physiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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