Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases

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Publisher : Frontiers Media SA
ISBN 13 : 2832546528
Total Pages : 355 pages
Book Rating : 4.8/5 (325 download)

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Book Synopsis Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases by : Chengjin Gao

Download or read book Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases written by Chengjin Gao and published by Frontiers Media SA. This book was released on 2024-03-19 with total page 355 pages. Available in PDF, EPUB and Kindle. Book excerpt: The systemic inflammatory response is evident in inflammatory diseases, and the immune system secretes many cytokines involved, resulting in a robust immune response. For example, the pathogenesis of sepsis includes abnormal immune cell activation in the early stages as well as sepsis-related immunosuppression. During the immunosuppressive phase, CD4+ T cells, CD8+ T cells, Th17 cells, and γδ T cells are reduced while regulatory T cells increase. At the same time, T lymphocytes and neutrophils, as immune effector cells, interact with each other and play a key role in regulating the immune response to immune-inflammatory diseases. The increased release of neutrophil extracellular trap networks (NETs) by neutrophils leads to a significant upregulation of NETs-DNA-MPO, which further aggravates the septic inflammatory response and organ functional impairment. Therefore, it is important to deeply investigate the characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases, and targeting therapies against them may provide new ideas for the precise treatment of diseases.

Polymyositis and Dermatomyositis

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Publisher : Butterworth-Heinemann
ISBN 13 : 1483163040
Total Pages : 362 pages
Book Rating : 4.4/5 (831 download)

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Book Synopsis Polymyositis and Dermatomyositis by : Marinos C. Dalakas

Download or read book Polymyositis and Dermatomyositis written by Marinos C. Dalakas and published by Butterworth-Heinemann. This book was released on 2013-10-22 with total page 362 pages. Available in PDF, EPUB and Kindle. Book excerpt: Polymyositis and Dermatomyositis provides extensive information regarding Polymyositis and Dermatomyositis (PM/DM), which is described as a heterogeneous disease complex. This book is divided into four sections: Part I (Clinical Features) covers the classification of PM/DM, details of the clinical presentation, and the disease's association with the other connective tissue disorders and malignancies. Part II (Etiology and Mechanisms) covers advances in the immunopathology and viral etiology of PM/DM along with a frequently recognized entity: inclusion body myositis. Part III (Diagnosis and Treatment) covers the histologic, muscle enzyme histochemical, electron microscopic, and resin histology features of PM/DM along with those electromyographic features that could help make a more accurate diagnosis. Part IV (Overview) summarizes the issues that may not have been clear and highlights differing and unsettled views or present available data. This text is directed to clinicians in private practice or in academic institutions concerned with PM/DM patients, including neurologists, rheumatologists, pediatricians, dermatologists, physiatrists, and neuromuscular investigators. This book is intended as well for neuromuscular pathologists who interpret muscle biopsy specimens and electromyographers who perform EMG studies to help determine the clinical diagnosis. Researchers in immunology and immunopathology of neuromuscular diseases will find discussions in this book invaluable.

Inflammation, 4 Volume Set

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Publisher : John Wiley & Sons
ISBN 13 : 3527338993
Total Pages : 1818 pages
Book Rating : 4.5/5 (273 download)

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Book Synopsis Inflammation, 4 Volume Set by : Jean-Marc Cavaillon

Download or read book Inflammation, 4 Volume Set written by Jean-Marc Cavaillon and published by John Wiley & Sons. This book was released on 2018-02-20 with total page 1818 pages. Available in PDF, EPUB and Kindle. Book excerpt: Dieses Fachbuch erläutert die molekularen Grundlagen von Entzündungen, spannt den Bogen zu Infektionskrankheiten und den Zusammenhang zwischen Entzündungen und chronischen Erkrankungen, behandelt abschließend den Heilungsprozess und zeigt Therapiemöglichkeiten.

Inflammation and Cancer

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Publisher : Springer
ISBN 13 : 3034808372
Total Pages : 489 pages
Book Rating : 4.0/5 (348 download)

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Book Synopsis Inflammation and Cancer by : Bharat B. Aggarwal

Download or read book Inflammation and Cancer written by Bharat B. Aggarwal and published by Springer. This book was released on 2014-05-12 with total page 489 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume examines in detail the role of chronic inflammatory processes in the development of several types of cancer. Leading experts describe the latest results of molecular and cellular research on infection, cancer-related inflammation and tumorigenesis. Further, the clinical significance of these findings in preventing cancer progression and approaches to treating the diseases are discussed. Individual chapters cover cancer of the lung, colon, breast, brain, head and neck, pancreas, prostate, bladder, kidney, liver, cervix and skin as well as gastric cancer, sarcoma, lymphoma, leukemia and multiple myeloma.

Adverse Effects of Vaccines

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Publisher : National Academies Press
ISBN 13 : 0309214351
Total Pages : 894 pages
Book Rating : 4.3/5 (92 download)

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Book Synopsis Adverse Effects of Vaccines by : Institute of Medicine

Download or read book Adverse Effects of Vaccines written by Institute of Medicine and published by National Academies Press. This book was released on 2012-04-26 with total page 894 pages. Available in PDF, EPUB and Kindle. Book excerpt: In 1900, for every 1,000 babies born in the United States, 100 would die before their first birthday, often due to infectious diseases. Today, vaccines exist for many viral and bacterial diseases. The National Childhood Vaccine Injury Act, passed in 1986, was intended to bolster vaccine research and development through the federal coordination of vaccine initiatives and to provide relief to vaccine manufacturers facing financial burdens. The legislation also intended to address concerns about the safety of vaccines by instituting a compensation program, setting up a passive surveillance system for vaccine adverse events, and by providing information to consumers. A key component of the legislation required the U.S. Department of Health and Human Services to collaborate with the Institute of Medicine to assess concerns about the safety of vaccines and potential adverse events, especially in children. Adverse Effects of Vaccines reviews the epidemiological, clinical, and biological evidence regarding adverse health events associated with specific vaccines covered by the National Vaccine Injury Compensation Program (VICP), including the varicella zoster vaccine, influenza vaccines, the hepatitis B vaccine, and the human papillomavirus vaccine, among others. For each possible adverse event, the report reviews peer-reviewed primary studies, summarizes their findings, and evaluates the epidemiological, clinical, and biological evidence. It finds that while no vaccine is 100 percent safe, very few adverse events are shown to be caused by vaccines. In addition, the evidence shows that vaccines do not cause several conditions. For example, the MMR vaccine is not associated with autism or childhood diabetes. Also, the DTaP vaccine is not associated with diabetes and the influenza vaccine given as a shot does not exacerbate asthma. Adverse Effects of Vaccines will be of special interest to the National Vaccine Program Office, the VICP, the Centers for Disease Control and Prevention, vaccine safety researchers and manufacturers, parents, caregivers, and health professionals in the private and public sectors.

Early Rheumatoid Arthritis

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Publisher :
ISBN 13 : 9781416027676
Total Pages : 0 pages
Book Rating : 4.0/5 (276 download)

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Book Synopsis Early Rheumatoid Arthritis by : Paul Emery

Download or read book Early Rheumatoid Arthritis written by Paul Emery and published by . This book was released on 2005 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This issue covers the latest developments in the understanding of rheumatoid arthritis at the early stage. Treatments such as with newer biologic agents and conventional disease-modifying antirheumatic drugs are reviewed. Also included are articles on imaging modalities as a means of identifying those in the early stages and monitoring response to treatment.

Molecular Pathology

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Publisher : Academic Press
ISBN 13 : 0128027878
Total Pages : 805 pages
Book Rating : 4.1/5 (28 download)

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Book Synopsis Molecular Pathology by : William B. Coleman

Download or read book Molecular Pathology written by William B. Coleman and published by Academic Press. This book was released on 2017-11-09 with total page 805 pages. Available in PDF, EPUB and Kindle. Book excerpt: As the molecular basis of human disease becomes better characterized, and the implications for understanding the molecular basis of disease becomes realized through improved diagnostics and treatment, Molecular Pathology, Second Edition stands out as the most comprehensive textbook where molecular mechanisms represent the focus. It is uniquely concerned with the molecular basis of major human diseases and disease processes, presented in the context of traditional pathology, with implications for translational molecular medicine. The Second Edition of Molecular Pathology has been thoroughly updated to reflect seven years of exponential changes in the fields of genetics, molecular, and cell biology which molecular pathology translates in the practice of molecular medicine. The textbook is intended to serve as a multi-use textbook that would be appropriate as a classroom teaching tool for biomedical graduate students, medical students, allied health students, and others (such as advanced undergraduates). Further, this textbook will be valuable for pathology residents and other postdoctoral fellows that desire to advance their understanding of molecular mechanisms of disease beyond what they learned in medical/graduate school. In addition, this textbook is useful as a reference book for practicing basic scientists and physician scientists that perform disease-related basic science and translational research, who require a ready information resource on the molecular basis of various human diseases and disease states. - Explores the principles and practice of molecular pathology: molecular pathogenesis, molecular mechanisms of disease, and how the molecular pathogenesis of disease parallels the evolution of the disease - Explains the practice of "molecular medicine and the translational aspects of molecular pathology - Teaches from the perspective of "integrative systems biology - Enhanced digital version included with purchase

Liver Immunology

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Publisher : Springer Science & Business Media
ISBN 13 : 331902096X
Total Pages : 482 pages
Book Rating : 4.3/5 (19 download)

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Book Synopsis Liver Immunology by : M. Eric Gershwin

Download or read book Liver Immunology written by M. Eric Gershwin and published by Springer Science & Business Media. This book was released on 2013-11-19 with total page 482 pages. Available in PDF, EPUB and Kindle. Book excerpt: Liver Immunology: Principles and Practice, Second Edition begins with important information about the epidemiology and mortality of liver disease worldwide. This information is followed by chapters related to basic immunology, application of liver immunology for diagnosis, and several excellent chapters that provide a solid foundation for understanding immune-mediated liver disease, including those associated with the biliary tree. A chapter on non-hepatic manifestations of immune mediated liver disease helps provide context for how these diseases affect the patient overall. In addition, chapters discuss various discrete immunologically-mediated infectious liver disorders including those related to bacteria, parasites, and all of the classic viruses. Chapters on the traditional autoimmune liver diseases -- primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis as well as overlap syndrome – are also included. The breadth of this comprehensive second edition is highlighted by chapters on alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver disease, among others. This invaluable new edition ends with a forward-looking view of future directions and how the field might meet the challenge of refractory patients. Developed by a renowned group of authors, Liver Immunology: Principles and Practice, Second Edition will again serve as a comprehensive textbook by providing an excellent overview for this rapidly evolving field. It greatly adds to the understanding of the pathogenesis of these diseases, while also providing novel insights that can be harnessed into helping improve the care of patients afflicted with various immune-mediated diseases. This volume will again be a must-read for clinicians at all levels, investigators and students.

Newman and Carranza's Clinical Periodontology and Implantology E-Book

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Publisher : Elsevier Health Sciences
ISBN 13 : 0323878881
Total Pages : 1877 pages
Book Rating : 4.3/5 (238 download)

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Book Synopsis Newman and Carranza's Clinical Periodontology and Implantology E-Book by : Michael G. Newman

Download or read book Newman and Carranza's Clinical Periodontology and Implantology E-Book written by Michael G. Newman and published by Elsevier Health Sciences. This book was released on 2023-04-28 with total page 1877 pages. Available in PDF, EPUB and Kindle. Book excerpt: **Selected for Doody's Core Titles® 2024 in Dentistry** Learn and master a range of clinical techniques and achieve therapeutic goals with Newman and Carranza's Clinical Periodontology and Implantology, 14th Edition! Unmatched for its comprehensive approach, this resource provides detailed, up-to-date information on the etiology and pathogenesis of periodontal disease. Basic and advanced evidence-based information on the various treatment modalities employed in periodontics and implantology is presented in an easy-to-read format, with callout boxes throughout the text highlighting the clinical relevance of foundational basic science information. Full-color photos and radiographic images depict periodontal conditions and procedures, and the Atlas of Periodontal Pathology is one of the most comprehensive ever compiled in a periodontal textbook. Written by a team of leading experts led by Michael G. Newman, this text not only demonstrates how to perform periodontal procedures but explains the evidence supporting each treatment and provides knowledge on how to achieve the best possible outcomes of periodontal therapy and implant treatment. An eBook version is included with print purchase, providing access to all the text, figures, and references, plus the ability to search, customize content, make notes and highlights, and have content read aloud. The eBook version included with print purchase also includes Periopixel 3D color illustrations, a periodontal classification calculator and interactive learning tool, review questions, case studies, videos, 3D animations, and more! This edition features new chapters on Precision Medicine, Pocket Reduction Therapy, Periodontal Referral, and Digital Implant Workflows, as well as an updated glossary of terms linked to the eBook. It also features first-of-its-kind content on the effects of COVID-19 on treatment from key opinion leaders in this area. Case studies reflect the new format of the Integrated National Board Dental Exam (INBDE). - Full-color photos, illustrations, radiographs, animations, simulations, and videos demonstrate how to perform periodontal and implant procedures. - Current information on clinical techniques in periodontology and the latest advances in basic science. - Evidence-based treatment planning provides knowledge on how to achieve the best possible outcomes of periodontal therapy and implant treatment. - Extensive color atlas of periodontal pathology - Internationally known experts contribute chapters on their areas of specialty. - An eBook version is included with print purchase, providing access to all the text, figures, and references, plus the ability to search, customize content, make notes and highlights, and have content read aloud.

Idiotypes in Medicine: Autoimmunity, Infection and Cancer

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Publisher : Elsevier
ISBN 13 : 0080534430
Total Pages : 557 pages
Book Rating : 4.0/5 (85 download)

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Book Synopsis Idiotypes in Medicine: Autoimmunity, Infection and Cancer by : R.C. Kennedy

Download or read book Idiotypes in Medicine: Autoimmunity, Infection and Cancer written by R.C. Kennedy and published by Elsevier. This book was released on 1997-11-19 with total page 557 pages. Available in PDF, EPUB and Kindle. Book excerpt: This is the most comprehensive review of the idiotypic network available. All the current knowledge of idiotypes of the various antibodies is incorporated in this volume. The pathogenic role of idiotypes in autoimmunity and cancer is reviewed in depth. The therapeutic part focusses on harnessing anti-idiotypes for treating autoimmunological disorders, and on the employment of idiotypes for vaccines in cancer and infectious diseases, as well as explaining the manipulation of the idiotypic network in autoimmunity and cancer idiotypes and vaccines.

Mitochondrial Dysfunction

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Publisher : Elsevier
ISBN 13 : 1483218619
Total Pages : 527 pages
Book Rating : 4.4/5 (832 download)

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Book Synopsis Mitochondrial Dysfunction by : Lawrence H. Lash

Download or read book Mitochondrial Dysfunction written by Lawrence H. Lash and published by Elsevier. This book was released on 2013-10-22 with total page 527 pages. Available in PDF, EPUB and Kindle. Book excerpt: Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.

Stress Challenges and Immunity in Space

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Publisher : Springer Nature
ISBN 13 : 3030169960
Total Pages : 756 pages
Book Rating : 4.0/5 (31 download)

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Book Synopsis Stress Challenges and Immunity in Space by : Alexander Choukèr

Download or read book Stress Challenges and Immunity in Space written by Alexander Choukèr and published by Springer Nature. This book was released on 2019-11-27 with total page 756 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book explains how stress – either psychological or physical – can activate and/or paralyse human innate or adaptive immunity. Adequate immunity is crucial for maintaining health, both on Earth and in space. During space flight, human physiology is specifically challenged by complex environmental stressors, which are most pronounced during lunar or interplanetary missions. Adopting an interdisciplinary approach, the book identifies the impact of these stressors – the space exposome – on immunity as a result of (dys-)functions of specific cells, organs and organ networks. These conditions (e.g. gravitation changes, radiation, isolation/confinement) affect immunity, but at the same time provide insights that may help to prevent, diagnose and address immune-related health alterations. Written by experts from academia, space agencies and industry, the book is a valuable resource for professionals, researchers and students in the field of medicine, biology and technology. The chapters “The Impact of Everyday Stressors on the Immune System and Health”, “Stress and Radiation Responsiveness” and “Assessment of Radiosensitivity and Biomonitoring of Exposure to Space adiation” are available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

Biological Microarrays

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Publisher : Humana Press
ISBN 13 : 9781934115954
Total Pages : 0 pages
Book Rating : 4.1/5 (159 download)

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Book Synopsis Biological Microarrays by : Ali Khademhosseini

Download or read book Biological Microarrays written by Ali Khademhosseini and published by Humana Press. This book was released on 2010-10-28 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent developments in microarray technology have changed the landscape of biology and biomedical research, and they have revolutionized RNA and DNA research. In Biological Microarrays: Methods and Protocols, expert researchers explore exciting new developments in the field, providing a comprehensive approach to biological microarrays that conveys not only the state-of-the-art fundamentals, but also includes applications of the most innovative methods. Chapters address both the application of biological microarrays, including DNA/RNA, apatmer, proteins, tissues, oligonucleotides, carbohydrates, biomaterials, cells, bacteria, and virus microarrays, and also explore the different techniques used for generating microarray platforms. Composed in the highly successful Methods in Molecular BiologyTM series format, each chapter contains a brief introduction, step-by-step methods, a list of necessary materials, and a Notes section which shares tips on troubleshooting and avoiding known pitfalls. Wide-ranging and revolutionary, Biological Microarrays: Methods and Protocols serves as a primary source for academics, practitioners, and professionals in related fields, including biologists, biotechnologists, biochemists, analytical chemists, and biomedical, physical, and microsystems engineers, to name a few, appealing to all of those interested in the present and future state of biological microarray research.

Pathophysiology - E-Book

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Publisher : Elsevier Health Sciences
ISBN 13 : 032341320X
Total Pages : 1720 pages
Book Rating : 4.3/5 (234 download)

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Book Synopsis Pathophysiology - E-Book by : Kathryn L. McCance

Download or read book Pathophysiology - E-Book written by Kathryn L. McCance and published by Elsevier Health Sciences. This book was released on 2018-01-10 with total page 1720 pages. Available in PDF, EPUB and Kindle. Book excerpt: Learn the what, how, and why of pathophysiology! With easy-to-read, in-depth descriptions of disease, disease etiology, and disease processes, Pathophysiology: The Biologic Basis for Disease in Adults and Children, 8th Edition helps you understand the most important and most complex pathophysiology concepts. This updated text includes more than 1,300 full-color illustrations and photographs to make it easier to identify normal anatomy and physiology, as well as alterations of function. This edition includes a NEW chapter on obesity and nutritional disorders, along with expanded coverage of rare diseases and epigenetics. It's the most comprehensive and authoritative pathophysiology text available! - The most comprehensive and authoritative pathophysiology text on the market provides unparalleled coverage of Pathophysiology content. - Over 1,300 full-color illustrations and photographs depict the clinical manifestations of disease and disease processes — more than in any other pathophysiology text. - Consistent presentation of diseases includes pathophysiology, clinical manifestations, and evaluation and treatment. - Lifespan content includes ten separate pediatric chapters and special sections with aging and pediatrics content. - Outstanding authors Kathryn McCance and Sue Huether have extensive backgrounds as researchers and instructors, and utilize expert contributors, consultants, and reviewers in developing this edition. - Algorithms and flowcharts of diseases and disorders make it easy for you to follow the sequential progression of disease processes. - Additional What's New boxes highlight the most current research and clinical development. - Nutrition and Disease boxes explain the link between concepts of health promotion and disease. - Chapter summary reviews provide concise synopses of the main points of each chapter. - NEW! Chapter on obesity and nutritional disorders thoroughly covers these growing global concerns. - NEW! Added coverage of rare diseases and epigenetics further explore genetic disease traits. - NEW! Over 50 new or heavily revised illustrations visually highlight pathophysiology concepts. - NEW! More than 30 new 3D animations on Evolve bring difficult concepts to life for a new perspective on disease processes.

Mechanisms of Vascular Disease

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Publisher : University of Adelaide Press
ISBN 13 : 1922064009
Total Pages : 589 pages
Book Rating : 4.9/5 (22 download)

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Book Synopsis Mechanisms of Vascular Disease by : Robert Fitridge

Download or read book Mechanisms of Vascular Disease written by Robert Fitridge and published by University of Adelaide Press. This book was released on 2011 with total page 589 pages. Available in PDF, EPUB and Kindle. Book excerpt: New updated edition first published with Cambridge University Press. This new edition includes 29 chapters on topics as diverse as pathophysiology of atherosclerosis, vascular haemodynamics, haemostasis, thrombophilia and post-amputation pain syndromes.

Primary Immunodeficiency Disorders

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Publisher : Academic Press
ISBN 13 : 0124115543
Total Pages : 377 pages
Book Rating : 4.1/5 (241 download)

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Book Synopsis Primary Immunodeficiency Disorders by : Amos Etzioni

Download or read book Primary Immunodeficiency Disorders written by Amos Etzioni and published by Academic Press. This book was released on 2014-09-13 with total page 377 pages. Available in PDF, EPUB and Kindle. Book excerpt: Primary Immunodeficiency Disorders: A Historic and Scientific Perspective provides a complete historical context that is crucial for students and researchers concerned with primary immunodeficiency. When researchers have a poor understanding of the way we arrived where we are in research, they can miss important points about a disease, or miss out on how to approach new diseases. This historical knowledge of research can assist greatly by showing how it was done in the past, demonstrating the successes and failures, so that it can be done better in the future. This book provides an understanding of the process going from clinical problem to lab and back to the clinic, based on historical experiences. Its chapters proceed from the discovery of the T and B cell lineages through the first BMT for immunodeficiency disorder; lab investigation and gene therapy for PID; the discovery of the gene for AT and its function; understanding cytokine defects; and many other stops along the way. - Facilitates communication among physicians and other investigators concerned with immunological and inflammatory diseases - Summarizes for the first time all the known facts from 60 years of primary immunodeficiency research, and teaches how an important field in medicine was established - Provides stimulating discussions on developing new medical therapiesHighlights the importance of studying humans to understand mechanisms of disease that affect humans

Molecular Mechanisms in Stress and Trauma Related Disorders

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Publisher : Frontiers Media SA
ISBN 13 : 2889636534
Total Pages : 142 pages
Book Rating : 4.8/5 (896 download)

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Book Synopsis Molecular Mechanisms in Stress and Trauma Related Disorders by : Anthony S. Zannas

Download or read book Molecular Mechanisms in Stress and Trauma Related Disorders written by Anthony S. Zannas and published by Frontiers Media SA. This book was released on 2020-04-20 with total page 142 pages. Available in PDF, EPUB and Kindle. Book excerpt: This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.