Author: Gabor G. Kovacs
Publisher: Cambridge University Press
ISBN: 1316337650
Category : Medical
Languages : en
Pages : 320
Book Description
This practical guide to the diagnosis of neurodegenerative diseases discusses modern molecular techniques, morphological classification, fundamentals of clinical symptomology, diagnostic pitfalls and immunostaining protocols. It is based on the proteinopathy concept of neurodegenerative disease, which has influenced classification and provides new strategies for therapy. Numerous high-quality images, including histopathology photomicrographs and neuroradiology scans, accompany the description of morphologic alterations and interpretation of immunoreactivities. Diagnostic methods and criteria are placed within recent developments in neuropathology, including the now widespread application of immunohistochemistry. To aid daily practice, the guide includes diagnostic algorithms and offers personal insights from experienced experts in the field. Special focus is given to the way brain tissue should be handled during diagnosis. This is a must-have reference for medical specialists and specialist medical trainees in the fields of pathology, neuropathology and neurology working with neuropathologic features of neurodegenerative diseases.
Neuropathology of Neurodegenerative Diseases
Author: Gabor G. Kovacs
Publisher: Cambridge University Press
ISBN: 1316337650
Category : Medical
Languages : en
Pages : 320
Book Description
This practical guide to the diagnosis of neurodegenerative diseases discusses modern molecular techniques, morphological classification, fundamentals of clinical symptomology, diagnostic pitfalls and immunostaining protocols. It is based on the proteinopathy concept of neurodegenerative disease, which has influenced classification and provides new strategies for therapy. Numerous high-quality images, including histopathology photomicrographs and neuroradiology scans, accompany the description of morphologic alterations and interpretation of immunoreactivities. Diagnostic methods and criteria are placed within recent developments in neuropathology, including the now widespread application of immunohistochemistry. To aid daily practice, the guide includes diagnostic algorithms and offers personal insights from experienced experts in the field. Special focus is given to the way brain tissue should be handled during diagnosis. This is a must-have reference for medical specialists and specialist medical trainees in the fields of pathology, neuropathology and neurology working with neuropathologic features of neurodegenerative diseases.
Publisher: Cambridge University Press
ISBN: 1316337650
Category : Medical
Languages : en
Pages : 320
Book Description
This practical guide to the diagnosis of neurodegenerative diseases discusses modern molecular techniques, morphological classification, fundamentals of clinical symptomology, diagnostic pitfalls and immunostaining protocols. It is based on the proteinopathy concept of neurodegenerative disease, which has influenced classification and provides new strategies for therapy. Numerous high-quality images, including histopathology photomicrographs and neuroradiology scans, accompany the description of morphologic alterations and interpretation of immunoreactivities. Diagnostic methods and criteria are placed within recent developments in neuropathology, including the now widespread application of immunohistochemistry. To aid daily practice, the guide includes diagnostic algorithms and offers personal insights from experienced experts in the field. Special focus is given to the way brain tissue should be handled during diagnosis. This is a must-have reference for medical specialists and specialist medical trainees in the fields of pathology, neuropathology and neurology working with neuropathologic features of neurodegenerative diseases.
Neurodegeneration
Author: Dennis Dickson
Publisher: John Wiley & Sons
ISBN: 1405196939
Category : Medical
Languages : en
Pages : 497
Book Description
Most textbooks on neurodegenerative disorders have used a classification scheme based upon either clinical syndromes or anatomical distribution of the pathology. In contrast, this book looks to the future and uses a classification based upon molecular mechanisms, rather than clinical or anatomical boundaries. Major advances in molecular genetics and the application of biochemical and immunocytochemical techniques to neurodegenerative disorders have generated this new approach. Throughout most of the current volume, diseases are clustered according to the proteins that accumulate within cells (e.g. tau, α-synuclein and TDP-43) and in the extracellular compartments (e.g. β-amyloid and prion proteins) or according to a shared pathogenetic mechanism, such as trinucleotide repeats, that are a feature of specific genetic disorders. Chapters throughout the book conform to a standard lay-out for ease of access by the reader and are written by a panel of International Experts Since the first edition of this book, major advances have been made in the discovery of common molecular mechanisms between many neurodegenerative diseases most notably in the frontotemporal lobar degenerations (FTLD) and motor neuron disease or amyotrophic lateral sclerosis. This book will be essential reading for clinicians, neuropathologists and basic neuroscientists who require the firm up-to-date knowledge of mechanisms, diagnostic pathology and genetics of Neurodegenerative diseases that is required for progress in therapy and management.
Publisher: John Wiley & Sons
ISBN: 1405196939
Category : Medical
Languages : en
Pages : 497
Book Description
Most textbooks on neurodegenerative disorders have used a classification scheme based upon either clinical syndromes or anatomical distribution of the pathology. In contrast, this book looks to the future and uses a classification based upon molecular mechanisms, rather than clinical or anatomical boundaries. Major advances in molecular genetics and the application of biochemical and immunocytochemical techniques to neurodegenerative disorders have generated this new approach. Throughout most of the current volume, diseases are clustered according to the proteins that accumulate within cells (e.g. tau, α-synuclein and TDP-43) and in the extracellular compartments (e.g. β-amyloid and prion proteins) or according to a shared pathogenetic mechanism, such as trinucleotide repeats, that are a feature of specific genetic disorders. Chapters throughout the book conform to a standard lay-out for ease of access by the reader and are written by a panel of International Experts Since the first edition of this book, major advances have been made in the discovery of common molecular mechanisms between many neurodegenerative diseases most notably in the frontotemporal lobar degenerations (FTLD) and motor neuron disease or amyotrophic lateral sclerosis. This book will be essential reading for clinicians, neuropathologists and basic neuroscientists who require the firm up-to-date knowledge of mechanisms, diagnostic pathology and genetics of Neurodegenerative diseases that is required for progress in therapy and management.
Tau oligomers
Author: Jesus Avila
Publisher: Frontiers E-books
ISBN: 288919261X
Category : Medicine (General)
Languages : en
Pages : 114
Book Description
Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
Publisher: Frontiers E-books
ISBN: 288919261X
Category : Medicine (General)
Languages : en
Pages : 114
Book Description
Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
Handbook of Research on Critical Examinations of Neurodegenerative Disorders
Author: Uddin, Md. Sahab
Publisher: IGI Global
ISBN: 1522552839
Category : Medical
Languages : en
Pages : 621
Book Description
Neurodegeneration is a key feature of several diseases that are referred to as neurodegenerative diseases. The process of neurodegeneration is not well-understood so the diseases that stem from it have, as yet, no cures. As such, studying the effects of these disorders can provide insight into the treatment, prevention, and future opportunities and challenges in this growing field. The Handbook of Research on Critical Examinations of Neurodegenerative Disorders is a critical scholarly resource that provides an extensive explanation of various neurodegenerative disorders based on existing studies to clarify etiology, pathological mechanisms, diagnosis, therapeutic interventions, as well as current status and future opportunities and challenges. Featuring coverage on a broad range of topics such as dementia, mitochondrial dysfunction, and risk factors, this book is geared towards neurobiologists, neuropsychologists, neurophysiologists, neuropathologists, medical professionals, academicians, and researchers seeking research on the complexity of neurodegenerative disorders.
Publisher: IGI Global
ISBN: 1522552839
Category : Medical
Languages : en
Pages : 621
Book Description
Neurodegeneration is a key feature of several diseases that are referred to as neurodegenerative diseases. The process of neurodegeneration is not well-understood so the diseases that stem from it have, as yet, no cures. As such, studying the effects of these disorders can provide insight into the treatment, prevention, and future opportunities and challenges in this growing field. The Handbook of Research on Critical Examinations of Neurodegenerative Disorders is a critical scholarly resource that provides an extensive explanation of various neurodegenerative disorders based on existing studies to clarify etiology, pathological mechanisms, diagnosis, therapeutic interventions, as well as current status and future opportunities and challenges. Featuring coverage on a broad range of topics such as dementia, mitochondrial dysfunction, and risk factors, this book is geared towards neurobiologists, neuropsychologists, neurophysiologists, neuropathologists, medical professionals, academicians, and researchers seeking research on the complexity of neurodegenerative disorders.
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging
Author: M. A. Hayat
Publisher: Academic Press
ISBN: 0128094273
Category : Medical
Languages : en
Pages : 431
Book Description
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. - Presents the most advanced information regarding the role of the autophagic system in life and death - Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both - Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation - Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment - Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available
Publisher: Academic Press
ISBN: 0128094273
Category : Medical
Languages : en
Pages : 431
Book Description
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. - Presents the most advanced information regarding the role of the autophagic system in life and death - Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both - Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation - Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment - Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available
Tau Biology
Author: Akihiko Takashima
Publisher: Springer Nature
ISBN: 9813293586
Category : Medical
Languages : en
Pages : 405
Book Description
This book presents essential studies and cutting-edge research results on tau, which is attracting increasing interest as a target for the treatment of Alzheimer's disease. Tau is well known as a microtubule-associated protein that is predominantly localized in the axons of neurons. In various forms of brain disease, neuronal loss occurs, with deposition of hyperphosphorylated tau in the remaining neurons. Important questions remain regarding the way in which tau forms hyperphosphorylated and fibrillar deposits in neurons, and whether tau aggregation represents the toxic pathway leading to neuronal death. With the help of new technologies, researchers are now solving these long-standing questions. In this book, readers will find the latest expert knowledge on all aspects of tau biology, including the structure and role of the tau molecule, tau localization and function, the pathology, drivers, and markers of tauopathies, tau aggregation, and treatments targeting tau. Tau Biology will be an invaluable source of information and fresh ideas for those involved in the development of more effective therapies and for all who seek a better understanding of the biology of the aging brain.
Publisher: Springer Nature
ISBN: 9813293586
Category : Medical
Languages : en
Pages : 405
Book Description
This book presents essential studies and cutting-edge research results on tau, which is attracting increasing interest as a target for the treatment of Alzheimer's disease. Tau is well known as a microtubule-associated protein that is predominantly localized in the axons of neurons. In various forms of brain disease, neuronal loss occurs, with deposition of hyperphosphorylated tau in the remaining neurons. Important questions remain regarding the way in which tau forms hyperphosphorylated and fibrillar deposits in neurons, and whether tau aggregation represents the toxic pathway leading to neuronal death. With the help of new technologies, researchers are now solving these long-standing questions. In this book, readers will find the latest expert knowledge on all aspects of tau biology, including the structure and role of the tau molecule, tau localization and function, the pathology, drivers, and markers of tauopathies, tau aggregation, and treatments targeting tau. Tau Biology will be an invaluable source of information and fresh ideas for those involved in the development of more effective therapies and for all who seek a better understanding of the biology of the aging brain.
Progressive Supranuclear Palsy
Author: E. Tolosa
Publisher: Springer Science & Business Media
ISBN: 9783211825419
Category : Medical
Languages : en
Pages : 308
Book Description
When Steele, Richardson and Olszewski described Progressive Supranuclear Palsy in Archives of Neurology in 1964, it was thought to be a rare disease. Recent pathological studies of large numbers of patients diagnosed as having Parkinson's disease in life have highlighted the fact that at least one in ten of such cases have some other condition. Progressive Supranuclear Palsy is one of the commonest alternative diagnoses. This book is therefore a timely review of present understanding of Progressive Supranuclear Palsy. Much has been learnt about this sporadic illness of middle and late life although its cause remains unknown, and its treatment continues to be difficult. The Editors have selected a team of authors who review the clinical aspects, neuro-imaging find ings, neuropathology, neurochemistry, epidemiology, and therapy of Progres sive Supranuclear Palsy. All are to congratulated on producing an excellent and detailed picture of contemporary knowledge of the condition. Anyone interested in Progressive Supranuclear Palsy cannot do better than to start by reading this book. It is to be hoped that it will prompt further investigation to establish its cause and cure. C. D. MARSDEN, London Preface Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder charac terized clinically by the appearance of a supranuclear gaze palsy and extra pyramidal features which include bradykinesia and axial dystonia. Postural instability and falls and frontal-type behavioural and cognitive disturbances complete the clinical picture of this progressive disorder.
Publisher: Springer Science & Business Media
ISBN: 9783211825419
Category : Medical
Languages : en
Pages : 308
Book Description
When Steele, Richardson and Olszewski described Progressive Supranuclear Palsy in Archives of Neurology in 1964, it was thought to be a rare disease. Recent pathological studies of large numbers of patients diagnosed as having Parkinson's disease in life have highlighted the fact that at least one in ten of such cases have some other condition. Progressive Supranuclear Palsy is one of the commonest alternative diagnoses. This book is therefore a timely review of present understanding of Progressive Supranuclear Palsy. Much has been learnt about this sporadic illness of middle and late life although its cause remains unknown, and its treatment continues to be difficult. The Editors have selected a team of authors who review the clinical aspects, neuro-imaging find ings, neuropathology, neurochemistry, epidemiology, and therapy of Progres sive Supranuclear Palsy. All are to congratulated on producing an excellent and detailed picture of contemporary knowledge of the condition. Anyone interested in Progressive Supranuclear Palsy cannot do better than to start by reading this book. It is to be hoped that it will prompt further investigation to establish its cause and cure. C. D. MARSDEN, London Preface Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder charac terized clinically by the appearance of a supranuclear gaze palsy and extra pyramidal features which include bradykinesia and axial dystonia. Postural instability and falls and frontal-type behavioural and cognitive disturbances complete the clinical picture of this progressive disorder.
Neuroanatomy and Pathology of Sporadic Alzheimer's Disease
Author: Heiko Braak
Publisher: Springer
ISBN: 3319126792
Category : Medical
Languages : en
Pages : 168
Book Description
As indicated by its title, this monograph deals chiefly with morphologically recognizable deviations from the normal anatomical condition of the human CNS. The AD-associated pathology is illustrated from its beginnings (sometimes even in childhood) to its final form, which is reached late in life. The AD process commences much earlier than the clinically recognizable phase of the disorder, and its timeline includes an extended preclinical phase. The further the pendulum swings away from the symptomatic final stages towards the early pathology, the more obvious the lesions become, although from a standpoint of severity they are more unremarkable and thus frequently overlooked during routine neuropathological assessment. For this reason, the authors deal with the hallmark lesions in the early phases of the AD process in considerable detail
Publisher: Springer
ISBN: 3319126792
Category : Medical
Languages : en
Pages : 168
Book Description
As indicated by its title, this monograph deals chiefly with morphologically recognizable deviations from the normal anatomical condition of the human CNS. The AD-associated pathology is illustrated from its beginnings (sometimes even in childhood) to its final form, which is reached late in life. The AD process commences much earlier than the clinically recognizable phase of the disorder, and its timeline includes an extended preclinical phase. The further the pendulum swings away from the symptomatic final stages towards the early pathology, the more obvious the lesions become, although from a standpoint of severity they are more unremarkable and thus frequently overlooked during routine neuropathological assessment. For this reason, the authors deal with the hallmark lesions in the early phases of the AD process in considerable detail
Cerebrospinal Fluid Biomarkers
Author: Charlotte E. Teunissen
Publisher: Humana
ISBN: 9781071613214
Category : Medical
Languages : en
Pages : 236
Book Description
This volume covers the latest methods used in clinical neurochemistry laboratories for both clinical practice and research. Chapters in this book discuss topics such as techniques for cerebrospinal fluid (CSF) collection, pre-analytical processing, and basic CSF analysis; an examination of biomarkers including ELISA and automated immunochemical assays for amyloid and tau markers for Alzheimer’s disease; the analysis of neurofilaments by digital ELISA; and an example of successful novel immunoassay development. In the Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and thorough, Cerebrospinal Fluid Biomarkers is a valuable resource for clinicians and researchers to use in CSF labs and CSF courses.
Publisher: Humana
ISBN: 9781071613214
Category : Medical
Languages : en
Pages : 236
Book Description
This volume covers the latest methods used in clinical neurochemistry laboratories for both clinical practice and research. Chapters in this book discuss topics such as techniques for cerebrospinal fluid (CSF) collection, pre-analytical processing, and basic CSF analysis; an examination of biomarkers including ELISA and automated immunochemical assays for amyloid and tau markers for Alzheimer’s disease; the analysis of neurofilaments by digital ELISA; and an example of successful novel immunoassay development. In the Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and thorough, Cerebrospinal Fluid Biomarkers is a valuable resource for clinicians and researchers to use in CSF labs and CSF courses.
Cyclin Dependent Kinase 5 (Cdk5)
Author: Nancy Y. Ip
Publisher: Springer Science & Business Media
ISBN: 0387788875
Category : Medical
Languages : en
Pages : 326
Book Description
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.
Publisher: Springer Science & Business Media
ISBN: 0387788875
Category : Medical
Languages : en
Pages : 326
Book Description
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.