Author: Enrico Agabiti-Rosei
Publisher: Springer Nature
ISBN: 3030478017
Category : Medical
Languages : en
Pages : 215
Book Description
This book offers an extensive review of the most recent data on the pathophysiological role of structural and functional alterations in the microcirculation, particularly focusing on hypertension and diabetes. It covers several relevant and innovative aspects, including the possible mechanisms involved in the development of microvascular remodeling and rarefaction, the technical approaches available for the detection of microvascular alterations, including non-invasive evaluations, the prognostic role of changes in small resistance artery structure, the possibility of preventing or regressing such alterations with appropriate treatment, and the potential clinical advantages of such intervention. A number of innovative areas of research are considered, including the role of the immune system, inflammation and oxidative stress in the development of microvascular alterations. Lastly, it examines the availability of recent non-invasive methods for the evaluation of small resistance artery morphology in the retina, which in the near future may provide a useful tool for the stratification of cardiovascular risk and even for clinical decisions regarding drug treatment, thus providing physicians with a clinically relevant instrument for improving and optimizing the management of hypertensive and diabetic patients. The book provides valuable, clinically relevant information for specialists (cardiology, internal medicine, and endocrinology) and general practitioners, and also offers novel and stimulating data to basic and clinical researchers.
Microcirculation in Cardiovascular Diseases
Author: Enrico Agabiti-Rosei
Publisher: Springer Nature
ISBN: 3030478017
Category : Medical
Languages : en
Pages : 215
Book Description
This book offers an extensive review of the most recent data on the pathophysiological role of structural and functional alterations in the microcirculation, particularly focusing on hypertension and diabetes. It covers several relevant and innovative aspects, including the possible mechanisms involved in the development of microvascular remodeling and rarefaction, the technical approaches available for the detection of microvascular alterations, including non-invasive evaluations, the prognostic role of changes in small resistance artery structure, the possibility of preventing or regressing such alterations with appropriate treatment, and the potential clinical advantages of such intervention. A number of innovative areas of research are considered, including the role of the immune system, inflammation and oxidative stress in the development of microvascular alterations. Lastly, it examines the availability of recent non-invasive methods for the evaluation of small resistance artery morphology in the retina, which in the near future may provide a useful tool for the stratification of cardiovascular risk and even for clinical decisions regarding drug treatment, thus providing physicians with a clinically relevant instrument for improving and optimizing the management of hypertensive and diabetic patients. The book provides valuable, clinically relevant information for specialists (cardiology, internal medicine, and endocrinology) and general practitioners, and also offers novel and stimulating data to basic and clinical researchers.
Publisher: Springer Nature
ISBN: 3030478017
Category : Medical
Languages : en
Pages : 215
Book Description
This book offers an extensive review of the most recent data on the pathophysiological role of structural and functional alterations in the microcirculation, particularly focusing on hypertension and diabetes. It covers several relevant and innovative aspects, including the possible mechanisms involved in the development of microvascular remodeling and rarefaction, the technical approaches available for the detection of microvascular alterations, including non-invasive evaluations, the prognostic role of changes in small resistance artery structure, the possibility of preventing or regressing such alterations with appropriate treatment, and the potential clinical advantages of such intervention. A number of innovative areas of research are considered, including the role of the immune system, inflammation and oxidative stress in the development of microvascular alterations. Lastly, it examines the availability of recent non-invasive methods for the evaluation of small resistance artery morphology in the retina, which in the near future may provide a useful tool for the stratification of cardiovascular risk and even for clinical decisions regarding drug treatment, thus providing physicians with a clinically relevant instrument for improving and optimizing the management of hypertensive and diabetic patients. The book provides valuable, clinically relevant information for specialists (cardiology, internal medicine, and endocrinology) and general practitioners, and also offers novel and stimulating data to basic and clinical researchers.
Coronary Microvascular Dysfunction
Author: Filippo Crea
Publisher: Springer Science & Business Media
ISBN: 8847053676
Category : Medical
Languages : en
Pages : 263
Book Description
In the past two decades a number of studies have shown that abnormalities in the function and structure of coronary microcirculation can be detected in several cardiovascular diseases. On the basis of the clinical setting in which it occurs, coronary microvascular dysfunction (CMD) can be classified into four types: CMD in the absence of any other cardiac disease; CMD in myocardial diseases; CMD in obstructive epicardial coronary artery disease; and iatrogenic CMD. In some instances CMD represents an epiphenomenon, whereas in others it represents an important marker of risk or may contribute to the pathogenesis of myocardial ischemia, thus becoming a possible therapeutic target. This book provides an update on coronary physiology and a systematic assessment of microvascular abnormalities in cardiovascular diseases, in the hope that it will assist clinicians in prevention, detection and management of CMD in their everyday activity.
Publisher: Springer Science & Business Media
ISBN: 8847053676
Category : Medical
Languages : en
Pages : 263
Book Description
In the past two decades a number of studies have shown that abnormalities in the function and structure of coronary microcirculation can be detected in several cardiovascular diseases. On the basis of the clinical setting in which it occurs, coronary microvascular dysfunction (CMD) can be classified into four types: CMD in the absence of any other cardiac disease; CMD in myocardial diseases; CMD in obstructive epicardial coronary artery disease; and iatrogenic CMD. In some instances CMD represents an epiphenomenon, whereas in others it represents an important marker of risk or may contribute to the pathogenesis of myocardial ischemia, thus becoming a possible therapeutic target. This book provides an update on coronary physiology and a systematic assessment of microvascular abnormalities in cardiovascular diseases, in the hope that it will assist clinicians in prevention, detection and management of CMD in their everyday activity.
Coronary Microvascular Obstruction in Acute Myocardial Infarction
Author: Giampaolo Niccoli
Publisher: Academic Press
ISBN: 0128133619
Category : Medical
Languages : en
Pages : 401
Book Description
Coronary Microvascular Obstruction in Acute Myocardial Infarction: From Mechanisms to Treatment provides a comprehensive understanding of the phenomenon of coronary microvascular obstruction (CMVO) that is the main limitation of reperfusion therapies in ST-elevation myocardial infarction. It provides in-depth coverage of the phenomenon of CMVO which heavily affects prognosis by increasing the risk of death and heart failure at follow-up. A first of its kind reference dedicated solely to this topic, it is appropriate for a wide audience, from researchers, to those who aid in the management, prevention and treatment of CMVO. - Provides in-depth coverage of coronary microvascular obstruction (CMVO), spanning research, management, prevention and treatment - Includes the most up-to-date information on CMVO as presented from top experts around the word - Provides access to a companion website with extra material, including tables, additional references and instructional videos - Gives extensive coverage on how to measure CMVO, including in-depth indexes that can be used to detect and quantify the phenomenon
Publisher: Academic Press
ISBN: 0128133619
Category : Medical
Languages : en
Pages : 401
Book Description
Coronary Microvascular Obstruction in Acute Myocardial Infarction: From Mechanisms to Treatment provides a comprehensive understanding of the phenomenon of coronary microvascular obstruction (CMVO) that is the main limitation of reperfusion therapies in ST-elevation myocardial infarction. It provides in-depth coverage of the phenomenon of CMVO which heavily affects prognosis by increasing the risk of death and heart failure at follow-up. A first of its kind reference dedicated solely to this topic, it is appropriate for a wide audience, from researchers, to those who aid in the management, prevention and treatment of CMVO. - Provides in-depth coverage of coronary microvascular obstruction (CMVO), spanning research, management, prevention and treatment - Includes the most up-to-date information on CMVO as presented from top experts around the word - Provides access to a companion website with extra material, including tables, additional references and instructional videos - Gives extensive coverage on how to measure CMVO, including in-depth indexes that can be used to detect and quantify the phenomenon
Molecular Basis for Microcirculatory Disorders
Author: Geert W. Schmid-Schönbein
Publisher: Springer Science & Business Media
ISBN: 9782287005039
Category : Medical
Languages : en
Pages : 676
Book Description
A large number of cardiovascular diseases are accompanied by inflammation. This volume on the molecular basis of microcirculatory disorders gives a comprehensive summary of key steps in the inflammatory cascade. Leading investigators present a state-of-the-art analysis of the molecular determinants of leukocyte-endothelial cell adhesion, mechanotransduction in endothelial and inflammatory cells, mechanisms of cell activation, microvascular apoptosis with applications to ischemia-reperfusion in the brain, the heart and in venous disease, diabetes and hypertension. The book provides the latest thinking in these important cardiovascular problems, with the most contemporary literature and a look at the increasingly complex events during inflammation. Molecular biology tools, microvascular and modern bioengineering analysis are seamlessly integrated into the analysis of clinical problems. The book helps not only newcomers to gain entry into the interesting problems associated with microvascular disorders, but lays the foundation for the design of new therapeutic interventions.
Publisher: Springer Science & Business Media
ISBN: 9782287005039
Category : Medical
Languages : en
Pages : 676
Book Description
A large number of cardiovascular diseases are accompanied by inflammation. This volume on the molecular basis of microcirculatory disorders gives a comprehensive summary of key steps in the inflammatory cascade. Leading investigators present a state-of-the-art analysis of the molecular determinants of leukocyte-endothelial cell adhesion, mechanotransduction in endothelial and inflammatory cells, mechanisms of cell activation, microvascular apoptosis with applications to ischemia-reperfusion in the brain, the heart and in venous disease, diabetes and hypertension. The book provides the latest thinking in these important cardiovascular problems, with the most contemporary literature and a look at the increasingly complex events during inflammation. Molecular biology tools, microvascular and modern bioengineering analysis are seamlessly integrated into the analysis of clinical problems. The book helps not only newcomers to gain entry into the interesting problems associated with microvascular disorders, but lays the foundation for the design of new therapeutic interventions.
Physiological Assessment of Coronary Stenoses and the Microcirculation
Author: Javier Escaned
Publisher: Springer
ISBN: 144715245X
Category : Medical
Languages : en
Pages : 301
Book Description
Since the introduction of coronary angiography, a key technique in understanding coronary artery disease, a number of paradigms regarding its study and interpretation have taken place. Following an emphasis on improved angiographic and subsequent intracoronary imaging techniques, functional assessment of coronary circulation has demonstrated to have major implications for diagnosis and treatment of coronary artery disease. Fractional flow reserve, a pressure derived index of stenosis severity, constitutes the best example of the current importance of physiological assessment in clinical practice. However, the acceptance of FFR by cardiologists contrasts with important voids in knowledge on the basic principles of coronary physiology and of other available techniques that, as an alternative to FFR, allow a more comprehensive assessment of coronary circulation. This is particularly noticeable in the assessment of microcirculation, an unavoidable compartment of coronary circulation that is frequently affected in acute coronary syndromes of in the presence of cardiovascular risk factors or non-coronary heart disease. A deeper understanding of the relationship between epicardial vessel and microcirculatory involvement has started with the advent of newer imaging techniques like invasive optical coherence tomography, and non-invasive CT and NMR techniques. This book aims to be an indispensable tool for clinicians and researches in the field of coronary artery disease. It provides a balanced, comprehensive review of anatomy, physiology and available techniques, discusses both the diagnosis of epicardial vessel and microcirculatory disease, the impact of different diseases at different levels of coronary circulation, and the best way to address a separate or combined assessment of different levels of coronary circulation.
Publisher: Springer
ISBN: 144715245X
Category : Medical
Languages : en
Pages : 301
Book Description
Since the introduction of coronary angiography, a key technique in understanding coronary artery disease, a number of paradigms regarding its study and interpretation have taken place. Following an emphasis on improved angiographic and subsequent intracoronary imaging techniques, functional assessment of coronary circulation has demonstrated to have major implications for diagnosis and treatment of coronary artery disease. Fractional flow reserve, a pressure derived index of stenosis severity, constitutes the best example of the current importance of physiological assessment in clinical practice. However, the acceptance of FFR by cardiologists contrasts with important voids in knowledge on the basic principles of coronary physiology and of other available techniques that, as an alternative to FFR, allow a more comprehensive assessment of coronary circulation. This is particularly noticeable in the assessment of microcirculation, an unavoidable compartment of coronary circulation that is frequently affected in acute coronary syndromes of in the presence of cardiovascular risk factors or non-coronary heart disease. A deeper understanding of the relationship between epicardial vessel and microcirculatory involvement has started with the advent of newer imaging techniques like invasive optical coherence tomography, and non-invasive CT and NMR techniques. This book aims to be an indispensable tool for clinicians and researches in the field of coronary artery disease. It provides a balanced, comprehensive review of anatomy, physiology and available techniques, discusses both the diagnosis of epicardial vessel and microcirculatory disease, the impact of different diseases at different levels of coronary circulation, and the best way to address a separate or combined assessment of different levels of coronary circulation.
Inflammation and the Microcirculation
Author: D. Neil Granger
Publisher: Morgan & Claypool Publishers
ISBN: 1615041656
Category : Medical
Languages : en
Pages : 99
Book Description
The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References
Publisher: Morgan & Claypool Publishers
ISBN: 1615041656
Category : Medical
Languages : en
Pages : 99
Book Description
The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References
Regulation of Tissue Oxygenation, Second Edition
Author: Roland N. Pittman
Publisher: Biota Publishing
ISBN: 1615047212
Category : Medical
Languages : en
Pages : 117
Book Description
This presentation describes various aspects of the regulation of tissue oxygenation, including the roles of the circulatory system, respiratory system, and blood, the carrier of oxygen within these components of the cardiorespiratory system. The respiratory system takes oxygen from the atmosphere and transports it by diffusion from the air in the alveoli to the blood flowing through the pulmonary capillaries. The cardiovascular system then moves the oxygenated blood from the heart to the microcirculation of the various organs by convection, where oxygen is released from hemoglobin in the red blood cells and moves to the parenchymal cells of each tissue by diffusion. Oxygen that has diffused into cells is then utilized in the mitochondria to produce adenosine triphosphate (ATP), the energy currency of all cells. The mitochondria are able to produce ATP until the oxygen tension or PO2 on the cell surface falls to a critical level of about 4–5 mm Hg. Thus, in order to meet the energetic needs of cells, it is important to maintain a continuous supply of oxygen to the mitochondria at or above the critical PO2 . In order to accomplish this desired outcome, the cardiorespiratory system, including the blood, must be capable of regulation to ensure survival of all tissues under a wide range of circumstances. The purpose of this presentation is to provide basic information about the operation and regulation of the cardiovascular and respiratory systems, as well as the properties of the blood and parenchymal cells, so that a fundamental understanding of the regulation of tissue oxygenation is achieved.
Publisher: Biota Publishing
ISBN: 1615047212
Category : Medical
Languages : en
Pages : 117
Book Description
This presentation describes various aspects of the regulation of tissue oxygenation, including the roles of the circulatory system, respiratory system, and blood, the carrier of oxygen within these components of the cardiorespiratory system. The respiratory system takes oxygen from the atmosphere and transports it by diffusion from the air in the alveoli to the blood flowing through the pulmonary capillaries. The cardiovascular system then moves the oxygenated blood from the heart to the microcirculation of the various organs by convection, where oxygen is released from hemoglobin in the red blood cells and moves to the parenchymal cells of each tissue by diffusion. Oxygen that has diffused into cells is then utilized in the mitochondria to produce adenosine triphosphate (ATP), the energy currency of all cells. The mitochondria are able to produce ATP until the oxygen tension or PO2 on the cell surface falls to a critical level of about 4–5 mm Hg. Thus, in order to meet the energetic needs of cells, it is important to maintain a continuous supply of oxygen to the mitochondria at or above the critical PO2 . In order to accomplish this desired outcome, the cardiorespiratory system, including the blood, must be capable of regulation to ensure survival of all tissues under a wide range of circumstances. The purpose of this presentation is to provide basic information about the operation and regulation of the cardiovascular and respiratory systems, as well as the properties of the blood and parenchymal cells, so that a fundamental understanding of the regulation of tissue oxygenation is achieved.
Microcirculation of the Heart
Author: H. Tillmanns
Publisher: Springer Science & Business Media
ISBN: 3642684858
Category : Medical
Languages : en
Pages : 554
Book Description
Microcirculation is a rather new field which has been of predominant interest to basic scientists, linking togeth~r technical, hemodynamic, and biochemical aspects. The fmdings elaborated, however, are not only of theoretical interest, but bear in addition great clinical implications. In clinical cardiology this became quite evident by the use of tracers in order to study myocardial perfuSion and by the deSCription of certain clinical entities - such as angina with normal coro nary arteries - which are best explained by "disturbed microcirculation". With respect to this new developing theoretical and clinical field of cardiac microcirculation it was the aim of the Microcirculation Working Group of the European Society of Cardiology to have a symposium on which all different but clinically relevant aspects of cardiac microcirculation will be covered. This symposium, held in Heidelberg in January 1980, was planned not only for the exchange of concepts and ideas, but was expected to be in addition partially a teaching session; the basic scientists should be directed toward a better under standing of the clinical problems, and the clinicians should learn more about the basic mechanisms regulating substrate and ion exchange in such an impor tant organ as the heart, and furthermore the theoretical limitations of some of the diagnostic and therapeutical procedures should be taught. Without a lot of help we would never have succeeded in organizing the sym posium and editing its results.
Publisher: Springer Science & Business Media
ISBN: 3642684858
Category : Medical
Languages : en
Pages : 554
Book Description
Microcirculation is a rather new field which has been of predominant interest to basic scientists, linking togeth~r technical, hemodynamic, and biochemical aspects. The fmdings elaborated, however, are not only of theoretical interest, but bear in addition great clinical implications. In clinical cardiology this became quite evident by the use of tracers in order to study myocardial perfuSion and by the deSCription of certain clinical entities - such as angina with normal coro nary arteries - which are best explained by "disturbed microcirculation". With respect to this new developing theoretical and clinical field of cardiac microcirculation it was the aim of the Microcirculation Working Group of the European Society of Cardiology to have a symposium on which all different but clinically relevant aspects of cardiac microcirculation will be covered. This symposium, held in Heidelberg in January 1980, was planned not only for the exchange of concepts and ideas, but was expected to be in addition partially a teaching session; the basic scientists should be directed toward a better under standing of the clinical problems, and the clinicians should learn more about the basic mechanisms regulating substrate and ion exchange in such an impor tant organ as the heart, and furthermore the theoretical limitations of some of the diagnostic and therapeutical procedures should be taught. Without a lot of help we would never have succeeded in organizing the sym posium and editing its results.
Regulation of Coronary Blood Flow
Author: Michitoshi Inoue
Publisher: Springer Science & Business Media
ISBN: 4431683674
Category : Medical
Languages : en
Pages : 330
Book Description
Research centering on blood flow in the heart continues to hold an important position, especially since a better understanding of the subject may help reduce the incidence of coronary arterial disease and heart attacks. This book summarizes recent advances in the field; it is the product of fruitful cooperation among international scientists who met in Japan in May, 1990 to discuss the regulation of coronary blood flow.
Publisher: Springer Science & Business Media
ISBN: 4431683674
Category : Medical
Languages : en
Pages : 330
Book Description
Research centering on blood flow in the heart continues to hold an important position, especially since a better understanding of the subject may help reduce the incidence of coronary arterial disease and heart attacks. This book summarizes recent advances in the field; it is the product of fruitful cooperation among international scientists who met in Japan in May, 1990 to discuss the regulation of coronary blood flow.
Encyclopedia of Cardiovascular Research and Medicine
Author:
Publisher: Elsevier
ISBN: 012805154X
Category : Medical
Languages : en
Pages : 2854
Book Description
Encyclopedia of Cardiovascular Research and Medicine, Four Volume Set offers researchers over 200 articles covering every aspect of cardiovascular research and medicine, including fully annotated figures, abundant color illustrations and links to supplementary datasets and references. With contributions from top experts in the field, this book is the most reputable and easily searchable resource of cardiovascular-focused basic and translational content for students, researchers, clinicians and teaching faculty across the biomedical and medical sciences. The panel of authors chosen from an international board of leading scholars renders the text trustworthy, contemporary and representative of the global scientific expertise in these domains. The book's thematic structuring of sections and in-depth breakdown of topics encourages user-friendly, easily searchable chapters. Cross-references to related articles and links to further reading and references will further guide readers to a full understanding of the topics under discussion. Readers will find an unparalleled, one-stop resource exploring all major aspects of cardiovascular research and medicine. Presents comprehensive coverage of every aspect of cardiovascular medicine and research Offers readers a broad, interdisciplinary overview of the concepts in cardiovascular research and medicine with applications across biomedical research Includes reputable, foundational content on genetics, cancer, immunology, cell biology and molecular biology Provides a multi-media enriched color-illustrated text with high quality images, graphs and tables.
Publisher: Elsevier
ISBN: 012805154X
Category : Medical
Languages : en
Pages : 2854
Book Description
Encyclopedia of Cardiovascular Research and Medicine, Four Volume Set offers researchers over 200 articles covering every aspect of cardiovascular research and medicine, including fully annotated figures, abundant color illustrations and links to supplementary datasets and references. With contributions from top experts in the field, this book is the most reputable and easily searchable resource of cardiovascular-focused basic and translational content for students, researchers, clinicians and teaching faculty across the biomedical and medical sciences. The panel of authors chosen from an international board of leading scholars renders the text trustworthy, contemporary and representative of the global scientific expertise in these domains. The book's thematic structuring of sections and in-depth breakdown of topics encourages user-friendly, easily searchable chapters. Cross-references to related articles and links to further reading and references will further guide readers to a full understanding of the topics under discussion. Readers will find an unparalleled, one-stop resource exploring all major aspects of cardiovascular research and medicine. Presents comprehensive coverage of every aspect of cardiovascular medicine and research Offers readers a broad, interdisciplinary overview of the concepts in cardiovascular research and medicine with applications across biomedical research Includes reputable, foundational content on genetics, cancer, immunology, cell biology and molecular biology Provides a multi-media enriched color-illustrated text with high quality images, graphs and tables.