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1
Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.
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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα) and in patients who have failed TNFα inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.
2
Gluckman, Sir Peter, Mark Hanson, Chong Yap Seng, and Anne Bardsley. Vitamin B3 (niacin) in pregnancy and breastfeeding. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780198722700.003.0009.
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Niacin (as nicotinamide) is a component of coenzyme systems that function in the reductive biosynthesis of fatty acids and steroids, including cholesterol, and are involved in cell signalling. Niacin deficiency is rare, as the daily requirement can usually be met by food sources, and also via synthesis from tryptophan, which is present in dietary proteins. The prevalence of niacin deficiency is higher in populations consuming mainly corn or sorghum as a dietary staple. Corn contains niacin, but only in a bound form that is nutritionally unavailable. The additional needs for niacin during pregnancy are mirrored by the increased energy intake needs, and dietary supplementation is only necessary in cases of overall poor nutritional intake.
3
D’Amato, Gaetano, Guillermo Luxán, and José Luis de la Pompa. Defining cardiac domains from the inside: NOTCH in endocardial–myocardial interactions. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0011.
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In this chapter we illustrate the signalling interactions of the endocardium with the other cardiac tissues to coordinate cardiac development. First, we describe the developmental origins of the endocardium. Then we focus on the Notch pathway because of its unique signalling activity in the endocardium, and briefly describe the elements of this signalling mechanism and the key cardiogenic processes that require endocardial Notch signalling: patterning of the early embryonic endocardium into prospective territories for valves and ventricular chambers, early valve formation, ventricular trabeculation, and compaction. Finally, we discuss how Notch dysfunction in the endocardium results in cardiac structural malformations that can lead to congenital heart disease.
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Monaco, Claudia, and Giuseppina Caligiuri. Molecular mechanisms. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0014.
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The development of the atherosclerotic plaque relies on specific cognate interactions between ligands and receptors with the ability to regulate cell recruitment, inflammatory signalling, and the production of powerful inflammatory and bioactive lipid mediators. This chapter describes how signalling is engaged by cell-cell surface interactions when the endothelium interacts with platelets and leukocytes enhancing leukocyte recruitment during atherogenesis. It also exemplifies intracellular signalling pathways induced by the activation of innate immune receptors, the most potent activators of inflammation in physiology and disease. Differences are highlighted in innate signalling pathways in metabolic diseases such as atherosclerosis compared to canonical immunological responses. Finally, the key lipid mediators whose production can affect endothelial function, inflammation, and atherosclerosis development are summarized. This Chapter will take you through these fundamental steps in the development of the atherosclerotic plaque by summarizing very recent knowledge in the field and highlighting recent or ongoing clinical trials that may enrich our ability to target cardiovascular disease in the future.
5
Zaffran, Stéphane. Cardiac growth II: Cardiomyocyte polarization. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0010.
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During vertebrate embryogenesis, the planar cell polarity (PCP) signalling pathway is responsible for cell movements essential for convergent extension during gastrulation, neural tube closure, neural crest cell migration, and heart morphogenesis. In the heart, the non-canonical Wnt/PCP pathway regulates cell polarity, cell shape, and cell dynamics during formation of the cardiac crescent and deployment of second heart field cardiac progenitors to the poles of the heart tube. PCP signalling is also essential for the establishment of left–right patterning in the early embryo. This chapter reviews our current understanding of PCP signalling in heart morphogenesis and how it affects the pathogenesis of congenital heart diseases.
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Alves, Ines Teles, Jan Trapman, and Guido Jenster. Molecular biology of prostate cancer. Edited by James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0059.
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Prostate cancer is a heterogeneous disease that arises through the acquisition of key malignant hallmarks. At the molecular level, prostate tumours are dependent upon the androgen receptor pathway, which affects cell function, growth, and behaviour through downstream androgen-regulated genes. Prostate cancer requires this activity and manipulates the AR pathway to maintain signalling. For example, mutation of the AR (to bind ligands other than androgens) or amplification/duplication of the AR allows signalling to continue in the absence of testosterone. Around 50% of prostate cancers have a gene fusion between the androgen-regulated component of the TMPRSS2 gene and a transcription factor (e.g. ETS family members ERG and ETV1). This results in aberrant androgen stimulated cell growth. Current research is using molecular knowledge to identify biomarkers, such as PCA3, and new therapies, such as enzalutamide or abiraterone acetate.
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Cahill, Thomas J., and Paul R. Riley. Epicardial and coronary vascular development. Edited by Miguel Torres. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0009.
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The coronary circulation is essential for human life. In embryonic development, abnormal formation of the coronary vasculature can cause death in utero or after birth. In adulthood, atherosclerosis of the coronary arteries is the commonest cause of death worldwide. The last decade has witnessed significant strides forward in our understanding of coronary development. Multiple sources of coronary endothelial cells have been identified using genetic tools for fate mapping. The epicardium, the outermost layer of the developing heart, has emerged as both a source of cell progenitors and key signalling mediators. Knowledge of the specific genes underlying formation, function, and heterogeneity of the epicardium is expanding. Significant challenges remain, however, in understanding the spatiotemporal signalling patterns required for organized migration, differentiation, and patterning of the vasculature. In addition, dissecting how coronary development is perturbed in patients with congenital coronary anomalies is a major ongoing focus of research.
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Beattie, R. Mark, Anil Dhawan, and John W.L. Puntis. The pancreas. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780198569862.003.0046.
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Congenital anomalies 326Pancreatitis 328Pancreatic insufficiency 335These are rare. Most anomalies are sporadic. Only the gene coding for the homeodomain protein PDX1 is clearly demonstrated to be causal of pancreatic agenesis. Inactivation or inhibition of signalling molecule sonic hedgehog (Shh) could potentially lead to annular pancreas, pancreatic divisum, and pancreatic ectopia....
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Geri, Guillaume, and Jean-Paul Mira. Host–pathogen interactions in the critically ill. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0306.
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Infection by a pathogenic micro-organism triggers a coordinated activation of both innate and adaptive immune responses. The innate immune response quickly triggers an antimicrobial response that will initiate development of a pathogen-specific, long-lasting adaptive immune response. Accurate recognition of microbial-associated molecular patterns by pattern-recognition receptors (PRRs) is the cornerstone of this immediate response. Most studied PRRs are Toll-like receptors (TLRs) and their kinase signalling cascades that activate nuclear transcription factors, and induce gene expression and cytokine production. Deficiencies or genetic variability in these different signalling pathways may lead to recurrent pyogenic infections and severe invasive diseases. After initial contact between the host and pathogen, numerous factors mediate the inflammatory response, as pro-inflammatory cytokines and chemokines. Apart from host genetic variability, pathogen diversity also influences the phenotypic features of various infectious diseases. Genomic analysis may assist in the development of targeted therapies or new therapeutic strategies based on both patient and microorganism genotype.
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Rammah, Mayyasa, Francesca Rochais, and Robert G. Kelly. Incorporation of myocardial progenitors at the arterial pole of the heart. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0007.
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The arterial pole of the heart is a hotspot for life-threatening forms of congenital heart defects (CHDs). It is formed by progressive addition of myocardium from epithelial progenitor cells in the second heart field (SHF). SHF cells contribute successively to the right ventricle and proximal and distal outflow tract myocardial walls which, after neural crest influx and cardiac septation, give rise to myocardium at the base of the aorta and pulmonary trunk. SHF cells are characterized by continued proliferation and differentiation delay controlled by an array of transcriptional regulators and signalling pathways which define the SHF progenitor cell niche in pharyngeal mesoderm. Failure of normal SHF deployment leads to a shortened outflow tract and failure of ventriculo-arterial alignment, resulting in a spectrum of conotruncal CHD. We discuss the origins of the SHF in cardiopharyngeal mesoderm and focus on the mechanisms driving SHF deployment, summarizing current understanding of critical signalling pathways and transcription factors.
11
Newell-Price, John, Alia Munir, and Miguel Debono. Normal function of the endocrine system. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0182.
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Endocrinology is the study of hormones (and their glands of origin), their receptors, the intracellular signalling pathways they invoke, and their associated diseases. The clinical specialty of endocrinology focuses specifically on the endocrine organs, that is, the organs whose primary function is hormone secretion, including the hypothalamus, the pituitary, the thyroid, the parathyroid, the adrenal glands, the pancreas, and the reproductive organs.
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Chang, Victor T. Visceral pain. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199656097.003.0134.
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Visceral pain is pain that arises from, in, or around internal organs. Common examples include chest pain and functional abdominal pain. In palliative medicine, well-known visceral pain syndromes include pain from pancreatic cancer and bowel obstruction. Recent advances have increased our understanding of the diagnostic challenges and therapeutic possibilities for patients with visceral pain syndromes. Understanding the basis of referred pain is a key component of patient assessment. The complexity of visceral nociception and pain signalling is being unravelled through anatomical, immunohistochemical, and functional studies. On a molecular level, families of receptors and signalling proteins have now been described that will lead to a future with innovative therapies. This knowledge has developed within the paradigms of pain pathways, peripheral activation and peripheral and central sensitization, thereby linking and distinguishing visceral pain from somatic and neuropathic pain. Treatment options for visceral pain in palliative care encompass a wide variety of medical, interventional, and psychological approaches. With appropriate diagnostic measures and careful consideration of therapeutic options, most patients can achieve satisfactory relief.
13
Wordsworth, B. P. Skeletal dysplasias. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0150.
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Bone is metabolically active throughout life and metabolic disturbances may have wide-ranging consequences that are not restricted to altering its mechanics. The study of some genetic bone diseases has already provided remarkable insights into the normal regulation of bone metabolism. Skeletal dysplasias are developmental disorders of the chondro-osseous tissues commonly resulting in short stature, which is often disproportionate. The underlying mutations are often in the structural genes encoding components of the matrix but may also involve growth factors or cell signalling. In contrast, the dysostoses tend to affect single bones or groups of bones, reflecting the transient nature of the many different signalling factors to which they are responsive during development. Abnormalities of bone density (high or low) may be due to primary deficiency of bone matrix synthesis (e.g. osteogenesis imperfecta and hypophosphatasia) but may also reflect an imbalance between bone formation and resorption. This may be caused by abnormalities of bone formation (e.g. hyperostosis/sclerosteosis and osteoporosis pseudoglioma syndrome) or bone resorption (e.g. classic osteopetrosis and fibrous dysplasia).
14
Saleem, Moin A., and Corinne Antignac. Molecular basis of nephrotic syndrome. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0327_update_001.
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Nephrotic syndrome is broadly a disorder of the glomerular filtration barrier, but in practice the site of dysfunction in the great majority of pathologies is in the podocyte. Genetic causes of nephrotic syndrome provide the strongest proof of this. Almost all the genetic associations with nephrotic syndrome are podocyte proteins. Some basement membrane protein mutations associated with nephrotic syndrome may act through signalling to podocytes, or by causing severe disruption to their environment.
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Garcia-Pavia, Pablo, and Fernando Dominguez. Left ventricular non-compaction: genetics and embryology. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0362.
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Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.
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Hodgkiss, Andrew. Introduction to cancer biology. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198759911.003.0001.
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A brief introduction to cancer biology, aimed at psychiatrists, is offered. Selective DNA transcription, the cell cycle, receptor tyrosine kinases, and cell signalling pathways are introduced, using the EGFR/RAS/MAPK pathway as an exemplar. The molecular pathology of oncogenesis is summarized, including discussion of oncogenes, tumour suppressor genes, and examples of driver mutations. The exploitation of such mutations in stratified medicine, using molecularly targeted agents, is mentioned. Finally, Hanahan and Weinberg’s six hallmarks of cancer are listed, adding angiogenesis and metastasis to the picture of oncogenesis.
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van der Kraan, Peter M., and Esmeralda N. Blaney Davidson. Cartilage (including meniscus). Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199668847.003.0004.
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This chapter provides an overview of tissues unique to synovial joints, articular cartilage, and meniscus. The development and cellular and (bio)chemical composition are described, as well as the role of mechanical stimuli. In addition, the role of growth factors in cartilage and meniscus homeostasis, cellular differentiation, and chondrocyte hypertrophy are discussed. Furthermore, the involvement of aggrecanases and matrix metalloproteinases in cartilage and meniscus matrix degradation and osteoarthritis are described. Finally, the current status of repair of articular cartilage and meniscus is provided. This chapter reflects the changes in cellular differentiation, growth factor signalling, and altered matrix composition that contribute to osteoarthritis.
18
Menasché, Philippe. Stem Cell Therapy Post-AMI. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780199544769.003.0010.
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• Experimental studies suggest that bone marrow-derived stem cells can improve function of infarcted myocardium• This benefit seems to involve paracrine signalling and limitation of left ventricular remodelling rather than true regeneration of cardiomyocytes from donor cells• These experimental findings have been translated in the clinical setting into significant, although moderate, improvements in cardiac function and LV remodelling but the extent to which these benefits impact on event-free long term survival remains to be determined• Optimisation of this therapeutic strategy will require a more comprehensive characterisation of cell functionality and an improvement in the methods used in cell transfer, engraftment, survival and integration.
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Brown, Matthew. Genetics of spondyloarthropathies. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0041.
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Spondyloarthropathies are a diverse group of conditions, of which ankylosing spondylitis is the prototypic disease, with shared clinical features, genetic risk factors, and histopathological characteristics. These conditions are highly familial and heritable. Several genes have been associated with spondyloarthropathies, with genes in the IL-23 signalling pathway being shared by the major types of spondyloarthritis. These discoveries have already led to the development and successful clinical introduction of novel treatments for psoriasis and psoriatic arthritis, and major advances in our understanding of the pathogenesis of the conditions. Many more genes remain to be identified which are involved in these common conditions; identifying these genes is likely to be highly informative as to their causes.
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Brown, Matthew. Genetics of spondyloarthropathies. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199642489.003.0041_update_003.
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Spondyloarthropathies are a diverse group of conditions, of which ankylosing spondylitis is the prototypic disease, with shared clinical features, genetic risk factors, and histopathological characteristics. These conditions are highly familial and heritable. Several genes have been associated with spondyloarthropathies, with genes in the IL-23 signalling pathway being shared by the major types of spondyloarthritis. These discoveries have already led to the development and successful clinical introduction of novel treatments for psoriasis and psoriatic arthritis, and major advances in our understanding of the pathogenesis of the conditions. Many more genes remain to be identified which are involved in these common conditions; identifying these genes is likely to be highly informative as to their causes.
21
Endlich, Karlhans, and Rodger Loutzenhiser. Regulation of vasomotor tone in the afferent and efferent arterioles. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0208.
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Pre-glomerular vessels are regulated by membrane potential alterations affecting the activity of L-type voltage-activated Ca2+ channels; whereas voltage-independent mechanisms regulate the efferent arteriole, notably influenced by angiotensin II and therefore by angiotensin converting enzyme inhibitors, and by non-steroidal anti-inflammatory drugs.These properties underlie the physiologic control of glomerular capillary pressure, for example, by prostaglandin E2, during conditions of reduced renal perfusion and the stabilization of glomerular capillary pressure when the kidney is exposed to pressure fluctuations. A wealth of hormones affects the tone of renal vessels. The chapter focuses on basic regulatory and signalling mechanisms, emphasizing the unique aspects of the renal vasculature and the underlying features that facilitate the independent regulation of pre-glomerular and post-glomerular tone.
22
Gordon-Williams, Richard M., and Anthony H. Dickenson. Pathophysiology of pain in cancer and other terminal illnesses. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199656097.003.0092.
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Cancer pain involves a myriad of peripheral changes in the function of tissue and nerves, at the site of the tumour growth, as well as a number of consequent changes in the processing of pain messages at the spinal cord level with implications for the pain experience at higher centres. This chapter reviews the changes in peripheral pain signalling, notes the likely prevalence of both inflammatory and neuropathic components, and describes the altered events at spinal levels that can come some way towards explaining ongoing pain, hyperalgesia, and allodynias that patients with cancer and other terminal illnesses such as HIV/AIDs experience. Finally, changes induced by cancer at the level of the brain are discussed. The mechanisms of action of therapies, both existing and potential novel approaches, are included at peripheral and central levels.
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Valdes, Ana M. Genetics. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199668847.003.0009.
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Epidemiological studies have demonstrated that osteoarthritis (OA) is a complex trait with numerous environmental and genetic risk factors. A great deal of effort has been spent elucidating these risk factors and progress has been made. It is clear however that the causes behind OA development and progression continue to remain largely elusive. Identification of those genes that, in conjunction with environmental factors, predispose to OA severity will lead to a better understanding of the mechanisms underlying disease development and thus promote improved health strategies for prevention. An understanding of the molecular signalling pathways involved in the initiation and progression of the disease will improve clinical diagnosis and help identify improved, tailored treatment regimens. This chapter focuses on these issues, exploring the heritability of OA, known genetic risk factors, and specific traits and outcomes studied in the genetics of OA.
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Campione, Marina, Amelia Aranega, and Diego Franco. Cardiac looping and laterality. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0014.
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Dextral looping is a complex process which progresses concomitantly with cardiac chamber differentiation and ultimately leads to the final alignment of the cardiac regions. Generation of cardiac asymmetry is crucial to ensure the proper form and consequent function of the heart and thus is a highly regulated process. Molecular signals originate long before morphological asymmetry and therefore can direct it; a complex regulatory network has been characterized which invariably converges on the Tgf-β signalling molecule Nodal and its downstream target, the homeobox transcription factor Pitx2. We review current data regarding the cellular and molecular bases of cardiac looping and laterality, and describe current understaning of the role of Nodal and Pitx2. The morphogenetic role of the Pitx2 gene and its modulation of transcription and function, which have recently linked laterality to atrial fibrillation, are emphasized.
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Dyer, Laura A., and Margaret L. Kirby. The role of the neural crest in cardiac development. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0019.
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The cardiac neural crest (CNC) plays pivotal roles in numerous steps of cardiac development. Every aspect of the CNC cell’s lifespan is highly orchestrated, from its induction in the dorsal neural tube to its migration to its differentiation at its final destination. During migration, CNC cells are affected by their environment and simultaneously modulate the extra-cellular milieu through which they migrate. In the pharyngeal arches, CNC cells repattern the originally symmetrical arch arteries, producing the great arteries. Because the cardiac neural crest is essential for many aspects of heart development, it is unsurprising that human CNC-related syndromes have severe phenotypes. This chapter describes how CNC cells are formed and contribute to their final destinations. Essential signalling pathways are presented in the context of CNC development, and CNC-related syndromes are included to highlight this population’s broad importance during development.
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Lories, Rik J., and Georg Schett. Pathology: bone. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198734444.003.0010.
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Axial spondyloarthritis is associated with different types of skeletal damage. Inflammation at the affected sites is linked with both loss of trabecular bone and new bone formation on the cortical side, potentially leading to joint or spine ankylosis. Both aspects of the disease can result in a significant burden for the patient. Bone loss is directly linked to proinflammatory cytokines and activation of osteoclasts. Control of inflammation is therefore the best strategy to prevent loss of bone. The nature of the new bone formation process is less defined. A prominent role for developmental signalling pathways has been proposed. Current therapies have limited or no impact on this process. However, emerging data suggest that early control of disease activity may be part of a window of opportunity to prevent structural damage, as biomechanical factors and instability following inflammation may also play a role.
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Winchester, Robert, Darren D. O’Rielly, and Proton Rahman. Genetics of psoriatic arthritis. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198737582.003.0006.
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The psoriatic phenotype is clinically heterogeneous with psoriatic arthritis (PsA) itself being heterogeneous. Studies have consistently demonstrated that PsA has a strong genetic component and disease pathogenesis encompasses a complex interplay between genetic, immunological, and environmental factors. In this chapter, we will review the genetics of PsA including the major histocompatibility complex (MHC) region and non-MHC loci. We will detail how susceptibility genes can be grouped into barrier integrity, innate immune response, and adaptive immune response (particularly Th-17 lymphocyte signalling). We will articulate how these studies strongly support PsA as genetically different from PsV and that the genetic heterogeneity is likely attributed to different HLA susceptibility alleles within the MHC region that an individual carries. Furthermore, we will highlight new emerging technologies, in particular, next-generation sequencing, which may lead to new genetic discoveries in PsA.
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Wentzel, Jolanda J., Ethan M. Rowland, Peter D. Weinberg, and Robert Krams. Biomechanical theories of atherosclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0012.
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Atherosclerosis, the disease underlying most heart attacks and strokes, occurs predominantly at certain well-defined sites within the arterial system. Its development may therefore depend not only on systemic risk factors but also on locally varying biomechanical forces. There are three inter-related theories explaining the effect of biomechanics on atherosclerosis. In the first theory, a central role is played by lipid transport into the vessel wall, which varies as a result of mechanical forces. In the second theory, haemodynamic wall shear stress-the frictional force per unit area of endothelium arising from the movement of blood-activates signalling pathways that affect endothelial cell properties. In the third, strain-the stretch of the wall arising from changes in blood pressure-is the key biomechanical trigger. All three theories are discussed from historical, molecular, and clinical perspectives.
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Dickenson, Tony. Endogenous opioids in the CNS. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0019.
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This short and concise paper was the first to unequivocally reveal that there were endogenous opioids in the central nervous system (CNS), identify their peptide nature and sequence, and show that they exerted physiological inhibitory effects. The idea that there were natural opioids fitted with concurrent reports of opiate-binding sites, and this led to the description of multiple receptors with their own families of peptide transmitters. No truly novel opioid drugs have emerged since, and attempts to protect and manipulate the enkephalins for pain control have yet to be successful. This does not detract from this key study, which made us think about pain modulation in a different way, and subsequent work has clearly shown how endogenous opioid signalling is critical in CNS function, perhaps most importantly in endogenous pain control, such as that harnessed by placebo analgesia.
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Rosengart, Matthew R. Disorders of calcium in the critically ill. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0253.
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Calcium is vitally important for normal cellular signalling and function. However, its toxicity necessitates that intracellular calcium concentration [Ca2+] be tightly regulated and compartmentalized. Evolutionary pressures have yielded several regulatory mechanisms to maintain intracellular and extracellular ionized calcium concentrations compatible with life. During periods of critical illness these process are commonly overwhelmed, and disorders of calcium homeostasis are highly prevalent among intensive care unit (ICU) patients. Indeed, hypocalcaemia occurs in up to 88% of critically-ill ICU patients suffering from trauma, sepsis, and burns. Contemporary evidence suggests that although hypocalcaemia may be associated with ICU mortality, it is not in the causal pathway. A systematic review concluded there are no data to support the routine parenteral administration of calcium in the management of asymptomatic critical illness-related hypocalcaemia. Asymptomatic hypocalcaemia of critical illness does not necessitate replacement. However, acute, symptomatic hypocalcaemia necessitates parenteral supplementation to prevent tetany, seizures, and cardiac arrhythmias
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Siebert, Stefan, Sengupta Raj, and Alexander Tsoukas. Drug treatment for axial spondyloarthritis. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198755296.003.0015.
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The pharmacological therapy for patients with axial spondyloarthritis (axSpA), especially those with severe disease, has been transformed by the introduction of the biologic therapies, and anti-TNF therapy in particular. Until approximately 2005, treatment options for ankylosing spondylitis (AS) were limited to exercise therapy and non-steroidal anti-inflammatory drugs (NSAIDs). The TNF inhibitors appear to have a good safety profile in axSpA, with no new safety signals. The high cost of innovator biologics remains an issue and it will be interesting to observe the effect of the introduction of multiple biosimilar TNF inhibitors in clinical practice. New therapeutics targeting different cytokine and signalling pathways should also become available over the next few years, so it remains to be seen what their role will be in the management of axSpA. This chapter reviews some of the key drug therapies and advances in the management of axSpA.
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Bradbury, Elizabeth J., and Nicholas D. James. Mapping of neurotrophin receptors on adult sensory neurons. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0022.
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The paper discussed in this chapter describes the first mapping of neurotrophin receptors in adult sensory neurons. Neurotrophins and their receptors were a particularly hot topic at the time, but the primary focus of interest had been in their role in development. In this paper, McMahon and colleagues characterized both mRNA and protein expression of the recently discovered trk receptors on defined populations of adult sensory neurons, correlating trk expression with other primary afferent projection neuron properties such as cell size and neuronal function. Furthermore, by showing clear correlations between the expression of different trk receptors and the physical and functional properties of defined primary afferent projections, the authors provided key evidence suggesting that nerve growth factor and neurotrophin-3 acted on functionally distinct populations of adult sensory neurons. This paper provided the basis for subsequent research on neurotrophin signalling and function in both the healthy and the diseased nervous system.
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Gluckman, Sir Peter, Mark Hanson, Chong Yap Seng, and Anne Bardsley. Choline in pregnancy and breastfeeding. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780198722700.003.0014.
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Choline is required for the structural integrity of cell membranes and is involved in methyl-group metabolism, neurotransmission, transmembrane signalling, and lipid and cholesterol transport and metabolism. Choline is critical during fetal and neonatal life to ensure optimal brain and cognitive development. There is an intersection of the pathways of choline, folate, and vitamin B12 in the formation of methionine from homocysteine. Maternal peri-conceptional deficiency for choline, like folate, is associated with an increased risk of neural tube defects in the offspring. It is recommended that pregnant women do not restrict fat severely from their diets, as choline is derived from the lipid content of food. Strict vegetarian or vegan diets may be low in choline. The high secretion rate of choline into breast milk means that lactating women have a high demand, and multivitamins containing choline may be helpful for both pregnancy and breastfeeding.
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Weiner, Howard, and Peter B. Crino. Familial tumour syndromes: tuberous sclerosis complex. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0017.
Full textAbstract:
Tuberous sclerosis complex (TSC) is a multisystem, genetic disorder that results from mutations in TSC1 or TSC2 genes. Neurological and neuropsychiatric disabilities include epilepsy, intellectual disability, autism, attention deficit disorder, and generalized anxiety. Cortical dysplasias (also known as tubers) are developmental abnormalities of the cerebral cortex that are believed to be responsible for seizures, cognitive disability, and autism. Subependymal giant cell astrocytomas (SEGAs) are intraventricular tumours that can cause hydrocephalus, increased intracranial pressure, and death. TSC results from hyperactivation of the mammalian target of rapamycin (mTOR) pathway in neurons in the brain. This chapter reviews the clinical presentations of TSC as well as diagnostic approaches for epilepsy and SEGAs. It discusses the genetics and cellular pathogenesis of TSC as well as reviewing the link to mTOR signalling. This chapter also presents evidence for different treatment modalities for seizures and SEGAs. It is written for qualified specialist physicians and caregivers.
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Puthucheary, Zudin, Hugh Montgomery, Nicholas Hart, and Stephen Harridge. Skeletal Muscle Mass Regulation in Critical Illness. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199653461.003.0035.
Full textAbstract:
Muscle is a dynamic, plastic, and malleable tissue that is highly sensitive to mechanical and metabolic signals. Muscle mass is regulated by protein homeostasis, with protein being continually turned over, reflecting a balance between synthesis and breakdown. This chapter discusses the effect of critical illness on skeletal muscle mass, protein homeostasis, and the intracellular signalling driving anabolism and catabolism. The focus will be on the unique challenges to which the skeletal muscle are exposed, such as inflammation, sepsis, sedation, and inadequate nutrition, which, in combination with the disuse signals of immobilization and bed rest, engender dramatic changes in muscle structure and function. The mechanisms regulating muscle loss during critical illness are being unravelled, but many questions remain unanswered. Detailed understanding of these mechanisms will help drive strategies to minimize or prevent intensive care-acquired muscle weakness and the long-term consequences experienced by ICU survivors.
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Jafri, Mariam, and Eamonn R. Maher. Genetics and molecular biology of renal cancer. Edited by James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0084.
Full textAbstract:
Renal cell carcinoma (RCC) is the exemplar of how the understanding of the molecular pathogenesis of rare inherited disorders can inform an understanding of the key pathways involved in the pathogenesis of sporadic cancer. In this chapter we describe the clinical and pathological features of the inherited kidney cancer syndromes: von Hippel Lindau disease (VHL); Birt-Hogg-Dube syndrome; hereditary leiomyomatosis and renal cancer syndrome; succinate dehydrogenase disorders; hereditary papillary renal cancer; and translocation-associated kidney cancer. Though individually rare, recognition of individuals with familial kidney cancer is important as they present specific clinical challenges to the urological surgeon because of their propensity to develop multicentric/bilateral tumours. Furthermore, different familial RCC predisposition syndromes are associated with different extra renal clinical features and have specific surveillance needs. Despite differences in clinical features, there is some overlap in the molecular pathophysiology between the disorders and these highlight the key signalling pathways for RCC oncogenesis.
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MacGrogan, Donal, José Maria Pérez-Pomares, Bill Chaudhry, José Luis de la Pompa, and Deborah J. Henderson. From cushions to leaflets: morphogenesis of cardiac atrioventricular valves. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0017.
Full textAbstract:
At the looping stage of heart development, tissue patterning of myocardium and endocardium at the atrioventricular (AV) junction defines a morphogenic field competent to form valves that initially appear as protrusions of proteoglycan-rich extracellular matrix (ECM) called endocardial cushions (ECs) which are cellularized by an endocardial-mesenchymal transition (EMT). Cellular proliferation results in fusion of the major AV mesenchymal cushions and AV septation, whereas smaller cushions receive a supply from epicardially derived cells. These various sources of mesenchyme precursors give rise to most of the valve structures, leaflets, annuli, and supporting tension apparatus. During valve leaflet maturation, the ECM matrix accumulates collagen and elastin and assembles into a thin flexible fibrous structure, which is remarkably tough. Valve development is regulated by the cross-talk between developmental signalling pathways. Pathogenic mutations in a subset of developmentally important genes have been linked to valve disease, suggesting that developmental defects may underlie valve disease in adulthood.
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Wackerhage, Henning, Jonathon Smith, and Darren Wisniewski. Molecular exercise physiology. Edited by Neil Armstrong and Willem van Mechelen. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198757672.003.0031.
Full textAbstract:
Molecular exercise physiology is the study of exercise physiology using molecular biology methods. The development of differentiated cell types is regulated by transcription factors like the muscle-making MyoD that specifies cell type, while others regulate the development of muscle, tendons, and bones. Maternal nutrition and exercise commonly affect embryonic development through epigenetic mechanisms. Adaptation to exercise involves sensor proteins detecting exercise-related signals, the processing of signals by signalling proteins and networks, and the regulation of the actual adaptations by effector proteins. Many sport- and exercise-related traits depend on both common and rare DNA sequence variations, including the muscle mass-increasing myostatin (GDF8) loss-of-function and the haematocrit-increasing EPOR gain-of-function mutations. Additionally, common DNA sequence variations contribute to the inherited variability of development, body height, strength, and endurance. Finally, in addition to ethical concerns, current genetic performance tests only explain a fraction of the variation of sport and exercise-related traits.
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Carmeliet, Peter, Guy Eelen, and Joanna Kalucka. Arteriogenesis versus angiogenesis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0008.
Full textAbstract:
Higher organisms have a cardiovascular circulatory system with blood vessels to supply vital nutrients and oxygen to distant tissues. It is therefore not surprising that vascular disorders are leading causes of mortality. Understanding how new blood vessels form, creates opportunities to cure these life-threatening diseases. After birth, growth of blood vessels mainly occurs via two distinct mechanisms depending on the initial trigger: angiogenesis (referred here as capillary sprouting) is induced primarily by hypoxia, whereas arteriogenesis (referred here as the rapid enlargement of pre-existing collateral arteries, induced by vascular occlusion) is mainly driven by fluid shear stress. Arteriogenesis allows conductance of much larger volumes of blood per unit of time than does the increase in capillary density during angiogenesis. Notwithstanding these major differences, angiogenesis and arteriogenesis share a number of underlying mechanisms, e.g. the involvement of growth factor signalling. This chapter highlights the cellular and molecular events driving the two processes and discusses the therapeutic potential of targeting angiogenesis in cancer and arteriogenesis in cardiovascular diseases.
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Hanajima, Ritsuko, and Yoshikazu Ugawa. Paired-pulse measures. Edited by Charles M. Epstein, Eric M. Wassermann, and Ulf Ziemann. Oxford University Press, 2012. http://dx.doi.org/10.1093/oxfordhb/9780198568926.013.0011.
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This article reviews the physiology and application of the currently available paired-pulse protocols. Paired-pulse transcranial magnetic stimulation (TMS) techniques study the modulation of human motor cortical excitability. Paired-pulse experiments are designed to give insight into the nature of the cortical circuitry activated by TMS. Changes in motor cortical excitability produced by the conditioning pulse are estimated by changes in the size of the conditioned motor-evoked potential (MEP). It is possible to identify specific abnormalities in the balance between inhibitory and facilitatory processes, even if the pathology lies in abnormal afferent signalling to the motor cortex rather than in the motor cortex itself. The conclusion that emerges from the studies on interhemispheric interactions is that it is now possible by means of TMS protocols to chart long-range functional interhemispheric connectivity of remote areas of the human brain.
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Pezzella, Francesco, Mahvash Tavassoli, and David J. Kerr, eds. Oxford Textbook of Cancer Biology. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.001.0001.
Full textAbstract:
The study of the biology of tumours has grown to become markedly interdisciplinary, involving chemists, statisticians, epidemiologists, mathematicians, bioinformaticians, and computer scientists alongside medical scientists. Oxford Textbook of Cancer Biology brings together the developments from different branches of research into one volume. Structured in seven sections, the book starts with a review of the development and biology of multicellular organisms, how they maintain a healthy homeostasis in an individual, and a description of the molecular basis of cancer development. The book then illustrates how, once cells become neoplastic, their signalling network is altered and pathological behaviour follows. Changes that cancer cells can induce in nearby normal tissue are explored, and the new relationship established between them and the stroma is explicated. Finally, the authors illustrate the contribution provided by high throughput techniques to map cancer at different levels, from genomic sequencing to cellular metabolic functions, and how information technology with its vast amounts of data are integrated with traditional cell biology to provide a global view of the disease. The book concludes by summarizing what we know to date about cancer, and in what direction our understanding of cancer is moving.
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Kühn, Wolfgang, and Gerd Walz. The molecular basis of ciliopathies and cyst formation. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0303.
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Abnormalities of the cilium, termed ‘ciliopathies’, are the prime suspect in the pathogenesis of renal cyst formation because the gene products of cystic disease-causing genes localize to them, or near them. However, we only partially understand how cilia maintain the geometry of kidney tubules, and how abnormal cilia lead to renal cysts, and the diverse range of diseases attributed to them. Some non-cystic diseases share pathology of the same structures. Although still incompletely understood, cilia appear to orient cells in response to extracellular cues to maintain the overall geometry of a tissue, thereby intersecting with the planar cell polarity (PCP) pathway and the actin cytoskeleton. The PCP pathway controls two morphogenetic programmes, oriented cell division (OCD) and convergent extension (CE) through cell intercalation that both seem to play a critical role in cyst formation. The two-hit theory of cystogenesis, by which loss of the second normal allele causes tubular epithelial cells to form kidney cysts, has been largely borne out. Additional hits and influences may better explain the rate of cyst formation and inter-individual differences in disease progression. Ciliary defects appear to converge on overlapping signalling modules, including mammalian target of rapamycin and cAMP pathways, which can be targeted to treat human cystic kidney disease irrespective of the underlying gene mutation.
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Guzik, Tomasz J., and Rhian M. Touyz. Vascular pathophysiology of hypertension. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0019.
Full textAbstract:
Hypertension is a multifactorial disease, in which vascular dysfunction plays a prominent role. It occurs in over 30% of adults worldwide and an additional 30% are at high risk of developing the disease. Vascular pathology is both a cause of the disease and a key manifestation of hypertension-associated target-organ damage. It leads to clinical symptoms and is a key risk factor for cardiovascular disease. All layers of the vascular wall and the endothelium are involved in the pathogenesis of hypertension. Pathogenetic mechanisms, whereby vascular damage contributes to hypertension, are linked to increased peripheral vascular resistance. At the vascular level, processes leading to change sin peripheral resistance include hyper-contractility of vascular smooth muscle cells, endothelial dysfunction, and structural remodelling, due to aberrant vascular signalling, oxidative and inflammatory responses. Increased vascular stiffness due to vascular remodelling, adventitial fibrosis, and inflammation are key processes involved in sustained and established hypertension. These mechanisms are linked to vascular smooth muscle and fibroblast proliferation, migration, extracellular matrix remodelling, calcification, and inflammation. Apart from the key role in the pathogenesis of hypertension, hypertensive vasculopathy also predisposes to atherosclerosis, another risk factor for cardiovascular disease. This is linked to increased transmural pressure, blood flow, and shear stress alterations in hypertension, as well as endothelial dysfunction and vascular stiffness. Therefore, understanding the mechanisms and identifying potential novel treatments targeting hypertensive vasculopathy are of primary importance in vascular medicine.
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Badimon, Lina, Felix C. Tanner, Giovanni G. Camici, and Gemma Vilahur. Pathophysiology of thrombosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0018.
Full textAbstract:
Ischaemic heart disease and stroke are major causes of death and morbidity worldwide. Coronary and cerebrovascular events are mainly a consequence of a sudden thrombotic occlusion of the vessel lumen. Arterial thrombosis usually develops on top of a disrupted atherosclerotic plaque because of the exposure of thrombogenic material, such as collagen fibrils and tissue factor (TF), to the flowing blood. TF, either expressed by subendothelial cells, macrophage- and/or vascular smooth muscle-derived foam-cells in atherosclerotic plaques, is a key element in the initiation of thrombosis due to its ability to induce thrombin formation (a potent platelet agonist) and subsequent fibrin deposition at sites of vascular injury. Adhered platelets at the site of injury also play a crucial role in the pathophysiology of atherothrombosis. Platelet surface receptors (mainly glycoproteins) interact with vascular structures and/or Von Willebrand factor triggering platelet activation signalling events, including an increase in intracellular free Ca2+, exposure of a pro-coagulant surface, and secretion of platelet granule content. On top of this, interaction between soluble agonists and platelet G-coupled protein receptors further amplifies the platelet activation response favouring integrin alpha(IIb)beta(3) activation, an essential step for platelet aggregation. Blood-borne TF and microparticles have also been shown to contribute to thrombus formation and propagation. As thrombus evolves different circulating cells (red-blood cells and leukocytes, along with occasional undifferentiated cells) get recruited in a timely dependent manner to the growing thrombus and further entrapped by the formation of a fibrin mesh.