{"title":"Cardiovascular disease.","authors":"N. Severs","doi":"10.4135/9781473920781.n7","DOIUrl":"https://doi.org/10.4135/9781473920781.n7","url":null,"abstract":"Gap junctions play essential roles in the normal function of the heart and arteries, mediating the spread of the electrical impulse that stimulates synchronized contraction of the cardiac chambers, and contributing to co-ordination of function between cells of the arterial wall. Altered gap junctional coupling is implicated in the genesis of arrhythmia, a major cause of death in heart disease. Two abnormalities in myocardial gap junctions distribution at the border zone of infarcts and reduced levels of connexin43 (Cx43; alpha 1)--may lead to heterogeneous wavefront propagation and lowered conduction velocity, key factors that precipitate arrhythmia. In the major arteries, endothelial cells express Cx40 (alpha 5) and Cx37 (alpha 4) and, in some instances, also Cx43, whereas underlying medial smooth muscle cells express only Cx43. Increased Cx43 expression between medial smooth muscle cells is intimately linked to phenotypic transformation to the synthetic state in both early human coronary phenotypic transformation to the synthetic state in both early human coronary atherosclerosis, and in the response of the arterial wall to injury. The accumulating evidence suggests that gap junctions in both their guises--as pathways for cell-to-cell signalling in the vessel wall and as pathways for impulse conduction in the heart--may have key roles in the initial pathogenesis and eventual clinical manifestation of human cardiovascular disease.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"219 1","pages":"188-206; discussion 206-11"},"PeriodicalIF":0.0,"publicationDate":"2018-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48102310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Normal and neoplastic stem cells.","authors":"I. Weissman","doi":"10.1002/0470091452.CH4","DOIUrl":"https://doi.org/10.1002/0470091452.CH4","url":null,"abstract":"Stem cells are cells that at the single cell level both self-renew and give rise to differentiated progeny. Self renewal is the property that distinguishes stem cells and progenitors, and in the blood-forming system explains why haematopoietic stem cells (HSCs), not progenitors, are the only cells capable of providing rapid and sustained regeneration of the blood-forming system after ablation by cancer chemo- and radiotherapies. Cancer-free prospectively purified HSCs regenerate the haematopoietic system of patients as rapidly as a marrow or mobilized blood transplant, but without the risk of re-seeding the body with cancer cells. Further, purified allogeneic HSCs can establish donor-specific tolerance to subsequent tissue grafts. However, in contrast to widely-publicized reports of HSC plasticity, we have not been able to show transdifferentiation of HSC to muscle, heart, brain or gut, and conclude that rare cell fusions and incomplete purifications are likely explanations for the other published results. The ability to self-renew is also potentially dangerous, as poorly regulated self renewal is, we believe, a central lesion in all cancers. We have recently shown that myeloid leukaemias in mouse and human are often driven by rare leukaemia (cancer) stem cells which are at the progenitor stage of differentiation, but have activated the self-renewing cell division pathway normally used only by HSCs. Similar cancer stem cells have been isolated in other tumours.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"208 2","pages":"35-50; discussion 50-4, 92-7"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470091452.CH4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50759836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Outer mitochondrial membrane protein degradation by the proteasome.","authors":"A. Neutzner, R. Youle, M. Karbowski","doi":"10.1016/J.BBABIO.2010.04.376","DOIUrl":"https://doi.org/10.1016/J.BBABIO.2010.04.376","url":null,"abstract":"","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"287 1","pages":"4-14; discussion 14-20"},"PeriodicalIF":0.0,"publicationDate":"2010-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/J.BBABIO.2010.04.376","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54173410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"HDAC7 regulates apoptosis in developing thymocytes.","authors":"E. Verdin, F. Dequiedt, H. Kasler","doi":"10.1002/0470862637.CH8","DOIUrl":"https://doi.org/10.1002/0470862637.CH8","url":null,"abstract":"Central immune tolerance is established in the thymus for T cells via a complex selection process that involves interactions between CD4+CD8+ double-positive thymocytes and antigen-presenting cells. Cells that express antigen receptors interacting strongly with self peptide MHC complexes are deleted from the repertoire via activation-induced apoptosis, a process termed negative selection. Cells that express an appropriate signal are positively selected and mature into single positive naïve T cells, either CD4 or CD8 positive. The balance between positive and negative selection is thought to play a critical role in the elimination of self-reactive clones and in the establishment of central immune tolerance. We have recently reported that HDAC7, a class II histone deacetylase, is highly expressed in CD4+CD8+ double positive thymocytes. HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection. The inhibitory effect of HDAC7 on the Nur77 promoter is mediated via the transcription factor MEF2D. During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes and indicate that HDAC7 is likely to play an important role in the control of central immune tolerance.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"259 1","pages":"115-29; discussion 129-31, 163-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470862637.CH8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50777200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy.","authors":"W. Macnee","doi":"10.1002/0470868678.CH11","DOIUrl":"https://doi.org/10.1002/0470868678.CH11","url":null,"abstract":"There is now considerable evidence for an increased oxidant burden in smokers, particularly in those smokers who develop chronic obstructive pulmonary disease (COPD), as shown by increased markers of oxidative stress in the airspaces, breath, blood and urine. The presence of increased oxidative stress is a critical feature in the pathogenesis of COPD, since it results in inactivation of antiproteinases, airspace epithelial injury, mucus hypersecretion, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of pro-inflammatory mediators. The sources of the increased oxidative stress in patients with COPD derive from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Antioxidant depletion or deficiency in antioxidants also contributes to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants and hence dietary supplementation may be a beneficial therapeutic intervention in this condition. Oxidative stress also has a role in enhancing the airspace inflammation, which occurs in smokers and patients with COPD through the activation of redox-sensitive transcriptions factors such as NF-kappa B and AP-1, which regulate the genes for pro-inflammatory mediators and protective antioxidant gene expression. Antioxidants that have good bioavailability or molecules that have antioxidant enzyme activity are therefore therapies that not only protect against the direct injurious effects of oxidants, but also may fundamentally alter the inflammatory events which have a central role in the pathogenesis of COPD.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"95 4","pages":"169-85; discussion 185-8"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470868678.CH11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50779410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The versatility and complexity of calcium signalling.","authors":"M. Berridge","doi":"10.1002/0470846674.CH6","DOIUrl":"https://doi.org/10.1002/0470846674.CH6","url":null,"abstract":"Ca2+ is a universal second messenger used to regulate a wide range of cellular processes such as fertilization, proliferation, contraction, secretion, learning and memory. Cells derive signal Ca2+ from both internal and external sources. The Ca2+ flowing through these channels constitute the elementary events of Ca2+ signalling. Ca2+ can act within milliseconds in highly localized regions or it can act much more slowly as a global wave that spreads the signal throughout the cell. Various pumps and exchangers are responsible for returning the elevated levels of Ca2+ back to the resting state. The mitochondrion also plays a critical role in that it helps the recovery process by taking Ca2+ up from the cytoplasm. Alterations in the ebb and flow of Ca2+ through the mitochondria can lead to cell death. A good example of the complexity of Ca2+ signalling is its role in regulating cell proliferation, such as the activation of lymphocytes. The Ca2+ signal needs to be present for over two hours and this prolonged period of signalling depends upon the entry of external Ca2+ through a process of capacitative Ca2+ entry. The Ca2+ signal stimulates gene transcription and thus initiates the cell cycle processes that culminate in cell division.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"81 11","pages":"52-64; discussion 64-7, 150-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846674.CH6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50768730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Early intervention and brain plasticity in autism.","authors":"G. Dawson, K. Zanolli","doi":"10.1002/0470869380.CH16","DOIUrl":"https://doi.org/10.1002/0470869380.CH16","url":null,"abstract":"Autism is associated with impairments in brain systems that come on line very early in life. One such system supports the development of face processing. Dawson and colleagues found that 3 year old children with autism failed to show differential event-related potentials (ERPs) to photographs of their mother's versus a stranger's face. Since differential ERP activity to familiar and unfamiliar faces is typically present by 6 months, this represents early brain dysfunction. McPartland and colleagues found that the face-specific ERP component ('N170') is atypical in older individuals with autism. N170 is typically larger to faces than non-faces, and prominent over the right hemisphere. In individuals with autism, N170 was larger for furniture than faces and bilaterally distributed. Biology and experience contribute to the development of face-processing systems. Newborns are capable of recognizing faces. Early face recognition abilities are thought to be served by a subcortical system, which is replaced by an experience-dependent cortical system. Development of a neural system specialized for faces may depend on experience with faces during an early sensitive period. Because children with autism fail to attend to faces, they might not acquire the expertise needed for a specialized face processing system to develop normally. Early interventions that enhance social attention should result in changes in brain activity, as reflected in ERPs to face stimuli, with those children showing the greatest social improvement exhibiting more normal brain activity.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"20 11","pages":"266-74; discussion 274-80, 281-97"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470869380.CH16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50784097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The neuropathology of the autism spectrum disorders: what have we learned?","authors":"M. Bauman, T. Kemper","doi":"10.1002/0470869380.CH8","DOIUrl":"https://doi.org/10.1002/0470869380.CH8","url":null,"abstract":"Autism is a behaviourally defined disorder, initially described by Kanner in 1943. By definition, symptoms are manifested by 36 months of age and are characterized by delayed and disordered language, impaired social interaction, abnormal responses to sensory stimuli, events and objects, poor eye contact, an insistence on sameness, an unusual capacity for rote memory, repetitive and stereotypic behaviour and a normal physical appearance. Relatively few neuropathological studies have been performed on the brains of autistic subjects. Of those reported, abnormalities have been described in the cerebral cortex, the brainstem, the limbic system and the cerebellum. Although those with the disorder present with a specific set of core characteristics, each individual patient is somewhat different from another. Thus, it should not be surprising that the brains of these subjects should show a wide range of abnormalities. However, it is important to delineate the anatomic features, which are common to all cases, regardless of age, sex and IQ, in order to begin to understand the central neurobiological profile of this disorder. The results of our systematic studies indicate that the anatomic features that are consistently abnormal in all cases include reduced numbers of Purkinje cells in the cerebellum, and small tightly packed neurons in the entorhinal cortex and in the medially placed nuclei of the amygdala. It is known that the limbic system is important for learning and memory, and that the amygdala plays a role in emotion and behaviour. Research in the cerebellum indicates that this structure is important as a modulator of a variety of brain functions and impacts on language processing, anticipatory and motor planning, mental imagery and timed sequencing. Defining the differences and similarities in brain anatomy in autism and correlating these observations with detailed clinical descriptions of the patient may allow us greater insight into the underlying neurobiology of this disorder.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"7 7-8","pages":"112-22; discussion 122-8, 281-97"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470869380.CH8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50784324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mucus hypersecretion in chronic obstructive pulmonary disease.","authors":"D. Rogers","doi":"10.1002/0470868678.CH5","DOIUrl":"https://doi.org/10.1002/0470868678.CH5","url":null,"abstract":"Most patients with chronic obstructive pulmonary disease (COPD) exhibit characteristics of airway mucus hypersecretion, namely sputum production, increased luminal mucus, submucosal gland hypertrophy and goblet cell hyperplasia. The clinical consequences of hypersecretion are impaired gas exchange and compromised mucociliary clearance, which encourages bacterial colonization and associated exacerbations. However, the extent of the contribution of mucus to pathophysiology of COPD is controversial. Early epidemiological studies found little evidence for the involvement of mucus in the age-related decline in lung function and mortality associated with COPD and concluded that chronic airflow obstruction and mucus hypersecretion were independent processes. Later studies found positive associations between phlegm production and decline in lung function, hospitalization and death. Thus, although not diagnostic for the condition, mucus hypersecretion contributes to morbidity and mortality in certain groups of patients with COPD. This suggests that it is important to develop drugs that inhibit mucus hypersecretion in these patients. Unfortunately, ambiguity in clinical studies of mucoactive drugs means that mucolytics are not recommended in clinical management. Future research should determine whether there is an intrinsic abnormality in mucus in COPD, which will determine development of appropriate inhibitors, which in turn can be used in 'proof of concept' and in treatment.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"63 3","pages":"65-77; discussion 77-83"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470868678.CH5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50779670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microbiology and immunology of autism spectrum disorders.","authors":"W. Lipkin, M. Hornig","doi":"10.1002/0470869380.CH9","DOIUrl":"https://doi.org/10.1002/0470869380.CH9","url":null,"abstract":"Both generic and environmental factors are likely to contribute to the pathogenesis of neurodevelopmental disorders. Even in heritable disorders of high penetrance, variability in timing of onset or severity of disease indicate a role for modifying principles. Investigation in animal models of the consequences of interactions between host response genes and microbes, toxins, and other environmental agents in a temporal context may elucidate the pathophysiology of a wide spectrum of chronic diseases. Here we review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline plans for translational research in animal models and prospective human birth cohorts.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"6 4","pages":"129-43; discussion 144-8, 281-97"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470869380.CH9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50784451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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