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Fiocchi C 《Minerva gastroenterologica e dietologica》2002,48(3):215-226
Inflammatory bowel disease (IBD) still presents major challenges to the understanding of its cause, mechanisms of inflammation, and therapeutic choices to control the damaged tissue. Both types of IBD, ulcerative colitis and Crohn's disease, have been known and investigated for over half century but neither one is fully understood nor can be satisfactorily managed. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology but mainly in the mechanisms underlying the chronic inflammatory response. The pattern of IBD epidemiology has drastically changed since World War II, with an increased frequency in countries that have adopted a 'westernized' life style. A parallel and important phenomenon is the continuous drop in age of onset in children. Unfortunately, only few epidemiological clues are available, with the exception of smoking and diet. What in smoking alters the course of IBD is still a mystery and which, among thousands of additives, could represent a risk factor will remain unknown for the foreseeable future. The current emphasis on the study of the enteric flora as the source of potential antigens against which the mucosal immune system reacts appear well justified. The data from animal models appears particularly convincing. Thus, after decades of relying almost exclusively on patient-derived information, numerous animal models are generating precious new information on IBD pathogenesis. In experimental IBD the genetic background of the animal markedly influences the course of the disease, and the same is probably true in humans. The identification of NOD2 as the first mutated gene associated with a subgroup of Crohn's disease patients is the first evidence that genetics are pointing to the right direction for understanding how the environment interacts with genes to cause IBD. For many years immunology has been the main source of scientific information on mechanisms of IBD. Cytokines, chemokines and other soluble factors dominate immunological studies aimed at understanding how different anti-inflammatory and pro-inflammatory mediators are improperly regulated and how immune imbalance can be restored. The extent to which T-cells live or die is also a key determinant of chronicity. In addition to classical immune cells, epithelial, endothelial, mesenchymal and nerve cells are slowly gaining more importance in IBD pathogenesis, as they contribute to the ultimate fate of tissue damage. Medical and surgical therapies are vastly better now that they were only a couple of decades ago, but they are still far from satisfactory. Steroid and aminosalicylates are still the most common drugs after 60 years of use, and it is time to renovate our therapeutic approach to a more effective one. The value of biologicals has been highlighted by the recent success of anti-TNF therapy. Timing of therapy must also change. The concept of the step-by-step approach is slowly fading away, and the idea of an 'all-out' approach with multiple concomitant drugs early in the disease is gaining credibility. New reports on early aggressive therapies, and the demonstration that early and late experimental IBD are caused by different mechanisms are changing the way we think about managing IBD. Both ulcerative colitis and Crohn's disease will continue to challenge the medical establishment for year to come, but the possibility that IBD can be conquered is more realistic now that never before. 相似文献
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Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy 总被引:43,自引:0,他引:43
Selman M King TE Pardo A;American Thoracic Society;European Respiratory Society;American College of Chest Physicians 《Annals of internal medicine》2001,134(2):136-151
Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast-myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies. 相似文献
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Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis 总被引:4,自引:0,他引:4
Low-density lipoprotein (LDL) is the most abundant and the most atherogenic class of cholesterol-carrying lipoproteins in human plasma. The level of plasma LDL is regulated by the LDL receptor, a cell surface glycoprotein that removes LDL from plasma by receptor-mediated endocytosis. Defects in the gene encoding the LDL receptor, which occur in patients with familial hypercholesterolemia, elevate the plasma LDL level and produce premature coronary atherosclerosis. The physiologically important LDL receptors are located primarily in the liver, where their number is regulated by the cholesterol content of the hepatocyte. When the cholesterol content of hepatocytes is raised by ingestion of diets high in saturated fat and cholesterol, LDL receptors fall and plasma LDL levels rise. Conversely, maneuvers that lower the cholesterol content of hepatocytes, such as ingestion of drugs that inhibit cholesterol synthesis (mevinolin or compactin) or prevent the reutilization of bile acids (cholestyramine or colestipol), stimulate LDL receptor production and lower plasma LDL levels. The normal process of receptor regulation can therefore be exploited in powerful and novel ways so as to reverse hypercholesterolemia and prevent atherosclerosis. 相似文献
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G M Kostner 《Cardiology》1991,78(3):194-201
The causes of atherosclerosis are numerous, but disturbances in lipid and lipoprotein (LP) metabolism undoubtedly play a key role. Although there exist multiple forms of genetic and secondary hyperlipoproteinemias linked with premature vascular diseases there are only a few LP that need to be considered: low-density LP, beta-very-low-density LP, chylomicron remnants and LP(a). In addition, low HDL levels have been found to represent an independent risk factor. Prolonged residence times of these LP lead to chemical modification and interaction with platelets, smooth muscle cells, endothelial cells and macrophages. Atherogenesis is thus a concerted action. Knowledge of the metabolic pathways of most of these LP is necessary in order to be able to specifically influence hyperlipoproteinemia with dietary measures or, ultimately, with lipid-lowering drugs. 相似文献
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Sherer K Li Y Cui X Eichacker PQ 《American journal of respiratory and critical care medicine》2007,175(3):211-221
Recent research regarding the structure and function of Bacillus anthracis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopeptidase targeting mitogen-activated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response. In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx. Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research. 相似文献
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Golledge J Muller J Daugherty A Norman P 《Arteriosclerosis, thrombosis, and vascular biology》2006,26(12):2605-2613
Abdominal aortic aneurysm (AAA) affects approximately 5% of elderly men and is responsible for a significant number of deaths in Western Countries. At present surgery by open or endovascular means is the only widely used therapy for this condition. In this review we examine the risk factors, serum, and genetic associations of AAA. Epidemiology studies suggest that smoking cessation and control of cholesterol and blood pressure should reduce the number of patients developing AAA. Natural history studies suggest that smoking cessation should reduce the rate of progression of AAA. Clear level 1 evidence for drug treatments of AAA are presently lacking; however, animal and human in vitro studies suggest that medication targeted at reducing inflammation and proteolysis are most likely to be beneficial, with limited data to support the use of statins, Angiotensin II inhibitors, and macrolides. Work has commenced in understanding which patients, identified by clinical, serum, and genotype, are more at risk of AAA progression and thus should be selected out for aggressive treatment. Well designed large multicenter randomized controlled trials are required to examine the medical treatment of AAA. 相似文献
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Recent studies provide clear and convincing evidence that psychosocial factors contribute significantly to the pathogenesis and expression of coronary artery disease (CAD). This evidence is composed largely of data relating CAD risk to 5 specific psychosocial domains: (1) depression, (2) anxiety, (3) personality factors and character traits, (4) social isolation, and (5) chronic life stress. Pathophysiological mechanisms underlying the relationship between these entities and CAD can be divided into behavioral mechanisms, whereby psychosocial conditions contribute to a higher frequency of adverse health behaviors, such as poor diet and smoking, and direct pathophysiological mechanisms, such as neuroendocrine and platelet activation. An extensive body of evidence from animal models (especially the cynomolgus monkey, Macaca fascicularis) reveals that chronic psychosocial stress can lead, probably via a mechanism involving excessive sympathetic nervous system activation, to exacerbation of coronary artery atherosclerosis as well as to transient endothelial dysfunction and even necrosis. Evidence from monkeys also indicates that psychosocial stress reliably induces ovarian dysfunction, hypercortisolemia, and excessive adrenergic activation in premenopausal females, leading to accelerated atherosclerosis. Also reviewed are data relating CAD to acute stress and individual differences in sympathetic nervous system responsivity. New technologies and research from animal models demonstrate that acute stress triggers myocardial ischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcentration. In the presence of underlying atherosclerosis (eg, in CAD patients), acute stress also causes coronary vasoconstriction. Recent data indicate that the foregoing effects result, at least in part, from the endothelial dysfunction and injury induced by acute stress. Hyperresponsivity of the sympathetic nervous system, manifested by exaggerated heart rate and blood pressure responses to psychological stimuli, is an intrinsic characteristic among some individuals. Current data link sympathetic nervous system hyperresponsivity to accelerated development of carotid atherosclerosis in human subjects and to exacerbated coronary and carotid atherosclerosis in monkeys. Thus far, intervention trials designed to reduce psychosocial stress have been limited in size and number. Specific suggestions to improve the assessment of behavioral interventions include more complete delineation of the physiological mechanisms by which such interventions might work; increased use of new, more convenient "alternative" end points for behavioral intervention trials; development of specifically targeted behavioral interventions (based on profiling of patient factors); and evaluation of previously developed models of predicting behavioral change. The importance of maximizing the efficacy of behavioral interventions is underscored by the recognition that psychosocial stresses tend to cluster together. When they do so, the resultant risk for cardiac events is often substantially elevated, equaling that associated with previously established risk factors for CAD, such as hypertension and hypercholesterolemia. 相似文献
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Benign prostatic hyperplasia: pathogenesis and medical therapy. 总被引:2,自引:0,他引:2
J Geller 《Journal of the American Geriatrics Society》1991,39(12):1208-1216
Epidemiologic studies in castrates strongly support the key role of the testis in the pathogenesis of benign prostatic hyperplasia (BPH). Since the testis secretes androgen and estrogen, both of these hormones have been implicated in BPH. Much information supports the important role of dihydrotestosterone (DHT) in BPH, including intraprostatic activities of enzymes that regulate DHT. Although controversy still exists, DHT levels in BPH may be higher than in normal prostate tissue. Based upon these findings and the ability to quantitate prostate size and function with reliable new techniques, suppression of androgen-mediated action has been tested to assess the validity of the DHT theory. A variety of drugs has been demonstrated to decrease prostate size by approximately 30% by either blocking secretion of circulating testosterone and adrenal androgen, inhibiting 5 alpha-reductase to prevent DHT formation, or blocking DHT binding to androgen receptors. Accompanying these changes in size was significant improvement in clinical symptoms of prostatism in about 50% of patients, when double-blind, large multicenter studies were conducted with one of these drugs. Although these results suggest a very important role for androgen, particularly DHT, in the pathogenesis of BPH, other abnormalities may coexist since significant numbers of patients do not show a total reversal of disease. There is strong indirect evidence for a possible role for estrogen in the pathogenesis of BPH, and studies are under way to test the effects of estrogen withdrawal on prostate size and symptoms. Similarly, dynamic aspects of prostatic obstruction, which are under alpha-adrenergic regulation, may also be a component of this disease and amenable to therapy with alpha-adrenergic blockers.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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LiPuma JJ 《Current opinion in pulmonary medicine》1998,4(6):337-341
Much has been learned during the past 2 years about the microbiology and taxonomy of Burkholderia cepacia. Several distinct species have been identified in what is now referred to as the B. cepacia complex. Preliminary studies indicate that certain of these species are more likely to colonize and cause severe pulmonary infection in persons with cystic fibrosis. Ongoing investigations will expand these findings and have the potential to modify current infection control policies. The commercial use of B. cepacia as an antifungal biopesticide and in bioremediation has attracted increasing attention from industry recently and raises concerns within the cystic fibrosis community. Consensus regarding the potential threat of such uses to cystic fibrosis patients is being sought by governmental agencies and agricultural and biomedical researchers. 相似文献
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H Hamm B Pfalzer H Fabel 《Respiration; international review of thoracic diseases》1991,58(5-6):294-300
A chyliform effusion is an uncommon high lipid pleural effusion that does not result from a leakage of the thoracic duct. Characteristically, it emerges from chronic pleurisy and contains high levels of cholesterol. The origin of this cholesterol is unknown, but it is often attributed to the degeneration of red and white blood cells. In this study we have carried out detailed lipoprotein analyses in a chyliform effusion, a chronic tuberculous effusion and three inflammatory effusions of recent onset, in an attempt to elucidate the process of cholesterol accumulation and possible lipoprotein alterations. Mean cholesterol was 92 mg/dl in the inflammatory exudates and 1,237 mg/dl in the chyliform effusion. In inflammatory effusions of recent onset most cholesterol was bound to low density lipoprotein (LDL) with corresponding apoprotein B levels. The chronic tuberculous exudate showed a shift of cholesterol binding towards high density lipoprotein (HDL). In the chyliform effusion most cholesterol was found in the HDL region. Our results suggest that in acute inflammation, the pleural barrier opens to plasma LDL. We hypothesize that in chronicity this cholesterol becomes trapped in the pleural space and undergoes a change in lipoprotein binding characteristics. In a chyliform effusion, cholesterol further accumulates and builds complexes containing triglycerides and proteins. In clinical routine, total cholesterol values above 200 mg/dl strongly suggest a chyliform effusion. Since triglyceride values may be as high as in chylous effusions (greater than 110 mg/dl), the diagnostic routine in all suspected high lipid effusions should involve cholesterol and triglyceride measurements. 相似文献
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Richard H Hunt Carlo Fallone Sander Veldhuyzen Van Zanten Phil Sherman Nigel Flook Fiona Smaill Alan B R Thomson 《Journal canadien de gastroenterologie》2002,16(9):635-641
Dyspepsia describes a symptom complex thought to arise in the upper gastrointestinal tract and includes, in addition to epigastric pain or discomfort, symptoms such as heartburn, acid regurgitation, excessive burping or belching, a feeling of slow digestion, early satiety, nausea and bloating. Based on the evidence that heartburn cannot be reliably distinguished from other dyspeptic symptoms, the Rome definition appears to be too narrow and restrictive. It is particularly ill suited to the management of uninvestigated dyspepsia at the level of primary care. In patients presenting with uninvestigated dyspepsia, a symptom benefit is associated with a 'test and treat' approach for Helicobacter pylori infection. A substantial proportion of those who do not benefit prove to have esophagitis on endoscopy. In those with functional dyspepsia, the benefits of H pylori eradication, if any, appear to be modest. Hence, a 'symptom and treat' acid-suppression trial with proton pump inhibitors, and a 'test and treat' strategy for H pylori are two acceptable empirical therapies for patients with univestigated dyspepsia. 相似文献
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Tick-borne encephalitis (TBE) is an important and severe neurological illness occurring in large areas of Europe and northern Asia. Only a small proportion of those infected develop clinical symptoms. The symptomatic cases are, however, characterized with fevers and debilitating encephalitis that might progress into chronic disease or fatal infections. This review summarizes data on clinical presentation, pathogenesis and pathology of TBE in humans, and of experimental TBE in animal models with the purpose to explain why is TBE such a severe disease clinically. 相似文献
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Fifty to sixty percent of clinical hypertension is sensitive to sodium (Na) intake: known causes, primary aldosteronism, bilateral renal artery stenosis, mild azotemia, acromegaly, and low-renin hypertension account for only a fraction. We have identified a group of normal-renin hypertensives characterized by inability to modulate normally their renal vascular and adrenal responsiveness to angiotensin II. These patients handle shifts in Na intake abnormally, show more positive balance on a high-salt diet, and raise their blood pressure when shifted to a high-salt diet. Renal blood flow does not shift with Na intake, but does respond strikingly to converting enzyme inhibition, which also corrects altered renal and adrenal responsiveness, ability to handle a sodium load, and hypertension. These patients have a striking family history of hypertension; 50% of the offspring of hypertensives show similar features, including a renal vasodilator response to converting enzyme inhibitors or calcium channel blocking agents. Accumulating evidence suggests that the abnormality is inherited and may be the most common form of hypertension. 相似文献
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Sj?gren's syndrome is an autoimmune exocrinopathy, mainly affecting the lacrimal and salivary glands, and resulting in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown, and only palliative treatment is currently available. Data obtained from experimental animal and human studies using biological agents or gene therapeutics can offer insight into the disease process of Sj?gren's syndrome. This article reviews the current literature on these approaches and assesses the lessons learnt about the pathogenesis of Sj?gren's syndrome. 相似文献