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PubMed2002

The Role of Antigen-presenting Cells in HIV Pathogenesis.

The study of antigen-presenting cells (APC) in HIV pathogenesis has been ongoing for almost 20 years. The initial studies recognized the important role of APC as targets for HIV infection and their ability to serve as reservoirs of virus, particularly in tissues. The issue of whether HIV impacts the functional competency of APC has been more controversial, with some studies showing reduced expression of important costimulatory molecules on APC, but others showing the functional capacity of APC to be normal. The study of APC has advanced with recent interest in one class of APC, namely the dendritic cell. These cells have been shown to consist of numerous subsets and serve an important role in bridging innate and adaptive immune responses. The impact of HIV infection on dendritic cells has recently been characterized, as well as the critical functional role of these cells in host defenses in HIV-infected patients. One of the more exciting recent advances in APC biology is the ability to manipulate APC ex vivo for therapeutic purposes in an attempt to restore immune responses in HIV-infected persons. This review covers many of the advances of the field of APC biology and puts them into perspective with HIV pathogenesis.

Journal Article↗
PubMed2003

Immune Regulation and Its Role in the Pathogenesis of Candida Vaginitis.

The pathogenesis of vulvovaginal candidiasis, which is caused by Candida albicans, is poorly understood. Despite a strong protective role for cell-mediated immunity (CMI) against other mucosal candidal infections, numerous studies in humans and most animal models have revealed little to no role for CMI or other forms of acquired immunity against vaginal candidal infections. Studies suggest that this may be because of immunoregulatory mechanisms that inhibit more profound adaptive immune responses rather than the simple lack of responsiveness. Such regulatory mechanisms significantly influence the pathogenesis of Candida vaginitis.

Journal Article↗
PubMed1999

New Thoughts on Pathogenesis and Diagnosis of Encephalitis.

Knowledge regarding the pathogenesis of viral encephalitis, defined as inflammation and destruction of the central nervous system (CNS) from viral infection and the resulting immune response, has improved with advances in molecular biology techniques and recent advances in immunology and neuroscience research. An increasingly complex understanding has developed with regard to viral CNS infection. In addition to advances in viral genetics exploring increased viral spread and neurovirulence, improved understanding from research on neurochemistry, neurodevelopment, and cytokine expression in the CNS has led to new hypotheses regarding the mechanism of CNS damage during viral CNS infection. This review explores three advances in the understanding of viral encephalitis in the past few years: 1) the relationship between viral load and extent of viral CNS disease, 2) chemokines and their role in the CNS inflammatory response as well as in the pathogenesis of encephalitis, and 3) secondary damage from the release of neurotoxins during encephalitis. By examining this research, the reviewers intend to introduce novel therapeutic modalities that are developing for the management of patients with viral encephalitis beyond the timely use of antiviral therapy.

Journal Article↗
PubMed2003

The pathogenesis of neoplastic meningitis.

Neoplastic meningitis (NM) is a dreaded metastatic complication occurring in 5% to 10% of cancer patients. Survival is limited, usually ranging from 4 to 16 weeks. The pathogenesis of NM has not been extensively investigated but can be considered from the anatomic and molecular biologic standpoints. Malignant cells reach the cerebrospinal fluid (CSF) and meninges by direct invasion from tumors located near or within the central nervous system (CNS), or via the bloodstream or other pathways that contact the CNS. Symptoms of NM are caused by malignant cells invading and damaging nervous tissue, obstructing the vascular supply to nervous tissue, or obstructing CSF pathways. The molecular changes responsible for the development of NM are not well delineated, but it is likely that they involve changes in molecules responsible for tumor cell adhesion, migration, and proliferation. An understanding of the pathogenesis of NM will allow for its earliest possible diagnosis and ultimately lead to therapies targeted at the underlying molecular causes of this devastating condition.

Humans↗
PubMed2002

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27.

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.

Arthritis, Reactive↗
PubMed2006

Pathogenesis of idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies, myositis, are characterized by a chronic course with decreased muscle endurance and by infiltrates of T lymphocytes and macrophages in muscle tissue. Treatment with immunosuppressives rarely leads to recovery of muscle function, despite abolishment of inflammatory cell infiltrates in muscle tissue. Therefore, other mechanisms than immune-mediated muscle fiber damage are likely to contribute to the pathogenesis. One such non-immune-mediated muscle dysfunction could be caused by a disturbed microcirculation due to capillary loss or to phenotypically changed endothelial cells in the capillaries. These aberrations may affect the micro-environment of muscle tissue and lead to local tissue hypoxia with development of a secondary metabolic myopathy. Another possible non-immune-mediated mechanism leading to muscle dysfunction is the newly identified endoplasmatic reticulum (ER) stress response in myositis. The ER stress response is thought to be a consequence of the up-regulation of major histocompatibility complex class I in muscle fibers. These newly identified molecular pathways could play a major role in the pathogenesis of myositis and could be important targets in the development of new therapies.

Humans↗
PubMed1980

Psychosocial and behavioral influences in the pathogenesis of acquired cardiovascular disease.

When taken together, studies relating psychosocial and behavioral factors to cardiovascular disease phenomena provide justification for the conclusion that such factors are importantly involved. We would emphasize the need to study and evaluate the interaction of environmental and biological factors in both laboratory studies of pathogenesis as well as in clinical studies of management. Indeed, upon careful scrutiny, even the accepted "nonbehavioral" risk factors such as hypercholesterolemia, hypertension, cigarette smoking, obesity, and sedentary lifestyles are each composite manifestations rather than single pathogens whose identities are powerfully impregnanted and bolstered by varieties of behavioral and psychosocial underpinnings. In view of the awesome impact of contemporary cardiovascular disease, both in terms of its increasing socioeconomic importance and its biologic devastation, we can not long afford comprehensive public health programs without increased and improved attention to psychosocial and behavioral influences in the pathogenesis of acquired cardiovascular disease.

Animals↗
PubMed1993

Pathogenesis and treatment of hypertension associated with diabetes mellitus.

The pathogenesis of hypertension associated with diabetes mellitus (DM) involves an interplay of hereditary and acquired mechanisms. A familial trait for essential hypertension appears to be a risk factor for the development of both hypertension and nephropathy in type I DM and coexists commonly with impaired insulin sensitivity, relative hyperinsulinemia, and dyslipidemia, which can already be detected before the appearance of hypertension, obesity, or upper abdominal redistribution of body fat. The latter finding helps explain the frequent development of hypertension as well as dyslipidemia and/or type II DM in given individuals. Obesity is an important factor promoting these complications. Type I or II DM but not uncomplicated essential hypertension is characteristically accompanied by excess body Na+. This abnormality complements a tendency toward vascular hyperreactivity and a presumably morphologic and functional vasculopathy, thereby promoting the pathogenesis of hypertension in diabetic patients. For the treatment of hypertension in diabetic patients, nonpharmacologic measures are indispensable. If drugs are needed, angiotensin-converting enzyme (ACE) inhibitors and some but not all calcium antagonists are the preferred agents. Monotherapy or a combination of these drug types allows effective blood pressure control in most diabetic patients without further metabolic impairment; ACE inhibitors even tend to improve glucose control. Ketanserin may be a potential alternative, and if a diuretic is also needed, the metabolically neutral indapamide is a reasonable choice. If these agents do not allow satisfactory blood pressure highly selective beta 1-blockers or alpha 1-blockers may be introduced as a second choice. In diabetic patients with nephropathy, effective antihypertensive therapy can reduce proteinuria and slow the progression of the nephropathy; ACE inhibitors may improve diabetic proteinuria even at unchanged systemic blood pressure levels. Unless diuretics are needed for reasons other than hypertension, the treatment of diabetic patients with thiazides or loop diuretics in conventional dosage should probably be avoided until clarification of their influence on prognosis. Nevertheless, whether and to what extent other agents and nonpharmacologic measures can modify the prognosis in diabetic patients is also unclear, and the approach to antihypertensive therapy is therefore still largely empiric.

Antihypertensive Agents↗
PubMed1993

Role of coronary vasospasm in the pathogenesis of myocardial infarction: study in patients with no significant coronary stenosis.

The role of coronary vasospasm in the pathogenesis of myocardial infarction is unclarified. Among 212 patients with myocardial infarction in whom percutaneous transluminal coronary angioplasty (PTCA) or coronary thrombolysis was not performed at the acute stage, 21 patients (10%) showed no significant coronary stenosis (the degree of stenosis was less than 50% of the luminal diameter) by coronary angiography 4 weeks after myocardial infarction. Among them, 11 (52%) had preinfarction angina at rest, including two with variant angina, and nine (43%) had postinfarction angina at rest. Intracoronary ergonovine maleate induced coronary vasospasm in 12 (75%) of 16 patients examined. Coronary vasospasm occurred in the infarct-related coronary arteries in all patients, and importantly, multivessel coronary vasospasm occurred in 11 patients (69%). The infarct size was relatively small in these patients: (1) seven patients (33%) had Q wave myocardial infarction while 14 patients (67%) had non-Q wave myocardial infarction; (2) peak creatine phosphokinase (CPK) was lower than 1000 IU/ml in all patients; and (3) thallium-201 (Tl-201) scintigraphic study showed no perfusion defect in 8 of 18 patients. There was only one patient with congestive heart failure and no patient died. These results suggest that coronary vasospasm may play an important role in the pathogenesis of myocardial infarction in patients without significant coronary stenosis. The relatively small infarct size suggests that coronary reperfusion occurred in the early stages of myocardial infarction.

Adult↗
PubMed1992

Role of myocardial oxygen demand in the pathogenesis of silent ischemia during daily life.

The role of myocardial oxygen demand in the pathogenesis of silent ambulatory myocardial ischemia was evaluated by reviewing and assessing the methods and results of recent studies. The performance of simultaneous ambulatory electrocardiographic and blood pressure monitoring in 25 men with proven coronary artery disease (CAD) revealed significant increases in heart rate and blood pressure (p < 0.001) preceding most silent ischemic events. By plotting the mean heart rate obtained at 5-minute intervals during the 30 minutes before an ischemic event, the ischemic heart rate was shown to be significantly higher (95 +/- 15 vs 74 +/- 11 beats per minute [bpm]; p < 0.01) than the nonischemic heart rate. The evaluation of heart rate changes during ambulatory ischemia (in patients with CAD and ischemia induced by an exercise test using gradual work load increments) showed a significant heart rate increase (> 10 bpm) at 1-5 minutes preceding the onset of ST-segment depression. Heart rate increases during exercise testing according to the gradual work load increments of the National Institutes of Health protocol were compared with the heart rate preceding ischemic events during daily life monitored by ambulatory electrocardiography and were found to be closely related. In contrast, heart rate increases that occurred during exercise testing using the standard Bruce protocol were higher and correlated less with those preceding ischemia in daily life. Heart rate and blood pressure increased significantly in most silent ischemic episodes, indicating that increased myocardial oxygen demand plays a significant role in the pathogenesis of myocardial ischemia during daily life.

Activities of Daily Living↗
PubMed1978

Membranes nephropathy associated with renal cell carcinoma. Evidence against a role of renal tubular or tumor antibodies in pathogenesis.

A patient with the nephrotic syndrome due to membranous nephropathy was found to have renal cell carcinoma. Since membranous nephropathy in patients with malignancies has been attributed to a tumor antigen-antibody complex form of glomerulonephritis, an attempt was made to implicate tumor antigens and/or renal tubular epithelial antigens in the pathogenesis of membranous nephropathy in our patient with renal cell carcinoma. Antibodies directed against tumor antigens and renal tubular antigens and renal tubular eipthelial antigens were sought in his serum and in eluates of his glomeruli; no such antibodies were found. The concurrence of the two renal lesions may have been fortuitous in this patient. However, their association temporally suggests that they were related, and our immunologic studies demonstrate that tumor antigen-antibody complexes are not invariably involved in the pathogenesis of malignancy-associated membranous nephropathy.

Adenocarcinoma↗
PubMed1980

Pathogenesis of renal failure due to aminoglycosides and contrast media used in roentgenography.

The etiology of acute renal failure has changed in recent years due to the recognition of drug nephrotoxicity as a more common cause. In this communication we emphasize recent information concerning the pathophysiology of nephrotoxic acute renal failure produced by aminoglycoside antibiotics and the contrast media used in roentgenography. The aminoglycosides are excreted primarily by glomerular filtration; however, net tubular reabsorption and renal parenchymal accumulation do occur. The exact mechanism of uptake is not clear, but the luminal membrane seems primarily involved. The pathogenesis of nephrotoxicity, although probably linked to cortical accumulation, is complex since experimental animals recover from gentamicin-induced renal failure despite continued administration of the drug. Knowledge of the precise cellular mechanisms of injury awaits further studies. Histologic damage is usually limited to proximal tubular necrosis and, clinically, the renal failure is nonoliguric. Although reports of the contrast media used in roentgenography producing acute renal failure have increased, the pathogenesis is unclear. Evidence supporting various theories is reviewed.

Acute Kidney Injury↗
PubMed1981

Nodular regenerative hyperplasia of the liver associated with macroglobulinemia. A clue to the pathogenesis.

Nodular regenerative hyperplasia of the liver is an infrequent condition characterized by transformation of the hepatic parenchyma into nodules with only mild fibrosis. Little is known about the etiology except that there is usually an underlying chronic disease, such as Felty's syndrome, which antedates the development of clinical liver disease. It is poorly understood how the associated diseases contribute to the pathogenesis of nodular regenerative hyperplasia. Presented are four cases of nodular regenerative hyperplasia in which macroglobulinemia was also present. This new association suggests to us a hypothesis for the pathogenesis of nodular regenerative hyperplasia. Histologic examination of the livers in these and other cases of nodular regenerative hyperplasia reveals widespread obliteration of the small portal veins. Postmortem angiography of one liver in the present series demonstrated that the nodules were well perfused and that the atrophic areas were poorly perfused with portal blood. This supports the view that atrophy of lobules results from a lack of portal blood supply and that nodules develop from lobules well supplied with portal blood. In each of the clinical conditions associated with nodular regenerative hyperplasia, including macroglobulinemia, inflammatory or thrombotic vascular lesions are found in many organs. Therefore, nodular regenerative hyperplasia may be the hepatic expression of a more widespread vascular disease.

Adult↗
PubMed1983

New concepts about the pathogenesis of atherosclerosis in diabetes mellitus.

New concepts about the pathogenesis of atherosclerosis in diabetes mellitus are presented. Emphasis is given to alterations of endothelial function, as indicated by von Willebrand factor activity, prostacyclin release, and fibrinolytic activity in diabetes mellitus. Previous work on platelet aggregation and arachidonic acid metabolism is updated and recent findings are emphasized. The atherogenic mix of elevated low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol levels in uncontrolled diabetes mellitus is noted. The lipid hypothesis is extended by consideration of very low-density lipoprotein and intermediate-density lipoprotein metabolism in diabetes. Lipoprotein-cell interactions that may contribute to atherosclerosis are reviewed and suggestions are made for future research in order to clarify the pathogenesis of atherosclerosis in diabetes mellitus.

Animals↗
PubMed1991

Update on the pathogenesis of atherosclerosis.

The major components of atherosclerotic plaque, ultimately responsible for clinical effects, are deposited lipids--mostly cholesteryl esters and cholesterol, derived largely from the lower-density lipoproteins of the blood--and proliferated, modified arterial smooth muscle cells with their synthesized connective tissue products. Advanced plaques vary widely in the proportion of the two components, but evidence indicates that lipid deposition--especially of lipoprotein elements--often occurs in the lesion-prone intimal areas of the artery prior to the buildup of smooth muscle cells. The 1980s were remarkably productive for investigators who study the pathogenesis of atherosclerosis. We now know of the many forms of lower-density lipoproteins, i.e., low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), some of which are more likely to be associated with accelerated atherosclerosis and some of which are more likely to be influenced by diet. Among these forms of LDL and VLDL are LDL-1, beta-VLDL, and Lp(a). Work has been reported implicating various alterations of endothelial function in the permeability of the arterial endothelial barrier in the transport of these low-density, cholesterol-rich macromolecules. Of possibly greater interest is the developing evidence that such proliferation-stimulating molecules as platelet-derived growth factor (PDGF) can be produced by a number of cells likely to be involved in the progression of atherosclerotic plaque. In addition to platelets, these include activated monocytes and monocyte-derived macrophages, injured endothelial cells, and smooth muscle cells, which can undergo an autocrine conversion to PDGF synthesis--possibly stimulated by LDL from hyperlipidemic serum. Leukotrienes and other endothelium-associated regulatory molecules may also take part in the paracrine and autocrine mechanisms of stimulating smooth-muscle-cell proliferation. Additional recent developments that have led to a better understanding of atherosclerotic pathogenesis have occurred. The first is evidence of the involvement of oxidized LDL and its apolipoprotein B in atherogenesis. Research indicates that antioxidants have a suppressive effect on atherogenesis when oxidized LDL has been involved in lesion development. The data linking the development of autoimmune reactions to these oxidatively altered lipoproteins are also impressive. Further, there is increasing evidence that atherogenesis in nonhuman primates and in people in whom chronic sustained circulating immune complexes are involved is likely to be accelerated, even when few or no classic risk factors are present. These lesions appear to represent a distinct microarchitectural form of concentric and transmural atherosclerosis that is better classified as "atheroarteritis."

Adolescent↗
PubMed1991

The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping.

To delineate the pathogenesis and epidemiology of catheter-related infection with Swan-Ganz pulmonary artery (PA) catheters, a prospective clinical study of hospitalized adult medical and surgical patients was done. Role of catheter material was assessed by randomizing insertions to heparin-bonded PA catheters made of polyvinylchloride or polyurethane. Sources of infection and pathogenesis were studied by culturing skin, the introducer, the PA catheter tip, all hubs, infusate from each lumen, and the extravascular portion of the PA catheter beneath the external protective plastic sleeve. Concordance between isolates from sources and infected catheters was determined by speciation, antibiogram, and for coagulase-negative staphylococci, plasmid profile analysis. Risk factors for infection were determined by stepwise logistic regression. Overall, 65 (22%) of 297 Swan-Ganz catheters showed local infection of the introducer (58 catheters) or the intravascular portion of the PA catheter (20 catheters); only two catheters (0.7%) caused bacteremia. Eighty percent of infected Swan-Ganz catheters (the introducer or PA catheter) showed concordance with organisms cultured from skin of the insertion site, 17% with a contaminated hub and 18% with organisms contaminating the extravascular portion of the PA catheter beneath the sleeve. Isolates from infected PA catheters were most likely to show concordance with concomitantly infected introducers (71%). Cutaneous colonization of the insertion site with greater than 10(2) cfu/10 cm2 (relative risk [RR] 5.5; p less than 0.001), insertion into an internal jugular vein (RR 4.3; p less than 0.01), catheterization greater than 3 days (RR 3.1; p less than 0.01), and insertion in the operating room using less stringent barrier precautions (RR 2.1; p = 0.03) were each associated with a significantly increased risk of catheter-related infection. The risk of bacteremic infection with Swan-Ganz catheters is now low, in the range of 1%, with reasonable care. Swan-Ganz catheters are vulnerable to contamination from multiple sources, but the patient's skin is the single most important source of organisms causing invasive infection, which in most cases involves the introducer rather than the PA catheter. Heavy colonization of the insertion site, percutaneous insertion in the internal jugular vein rather than subclavian vein, catheterization longer than 3 days, and insertion with less stringent barrier precautions significantly increase the risk of catheter-related infection. These findings hold promise for application to management of Swan-Ganz catheters and research in catheter design to reduce the risk of catheter-related infection.

Adolescent↗
PubMed1984

Structural factors in the pathogenesis of ischemic optic neuropathy.

Some patients with nonarteritic ischemic optic neuropathy have no signs or symptoms of systemic vascular disease; therefore, nonvascular factors may play a role in the pathogenesis of this syndrome. We observed that the average cup-disk ratio of the unaffected optic disks in a group of patients with ischemic optic neuropathy was significantly (P = .005) smaller than the average ratio in a group of age-matched controls (0.36 +/- 0.19 vs 0.21 +/- 0.16). Fourteen of 30 patients but only two of 29 controls had cup-disk ratios equal to or less than 0.1. Mechanical factors, such as constriction of axons as they traverse the scleral canal, may contribute to the pathogenesis of ischemic optic neuropathy.

Adult↗
PubMed1989

Role of variant prealbumin in the pathogenesis of familial amyloidotic polyneuropathy: fate of normal and variant prealbumin in the circulation.

According to recent studies on protein chemistry and genetic engineering, replacement of the Val30 residue of prealbumin by methionine is believed to play a critical role in the formation of amyloid deposit and the pathogenesis of familial amyloidotic polyneuropathy (FAP). However, only limited information is available concerning the behavior of prealbumin in the circulation. To obtain the molecular insight into the mechanism of amyloid deposition, it is indispensable to know the fates of normal and variant prealbumin in vivo. Thus, the fates of prealbumin samples from normal and FAP patients were studied in normal rats as well as in animals that were challenged with acute inflammation induced by turpentine. The effect of in vitro photooxidation of prealbumin samples on their behavior was also examined in vivo. Kinetic analysis revealed no appreciable difference between prealbumin samples from normal and FAP patients. These results suggest that factors other than the rate of transfer of the variant form prealbumin from plasma to an extravascular compartment may play a critical role in the pathogenesis of amyloid deposition in FAP patients.

Amyloidosis↗