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PubMed1993

Effects of morphine dependence on the pathogenesis of swine herpesvirus infection.

To further understand the effects of opiates on the pathogenesis of infectious disease, naturally occurring pathogens were studied in a swine model. Swine were given morphine for 21-42 days to establish a tolerant, dependent state. On day 7 after morphine initiation, pigs were challenged with swine herpesvirus-1 (SHV-1); on day 14, selected animals were superinfected with Pasteurella multocida. Evaluations were made of the clinical disease, protective effect of SHV-1 vaccination, and pathology. Morphine-dependent animals developed significantly greater virus-induced and secondary bacterial pneumonia. Prior vaccination with SHV-1 was not protective against pneumonia in morphine-dependent pigs. Unexpectedly, clinical signs associated with neurologic disease were less pronounced, and mortality from viral encephalitis was decreased in morphine-treated animals. Collectively, the findings demonstrate that morphine dependence is associated with a marked alteration of the pathogenesis of SHV-1 and that the effects of this opiate on pathogenesis are determined by the specific site of infection.

Animals↗
PubMed2000

Spinocerebellar ataxia type 1--modeling the pathogenesis of a polyglutamine neurodegenerative disorder in transgenic mice.

Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene. One of the major cell types affected by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinje cell. Targeted expression of mutant ataxin-1 in Purkinje cells of transgenic mice produces an ataxic phenotype with pathological similarities to the human disease. Other transgenic experiments using altered forms of mutant ataxin-1 have shown that nuclear localization of the mutant protein is necessary for pathogenesis and that nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and other polyglutamine diseases, are not a requirement for pathogenesis in transgenic models of SCA1. Present and future generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related disorders.

Animals↗
PubMed2005

The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.

BACKGROUND: Uraemic pruritus (UP) is still one of the most vexing and disabling symptoms in chronic renal failure. The pathogenesis of UP is obscure and effective therapeutic strategies are elusive. Deduced from partial successful treatment modalities, there is evidence that an alteration of the immune system with a pro-inflammatory pattern along with a deranged T-helper-cell differentiation may be involved in the pathogenesis of UP. We, therefore, investigated whether UP is related to an augmented Th1-differentiation as measured by determination of intracytoplasmatic (i.c.) cytokines and expression of chemokine receptors. Additionally, pro-inflammatory cytokines were determined in serum. METHODS: In a multicentre study, 171 patients on haemodialysis (HD) were screened for UP. Finally, 13 HD patients with and 13 HD patients without UP, as well as 15 healthy controls were enrolled in the study. Peripheral blood mononuclear cells were isolated and the proportion of Th1- and Th2-cells was determined by flow cytometry. The expression of chemokine receptors on CD4 cells (CXCR3 preferentially on Th1 and CCR4 on Th2) and i.c. cytokines (IFNgamma for Th1 and IL4 for Th2) were measured after in vitro stimulation. Serum cytokine levels (IL6 and TNFalpha) and CRP were measured by ELISA. RESULTS: Compared to HD patients without UP, those complaining of UP showed a significantly enhanced proportion of Th1-cells as measured by both techniques. Additionally, serum CRP and IL6 levels were significantly higher in HD patients with UP, compared to HD patients without UP. CONCLUSIONS: These results point to a central role of inflammation in the pathogenesis of UP in HD patients.

Aged↗
PubMed1988

Enterobacterial involvement in the pathogenesis of secondary ankylosing spondylitis.

Ankylosing spondylitis (AS) is closely associated with the histocompatibility antigen HLA-B27. Pathogenesis of AS is thought to involve interactions between B27 and certain enterobacterial antigens. However, this is uncertain and contested by some. The present paper argues that the presence of statistically raised specific serum IgA to a common enterobacterial heat modifiable major outer membrane protein (h-momp; Mr 35,000) in active AS (N = 25; IgA = 1485 +/- 20) in comparison to controls, most notably hospital patients without known arthropathies or gastrointestinal disease (N = 12; IgA = 548 +/- 59), supports an inductive contribution of enterobacterial antigens to the pathogenesis of secondary AS. Serum IgG and IgM did not statistically differ. Raised specific serum IgA to h-momp might indicate enterobacterial antigenic stimulation from the gastrointestinal tract. It does not necessarily imply direct involvement in the pathogenesis of primary AS. H-momp appears to be a convenient tool for serological studies of AS and at present is likely to be more suitable than other bacterial antigens, notably those with B27-like epitopes. Namely, the confirmed presence in AS of enterobacteria with freely accessible B27-like antigenic epitopes on their cell surface might induce unusual tolerance to these organisms in B27 positive hosts, thus causing chronic inflammation, initially sacroiliitis (and spondylitis) due to the proximity of presacral and para-aortic colon draining lymph nodes, later becoming more generalized (for reasons unclear) to include other lesions (e.g. peripheral arthritis, uveitis, enthesopathies). Thus, antibodies to B27-like antigenic epitopes need not be detectable or may be absent. Also, cellular immune responsiveness to these antigens might be involved.

Bacterial Outer Membrane Proteins↗
PubMed1998

Interactions between spore morphogenetic mutations affect cell types, sporulation, and pathogenesis in Magnaporthe grisea.

We have previously defined four single-gene mutations, con1, con2, con4, and con7, that control various stages of spore morphogenesis in the rice blast fungus. To delineate the developmental pathway of spore morphogenesis, we investigated the interactions among these morphogenetic genes by generating strains with double mutations via transformation-mediated gene disruption. Plasmids containing portions of the inactivated CON4 and CON7 genes were introduced into strains harboring single mutation to produce double mutants. Interaction between con1 and con4 resulted in reduced vegetative growth and suppression of sporulation. Interaction between con1 and con7 suppressed spore production but not vegetative growth. The con2/con4 and con4/con7 double mutants produced hybrid spore types with characteristic features of both parental mutants. The con2/con7 mutant produced con2 type spores, indicating that con2 is epistatic to con7 in spore morphogenesis. The epistatic relationship, however, reversed when traits related to pathogenesis were considered. Double mutants harboring the con7 mutation could not form appressoria or colonize plant tissue, indicating that con7 is epistatic to con2 and con4 in appressorium formation and pathogenesis. Thus, morphogenetic genes interact at multiple levels leading to different epistatic relationships in the pathways of spore morphogenesis, appressorium formation, and pathogenesis.

Ascomycota↗
PubMed2006

BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.

Amyloid beta protein (Abeta), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from APP by sequential cleavages of beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) is the major beta-secretase in vivo. Beta-site APP cleaving enzyme 2 (BACE2) is the homologue of BACE1. The majority of people with Down syndrome (DS), also called Trisomy 21 syndrome, will develop AD neuropathology after middle age. We and others have shown that APP C99, the major beta-secretase product, and Abeta are markedly increased in DS. Since BACE2 is located on chromosome 21, it is speculated that BACE2 may play a role in AD pathogenesis in DS. In this report we found that BACE2 cleaves APP at a novel theta site downstream of the alpha site, abolishing Abeta production. Overexpression of BACE2 by lentivirus markedly reduced Abeta production in primary neurons derived from Swedish mutant APP transgenic mice. Despite an extra copy of the BACE2 gene in DS and the increase of its transcription, BACE2 protein levels are unchanged. Our data clearly demonstrate that BACE2, as a novel theta-secretase to cleave APP within the Abeta domain, is not involved in the AD pathogenesis of DS patients; instead, therapeutic interventions that potentiate BACE2 may prevent AD pathogenesis.

Alzheimer Disease↗
PubMed2006

The immunoregulatory effects of HIV-1 Nef on dendritic cells and the pathogenesis of AIDS.

Dendritic cells (DC) play a crucial role in the generation and regulation of immunity, and their interaction with HIV is relevant in the pathogenesis of AIDS favoring both the initial establishment and spread of the infection and the development of antiviral immunity. HIV-1 Nef is an essential factor for efficient viral replication and pathogenesis, and several studies have been addressed to assess the possible influence of endogenous or exogenous Nef on DC biology. Our findings and other reported data described in this review demonstrate that Nef subverts DC biology interfering with phenotypical, morphological, and functional DC developmental programs, thus representing a viral tool underlying AIDS pathogenesis. This review provides an overview on the mechanism by which Nef, hijacking DC functional activity, may favor both the replication of HIV-1 and the escape from immune surveillance. Overall, the findings described here may contribute to the understanding of Nef function, mechanism of action, and cellular partners. Further elucidation of genes induced through Nef signaling in DC could reveal pathways used by DC to drive HIV spread and will be critical to identify therapeutic strategies to bias the DC system toward activation of antiviral immunity instead of facilitating virus dissemination.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Recent developments in Campylobacter pathogenesis.

PURPOSE OF REVIEW: The Campylobacter species jejuni and coli are leading causes of enteritis and enterocolitis worldwide. Arthritis, Reiter syndrome, and Guillain-Barré syndrome represent post-infectious sequelae. Although the acute and chronic clinical manifestations highlight Campylobacter species as excellent models for the identification of mechanisms involved in pathogenesis, detailed investigations at the molecular level are complicated by the fastidious growth requirements of the bacteria and by the tremendous variability displayed by Campylobacter isolates. Thus, research activities in this field constitute a substantial challenge for scientists of many different disciplines. The genome information has greatly stimulated investigations at the molecular level and the resulting modern research trends lead to a better understanding of Campylobacter-associated diseases providing the basis for new developments in prevention and therapy. RECENT FINDINGS: This review summarizes results from the most recent investigations in the field of Campylobacter pathogenesis. Topics include genome analysis, surface structures and post-infectious complications, adaptation, host cell interaction and cell toxicity. SUMMARY: During its coevolution with human and other vertebrate hosts, Campylobacter species have developed specific survival strategies, which are required for host adaptation and establishment in the intestinal environment. The bacterial factors involved in these processes are the subject of intensive research activities. With a focus on molecular aspects of the most important human pathogen, C. jejuni, this review intends to summarize the recent trends and developments in Campylobacter research by highlighting selected publications in the field of microbial pathogenesis.

Arthritis, Reactive↗
PubMed2002

The pathogenesis of Hirschsprung disease.

Hirschsprung disease is the most common congenital malformation of the enteric nervous system. Phenotypic expression is variable because of incomplete penetrance, and the pathogenesis is multifactorial. Although mutations of the RET tyrosine kinase gene remain the most commonly identified cause, there are now eight separate human gene loci identified whose mutations result in this disease. Analysis of these gene products in experimental animal models and cell systems has led to an increasing elucidation of the signaling pathways that are in operation during specific embryonic time stages and that direct the spatial arrangements and differentiation of enteric neuroblasts. Mutation analysis through in vitro cell expression studies has led to detailed descriptions of the affected microdomains of signal pathway receptors and the cellular pathogenesis of abnormal signaling that leads to apoptosis of developing neurons before the completion of enteric nervous system development. The full description of the pathogenesis of this disorder awaits the definition of new genetic loci, multiple gene interactions, and the acknowledgment of random events that may lead to aganglionosis of the distal bowel.

Journal Article↗
PubMed2004

Update in inflammatory bowel disease pathogenesis.

PURPOSE OF REVIEW: During the last few years, significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). By gaining new insights, paradigms that seemed to be a safe basis of our knowledge on IBD pathogenesis have recently become doubtful. This review discusses and summarizes the most recent developments. RECENT FINDINGS: Important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for Crohn disease (CD). New data on CARD15/NOD2 function and nuclear factor-kappaB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional "innate" pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The "germ concept" and the "genetic concept" of IBD pathophysiology are converging. SUMMARY: New findings are changing our concepts of the pathogenesis of IBD. The innate immune system, early responses to bacterial products, and the modulation of T-cell responses are important aspects that are reviewed.

Journal Article↗
PubMed2000

Update on the pathogenesis and treatment of Kaposi sarcoma.

Kaposi sarcoma (KS), an unusual tumor of vascular origin, was one of the first recognized manifestations of AIDS. In the past few years, it has become clear that human herpesvirus-8 (HHV-8) is critical to the development of KS in the setting of immunosuppression, such as that seen with HIV infection. Other genetic and environmental factors may also play a role in the pathogenesis of KS. Of note, several endogenous substances elaborated by HIV-infected cells may promote angiogenesis and the growth of KS. With advances in our understanding of the pathogenesis of this tumor have come novel treatments for KS. Suppression of HIV replication has substantially decreased the incidence of KS in the western world, and treatment directed at angiogenesis or virus-induced tumorigenesis may ultimately lead to more effective control of KS. For most patients, however, standard chemotherapy, radiation therapy, topical therapies, and interferon-alpha remain the mainstays of treatment. In this review, recent advances in our understanding of the pathogenesis of KS are highlighted and a brief overview of current approaches to the treatment of this tumor is provided.

Antineoplastic Agents↗
PubMed1998

Pathogenesis and mechanisms of inflammation in the childhood rheumatic diseases.

The presence of CD4+ cells in the synovium of children with juvenile rheumatoid arthritis has led to the generally accepted hypothesis that aberrant activation or regulation of acquired immunity is central to the pathogenesis of this family of diseases; however, this hypothesis remains unproven, and, indeed, a specific role for T cells in the process of chronic synovitis in rheumatoid disease has yet to be identified for either adults or children. In contrast, processes associated with innate immunity are undeniably involved in the pathophysiology of chronic synovitis in both rheumatoid arthritis and juvenile rheumatoid arthritis. The presence of neutrophils in the synovial fluid, complement activation, and immune complex accumulation in the synovial fluid and serum all indicate an active inflammatory process. It is reasonable to hypothesize, therefore, that there are important clues to the cause of juvenile rheumatoid arthritis to be gleaned from a more careful study of inflammation or innate immunity. This review will focus on the roles of complement, immune complexes, and the vascular endothelium in the pathogenesis of juvenile rheumatoid arthritis. In so doing, it will reexamine the dogma of the central role of the T cell in juvenile rheumatoid arthritis disease pathogenesis and offer new paradigms with which to understand this and other rheumatic diseases of childhood.

Arthritis, Juvenile↗
PubMed2003

Anti-aminoacyl tRNA synthetase immune responses: insights into the pathogenesis of the idiopathic inflammatory myopathies.

PURPOSE OF REVIEW: One of the most striking humoral characteristics of the idiopathic inflammatory myopathies is the specific targeting of components of the translational machinery by the immune system. The most commonly targeted of these components are the aminoacyl tRNA synthetase (ARS) molecules. However, the relation between the immune responses to these molecules and the pathogenesis of the inflammatory myopathies remains obscure. This review will examine recent evidence that explores the links between the ARS molecules, inflammation, and apoptosis, with the aim of furthering our current understanding of the underlying pathogenesis of the myositis syndromes. RECENT FINDINGS: Several of the ARS molecules and their proteolytic fragments generated during inflammation and apoptosis have recently been shown to possess chemoattractant properties. The liberation of these fragments in the muscle microenvironment under certain circumstances may provide a proinflammatory context and lead to the influx of lymphocytes, macrophages, and specialized antigen-presenting cells to the site of muscle injury. The subsequent processing and presentation of these autoantigen fragments on major histocompatibility complex class I and II molecules may generate an ARS-specific autoimmune response, which may be responsible for amplification and propagation of muscle injury in these diseases. SUMMARY: The striking association between the inflammatory myopathies and anti-ARS antibodies implies a role for the ARS molecules in the pathogenesis of these syndromes. Recent data suggest that ARS molecules and their proteolytic fragments generated during the cell death process may be responsible for priming and sustaining a specific immune response in situ in myositis. How these molecules become altered and access the immune system in the disease microenvironment is an area of ongoing investigation.

Amino Acyl-tRNA Synthetases↗
PubMed2003

Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis, or Lou Gehrig disease, is a progressive neurodegenerative disease of adult onset characterized by a loss of motor neurons in the spinal cord and motor cortex. In the last several years, substantial progress has been made in defining the pathogenesis of motor neuron injury and relationships between disease mechanisms and the selective vulnerability of the motor neuron in both familial and sporadic forms of amyotrophic lateral sclerosis. RECENT FINDINGS: Current theories have shifted from a neuron-centered pathology to a focus on the interaction between motor neurons and glia, and their respective contributions to pathways implicated in amyotrophic lateral sclerosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of disease. SUMMARY: This article reviews the clinical aspects of amyotrophic lateral sclerosis and potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course. Evidence suggesting an important role for intercellular signaling is emphasized.

Amyotrophic Lateral Sclerosis↗
PubMed1993

Serotonin and its role in headache pathogenesis and treatment.

OBJECTIVE: This review tries to consolidate the literature on changes in serotonin and the importance of these changes for understanding headache pathogenesis and determining treatment. A model is presented that integrates previous serotonin studies and offers an explanation for apparent contradictions in the literature. DATA SOURCES: Fifty-four journal articles that described a relationship between serotonin and headache in animal and human models were identified through Medline search and bibliography and reviewed. Alterations in serotonin, headache, and clinical situations influencing headache activity were examined. DATA SYNTHESIS: Abnormalities in blood vessels have traditionally been implicated in the pathogenesis of migraine headaches, and excessive muscle contraction in tension-type headaches. Interestingly, both vascular and muscular changes occur in both migraine and tension-type headache. Recently, biochemical changes have been demonstrated in both types of headaches. These biochemical changes are postulated to precede and possibly cause the subsequent changes in blood vessels and muscle tone, known to occur in chronic headaches. Serotonin has been the most widely studied neurochemical in relation to headaches. Apparently contradictory results have been shown, such as increasing serotonin levels both increasing and decreasing headaches. CONCLUSIONS: Serotonin plays an important role in the pathogenesis of headaches. Changes in serotonin may precede the vascular and muscular changes of migraine and tension-type headaches. The influence of serotonin on headaches explains a number of clinical situations that affect headache activity and the variety of classes of effective headache medications.

Animals↗
PubMedDate not supplied

Pathogenesis of the migraine attack.

BACKGROUND: There is clinical experimental evidence that extracranial arterial vasodilation, extracranial neurogenic inflammation, and decreased inhibition of central pain transmission are involved in the pathogenesis of the migraine headache. The migraine aura is likely caused by a neurophysiologic phenomenon akin to Leão's cortical spreading depression, a wave of short-lasting neuronal excitation that travels over the cerebral cortex, followed by prolonged depression of cortical neuronal activity. METHOD: A concept of the pathogenesis of the migraine attack is presented, in which the relation of the mechanism of the migraine aura and that of the migraine headache is considered parallel rather than sequential in nature. CONCLUSIONS: The process driving the pathogenesis of the migraine attack and susceptible to the migraine trigger factors may be located in the brain stem.

Blood Flow Velocity↗
PubMed2000

Etiology and pathogenesis of acute pancreatitis: current concepts.

Acute pancreatitis is a disorder that has numerous causes and an obscure pathogenesis. Bile duct stones and alcohol abuse together account for about 80% of acute pancreatitis. Most episodes of biliary pancreatitis are associated with transient impaction of the stone in the ampulla (that causes obstruction of the pancreatic duct, with ductal hypertension) or passage of the stone though and into the duodenum. Other causes of acute pancreatitis are various toxins, drugs, other obstructive causes (such as malignancy or fibrotic sphincter of Oddi), metabolic abnormalities, trauma, ischemia, infection, autoimmune diseases, etc. In 10% of cases of acute pancreatitis, no underlying cause can be identified; this is idiopathic pancreatitis. Occult biliary microlithiasis may be the cause of two thirds of the cases of "idiopathic" acute pancreatitis. Intra-acinar activation of trypsinogen plays a central role in the pathogenesis of acute pancreatitis, resulting in subsequent activation of other proteases causing the subsequent cell damage. Ischemia/reperfusion injury is increasingly recognized as a common and important mechanism in the pathogenesis of acute pancreatitis and especially in the progression from mild edematous to severe necrotizing form. Increased intracellular calcium concentration also mediates acinar cell damage. Oxygen-derived free radicals and many cytokines (e.g., interleukin [IL]-1, IL-6, IL-8, tumor necrosis factor-alpha, platelet activating factor) are considered to be principal mediators in the transformation of acute pancreatitis from a local inflammatory process into a multiorgan illness.

Acute Disease↗
PubMed1997

The pathogenesis of hypertension in autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD), often occurring early in the disease before the renal function starts to decrease. The pathogenesis of this early hypertension is controversial. OBJECTIVE: To review studies on the pathogenesis of early and late hypertension in ADPKD. STUDY SELECTION: Studies on ADPKD and hypertension were retrieved from Medline from the last 20 years, with an emphasis on the last 10 years. These studies, together with selected published abstracts from recent hypertension and nephrology meetings, were reviewed critically. RESULTS: Cyst growth, renal handling of sodium, activation of the renin-angiotensin-aldosterone system, volume expansion, an elevated plasma volume, and increased plasma atrial natriuretic peptide and plasma endothelin levels have all been found to be associated with hypertension in ADPKD. In some studies an inappropriate activity of the renin-angiotensin-aldosterone system that could be related to cyst growth and intrarenal ischemia was found. An increase in renal vascular resistance has been demonstrated and might be caused by intrarenal release of angiotensin II. Interestingly, the protective effect of angiotensin converting enzyme inhibitors on the renal function could not be demonstrated in ADPKD patients with a moderately decreased renal function. The importance, if any, of endothelial vasodilatory factors is not known. Sympathetic nervous activity seems to be increased in ADPKD, but the importance of this for the blood pressure level is not known. CONCLUSION: The pathogenesis of hypertension in ADPKD is complex and likely to be dependent on the interaction of hemodynamic, endocrine and neurogenic factors.

Atrial Natriuretic Factor↗