Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathogenesis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources
PubMed2005

New insights into the pathogenesis of Hirschsprung's associated enterocolitis.

The management of Hirschsprung's disease (HD) has made dramatic strides over the last 20 years. Research into the embryological development and migration of ganglion cell has enabled a greater understanding of the pathogenesis of the disease. Coupled with new techniques in surgery, such as laparoscopy-assisted pull-through and the transanal pull-through, this knowledge has led to improved outcomes for children with HD. However, although our appreciation of Hirschsprung's associated enterocolitis and its aetiology has increased, there are continued references in the literature to a multitude of theories of pathogenesis. The purpose of this review is to delineate the theories and demonstrate the evidence supporting or otherwise contradicting each other.

Enterocolitis↗
PubMed1998

Pathogenesis of infantile hypertrophic pyloric stenosis: recent progress.

Although infantile hypertrophic pyloric stenosis (IHPS) is the most common condition requiring surgery in the first few months of life, its pathogenesis is not fully understood. Reviews of the recent progress in the pathogenesis of IHPS show: (1) there is increasing evidence to suggest that smooth-muscle cells in IHPS are not properly innervated; (2) because non-adrenergic, non-cholinergic nerves are mediators of smooth-muscle relaxation, it is likely that the absence of these nerves in pyloric muscle is the cause of excessively contracted hypertrophic circular pyloric muscle; (3) there are abnormal amounts of extracellular matrix proteins in hypertrophic pyloric muscle. Circular muscle cells in IHPS are actively synthesizing collagen, and this may be responsible for the characteristic "firm" nature of the pyloric tumor; and (4) the increased expression of insulin-like growth factor-I, transforming growth factor-beta 1, and platelet-derived growth factor-BB and their receptors in hypertrophic pyloric muscle suggests that increased local synthesis of growth factors may play an important role in smooth-muscle hypertrophy in IHPS.

Extracellular Matrix Proteins↗
PubMed2005

[Pathogenesis of RA: more than just immune cells].

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily affects the joints and results in their progressive destruction. Research during past years has shown that in addition to inflammatory cells and their mediators, resident fibroblasts of the synovial membrane play an important role in the pathogenesis of the disease. These cells exhibit features of stable cellular activation that is maintained in the absence of continuous inflammatory stimuli. In contrast to normal synovial fibroblasts or fibroblasts from patients with osteoarthritis, RA synovial fibroblasts show an upregulation of proto-oncogenes and transcription factors, which in a self-perpetuating manner mediate the expression of adhesion molecules and matrix degrading enzymes, and result in alterations in apoptosis. As a consequence, these activated fibroblasts attach to cartilage and bone and progressively destroy articular structures. A better understanding of the molecular mechanisms that lead to the stable activation of synovial fibroblasts in RA is, therefore, of utmost importance for elucidating the pathogenesis of RA as well as for the development of novel therapeutic strategies aimed at inhibiting joint destruction.

Animals↗
PubMed2005

[Do B cells play an important role in the pathogenesis of rheumatoid arthritis?].

The role of B cells for the pathogenesis of rheumatoid arthritis (RA) has been debated for a long time. Here we show that chronic inflammation in the affected joints leads to the development of ectopic germinal centers. A micro-environment is established which supports B cell activation and differentiation. Plasma cells may develop which secrete autoantibodies of high affinity directly into the synovial tissue. Antigen/antibody complex formation, the activation of the complement cascade and the stimulation of macrophages may contribute to the destruction of joints. Furthermore, B cells are efficient antigen presenting cells. They seem to play a pivotal role in the activation of synovial T cells and the induction of cytokine secretion. The success of B cell depletion therapy by using the monoclonal antibody Rituximab further emphasized the importance of B cells in the pathogenesis of RA.

Animals↗
PubMed2000

[Apoptosis and C1q: possible explanations for the pathogenesis of systemic lupus erythematosus].

Dysregulation of apoptosis may play a major role in the pathogenesis of systemic lupus erythematosus (SLE). A defective clearance of apoptotic cells or inappropriately high rates of apoptosis may lead to a pathologic accumulation of abnormal cell material with a secondary autoimmune response. Experimental findings in apoptotic keratinocytes and C1q knock-out mice suggest an important role of C1q in the clearance of apoptotic cell material. In addition, there are several links between C1q and SLE: Most the patients with C1q deficiency develop a SLE-like syndrome. SLE itself often causes secondary C1q deficiency and autoantibodies to C1q are detected in almost all patients with active lupus nephritis. These observations suggest a central role of C1q in apoptosis and in the pathogenesis of SLE.

Animals↗
PubMed2006

Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease.

Senile plaques (SPs), one of two defining lesions of Alzheimer's disease (AD), are composed of a mixture of full-length Abeta1-40/42, and N- or C-terminally truncated Abeta peptides, including Abeta11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases produces Abeta1-40/42, but beta-site APP-cleaving enzyme 1 (BACE1), the major beta-secretase, also generates Abeta11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Abeta11-40/42. The ratio of Abeta11-40/42 to Abeta1-40/42 depends on the ratio of BACE1 to APP, and Abeta11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Abeta11-40/42 in the pathogenesis of AD and Down's syndrome (DS) brains. We demonstrated significant amount of Abeta11-42 in DS brains by Western blots. While pyroAbeta11-42-modified Abeta species existed predominantly in mature SP cores in AD brain sections, both unmodified free Abeta11-40 and pyro-modified Abeta11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Abeta11-40/42 and pyroAbeta11-40/42, we showed that insoluble Abeta11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Abeta11-40/42 in neurodegenerative Abeta amyloidosis implicating Abeta11-40/42 in SP formation of AD and DS brains. The detection of Abeta11-42 in young DS brain suggests an early role for this N-terminally truncated Abeta peptide in the pathogenesis of SPs in AD and DS.

Adolescent↗
PubMed2006

Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra.

Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Indications for a tumor suppressor gene at 22q11 involved in the pathogenesis of ependymal tumors and distinct from hSNF5/INI1.

Ependymomas account for approximately 9% of all neuroepithelial tumors and represent the most frequent neuroepithelial tumors of the spinal cord. In adults, allelic loss of chromosome arm 22q occurs in up to 60% of the cases studied. Some of these tumors show an altered neurofibromatosis type 2 (NF2) gene; in others, NF2 appears to be unaffected, indicating the involvement of another tumor suppressor gene. Recently, the tumor suppressor gene hSNF5/INI1, located on 22q11.23, has been shown to contribute to the pathogenesis of renal and extrarenal rhabdoid tumors. In addition, this gene may be responsible for a new hereditary syndrome predisposing to a variety of tumors designated "rhabdoid predisposition syndrome." In the present study, we analyzed a series of 53 ependymal tumors of 48 patients [4 myxopapillary ependymomas (WHO grade I), 3 subependymomas (WHO grade I), 18 ependymomas (WHO grade II), 21 anaplastic ependymomas (WHO grade III) and 2 ependymoblastomas (WHO grade IV)] for mutations and homozygous deletions in the coding region of the hSNF5/INI1 gene and for allelic loss of its flanking chromosomal regions in 39 ependymal tumors of 35 patients. Allelic loss was detected in 11 of 35 informative primary ependymal tumors (31%) with a common region of overlap covered by the markers D22S257 and D22S310 on 22q11 including the marker D22S301. However, a detailed molecular analysis of 53 ependymal tumors for mutations and homozygous deletion of the hSNF5/INI1 gene revealed no alterations. We conclude that the hSNF5/INI1 gene is not involved in the pathogenesis of human ependymal tumors with allelic loss on chromosome arm 22q and an intact NF2 locus. In addition, our study localizes a putative ependymoma tumor suppressor gene(s) to a domain of chromosome arm 22q flanked by the microsatellite markers D22S257 and D22S310.

Adolescent↗
PubMed2006

The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?

Scleroderma is a fibrotic condition characterized by immunologic abnormalities, vascular injury and increased accumulation of extracellular matrix (ECM) proteins in the skin. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that ECM overproduction by activated fibroblasts results from complex interactions among endothelial cells, lymphocytes, macrophages and fibroblasts, via a number of mediators, such as cytokines, chemokines and growth factors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. We established a murine model of cutaneous sclerosis by local treatment of bleomycin. This model reproduces several histological as well as biochemical aspects of human scleroderma. However, it must be emphasized that studying animal models cannot answer all the problems of human scleroderma. In this review, we introduce current insights into the pathogenesis of bleomycin-induced scleroderma, and discuss its contribution to our understanding of the pathogenesis of, and treatments for, human scleroderma.

Animals↗
PubMed2003

Aggregation of alpha-synuclein in the pathogenesis of Parkinson's disease.

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). By raising a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuola-beled LBs, we found that alpha-synuclein is one of the major components of LBs. Thus, the deposition of alpha-synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells,was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post-translational modifications that characterize and underlie the aggregation of alpha-synuclein in synucleinopathy brains by mass spectrometry and using a s pecific antibody,and found that serine 129 of alpha-synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. These findings underscore the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

Antibodies, Monoclonal↗
PubMed2003

Pathogenesis of Adamantiades-Behçet's disease.

The aetiology of Adamantiades-Behçet's disease remains unknown and its pathogenesis is not fully understood. Linked intrinsic and extrinsic factors are thought to contribute to the development of the disease, which probably occurs by environmental triggering of a genetically determined disorder. Transmission is solely vertical, indicating that the disease is not contagious. Genetic factors have been investigated and a significant link of HLA-B51, especially of HLA-B5101, has been identified. However, none of the functional correlates of the disease appear to be restricted by HLA-B51. Recently, the role of the genes encoding TNF, Tap proteins and MICA has been emphasised. Extrinsic pathogenetic candidates have been identified, including bacterial ( Streptococcus sanguis, Mycoplasma fermentas) and viral (human herpes virus) antigens and environmental pollution, which may cross-react with oral mucosal antigens and induce immunological mechanisms. A common factor linking some of the possible pathogenetic agents is extrinsically induced tissue stress or heat shock proteins, which react with host tissues and elicit significant Th1 cell responses. Neutrophils may also play a role in the pathogenesis of the disease, as they are attracted by macrophages and activated endothelial cells, which release cytokines and chemokines (especially IL-8) at the site of the lesions, and thus contribute to tissue damage and self maintenance of inflammation. Endothelial activation leading to a chronic local inflammation process together with platelet and serum factors enhance coagulation and thrombosis.

Animals↗
PubMed2000

There is no disease-specific role for streptococci-responsive synovial T lymphocytes in the pathogenesis of psoriatic arthritis.

The initiation or exacerbation of psoriasis vulgaris is associated with infections by group A streptococci. T lymphocytes specific for streptococcal antigens or expressing a restricted, for streptococcal superantigens typical T cell receptor Vbeta chain repertoire have been described in psoriatic skin lesions. The aim of our study was, therefore, to clarify whether streptococci-reactive T lymphocytes played a role in the pathogenesis of psoriatic arthritis (PsA), and by which antigens they might be stimulated. Synovial membrane mononuclear cells from patients with PsA and other arthropathies, separated by collagenase digestion, were expanded in interleukin-2-supplemented medium and subsequently cloned in a representative cloning procedure. The T cell lines and about 30% of the T cell clones proliferated in response to preparations of group A streptococci but not to other bacteria as tested by [3H]thymidine incorporation assays. Interestingly, they did not proliferate in response to exotoxin-negative streptococci, but did so in response to the streptococcal pyrogenic exotoxins A and C, which are known to be superantigens. Accordingly, no HLA-DR restriction was seen for the proliferative response. The remaining 70% of the established T cell clones did not react to an antigen of group A streptococci. Our results show that in patients with PsA, osteoarthritis or rheumatoid arthritis a significant number of synovial T lymphocytes were responsive to streptococcal superantigens, but not to conventional streptococcal antigens. A disease-specific role of streptococci-reactive T lymphocytes in the pathogenesis of PsA is, therefore, unlikely.

Adult↗
PubMed2001

Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome.

The term hemolytic uremic syndrome (HUS) was first introduced to describe a heterogeneous group of diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Substantial progress has been made in our understanding of the etiology and pathogenesis of HUS. This article reviews some of the classic and new concepts related to the pathogenesis of Shiga toxin (Stx)-HUS and discusses their clinical relevance for the diagnosis and treatment of this syndrome. Infection with Stx-producing bacteria can induce HUS after a prodromal illness with or without diarrhea. Stx-induced renal endothelial injury is the primary pathogenic event. However, Stx also damages mesangial cells, as well as glomerular and renal tubular epithelial cells. Young children are at greatest risk for Stx-HUS because they express high levels of Stx receptors in renal glomeruli. Older children and adults express lower levels of glomerular Stx receptors and may develop Stx-HUS whenever the combined effects of lipopolysaccharide and cytokines upregulate the expression of Stx receptors and sensitize glomerular endothelial cells to Stx-induced injury, activate the coagulation-fibrinolytic system, and induce endothelial injury. Chemokine receptors and cytokines released by inflammatory cells (i.e., monocyte chemoattractant protein-1, interleukin-6, interleukin-8,) or injured endothelial cells (i.e., basic fibrobast growth factor) may play roles in this process. Measurement of the activity of a von Willebrand factor protease in plasma may help distinguish patients with thrombotic thrombocytopenic purpura from those with Stx-HUS.

Aging↗
PubMed1999

Genetic abnormalities involved in the pathogenesis of gallbladder carcinoma.

While considerable progress has been made in the understanding of the genetic changes involved in the pathogenesis of several human neoplasms, there is limited information about the genetic changes involved in the development of gallbladder carcinoma. Several studies indicate that TP53 (17p13) and p16(Ink4)/CDKN2 (9p21-22) gene loci abnormalities are frequent and early events in the pathogenesis of this neoplasm, in some cases preceding the onset of histological changes of invasion. Preliminary data also suggest that deletions at other chromosomal regions (8p21 and DCC at 18q21 loci) may play an important role in the development of gallbladder carcinoma; however, they need to be further analyzed. K-ras gene mutations appear to be an infrequent event in this neoplasm, except in gallbladder carcinomas associated with congenital abnormalities of the biliary tract. Genetic studies confirm that the sequence dysplasia-carcinoma in situ (CIS) is the usual route for the development of gallbladder carcinoma, and our recent data strongly suggest that adenomas are not precursors of this neoplasm.

Adenocarcinoma↗
PubMed2006

The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease.

BACKGROUND: It has recently been demonstrated that the Wilson disease (WD) protein directly interacts with the human homolog of the MURR1 protein in vitro and in vivo, and that this interaction is specific for the copper transporter. The aim of the present study was to clarify the role of MURR1 in the pathogenesis of WD as well as in other WD-like disorders of hepatic copper metabolism of unknown origin. METHODS: Using the single-strand conformation polymorphism (SSCP) method followed by sequencing, we analyzed the 5' untranslated region (UTR) and three exons of the MURR1 gene in three groups of patients: 19 WD: patients in whom no mutations were detected in the ATP7B gene, 53 WD: patients in whom only one mutation in the ATP7B gene was found, and 34 patients in whom clinical and laboratory data suggested a WD-like disorder of hepatic copper metabolism of unknown origin. RESULTS: We detected in these patients six rare nucleotide substitutions, namely one splice-site consensus sequence and one missense and four silent nucleotide substitutions. All substitutions except one were found in the heterozygous state. No difference in the frequencies of the various substitutions was observed between patients and controls. CONCLUSIONS: These data suggest that the MURR1 gene and its protein product are unlikely to play a primary role in the pathogenesis of Wilson disease. More extensive studies with larger numbers of clinically homogeneous patients should be carried out to establish whether nucleotide alterations in the MURR1 gene may have a role in causing WD or WD-like disorders or act as modifying factors in the phenotype variability in WD.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Does portal hypertension contribute to the pathogenesis of gastric ulcer associated with liver cirrhosis?

The prevalence of gastric ulcers in patients with liver cirrhosis is increased compared with that in the general population, and portal hypertension may contribute to the increased risk of gastric ulcer in cirrhosis patients. Aggressive factors involved in the pathogenesis of gastric ulcer are diminished in association with portal hypertension. In contrast, most of the important gastric mucosal defense mechanisms are shown to be impaired in portal hypertension; many of these mechanisms are also found to be altered in patients with liver cirrhosis. Portal hypotensive treatment with propranolol reduces ethanol-induced gastric mucosal damage in portal hypertensive rats and improves endoscopic signs of portal hypertensive gastropathy in cirrhosis patients. Together, these findings suggest portal hypertension-induced impairment of the gastric mucosal defenses to be an important factor in the pathogenesis of gastric ulcer in patients with liver cirrhosis. Prospective studies of portal pressure-reducing procedures, such as pharmacotherapy with propranolol, and their effect on the incidence of gastric ulcer in cirrhosis patients are needed to confirm this suggestion.

Humans↗
PubMed1998

Programmed cell death in the pathogenesis of rabbit hemorrhagic disease.

Rabbit hemorrhagic disease is a rapidly lethal infection caused by a calicivirus, characterized by acute liver damage and disseminated intravascular coagulation (DIC). Following morphological criteria and using a specific in situ labeling technique, we have found that liver cell death induced upon infection is due to apoptosis, and that programmed cell death is a constant feature in rabbits experimentally infected with RHDV. The process affected mainly hepatocytes, but also macrophages and endothelial cells presented morphologic hallmarks of apoptosis, expressing all these cell types viral antigens as determined by immunohistochemistry. The occurrence of programmed cell death was correlated with the appearance of the RHDV induced pathology in tissues by DNA fragmentation detection in situ. Hepatocyte apoptosis produced extensive parenchymal destruction causing a lethal, acute fulminant hepatitis that is characteristic of RHD. Apoptosis of intravascular monocytes and endothelial cell was observed together with fibrin thrombi in blood vessels. Since apoptotic cells are known sites of enhanced procoagulant activity, apoptosis of these cell populations might constitute a first step in the pathogenesis of DIC and a common pathway to other viral hemorrhagic fevers. In conclusion, apoptosis in RHD may be determinant in the development of the pathogenesis of this disease.

Animals↗
PubMed1999

Osteoporosis: current approaches and future prospects in diagnosis, pathogenesis, and management.

This review summarizes some of the major advances in our understanding and management of osteoporosis. Bone densitometry is the key to diagnosis but has limitations. Ultrasound and peripheral densitometry may provide new, rapid screening tools. Biochemical markers may provide an assessment of fracture risk as well as the response to therapy. Studies of the genetics of ostoporosis may also provide new approaches to diagnosis. The interactions between local and systemic factors, particularly between estrogen, cytokines, and prostaglandins, have suggested a mechanism for bone loss in rodent models. Nutritional deficits of calcium, vitamin D, and vitamin K may play a role in pathogenesis. Therapy is largely based on fracture prevention with calcium, vitamin D, and exercise programs, coupled with antiresorptive therapy. New approaches involving anabolic agents are under development. Our goal must be to increase our understanding of pathogenesis and to develop new cost-effective therapeutic agents as rapidly as possible so as to prevent an epidemic of osteoporotic fractures throughout the world in the next millennium.

Animals↗