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PubMed2005

Molecular pathogenesis of Parkinson disease.

Parkinson disease (PD), the most common neurodegenerative movement disorder, is characterized by an extensive and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of Lewy bodies, intracellular inclusions of aggregated alpha-synuclein. Although the cause and pathogenesis of selective loss of dopamine neurons and the accumulation of alpha-synuclein in PD remain elusive, growing lines of evidence from environmental risk factors and early-onset genetics point to a convergence between energy metabolism and the disposal of damaged proteins in the development of PD. These findings suggest that impairments in mitochondrial and ubiquitin-proteasome system function can significantly contribute to the pathogenesis of PD. This review will summarize recent insights gained from genetic and environmental studies of PD that underscore this association.

Animals↗

PubMed2001

The role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy of the cornea.

OBJECTIVE: To investigate the potential role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy of the cornea. METHODS: Twenty-one corneal buttons from patients with Fuchs dystrophy and 15 control corneas were studied. Apoptosis was assessed by the in situ end-labeling of double-stranded DNA breaks, and by immunohistochemical characterization of cellular markers associated with apoptosis (Fas, FasL, Bcl-2, and Bax). Expression of Bcl-2 and Bax mRNA in the corneal stroma and endothelium was separately analyzed by a semiquantitative reverse transcriptase polymerase chain reaction. Furthermore, cultivated keratocytes generated from diseased corneal buttons and donor rims were exposed to camptothecin, an apoptotic inducer, for 6 and 24 hours. They were then examined for protein and messenger RNA (mRNA) expression of apoptotic regulatory molecules. RESULTS: DNA fragmentation was seen in the epithelium, stroma, and endothelium in 6 of 7 corneas with Fuchs dystrophy. A statistically significant difference was identified in the expression of Bax and its mRNA in the stroma, but not in the endothelium of Fuchs dystrophy corneas. Following exposure to camptothecin, keratocytes from patients with Fuchs dystrophy responded with an increased level of Bax and a low level of Bcl-2. This trend was distinctively different from the response of normal keratocytes. CONCLUSIONS: The evidence in this study points to a disease-related disturbance in the regulation of apoptosis in Fuchs dystrophy. Our findings suggest that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs dystrophy.

Aged↗

PubMed2003

A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization.

OBJECTIVE: To evaluate the expression of connective tissue growth factor (CTGF) in choroidal neovascular membranes from patients with age-related macular degeneration and the effect of CTGF on choroidal endothelial cell (CEC) function. METHODS: Using immunohistochemical methods, we analyzed CTGF expression in 13 surgically excised choroidal neovascular membranes related to age-related macular degeneration. The expression of CTGF in retinal pigment epithelial and CEC cultures was determined by means of reverse transcriptase polymerase chain reaction and Western blot, and its regulation by vascular endothelial growth factor and transforming growth factor beta was determined. The effects of CTGF on bovine CEC proliferation, attachment, migration, and tube formation were measured. RESULTS: Vascularized human choroidal neovascular membranes showed strong CTGF immunoreactivity. Double staining disclosed colocalization of CTGF with retinal pigment epithelial cells and CECs. The CTGF induced a significant increase in attachment and migration of CECs; however, it did not stimulate CEC proliferation. The CTGF protein was up-regulated in retinal pigment epithelial cells and CECs by stimulation with transforming growth factor beta and vascular endothelial growth factor, respectively. CONCLUSIONS: The expression of CTGF in choroidal neovascular membranes, its regulation by angiogenic growth factors, and its proangiogenic effects on CEC function suggest that CTGF may play a role in the pathogenesis of choroidal neovascularization. Clinical Relevance Multiple growth factors are involved in the pathogenesis of choroidal neovascularization in age-related macular degeneration.

Aged↗

PubMed1977

Optic disc edema in raised intracranial pressure. V. Pathogenesis.

The pathogenesis of optic disc edema (ODE) in raised intracranial pressure is discussed in the light of recent observations on the subject. The findings indicate that ODE is a mechanical phenomenon. The raised cerebrospinal fluid pressure (CSFP) in the sheath of the optic nerve produces axoplasmic flow stasis in the optic nerve head. This results in swelling of the axons, which manifests as early ODE and secondarily produces the well-known optic disc and retinal vascular changes associated with ODE. The pathogenesis of ODE seen in different conditions without raised CSFP cannot be explained by any single mechanism in spite of the occurrence of axoplasmic flow stasis in most cases, because the stasis in different situations has different mechanisms.

Adolescent↗

PubMed2002

Inducible cyclooxygenase and interleukin 6 gene expressions in nasal polyp fibroblasts: possible implication in the pathogenesis of nasal polyposis.

BACKGROUND: Inflammation is believed to be related to the pathogenesis of nasal polyp (NP). Inducible cyclooxygenase (COX-2) and interleukin (IL) 6 are important mediators of inflammation. However, no information is available regarding the expression of these mediators in nasal polyp fibroblasts (NPFs). The inductive effects of proinflammatory cytokines (IL-1alpha or tumor necrosis factor alpha) alone or in combination with prostaglandin E(2) on IL-6 and COX-2 messenger RNA (mRNA) synthesis in NPFs were investigated. DESIGN: The expressions of IL-6 and COX-2 mRNAs in NPFs and in 34 surgical specimens of NP were detected by Northern blot and in situ hybridization. RESULTS: Significant amounts of constitutive IL-6 and COX-2 mRNAs were produced in NPFs. Cytokines induced IL-6 and COX-2 mRNA synthesis in NPFs. Meloxicam (a specific COX-2 inhibitor) suppressed the induction of cytokines on IL-6 mRNA levels, and these effects could be reversed by exogenous prostaglandin E(2). In situ hybridization revealed that IL-6 and COX-2 mRNAs were detected primarily in fibroblasts, macrophages, and plasma cells. Aggregation of plasma cells as well as collagen deposition in vicinity to IL-6 mRNA-producing fibroblasts was found. Rich vascularity around COX-2 mRNA(+) fibroblasts was also identified. CONCLUSIONS: The pathogenesis of nasal polyposis involves NPFs through synthesizing IL-6 to modulate the activation of immune responses (plasma cell formation) and synthesis of stroma. Inducible cyclooxygenase also contributes to NP development by promoting vasodilatation and modulating the cytokine-induced IL-6 gene expression in NPFs.

Antineoplastic Agents↗

PubMed2005

Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence.

OBJECTIVE: To determine the role of angiogenesis in the clinical behavior and pathogenesis of lymphangioma tumors. DESIGN: A retrospective study. Median follow-up period was 44.5 months. SETTING: Children's Memorial Hospital, Chicago, Ill. PATIENTS: Tumor specimens from 12 pediatric patients who underwent surgical excision of cervicofacial lymphangioma were examined for expression of angiogenic inducer vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) using immunohistochemical analysis. Specimens were divided into recurrent and nonrecurrent tumors based on clinical information. MAIN OUTCOME MEASURES: Staining patterns of VEGF and PEDF were evaluated in lymphangioma specimens. Staining patterns were then compared in both recurrent and nonrecurrent groups and graded in a blinded fashion. Histological evidence of increased angiogenesis including microvascular density, stromal fibrosis, and inflammation were graded in each group and correlated with recurrence. RESULTS: Lymphangioma specimens demonstrated histological evidence of increased angiogenic activity including multiple areas of increased VEGF staining combined with little PEDF staining. Sex, age at onset, or tumor location did not correlate with recurrence. Furthermore, recurrent specimens had increased histological evidence of angiogenesis as well as increased VEGF and decreased PEDF activity compared with nonrecurrent lesions. CONCLUSIONS: Lymphangiomas exhibit tumorlike pathogenesis owing to the high expression of angiogenic inducers compared with the low expression of inhibitors. Recurrence may be influenced by this imbalance of angiogenic mediators. Further research with antiangiogenic therapy using agents such as PEDF analogues or anti-VEGF receptor antibodies is indicated because they may stabilize or suppress the growth of these neoplasms.

Biomarkers, Tumor↗

PubMed1986

Parainfluenza virus bronchiolitis. Epidemiology and pathogenesis.

An investigation of the epidemiology and pathogenesis of bronchiolitis due to parainfluenza virus (PV) was carried out. Bronchiolitis due to PV occurred most commonly in non-Caucasian males. Breast-fed infants exhibited a reduced risk of developing bronchiolitis. Once an episode of PV bronchiolitis occurred, both exposure to cigarette smoke and bottle feeding were associated with an increased frequency of recurrent wheezing, and subsequent infection with respiratory virus almost uniformly resulted in wheezing. Cell-mediated immune responses to PV antigen and titers of PV-specific IgE were greater among patients with bronchiolitis than among patients with upper respiratory tract infection. The epidemiology and pathogenesis of bronchiolitis due to PV is similar to that of respiratory syncytial virus. Lower respiratory tract infection may predispose to episodes of bronchoconstriction on subsequent exposure to cigarette smoke or other viral infections.

Antigens, Viral↗

PubMed1987

The role of bacterial virulence factors and Tamm-Horsfall protein in the pathogenesis of Escherichia coli urinary tract infection in infants.

Forty-three patients and 70 controls were enrolled in an open study to evaluate the role of bacterial virulence factors and Tamm-Horsfall protein (THP) in the pathogenesis of urinary tract infection (UTI) due to Escherichia coli. The ages of the patients and controls ranged from 5 days to 6 months. Nine patients had upper UTIs and 33 patients had lower UTIs, based on bacteremia and radiographic evidence. There were no differences between patients and controls in the percentages of strains showing hemolytic activity of E coli strains isolated from periurethral and rectal cultures. Urinary E coli strains recovered from patients showed a significantly higher percentage of mannose-resistant hemagglutination, greater P and X fimbriation, more type 1 pili, and the presence of mannose-sensitive and mannose-resistant hemagglutination when compared with E coli strains recovered from the controls. The O but not the K pyelonephritogenic serotypes were more commonly recovered from patients than from controls. The mean THP concentrations in urine (micrograms of THP per milligrams of creatinine) were 29.9 and 91.4 micrograms/mg for patients and controls, respectively. With the exception of hemagglutination properties and certain pyelonephritogenic O serotypes, other virulence factors of E coli could not be defined in our infant population. The role of THP, if any, in the pathogenesis of UTI remains unresolved.

Escherichia coli↗

PubMed1998

Development of antibodies to the nonstructural protein NS1 of parvovirus B19 during acute symptomatic and subclinical infection in pregnancy: implications for pathogenesis doubtful.

At present little is known about the mechanisms influencing the course and severity of parvovirus B19 infection. Antibodies to the parvovirus nonstructural protein NS1 were reported in patients with parvovirus-associated arthritis and those with persisting infection but not in those without complications, suggesting a potential involvement of NS1 or anti-NS1 antibodies in pathogenesis. The immune response to NS1 was examined retrospectively in 33 pregnant women with acute parvovirus B19 infection, 14 of whom experienced symptomatic infection and 19 in whom the infection was subclinical. Antibodies to NS1 were found in 15 (45%) of the women, seven with symptomatic and eight with subclinical infection. No association was found between the development of anti-NS1 antibodies and the occurrence of fetal complications. Of the seven cases in which fetal complications were observed, anti-NS1 antibodies were detected in only three. The finding that an immune response to NS1 can also be demonstrated in patients with asymptomatic infection suggests that anti-NS1 antibodies do not appear to represent a marker for an altered or severe course of infection in pregnant women or to contribute significantly to pathogenesis. Since anti-NS1 antibodies first become detectable at least six weeks postinfection, their presence can be used to exclude acute infection in patients with unclear serology or be used to aid differential diagnosis of rashlike illnesses.

Acute Disease↗

PubMed1999

The neoplastic pathogenesis of solitary and multiple osteochondromas.

Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional 'skeletal dysplasia' theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma 'cell-of-origin' theories are discussed.

Bone Neoplasms↗

PubMed1999

K-ras and p53 mutations in the pathogenesis of classical and goblet cell carcinoids of the appendix.

BACKGROUND: Mutations in the K-ras oncogene and the p53 tumor suppressor gene are present in approximately 50% of colonic adenocarcinomas. Goblet cell carcinoids (GCCs) are uncommon neoplasms of the appendix that appear to be intermediate between carcinoid tumors and adenocarcinomas, both histologically and biologically. The current study was undertaken to examine the role of p53 and K-ras mutations in the pathogenesis of GCCs and typical carcinoids (TCs) of the appendix. METHODS: Archival materials from 22 GCCs and 18 TCs were analyzed. K-ras mutations in codons 12, 13, and 61 were studied by a polymerase chain reaction (PCR) based designed restriction fragment length polymorphism method using mismatched nested primers. Mutations in exons 5-8 of the p53 tumor suppressor gene were analyzed in 16 GCCs and 18 TCs by PCR and single-strand conformational polymorphism followed by direct sequencing. Immunostains for p53 and chromogranin were performed in all cases. RESULTS: K-ras mutations and nuclear accumulation of p53 by immunohistochemistry were not detected in any of the GCCs or TCs. p53 mutations were found in 4 of 16 GCCs (25%) and 8 of 18 TCs (44%). Immunoreactivity for chromogranin was seen in the vast majority of GCCs and TCs. CONCLUSIONS: p53 mutations appear to play a role in the pathogenesis of some GCCs and in approximately 50% of TCs of the appendix, whereas mutations in the K-ras oncogene do not appear to be important in the development of these tumors. The minimal cytologic atypia, low incidence of metastases, and lack of K-ras mutations in goblet cell appendiceal neoplasms suggest that they are variants of carcinoid tumors. Our findings lend support to the recommendation that the therapeutic guidelines applied to TCs of the appendix should be the same for GCCs.

Appendiceal Neoplasms↗

PubMed1996

Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review.

Cancer of the esophagus exists in 2 main forms with different etiological and pathological characteristics-squamous cell carcinoma (SCC) and adenocarcinoma (ADC). This review focuses on the occurrence of genetic alterations in SSC and ADC of the esophagus and on their possible implications for the elucidation of the etiology and pathogenesis of these cancers. The most common alterations found in esophageal cancers include allelic losses at chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, as well as mutations of p53 (mostly missense), Rb (deletions), cyclin DI (amplifications) and c-myc (amplifications). The sequence of occurrence of these alterations with respect to histopathological tumor progression is discussed. Our findings underscore the different etiology and pathogenesis of SCC vs. ADC and suggest that the genetic alterations observed may represent molecular fingerprints of critical risk involved in the development of these 2 cancers.

Adenocarcinoma↗

PubMed1998

Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma?

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposi's sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron-oxide-rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS-derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS-derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast-growth-factor-stimulated cells. These results may point to a novel therapeutic approach to KS.

Carcinogens↗

PubMed1999

The pathogenesis of vascular thrombosis and its impact in microvascular surgery.

As the use of free tissue transfer becomes more wide-spread, it is important for both the ablative surgeon and the reconstructive surgeon to understand the factors that contribute to successful revascularized tissue transfer. The purpose of this two part review is to provide a basic science overview of the problem of failed free tissue transfers. The first part will focus on the pathogenesis of thrombosis at the anastomotic site, and part two will discuss the pathogenesis of the no-reflow phenomenon. The pathophysiology and therapeutic interventions to prevent and treat anastomotic thrombosis and the no-reflow phenomenon will be discussed.

Anastomosis, Surgical↗

PubMed2000

Recent advances in understanding the pathogenesis of nitrofen-induced congenital diaphragmatic hernia.

In this review, we discuss recent advances in the study of the pathogenesis of congenital diaphragmatic hernia (CDH). Much of the research has involved the use of an animal model of CDH in which diaphragmatic defects are produced in fetal rats by administering the herbicide nitrofen to dams during mid-gestation. The animal model is described and the relevance to the human condition is discussed. The data derived from the animal studies are critically assessed in the context of commonly cited hypotheses proposed for the pathogenesis of CDH. Finally, experimental strategies are proposed for systematically examining the normal and pathological formation of the pleuroperitoneal fold. We conclude that a malformation of the primordial diaphragm, the pleuroperitoneal fold, underlies the muscle defects associated with CDH.

Animals↗

PubMed1998

MHC restriction to T-cell autoaggression: an emerging understanding of IDDM pathogenesis.

The Nobel prize-winning discovery of MHC restriction by Zinkernagel and Doherty has led to some of the most exciting advances in immunology over the past two decades. The ongoing progress in our conceptual understanding of the processes governing the immunology to infection, tolerance to self and consequently the immune dysregulation in autoimmunity have all assimilated the laws of restriction as a central tenet. The focus of much of this research has been the T-cell and its interactions. Refinement of the paradigm of MHC restriction at the molecular level has allowed a view of the pathogenesis of insulin-dependent diabetes mellitus (IDDM), a prototypic autoimmune disease, unprecedented in its detail. This article discusses the impact of MHC restriction on the central themes of immunology, and focuses on its utility as a framework in understanding the role of the T-cell in the pathogenesis of IDDM.

Animals↗

PubMed1998

Pathogenesis of puumala and other hantavirus infections.

Hantaviruses are rodent/insectivore-borne negative-stranded RNA viruses which belong to the Bunyaviridae family. They do not cause any symptomatic disease in their adult carrier rodents, but in humans they are aetiologic agents of haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), both associated with a significant mortality. In cell culture hantaviruses do not cause cytopathic effects and the mechanisms of disease in man are not well understood. Increased capillary permeability is a central phenomenon in the pathogenesis of hantavirus infections. Although the viruses have in vivo a predilection for endothelial cells, it is presumed that inflammatory mediators of the host immune response play a significant role in the capillary leak that may produce abrupt hypotension and shock in severely ill patients. Mediators released by activated macrophages including NO and TNF-alpha are considered important. The pathogenesis of renal failure in HFRS also awaits to be resolved. This review summarises what is known about these phenomena and discusses also the molecular basis of the putative virulence factors of hantaviruses. Finally, the genetic predisposition and HLA association with severe Puumala virus infection will be discussed. Copyright 1998 John Wiley & Sons, Ltd.

Journal Article↗

PubMed2000

LDL receptor-related protein (LRP) in Alzheimer's disease: towards a unified theory of pathogenesis.

To date, mutations in three genes, beta-amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), have been found to be causally related to familial Alzheimer's disease (AD). In addition, polymorphisms in three other genes (among others), apolipoprotein E (apoE), alpha2-macroglobulin (alpham), and the low density lipoprotein receptor-related protein (LRP), are implicated to contribute to AD pathogenesis. Interestingly, the encoded gene products are all functionally related in various ways to LRP. Specifically apoE, alpha2m, secreted APP, and amyloid beta-protein (Abeta) complexed to either apoE or alpha2m are ligands of LRP. Furthermore, over-expression of presenilin 1 results in decreased expression of LRP. Since levels of many LRP ligands are increased in Alzheimer's disease and LRP and its ligands are present in senile plaques, decreased LRP function may be a central component in AD pathogenesis. This review explores the current knowledge of LRP in AD and its relationship to the other known AD susceptibility markers.

Alzheimer Disease↗