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PubMed2001

Role of transcription factors in the pathogenesis of pituitary adenomas: a review.

The diversity inherent in every organ has its roots in gene-expression variation and is revealed through distinctions in the molecular profile and hence the identity of individual cell type. Study into the molecular mechanisms of the development of individual cell type within the pituitary, which is under the control of transcription factors, has provided a basis for a deeper insight into the molecular mechanisms underlying the pathogenesis of a variety of hormone-producing pituitary tumors. Identification of some of these transcription factors in pituitary adenomas further supports their role in the pathogenesis of pituitary adenomas. Understanding the molecular mechanisms of regulation of proliferation of pituitary cell types by transcription factors offers a basis for hope that rational genetic or pharmacologic therapies for pituitary tumors can be designed in the future.

Adenoma↗

PubMed2002

Modern concept on the role of phagocytes in the pathogenesis of complications during pregnancy.

Here we review modern concept of the role of phagocytes, the key cell component of natural immunity, in the course of pregnancy and in the pathogenesis of its complications. Phagocytes contribute to the development, maintenance, and favorable outcome of pregnancy. These cells play a role in the pathogenesis of various pregnancy complications, including fetal growth retardation, late gestosis, and intrauterine infections. The understanding of the pathophysiological mechanisms that occur in the mother-placenta-fetus system would allow us to improve diagnostic procedures, perform pathogenetically substantiated therapy, and decrease the incidence of obstetrical complications.

Abortion, Habitual↗

PubMed2003

Significance of an exaggerated meal-stimulated gastrin response in pathogenesis of Helicobacter pylori-negative duodenal ulcer.

The aim of this study was to clarify the pathogenesis of Helicobacter pylori-negative duodenal ulcer (DU) by investigating the meal-stimulated serum gastrin (SG) response. The subjects were 9 patients with H. pylori-negative DU, 28 H. pylori-positive DU, 11 H. pylori-positive volunteers, and 30 H. pylori-negative volunteers. Blood samples were taken before and after consumption of a test meal. The integrated 1-hr gastrin response (IGR) was taken to be the area under the SG time curve, calculated by the trapezoid method. H. pylori infection status was determined by histology, serology, and the [13C] urea breath test. The mean basal SG concentration was lower in the H. pylori-negative DU patients than in the H. pylori-positive DU patients, but an exaggerated IGR was observed in three patients (33.3%) with H. pylori-negative DU. In conclusion, our findings indicate that an exaggerated meal-stimulated gastrin response may contribute to the pathogenesis of H. pylori-negative DU.

Adolescent↗

PubMed2004

Gastric acid normosecretion is not essential in the pathogenesis of mild erosive gastroesophageal reflux disease in relation to Helicobacter pylori status.

In the pathogenesis of gastroesophageal reflux disease (GERD), gastric acid is considered to be one of the most important factors, but little is known about the degree of gastric acid secretion in GERD patients. In this study, we evaluated it in GERD patients and control subjects by 24-h intragastric pH, and serological and histological investigations, in relation to Helicobacter pylori (H. pylori) status. In H. pylori-negative GERD patients gastric acid secretion was similar to that in H. pylori-negative control subjects. In H. pylori-positive GERD patients, in particular, mild GERD patients, it decreased significantly compared to that in H. pylori-negative control subjects, but the degree of decrease was smaller than in H. pylori-positive control subjects. Results of serological and histological evaluation were supportive. In conclusion, in some GERD patients, gastric acid secretion was significantly decreased. Increased or maintained gastric acid secretion was not essential in the pathogenesis of mild GERD.

Adult↗

PubMed2004

Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders.

The expression of membrane drug transport systems in the central nervous system plays an important role in the brain disposition and efficacy of many pharmacological agents used in the treatment of neurological disorders such as neoplasia, epilepsy, and HIV-associated dementia. Of particular interest is P-glycoprotein, a membrane-associated, energy-dependent, efflux transporter that confers the multidrug resistance phenotype to many cells by extruding a broad range of xenobiotics from the cell, resulting in poor clinical outcomes. In addition, the expression pattern of P-glycoprotein has recently been suggested to play a key role in the etiology and pathogenesis of certain diseases such as Alzheimer's and Parkinson's diseases. This review will focus on the cellular localization, molecular expression, and functional activity of P-glycoprotein in several compartments of the central nervous system and address its relevance in the pathogenesis and pharmacological treatment of neurological disorders.

AIDS Dementia Complex↗

PubMed2002

Pathogenesis of hereditary tumors: beyond the "two-hit" hypothesis.

Knudson's 'two-hit' hypothesis has provided extremely important insights into the pathogenesis of tumors in autosomal dominant tumor predisposition syndromes, but recent evidence suggests that some such tumors may occur without a 'second hit' or require more than two mutations. Inactivation of both RB1 alleles appears to be insufficient by itself to cause malignancy in the tumors that develop in patients with hereditary retinoblastoma. On the other hand, certain tumors in patients with tuberous sclerosis complex appear to develop in haploinsufficient tissues that do not have 'second hit' mutations of a tuberous sclerosis gene. The molecular pathogenesis of certain other tumors in patients with tuberous sclerosis complex or neurofibromatosis 1 may not be fully explained by the 'two-hit' hypothesis either. Hereditary tumors, like non-hereditary tumors, may arise by a variety of molecular mechanisms, with loss of both alleles of a particular tumor suppressor gene being a frequent, but not invariably necessary or sufficient, event. Four models are presented to explain how various tumors may arise in patients with inherited tumor predisposition syndromes such as hereditary retinoblastoma, tuberous sclerosis complex or neurofibromatosis 1. Even tumors of one particular type may develop by more than one mechanism.

Genetic Diseases, Inborn↗

PubMed2002

Early and late pathogenesis of natural scrapie infection in sheep.

The pathogenesis of scrapie infection was studied in sheep carrying the PrP(VRQ)/PrP(VRQ) genotype, which is associated with a high susceptibility for natural scrapie. The sheep were killed at sequential time points during a scrapie infection covering both the early and late stages of scrapie pathogenesis. Various lymphoid and neural tissues were collected and immunohistochemically examined for the presence of the scrapie-associated prion protein PrP(Sc), a marker for scrapie infectivity The first stage of scrapie infection consisted of invasion of the palatine tonsil and Peyer's patches of the caudal jejunum and ileum, the so-called gut-associated lymphoid tissues (GALT). At the same time, PrP(Sc) was detected in the medial retropharyngeal lymph nodes draining the palatine tonsil and the mesenteric lymph nodes draining the jejunal and ileal Peyer's patches. From these initial sites of scrapie replication, the scrapie agent disseminated to other non-GALT-related lymphoid tissues. Neuroinvasion started in the enteric nervous system followed by retrograde spread of the scrapie agent via efferent parasympathetic and sympathetic nerve fibres innervating the gut, to the dorsal motor nucleus of the vagus in the medulla oblongata and the intermediolateral column of the thoracic spinal cord segments T8-T10, respectively.

Adrenergic Fibers↗

PubMed2001

A possible role of catenin dyslocalization in pemphigus vulgaris pathogenesis.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucosa due to the presence of autoantibodies against the components of desmosomes. To date, less is known about the expression levels of beta- and gamma-catenins in blistering diseases. The objective of this study was to evaluate the role of beta- and gamma-catenins in the pathogenesis of acantholysis in pemphigus vulgaris. METHODS: beta- and gamma-catenin expression was evaluated by immunohistochemistry in 30 cases of PV at various stages of the disease and, as controls, in 18 specimens of the skin/oral mucosa of healthy patients. RESULTS: Healthy skin and normal oral mucosa showed a strong beta- and gamma-catenin expression in basal and spinous layers with a prevalent cellular membrane distribution; the intensity of staining progressively decreased toward the superficial layers of epithelium. In PV patients, cytoplasmic expression of gamma-catenin was detected in 28/30 cases, and in 19/30 cases of PV for beta-catenin. Moreover, a progressive displacement of the signal toward the nucleus was found in 14/30 cases for beta-catenin, with dyslocalization toward the nucleus, particularly in areas with intense acantholysis, and in 22/30 cases of PV for gamma-catenin. CONCLUSIONS: Abnormal distribution of gamma-catenin, consequent to PV IgG, may be considered a direct consequence of Dg3 dissociation from catenin. gamma-catenin likely plays a direct role in PV pathogenesis through its dyslocalization toward the nucleus or indirectly through the beta-catenin dyslocalization toward the nucleus, which is thought to induce transcription of selected target genes, such as uPAR.

Acantholysis↗

PubMed2000

Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis.

The important role of chemokine receptors in HIV pathogenesis is becoming increasingly apparent. The level at which certain chemokine receptors that serve as HIV co-receptors are available influences the susceptibility of a CD4+ cell to viral infection and to certain HIV envelope-induced alterations in cellular function. Numerous pathogens, including HIV, can stimulate the production of chemokines and cytokines from a variety of cell types. Both cytokines and chemokines modulate CCR5 and CXCR4 availability, resulting in differential replication potentials for RS and X4 HIV strains depending on the milieu in the microenvironment. In addition, differential expression of CCR5 and CXCR4 on activated memory T cells appears to play an important role in preferential replication of RS HIV strains in vivo. However, expression of HIV co-receptors and CD4 may not be sufficient for effective HIV entry and replication. Intracellular signaling events, triggered by interaction between chemokine receptors and chemokines or HIV envelope, are important for efficient entry and completion of early replication events. Envelope proteins of different HIV isolates vary in their ability to transduce these signals, a characteristic that may play a role in determining the ability of a virus to productively infect certain cell types. Finally, the interaction between chemokine receptors and chemokines or HIV envelope has significant effects on cellular functions which likely play a role in HIV pathogenesis.

Cytokines↗

PubMed2001

Baboons as an animal model for human immunodeficiency virus pathogenesis and vaccine development.

Baboons (Papio cynocephalus) provide a valuable animal model for the study of human immunodeficiency virus (HIV) pathogenesis because HIV-2 infection of baboons causes a chronic viral disease that progresses over several years before clinical signs of acquired immunodeficiency syndrome (AIDS) appear. Since HIV-2-infected baboons develop a chronic viral infection, insights into the immuno-biology of viral latency, clinical stages of disease, virus infection of lymphatic tissue and HIV transmission can be gained using this animal model. The development of an AIDS-like disease in baboons is viral isolate and baboon subspecies dependent. Thus, viral virulence factors and host resistance can be studied as well as the mechanisms of innate and acquired immunity. The control of virus infection is dependent upon cytotoxic and non-cytotoxic antiviral activity of CD8+ T cells. In this regard, some of the HIV-2-infected baboons develop potent antiviral cellular immune responses that have a similar magnitude to that found in HIV-1-infected long-term survivors (or non-progressors). In our laboratory, baboons have been used to study DNA vaccine strategies using new cationic liposome formulations and granulocyte macrophage-colony stimulating factor and B7-2 as genetic adjuvants. The results demonstrate the value of using baboons as an animal model of AIDS pathogenesis and vaccine development.

AIDS Vaccines↗

PubMed2000

Functional genomics of Neisseria meningitidis pathogenesis.

The pathogenic bacterium Neisseria meningitidis is an important cause of septicemia and meningitis, especially in childhood. The establishment and maintenance of bacteremic infection is a pre-requisite for all the pathological sequelae of meningococcal infection. To further understand the genetic basis of this essential step in pathogenesis, we analyzed a library of 2,850 insertional mutants of N. meningitidis for their capacity to cause systemic infection in an infant rat model. The library was constructed by in vitro modification of Neisseria genomic DNA with the purified components of Tn10 transposition. We identified 73 genes in the N. meningitidis genome that are essential for bacteremic disease. Eight insertions were in genes encoding known pathogenicity factors. Involvement of the remaining 65 genes in meningocoocal pathogenesis has not been demonstrated previously, and the identification of these genes provides insights into the pathogenic mechanisms that underlie meningococcal infection. Our results provide a genome-wide analysis of the attributes of N. meningitidis required for disseminated infection, and may lead to new interventions to prevent and treat meningococcal infection.

Animals↗

PubMed2001

Complement facilitates early prion pathogenesis.

New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.

Animals↗

PubMed1989

Pathogenesis of pterygium.

This paper reviews the histological and epidemiological characteristics of pterygium which suggest that chronic exposure to ultraviolet radiation plays an important role in the pathogenesis of this disorder. However, there is conflicting evidence indicating that chronic inflammation from other causes can induce the disease. The results of two epidemiological surveys undertaken in Southern Africa show that pterygium is not closely linked to other chronic actinic disorders such as pinguecula and climatic droplet keratopathy. Pterygia differ from these disorders by their vascularity which is probably induced by chronic inflammation. On histological examination, we found that excised pterygia contained a lymphocytic infiltration consisting predominantly of T cells. In the pathogenesis of pterygium we believe that chronic irritation (from whatever cause) produces a chronic inflammatory cell infiltration with resultant inflammatory oedema, attempt at repair and cell induced angiogenesis. These processes, together with actinic damage, are responsible for the fibrovascular reaction so characteristic of a growing pterygium.

Adolescent↗

PubMed1976

Pathogenesis of the glomerulopathy associated with renal infarction in rats.

The present studies were designed to characterize the extent and pathogenesis of the glomerular lesions which occur in the viable portion of the kidney following partial renal infarction in rats. Control rats with two normal kidneys had a mean blood pressure of 112 mm Hg, minimal proteinuria and no glomerular pathology on light (LM), electron (EM) or immunofluorescence microscopy (IFM). Rats with two-thirds infarction of one kidney (stage II) became hypertensive, although less than 4% of the glomeruli from either kidney were abnormal. Rats with two-thirds infarction of one kidney and contralateral nephrectomy (stage III) developed proteinuria and hypertension whether fed a normal, low or high Na+ diet. By light microscopy 37% of glomeruli were abnormal 28 days after partial infarction and contralateral nephrectomy and thereafter the percent of abnormal glomeruli increased. Detectable amounts of immunoglobulin and complement (C3) were present in kidneys of stage II or III rats but were always accompanied by more extensive albumin and fibrin deposits. Basement membrane deposits characteristic of immune complexes were not seen on EM. Administration of antihypertensive medication to stage III rats significantly lowered blood pressure and reduced the number of abnormal glomeruli on LM; however, IFM abnormalities remained prominent. Platelet thrombi seen by EM and abundant glomerular fibrin deposits seen on IFM suggested that coagulation mechanisms may be prominent in the pathogenesis of the renal lesion. Heparin-treated stage III rats had significantly lower blood urea nitrogen concentrations, blood pressures and proportion of abnormal glomeruli although glomerular deposition of serum proteins was still present on IFM. These observations suggest that this glomerulopathy is initiated by an unknown agent(s) which increased capillary permeability. This lesion progresses via thrombotic mechanisms which are prevented by heparin administration.

Aneurysm↗

PubMed1997

Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis.

We studied the roles of acidosis, plasma osmolality, and organic osmolytes in the pathogenesis of cerebral edema in an animal model of diabetes mellitus. Normonatremic rats with streptozotocin-induced non-ketotic (NKD) and ketotic (DKA) diabetes were sacrificed before or after treatment with hypotonic saline and insulin. Brains were analyzed for water, electrolyte, and organic osmolyte content. Brain water decreased by 2% in untreated DKA and NKD despite a 12% increase in plasma osmolality due to hyperglycemia. After treatment of both NKD and DKA, brain water increased equivalently by 8%. The cerebral edema that occurred after treatment was associated with decreased brain sodium content and no change in total major brain organic osmolytes in both NKD and DKA. However, brain content of the individual osmolytes glutamine and taurine increased after treatment of DKA. In a separate study, brain water and solute content of rats with DKA were compared after treatment with either hypotonic or isotonic fluid. Animals treated with isotonic fluid had significantly less cerebral edema and higher brain sodium content than those treated with hypotonic fluid. In our studies, brain swelling after treatment of DKA and NKD was primarily due to a rapid reduction of plasma glucose and osmolality, and was not caused by sodium movement into the brain. Acidosis did not appear to play a major role in the pathogenesis of cerebral edema after treatment of DKA.

Animals↗

PubMed1997

Platelet-derived growth factor: a key regulator of connective tissue cells in embryogenesis and pathogenesis.

Studies of PDGF-A, PDGF-B and PDGF receptor-beta knock-out mice have revealed critical functions for the PDGF-PDGF receptor signaling systems in the ontogeny of connective tissue cells: the mesangial cells of kidney glomeruli and the alveolar smooth muscle cells (SMC) of the lung. The phenotypes of the PDGF mutant mice have also shed light on the identity and functions of these cell types, as well as revealed analogies suggesting that common morphogenetic principles have evolved for use in different organs, involving related growth factors and cell types. Although the lethality of PDGF knock-out mice has not allowed an investigation of the role of PDGF in SMC of the vessel wall, regulation of PDGF and its receptors in adult vessels following injury is consistent with a role for PDGF in the fibroproliferative response in the intima that occurs as part of the pathogenesis of atherosclerosis. PDGF modulation of connective tissue synthesis may thus be critical to connective tissue phenotype and proliferation in both embryogenesis and pathogenesis.

Animals↗

PubMed2000

The coexistence of low-grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei.

We examined 38 appendectomies with diagnoses of mucocele, diverticulum, or adenoma to study the coincidence of appendiceal diverticula and appendiceal low-grade mucinous neoplasms and to examine the possible role of diverticula in the pathogenesis of pseudomyxoma peritonei. Invasive adenocarcinomas and retention cysts were excluded (six cases). Cases were classified as adenomas or mucinous tumors of unknown malignant potential, with or without diverticula. Medical records were reviewed for multiple parameters, including presenting symptoms, presence of pseudomyxoma peritonei, and presence of associated malignancies. Binomial statistics were used to calculate the probability that the observed prevalence of low-grade mucinous neoplasms and diverticula together was significantly different from the expected prevalence of diverticula or low-grade mucinous neoplasms alone, using historical controls from the literature. Twenty-five percent of the total cases (8 of 32) contained both a low-grade mucinous neoplasm (7 cystadenomas and 1 mucinous tumor of unknown malignant potential) and a diverticulum. Thus, 8 of 19 low-grade mucinous neoplasms (42%) were associated with diverticula. Of the appendices with both low-grade mucinous neoplasms and diverticula, three contained dissecting acellular mucin within the appendiceal wall, four showed diverticular perforation, and one had pseudomyxoma peritonei associated with the ruptured diverticulum. A significant percentage (P < .001) of cases contained low-grade mucinous neoplasms and diverticula together. The case of coexistent low-grade mucinous neoplasm, diverticulum, and pseudomyxoma peritonei suggests that diverticula could play a role in the pathogenesis of pseudomyxoma peritonei. This could occur either by involvement of preexisting diverticula by the neoplasm or by distention of the appendiceal lumen by mucin, leading to increased intraluminal pressure and subsequent diverticulum formation at a weak area in the wall. Either mechanism might allow low-grade mucinous neoplasms to penetrate the appendiceal wall more easily.

Adult↗

PubMed2005

Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population.

An RNA virus population does not consist of a single genotype; rather, it is an ensemble of related sequences, termed quasispecies. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication. Although a high mutation rate is dangerous for a virus because it results in nonviable individuals, it has been hypothesized that high mutation rates create a 'cloud' of potentially beneficial mutations at the population level, which afford the viral quasispecies a greater probability to evolve and adapt to new environments and challenges during infection. Mathematical models predict that viral quasispecies are not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population. According to this view, viral populations, rather than individual variants, are the target of evolutionary selection. Here we test this hypothesis by examining the consequences of limiting genomic diversity on viral populations. We find that poliovirus carrying a high-fidelity polymerase replicates at wild-type levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. Notably, using chemical mutagenesis to expand quasispecies diversity of the high-fidelity virus before infection restores neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members in the quasispecies, indicating that selection indeed occurs at the population level rather than on individual variants. Our study provides direct evidence for a fundamental prediction of the quasispecies theory and establishes a link between mutation rate, population dynamics and pathogenesis.

Animals↗