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At least 865 records · Page 48Linked to original sources
PubMed2005

Cutaneous melanoma: pathogenesis and rationale for chemoprevention.

OBJECTIVE: To critically review aspects of melanoma pathogenesis that lend themselves to a chemoprevention strategy. To discuss potential candidate chemoprevention agents with an emphasis on the lipid lowering drugs, the statins, currently, the most promising agents. DATA SOURCES: A retrospective review of the literature. STUDY SELECTION: Studies included those relevant to melanoma pathogenesis, to the scientific rationale of chemoprevention, and pertinent epidemiologic, pre-clinical, and clinical studies. The referenced study designs and methodologies varied. DATA EXTRACTION AND SYNTHESIS: Data were extracted by two reviewers, and the main results are presented in a quantitative descriptive manner. CONCLUSION: Melanoma is a preventable disease by altering behavior (sun exposure) among at-risk individuals. There is also considerable evidence to suggest that melanoma development may be prevented or delayed by drugs of sufficiently low toxicity to make clinical trials of chemoprevention feasible and potentially successful. Among potential candidate agents, statins have compelling data for long-term safety and sufficient pre-clinical and clinical evidence for efficacy to justify their evaluation in well-designed trials in high-risk individuals, incorporating intermediate biologic endpoints.

Chemoprevention↗
PubMed2006

Role of monocyte chemotactic protein-1 and nuclear factor kappa B in the pathogenesis of proliferative diabetic retinopathy.

Intraocular concentrations of monocyte chemotactic protein-1 (MCP-1) are increased in proliferative diabetic retinopathy (PDR). Nuclear factor kappa B (NF-kappaB) is a transcription factor, and NF-kappaB binding site is located in gene promoter of MCP-1. This study was conducted to investigate the potential role of MCP-1 and NF-kappaB in the pathogenesis of PDR. Epiretinal membrane (ERM) samples were obtained during vitrectomy from 19 eyes with PDR and 16 eyes with idiopathic ERM. They were processed for RT-PCR analysis. Four PDR ERMs were processed for immunohistochemical analysis. In addition, cultured Müller glial cells were stimulated with glycated albumin or high glucose. After the stimulation, we examined nuclear localization of NF-kappaB p50, MCP-1 promoter activity, and MCP-1 concentration in culture media. MCP-1 mRNA expression was significantly higher in PDR (74%) than in idiopathic ERMs (38%) (P < 0.05). Immunohistochemical analysis revealed that MCP-1 protein is colocalized with active form of NF-kappaB p50. In vitro studies demonstrated that glycated albumin or high glucose induces NF-kappaB activation followed by up-regulation of MCP-1 promoter activity and protein production in glial cells. These results suggest that MCP-1, under the regulation of NF-kappaB, is involved in the pathogenesis of PDR.

Adult↗
PubMed2005

Small N-terminal mutant huntingtin fragments, but not wild type, are mainly present in monomeric form: Implications for pathogenesis.

N-terminal fragments of huntingtin containing an expanded polyglutamine stretch play an important role in the molecular pathogenesis of Huntington's disease. Their ultimate accumulation in insoluble protein aggregates constitutes an important pathological hallmark of Huntington's disease. We report on systematic biochemical comparison studies of soluble wild type and mutant N-terminal huntingtin fragments. The results show that soluble wild type exon 1 fragments are predominantly present in higher molecular weight complexes with a molecular size of approximately 300 kDa, while their mutant counterparts are mainly present in their monomeric form. In contrast, longer N-terminal fragments corresponding to peptides produced by caspase cleavage do not display these differential properties. These findings suggest that especially an increased amount of monomeric form of small N-terminal mutant huntingtin fragments may facilitate aberrant interactions both with itself via the polyglutamine stretch and with other proteins and thereby contribute to molecular pathogenesis.

Animals↗
PubMed2006

Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

Animals↗
PubMed2006

Role of microglia in the pathogenesis of osmotic-induced demyelination.

Osmotic demyelination is a serious disease caused by rapid correction of hyponatremia. In humans, demyelinative lesions occur preferentially in the central pons, and thus are termed central pontine myelinolysis. Although accumulation of microglia has been reported in such demyelinative lesions, their role in the pathogenesis of osmotic demyelination remains unclear. We examined the expression of cytokines in microglia that accumulated in the demyelinative lesions in a rat model of osmotic demyelination. Hyponatremia was induced in rats by a combination of dDAVP infusion and liquid diet feeding. After 7 days, serum sodium levels were rapidly corrected by hypertonic saline injection. The rats developed severe motor deficits, and marked demyelinative lesions were found in the midbrain and cerebral cortex. In the area of the demyelinative lesions, massive accumulations of microglia were observed that expressed the proinflammatory cytokines TNF-alpha and IFN-gamma as well as iNOS. In contrast, in hyponatremia corrected rats treated with lovastatin, which is known to inhibit microglial infiltration in various animal models of CNS disease, neurological impairments and the degree of demyelination were significantly ameliorated. Lovastatin also reduced the accumulation of microglia and decreased the expression of TNF-alpha in the demyelinative lesions. These results indicate that microglia play a detrimental role in the pathogenesis of osmotic demyelination by producing proinflammatory cytokines, and further suggest that lovastatin may be useful in repressing the demyelination.

Animals↗
PubMed2006

Tritrichomonas foetus: pathogenesis of acute infection in normal, estradiol-treated, and stressed mice.

Environmental stress and endocrine control can affect pathogenesis of sexually transmitted diseases such as trichomoniasis. Acute Tritrichomonas foetus infection was compared in female BALB/c mice to infections in mice treated with high doses of estradiol or housed in constant bright illumination (stressed). In untreated mice, T. foetus readily colonized the reproductive tract, causing minimal epithelial damage and inflammation. Several fold increases of IFN-gamma, TNF-alpha, MCP-1, and IL-6 cytokines were detected after estradiol-treatment of mice, resulting in greatly enhanced inflammation and tissue damage throughout the reproductive tract. Interestingly, estradiol-treatment of mice resulted in reduced T. foetus colonization compared to untreated mice. Infection in stressed mice resulted in increased tissue damage, inflammation, and inflammatory cytokine expression, although parasite colonization within the reproductive tract was similar to that in untreated mice. These results indicate that either estradiol-treatment or stress result in pathogenesis often observed during severe disease. Alternatively, infection in non-treated mice results in chronic colonization, with little inflammation or pathology.

Animals↗
PubMed2005

Molecular mimicry may contribute to pathogenesis of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with mucosal inflammation and ulceration of the colon. There seems to be no single etiological factor responsible for the onset of the disease. Autoimmunity has been emphasized in the pathogenesis of UC. Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are common in UC, and recently two major species of proteins immunoreactive to pANCA were detected in bacteria from the anaerobic libraries. This implicates colonic bacterial protein as a possible trigger for the disease-associated immune response. Autoantibodies and T-cell response against human tropomyosin isoform 5 (hTM5), an isoform predominantly expressed in colon epithelial cells, were demonstrated in patients with UC but not in Crohn's colitis. We identified two bacterial protein sequences in NCBI database that have regions of significant sequence homology with hTM5. Our hypothesis is that molecular mimicry may be responsible for the pathogenesis of UC.

Amino Acid Sequence↗
PubMed2005

Photoactivated perylenequinone toxins in fungal pathogenesis of plants.

Several genera of plant pathogenic fungi produce photoactivated perylenequinone toxins involved in pathogenesis of their hosts. These toxins are photosensitizers, absorbing light energy and generating reactive oxygen species that damage the membranes of the host cells. Studies with toxin-deficient mutants and on the involvement of light in symptom development have documented the importance of these toxins in successful pathogenesis of plants. This review focuses on the well studied perylenequinone toxin, cercosporin, produced by species in the genus Cercospora. Significant progress has been made recently on the biosynthetic pathway of cercosporin, with the characterization of genes encoding a polyketide synthase and a major facilitator superfamily transporter, representing the first and last steps of the biosynthetic pathway, as well as important regulatory genes. In addition, the resistance of Cercospora fungi to cercosporin and to the singlet oxygen that it generates has led to the use of these fungi as models for understanding cellular resistance to photosensitizers and singlet oxygen. These studies have shown that resistance is complex, and have documented a role for transporters, transient reductive detoxification, and quenchers in cercosporin resistance.

Ascomycota↗
PubMed2004

Shigella flexneri infection: pathogenesis and vaccine development.

Shigella flexneri is a gram-negative bacterium which causes the most communicable of bacterial dysenteries, shigellosis. Shigellosis causes 1.1 million deaths and over 164 million cases each year, with the majority of cases occurring in the children of developing nations. The pathogenesis of S. flexneri is based on the bacteria's ability to invade and replicate within the colonic epithelium, which results in severe inflammation and epithelial destruction. The molecular mechanisms used by S. flexneri to cross the epithelial barrier, evade the host's immune response and enter epithelial cells have been studied extensively in both in vitro and in vivo models. Consequently, numerous virulence factors essential to bacterial invasion, intercellular spread and the induction of inflammation have been identified in S. flexneri. The inflammation produced by the host has been implicated in both the destruction of the colonic epithelium and in controlling and containing the Shigella infection. The host's humoral response to S. flexneri also appears to be important in protecting the host, whilst the role of the cellular immune response remains unclear. The host's immune response to shigellosis is serotype-specific and protective against reinfection by the same serotype, making vaccination a possibility. Since the 1940s vaccines for S. flexneri have been developed with little success, however, the growing understanding of S. flexneri's pathogenesis and the host's immune response is assisting in the generation of more refined vaccine strategies. Current research encompasses a variety of vaccine types, which despite disparity in their efficacy and safety in humans represent promising progress in S. flexneri vaccine development.

Bacterial Vaccines↗
PubMed2004

Quantitative, tissue-specific analysis of cyclooxygenase gene expression in the pathogenesis of Barrett's adenocarcinoma.

Cyclooxygenase (Cox-2) is implicated in the pathogenesis of many cancers including esophageal adenocarcinoma (EAC), whereas the role of the isoform Cox-1 in carcinogenesis is not well understood. To further elucidate the role of these factors in the development of EAC, we measured the gene expressions (mRNA levels) of Cox-2 and Cox-1 by real-time quantitative polymerase chain reaction (QRT-PCR) in tissues from normal esophagus with and without erosive gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), dysplasia, adenocarcinoma, and in healthy gastric antrum. All tissues were purified by laser capture microdissection from endoscopic or surgical resection specimens. Median Cox-2 gene expression did not differ significantly among the esophageal control groups but was elevated 5-fold in BE, 8-fold in dysplasia and 16-fold in EAC compared to normal esophageal controls with no erosive GERD. Erosive GERD tissue had slightly higher median Cox-2 expression but Cox-2 expression in normal antrum was much higher than that in a normal esophagus, close to that of dysplasia. In contrast to that of Cox-2, Cox-1 expression was significantly decreased in all neoplastic tissues compared to normal controls. Cox-1 and Cox-2 expression varied over a wide range in the neoplastic tissues but over a relatively narrow range in the esophageal normal tissues. The occurrence of substantial alterations in Cox-1 and Cox-2 expression at the BE stage indicates that these are early events in the development of EAC. These results confirm the important role of Cox-2 amplification in the pathogenesis of esophageal adenocarcinoma, but the unexpected down-regulation of Cox-1 raises questions about its role in carcinogenesis.

Adenocarcinoma↗
PubMed2004

Immunomodulatory effects of the HIV-1 gp120 protein on antigen presenting cells: implications for AIDS pathogenesis.

Antigen presenting cell (APC) function is central to the development of an effective anti-viral immune response. Among APC, monocytes, macrophages and dendritic cells (DC) form the principal non-T cell compartment involved in in vivo HIV infection, and these cells play important and well-established roles in multiple aspects of viral pathogenesis. HIV infection may result in APC defects, which could ultimately contribute to the loss of CD4+ T cell responses observed early in HIV infection, when the CD4+ T cell number is still within the normal range. Extensive in vitro studies have demonstrated that the envelope glycoproteins of HIV-1 exert profound influences on various cell populations of the immune system, including hematopoietic progenitors, T and B lymphocytes, monocytes/ macrophages and DC, as well as on neuronal cells. The demonstration of the presence of envelope proteins both free in the circulation and bound to the surface of CD4+ cells suggests that gp120 interactions with non-infected cells can influence cellular functions in vivo, thus contributing to the immunopathogenesis of AIDS. This paper provides an overview of the present knowledge on gp120 binding, signal transduction triggering and interference with macrophage and DC functions and it highlights the importance of this interaction in the pathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Complement component C5 is not involved in scrapie pathogenesis.

During transmissible spongiform encephalopathy (TSE) infections the accumulation of abnormal prion protein within the brain is often accompanied by severe neurodegeneration. Studies have implicated complement, including the membrane attack complex (MAC, C5b-C9), in inducing pathology in some neurodegenerative diseases. Recent studies show the MAC is localized on neurons in the brains of TSE patients implicating complement-mediated cell lysis in TSE neuropathology. To determine the role of the MAC in TSEs, we compared scrapie pathogenesis in C5-deficient and C5-sufficient mice. C5-deficient mice developed clinical scrapie with incubation periods similar to C5-sufficient mice. Furthermore, the severity of the neuropathology was not significantly different between C5-deficient and C5-sufficient mice. These data show that C5, and the MAC, are not involved in TSE pathogenesis.

Animals↗
PubMed2005

Involvement of human natural killer cells in asthma pathogenesis: natural killer 2 cells in type 2 cytokine predominance.

BACKGROUND: T H 2 cells play a pivotal role in the pathogenesis of human asthma. Natural killer (NK) cells are also thought to divide into NK1 and NK2 subsets. OBJECTIVE: Whether NK1 or NK2 cells are involved in asthma remains unclear. METHODS: Triple-color flow cytometry for detecting intracellular cytokine and NK cell surface phenotype from asthmatic patients was used. The NK cell cloning and analysis with RT-PCR for cytokine expression and Western blotting for signal transducer and activator of transcription activation were performed. RESULTS: For the first time, we observed that the ratio of IL-4 + CD56 + NK2 cells in PBMCs of 8 asthmatic patients were higher than in healthy individuals. NK cell clones were then obtained by means of limited dilution, and the average mean of the relative intensity of PCR products for type 2 cytokines significantly increased in the asthmatic patients. Signal transducer and activator of transcription 6, a key transcript factor of type 2 phenotype, was constitutively activated in NK2 clones from asthmatic patients. We cocultured freshly purified NK cells from asthmatic patients with IFN-gamma and anti-IL-4 antibody in the presence of IL-15 and found that the content of IL-4 + NK2 cells significantly decreased after treatment. Interestingly, NK2-biased status in asthmatic patients was reversed when patients recovered from regular therapy. CONCLUSION: The results suggest that the NK2 cell subset is involved in the pathogenesis of asthma.

Adolescent↗
PubMed2005

Cherubism - new hypotheses on pathogenesis and therapeutic consequences.

AIMS: The hereditary occurrence of cherubism indicates a probable genetic aetiology: a correlation with a mutation in the gene SH3BP2 has been demonstrated. A convincing concept of formal pathogenesis is not yet available. The study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study including genetic findings and an evaluation of the literature. RESULTS AND CONCLUSION: Because of its association with the development of the second and third molars, cherubism could be defined as a genetically determined alteration of tooth development. In this context, disturbed PTHrP - PTHrP receptor interaction induced by the mutation in SH3BP2 is discussed. The temporal and spatial determination of the clinical symptoms is explained by an interaction of SH3BP2-dependent signal transduction pathways with jaw morphogenesis (e.g. Hox-gene Msx-1). Because of the disease-induced lack of determination of the cap phase of the second and third molar, a spatial compartmentation, which is necessary for normal dental development, does not take place. This leads to dysregulation of mesenchymal bone building tissue areas, and to the development of giant cell granulomas with high osteoclastic activity. Because of the genetic determination of cherubism and the associated dedifferentiation of the diseased tissue, a surgical removal should be exclusively restricted to specific indications. Therefore an attitude of wait and see is preferred.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow.

BACKGROUND/AIMS: The study aims were to determine the role of inflammation in the pathogenesis of increased intracranial pressure (ICP) in patients with acute liver failure (ALF) and its interplay with cerebral blood flow (CBF) and ammonia. METHODS: Twenty-one patients with ALF were studied from the time they were ventilated for grade 4 encephalopathy until receiving specific treatment for increased ICP. Depending upon the ICP, the patients were divided into two groups; those that required specific treatment (ICP>20 mmHg, group 1: n=8, ICP: 32 (28-54) mmHg); and those that did not (ICP< or =20 mmHg, group 2: n=13, ICP: 15 (10-20) mmHg). RESULTS: Inflammatory markers, arterial ammonia and CBF were significantly higher in the group 1 patients. TNFalpha levels correlated with CBF (r=0.80). Four patients from group 2 developed surges of increased ICP (32 (15-112) hours from enrolment). These were associated increases in markers of inflammation and TNFalpha, and an increase in CBF. There was no change in these inflammatory markers, CBF or ICP in the other 9 group 2 patients. CONCLUSIONS: The results of this study suggest that inflammation plays an important synergistic role in the pathogenesis of increased ICP possibly through its effects on CBF.

Adult↗
PubMed2006

Factors in the pathogenesis of Dupuytren's contracture.

This article reviews the basic science elements involved in the pathogenesis of Dupuytren's disease. Dupuytren's contracture is effected by a multitude of complex processes at the cellular level and the exact relative contribution of each is unknown. Various investigators have proposed different theories and documented individual findings regarding the pathophysiology of Dupuytren's contracture. The current report attempts to summarize many of these findings together in a schema of pathogenesis.

Algorithms↗
PubMed2005

Herpes simplex virus type 2 recurrent meningitis (Mollaret's meningitis): a consideration for the recurrent pathogenesis.

We report a 44-year-old Japanese woman with herpes simplex virus (HSV) type 2 recurrent meningitis (Mollaret's meningitis). The diagnosis was confirmed by nested polymerase chain reaction in her cerebrospinal fluid, but the patient's conventional HSV antibodies by complement fixation, neutralizing test or enzyme immunoassay showed low titres with low lymphoproliferative response. Several similar cases are discussed. Although the reason for the recurrent pathogenesis is uncertain, our report suggests that the low immune response including immune evasion may be involved in the pathogenesis of HSV type 2 recurrent meningitis. For this patient, long-term suppressive and patient-initiated therapies were conducted to prevent the recurrence of meningitis.

Acyclovir↗
PubMed2004

A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition.

Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of these mutations impair one or more steps of tRNA maturation and protein biosynthesis including 5'-end-processing, post-transcriptional base modification, structural stability, aminoacylation, and formation of tRNA-ribosomal complexes. tRNALeu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90 disease-associated mutations described to date. Here, the pathogenesis-associated base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA were tested for their effects on endonucleolytic 3'-end processing and CCA addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a less efficient substrate for CCA addition. These results support the view that pathogenesis may be elicited through cumulative effects of tRNA mutations: a mutation can impede several pre-tRNA processing steps, with each such reduction contributing to the overall impairment of tRNA function.

Humans↗