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Disease Pathogenesis (disease + pathogenesis)
Selected AbstractsEtiology of cicatricial alopecias: a basic science point of viewDERMATOLOGIC THERAPY, Issue 4 2008Kevin J. McElwee ABSTRACT: This article presents a short summary of our current knowledge of cicatricial alopecia disease pathogenesis and the hypothetical disease mechanisms that may be involved in scarring alopecia development. Several forms of scarring alopecia likely involve targeted cytotoxic action against hair follicle cells mediated by a folliculocentric inflammation. However, the specific nature of the inflammatory interference in hair follicle growth is open to question. A popular hypothesis of lymphocyte-mediated scarring alopecia development involves autoimmune targeting of hair follicle,specific self-antigens, although there is no direct evidence in support of such a view. Alternative hypotheses focus on defects in sebaceous gland function, destruction of hair follicle stem cells, and interference in the communication between hair follicle mesenchyme and epithelium. Many questions arise from these hypotheses, and addressing them with a systematic research approach may enable significant advances in understanding cicatricial alopecia etiology. [source] Metals and oxidative homeostasis in Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 3 2002George Perry Abstract Oxidative damage to every class of biological macromolecule has been characterized in Alzheimer's disease. Abnormalities in iron and copper metabolism are also being implicated as playing a crucial role in neurodegenerative disease pathogenesis. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed here with its relationship to oxidative stress. While there is documented evidence for alterations in transition metal homeostasis, redox-activity, and localization, it is also important to realize that alterations in specific copper- and iron-containing metalloenzymes also contribute to the neurodegenerative process. These changes offer the opportunity to identify pathways where modification of the disease process can offer new routes for clinical efficacy, from gene therapy to use of antioxidant and chelating drugs. Drug Dev. Res. 56:293,299, 2002. © 2002 Wiley-Liss, Inc. [source] The 28-amino acid form of an APLP1-derived A,-like peptide is a surrogate marker for A,42 production in the central nervous systemEMBO MOLECULAR MEDICINE, Issue 4 2009Kanta Yanagida Abstract Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-, (A,42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived A,-like peptides (APL1,) that are generated by ,- and ,-cleavages at a concentration of ,4.5,nM. These novel peptides, APL1,25, APL1,27 and APL1,28, were not deposited in AD brains. Interestingly, most ,-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of A,42 cause a parallel increase in the production of APL1,28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1,28 levels are higher than in non-AD controls, while the relative A,42 levels are unchanged or lower. Most strikingly, the relative APL1,28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1,28 in the CSF as a candidate surrogate marker for the relative level of A,42 production in the brain. [source] Novel therapeutic targets in multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2000Faith E. Davies The aim of this review is to focus on a number of key areas where recent advances in the biology of the disease have not only yielded an understanding of the disease pathogenesis but have also suggested novel treatment approaches. Factors mediating myeloma cell growth, survival and the complex interaction of myeloma cells with the bone marrowmicroenvironment have provided a framework for the rational design of therapeutic agents. The development of such biologically based treatments which target both the tumour cell and the microenvironment, in order to achieve more complete and selective eradication of myeloma cells and the maintenance of minimal residual disease states, may ultimately lead to improved disease-free survivial and potentially a cure. [source] Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4+ T-cell proliferation and IFN-, production in response to myelin basic protein and myelin oligodendrocyte glycoproteinEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Christopher T. Harp Abstract Recent evidence suggests that B- and T-cell interactions may be paramount in relapsing-remitting MS (RRMS) disease pathogenesis. We hypothesized that memory B-cell pools from RRMS patients may specifically harbor a subset of potent neuro-APC that support neuro-Ag reactive T-cell proliferation and cytokine secretion. To test this hypothesis, we compared CD80 and HLA-DR expression, IL-10 and lymphotoxin-, secretion, neuro-Ag binding capacity, and neuro-Ag presentation by memory B cells from RRMS patients to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HD). We identified memory B cells from some RRMS patients that elicited CD4+ T-cell proliferation and IFN-, secretion in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Notwithstanding the fact that the phenotypic parameters that promote efficient Ag presentation were observed to be similar between RRMS and HD memory B cells, a corresponding capability to elicit CD4+ T-cell proliferation in response to myelin basic protein and myelin oligodendrocyte glycoprotein was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B-cell pool in RRMS harbors neuro-Ag specific B cells that can activate T cells. [source] Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studiesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2003Dan Chen Abstract Linkage studies indicate close associations of certain HLA alleles with autoimmune diseases. To better understand how specific HLA alleles are related to disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing a 550-kb yeast artificial chromosome (YAC) construct containing the complete DR,, DR,1, DR,3, DQ,, and DQ, regions. The transgenic mouse (4D1/C2D) in an I-A,o background appears healthy with no signs of autoimmune diseases. Lymphoid tissues as well as CD4+ T cells develop normally. Characterization of the transgene expression demonstrates that ,90% of B cells express high levels of DR3 and 50,70% of B cells express DQ2. CD11c+ dendritic cells express high levels of DR and DQ. Approximately12,18% of resting T cells are positive for DR expression, and further up-regulation to 40,50% expression is seen upon activation with anti-CD3/anti-CD28 mAb. These results suggest that the transgenic construct confers a high fidelity to the normal human temporal and spatial expression profile. Analysis of T cell receptor repertoire in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection. Furthermore, transgenic mice respond to a DR3-restricted antigen, demonstrating antigen processing and presentation by antigen-presenting cells (APC). Purified T cells from ovalbumin (OVA)-immunized 4D1 mice respond to human APC co-cultured with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T cells. Immunoglobulin isotype switching is also observed, indicating functional T-B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid development and functionality that are mediated by HLA transgenes and can be used to investigate HLA-associated immunological questions. [source] Correlation of psoriasis activity with abundance of CD25+CD8+ T cells: conditions for cloning T cells from psoriatic plaquesEXPERIMENTAL DERMATOLOGY, Issue 10 2004Wayan M. Kohlmann Abstract:, The role of T cells in the pathogenesis of psoriasis is widely acknowledged. However, key aspects of their precise function in the disease as well as the relative pathogenic contribution of T-cell subsets are still unknown. T-cell clones have been isolated from psoriatic plaques but a study of conditions affecting the isolation and expansion of T-cell clones from psoriatic skin has not been reported to date. Here, we observe a correlation of disease activity with the frequency of the CD3+CD8+CD25+ subset. We show that prolonged in vitro culture changes the phenotypic subset distribution of T-cell lines derived from psoriatic skin and that T-cell clones can be isolated by sorting of CD25+ cells emigrated from skin fragments after 7 days. We evaluate various conditions affecting expansion of psoriatic T-cell clones in vitro and show that blocking apoptosis can facilitate proliferation of activated T-cell clones in vitro. Our results indicate a prominent role of the CD8+CD25+ T-cell subset in disease pathogenesis and should be useful in the design of experiments aiming at a systematic analysis of the specificity of clones present in psoriatic plaques. [source] Glycolipid receptor depletion as an approach to specific antimicrobial therapyFEMS MICROBIOLOGY LETTERS, Issue 1 2006Majlis Svensson Abstract Mucosal pathogens recognize glycoconjugate receptors at the site of infection, and attachment is an essential first step in disease pathogenesis. Inhibition of attachment may prevent disease, and several approaches have been explored. This review discusses the prevention of bacterial attachment and disease by agents that modify the glycosylation of cell surface glycoconjugates. Glycosylation inhibitors were tested in the urinary tract infection model, where P-fimbriated Escherichia coli rely on glycosphingolipid receptors for attachment and tissue attack. N -butyldeoxynojirimycin blocked the expression of glucosylceramide-derived glycosphingolipids and attachment was reduced. Bacterial persistence in the kidneys was impaired and the inflammatory response was abrogated. N -butyldeoxynojirimycin was inactive against strains which failed to engage these receptors, including type 1 fimbriated or nonadhesive strains. In vivo attachment has been successfully prevented by soluble receptor analogues, but there is little clinical experience of such inhibitors. Large-scale synthesis of complex carbohydrates, which could be used as attachment inhibitors, remains a technical challenge. Antibodies to bacterial lectins involved in attachment may be efficient inhibitors, and fimbrial vaccines have been developed. Glycosylation inhibitors have been shown to be safe and efficient in patients with lipid storage disease and might therefore be tested in urinary tract infection. This approach differs from current therapies, including antibiotics, in that it targets the pathogens which recognize these receptors. [source] Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes,HEPATOLOGY, Issue 5 2010Hua Liu Recent advances in induced pluripotent stem (iPS) cell research have significantly changed our perspective on regenerative medicine. Patient-specific iPS cells have been derived not only for disease modeling but also as sources for cell replacement therapy. However, there have been insufficient data to prove that iPS cells are functionally equivalent to human embryonic stem (hES) cells or are safer than hES cells. There are several important issues that need to be addressed, and foremost are the safety and efficacy of human iPS cells of different origins. Human iPS cells have been derived mostly from cells originating from mesoderm and in a few cases from ectoderm. So far, there has been no report of endoderm,derived human iPS cells, and this has prevented comprehensive comparative investigations of the quality of human iPS cells of different origins. Here we show for the first time reprogramming of human endoderm-derived cells (i.e., primary hepatocytes) to pluripotency. Hepatocyte-derived iPS cells appear indistinguishable from hES cells with respect to colony morphology, growth properties, expression of pluripotency-associated transcription factors and surface markers, and differentiation potential in embryoid body formation and teratoma assays. In addition, these cells are able to directly differentiate into definitive endoderm, hepatic progenitors, and mature hepatocytes. Conclusion: The technology to develop endoderm,derived human iPS cell lines, together with other established cell lines, will provide a foundation for elucidating the mechanisms of cellular reprogramming and for studying the safety and efficacy of differentially originated human iPS cells for cell therapy. For the study of liver disease pathogenesis, this technology also provides a potentially more amenable system for generating liver disease-specific iPS cells. (HEPATOLOGY 2010;51:1810,1819) [source] From HLA-B27 to spondyloarthritis: a journey through the ERIMMUNOLOGICAL REVIEWS, Issue 1 2010Robert A. Colbert Summary:, Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8+ T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleukin-23 (IL-23) in response to pattern recognition receptor agonists. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases. [source] Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeuticsIMMUNOLOGICAL REVIEWS, Issue 1 2008Marc Feldmann Summary: Advances in cDNA and monoclonal antibody technology in the 1980s fuelled the discovery and characterization of the properties of cytokines. It became apparent that because cytokines were expressed in tissues derived from autoimmune diseases, they were likely to be of fundamental importance in disease pathogenesis and developing a new class of biological therapeutics. In this review, we describe the history of bench to bedside translation of work that led to the identification of tumor necrosis factor (TNF) as a key regulator of the loss of homeostatic immune-inflammatory responses in rheumatoid arthritis (RA) and a good therapeutic target. First in human clinical trials in collaboration with a biotechnology company, the safety and efficacy of TNF blockade with a chimeric monoclonal antibody was substantiated in patients refractory to standard anti-rheumatoid drugs. Abnormal immune-inflammatory responses after therapy showed improvement and remain a focus of ongoing research in many laboratories. Longer term multi-center studies that followed with several anti-TNF biologicals have demonstrated the augmented efficacy, including inducing clinical remission, of low dose methotrexate and anti-TNF therapy co-therapy, but serious infections and lymphomas in a low frequency have been observed. In the course of the past decades, three ,blockbuster' anti-TNF biologicals are in the clinic. Over a million patients with RA and other immune-mediated diseases have been successfully treated, and a better perspective on the risk of harm and its management has become part of good clinical practice. This success has encouraged a burgeoning industry of biologicals for chronic diseases. [source] Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease lociIMMUNOLOGICAL REVIEWS, Issue 1 2001Marie M. Griffiths Summary: Collagen-induced arthritis (CIA) is a useful model for dissecting the genetic patterns underlying susceptibility to rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases. CIA exhibits three phenotypes characteristic of autoimmune disease pathogenesis: abnormal levels of immune reactivity to self antigens; chronic inflammation of target organs expressing that specific autoantigen; activation and direct participation of invading mononuclear cells and resident tissue fibroblasts in organ damage. Over 25 different quantitative trait loci (QTL) regulating arthritis severity and autoantibody in rats with CIA are mapped. QTL-congenic strains show that certain CIA,QTLs can modulate arthritis independently. These monogenic models are proving to be highly informative for fine mapping and function studies, revealing gender effects and evidence of gene clusters. Recent genome scans of RA populations identified RA-susceptibility loci in chromosome regions homologous to rat chromosomal segments housing CIA,QTLs. Also, CIA,QTLs frequently co-localize with susceptibility QTLs mapped in other rat arthritis models induced with non-immunogenic adjuvant oils and/or in rat autoimmune models of multiple sclerosis and diabetes. Common autoimmunity genes and inflammation genes important to several human diseases are likely being detected in the various rat disease models. Continued dissection of the genetic underpinnings of rat arthritis models should provide candidate genes for investigation in human patients and lead to a clearer understanding of the complex genetics of RA. [source] The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2005Konstantinos Karmiris MD Abstract Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD. [source] Probiotics and inflammatory bowel disease: Is there a scientific rationale?INFLAMMATORY BOWEL DISEASES, Issue 2 2000Dr. Fergus Shanahan Abstract Most conventional forms of drug therapy suppress or modify the host immunoinflammatory response and neglect the other contributor to disease pathogenesis,the environmental microflora. Probiotics are live microbial food ingredients that alter the enteric microflora and have a beneficial effect on health. The rationale for using probiotics in IBD is mainly based on evidence from human studies and experimental animal models implicating intestinal bacteria in the pathogenesis of these disorders. The relationship between bacteria and intestinal inflammation is complex and does not appear to reflect a simple cause and effect. Similarly, the field of probiotics is complex and in need of rigorous research. Until the indigenous flora are better characterized and mechanisms of probiotic action defined, the promise of probiotics in IBD is unlikely to be fulfilled. Because of strain-specific variability and clinical and therapeutic heterogeneity within Crohn's disease and ulcerative colitis, it cannot be assumed that a given probiotic is equally suitable for all individuals. Although preliminary results of probiotic therapy in animal models and humans with ulcerative colitis and pouchitis have been encouraging, their efficacy in treatment or maintenance of remission of Crohn's disease remains to be clarified. However, the circumstantial evidence for some form of biotherapeutic modification of the enteric flora in Crohn's disease seems compelling. In the future, probiotics may offer a simple adjunct to conventional therapy with the emphasis on diet shifting from one of nutritional replenishment alone to a more functional role. [source] Nonalcoholic fatty liver disease: is all the fat bad?INTERNAL MEDICINE JOURNAL, Issue 4 2004A. D. Clouston Abstract Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Laboratory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed. (Intern Med J 2004; 34: 187,191) [source] Searching for genes in diabetes and the metabolic syndromeINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2004G. A. Hitman Summary Evidence for a genetic basis for type 2 diabetes and the metabolic syndrome has been derived from studies of families, twins and populations with genetic admixture. Identification of genes associated with disease pathogenesis is now underway using techniques such as genome scanning by positional cloning and the candidate gene approach. Genome scanning in several different ethnic groups has identified chromosome regions harbouring type 2 diabetes susceptibility genes such as the novel gene, calpain 10 (CAPN10). The hepatic nuclear factor 4, (HNF4,) gene partly explains the linkage peak on chromosome 20, while the upstream transcription factor (USF1) is associated with familial combined hyperlipidaemia (FCHL) and maps close to the type 2 diabetes associated 1q peak. Peroxisome proliferator-activated receptor gamma (PPAR,) was identified as a candidate gene based on its biology. A Pro12Ala variant of this gene has been associated with an increased risk of type 2 diabetes. Many genes accounting for monogenic forms of diabetes have been identified , such as maturity onset diabetes of the young (MODY); glucokinase (GCK) and HNF1, mutations being the most common causes of MODY. GCK variants result in ,mild' diabetes or impaired glucose tolerance (IGT) and relatively few cardiovascular complications, while HNF1,- associated MODY is more typical of type 2 diabetes, frequently being treated with sulphonylureas or insulin and resulting in microvascular complications. Testing for single gene disorders associated with type 2 diabetes and obesity may determine cause, prognosis and appropriate treatment; however, for the more common polygenic diseases this is not the case. In type 2 diabetes, molecular genetics has the potential to enhance understanding of disease pathogenesis, and help formulate preventative and treatment strategies. [source] Mouse models in non-alcoholic fatty liver disease and steatohepatitis researchINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2006Quentin M. Anstee Summary Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis. [source] Analysing the effect of novel therapies on cytokine expression in experimental arthritisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 5 2005Richard O. Williams Summary Type II collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis that has been used extensively to address questions of disease pathogenesis and to validate novel therapeutic targets. Susceptibility to CIA is strongly associated with major histocompatibility complex class II genes, and the development of arthritis is accompanied by a robust T- and B-cell response to type II collagen. The main pathological features of CIA include proliferative synovitis with infiltration of inflammatory cells, pannus formation, cartilage degradation, erosion of bone and fibrosis. Pro-inflammatory cytokines, such as tumour necrosis factor , and interleukin-1,, are expressed in the arthritic joints in both murine CIA and human rheumatoid arthritis, and blockade of these molecules results in amelioration of disease. Hence, there is a great deal of interest in the development of small-molecular-weight inhibitors of pro-inflammatory cytokines. There is also interest in the development and testing of drugs with the capacity to modulate the immune pathways involved in driving the inflammatory response in arthritis. For these reasons, there is a need to monitor the effect of novel treatments on cytokine expression in vivo. In this review, we outline the various techniques used to detect cytokines in experimental arthritis and describe how these techniques have been used to quantify changes in cytokine expression following therapeutic intervention. [source] Apoptosis in chronic viral hepatitis parallels histological activity: An immunohistochemical investigation using anti-activated caspase-3 and M30 Cytodeath antibodyINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2005Jo L. McPartland Summary Apoptosis is implicated as a major pathogenic mechanism in chronic hepatitis B and C. Previous studies of the relationship between apoptotic rates and histological necroinflammatory activity have produced conflicting results. Hepatocyte apoptosis was assessed in liver tissue from 32 cases of chronic viral hepatitis, seven cases of hepatocellular carcinoma (HCC) and six cases of steatohepatitis as non-viral disease controls and eight cases of control liver. Apoptotic rates were measured using H&E morphological assessment and immunohistochemical staining with antibodies to activated caspase-3 and M30. Histological necroinflammatory activity of viral hepatitis cases was scored using the Knodell scoring system, and the cases were divided according to their score into group 1 (mean 2.43 ± 0.48) and group 2 (mean 7.80 ± 0.49). Apoptotic indices were significantly higher in group 2 than group 1 using H&E (11.53 ± 2.70 vs. 0 ± 0, P = 0.015) and activated caspase-3 (22.01 ± 5.27 vs. 1.79 ± 1.79, P = 0.03) methods but were not significantly higher with M30 (3.80 ± 1.74 vs. 0 ± 0, P = 0.207). Apoptotic scores using an antibody to activated caspase-3 are significantly higher in cases of chronic viral hepatitis with greater histological necroinflammatory scores, supporting a central role for apoptosis in disease pathogenesis. This method offers an alternative to routine histological assessment for measuring disease activity. [source] Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus Type-1 (HTLV-1)INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2001Julie M. Johnson Retroviruses are associated with a variety of diseases, including immunological and neurological disorders, and various forms of cancer. In humans, the Human T-cell Leukaemia/Lymphotropic virus type 1 (HTLV-1), which belongs to the Oncovirus family, is the aetiological agent of two diverse diseases: Adult T-cell leukaemia/lymphoma (ATLL) (Poiesz et al. 1980; Hinuma et al. 1981; Yoshida et al. 1982), as well as the neurological disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (Gessain et al. 1985; Rodgers-Johnson et al. 1985; Osame et al. 1986). HTLV-1 is the only human retrovirus known to be the aetiological agent of cancer. A genetically related virus, HTLV-2, has been identified and isolated (Kalyanaraman et al. 1982). However, there has been no demonstration of a definitive aetiological role for HTLV-2 in human disease to date. Simian T-cell lymphotropic viruses types 1 and 2 (STLV-1 and -2) and bovine leukaemia virus (BLV) have also been classified in same group, Oncoviridae, based upon their similarities in genetic sequence and structure to HTLV-1 and -2 (Burny et al. 1988; Dekaban et al. 1995; Slattery et al. 1999). This article will focus on HTLV-1, reviewing its discovery, molecular biology, and its role in disease pathogenesis. [source] Sex-specific association of the human PTPN22 1858T-allele with type 1 diabetesINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2007C. Nielsen Summary Type 1 diabetes (T1D) is a common organ-specific autoimmune disease of complex aetiology, involving the interaction of a large number of disease-associated genes. By comparison of a Danish population sample of 253 Caucasian children and adolescents with T1D and a control group consisted of 354 unrelated healthy blood donors, the present study provides evidence of an isolated association of the disease-associated PTPN22 1858T-allele with T1D to the female sex. Furthermore, the present data suggest that PTPN22 genotypes affect the age of onset in a sex-specific manner. The increased frequency of the risk allele and its association with age at onset in female T1D children and adolescents indicates that the genetic contribution to disease pathogenesis is more prominent in females in this population of Danish patients. [source] Detecting methylation patterns of p16, MGMT, DAPK and E-cadherin genes in multiple myeloma patientsINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 2 2010O. OZALP YUREGIR Summary Multiple myeloma (MM) is a B-cell neoplasia characterized by the clonal proliferation of plasma cells. Besides known genetic abnormalities, epigenetic changes are also known to effect MM pathogenesis. DNA methylation is an epigenetic mechanism that silences genes by adding methyl groups to cytosine-guanine dinucleotides at the promoter regions. In this study, the methylation status of four genes; p16, O6-methyl guanine DNA methyl transferase (MGMT), death-associated protein kinase (DAPK) and E-cadherin (ECAD); at the time of diagnosis was investigated using methylation-specific polymerase chain reaction (MS-PCR). In the 20 cases studied; methylation of the promoter regions of p16, MGMT, DAPK and ECAD genes was detected in 10%, 40%, 10% and 45% of the cases, respectively. In 65% (13/20) of cases, at least one of the genes studied had promoter methylation; while 35% of cases (7/20) had methylated promoters of more than one gene. There was a significant correlation between promoter hypermethylation of MGMT and the presence of extramedullary involvement; but for the other genes no correlation was found regarding disease properties like age, disease stage, clinical course and the presence of lytic bone lesions. Determining the methylation profiles of genes in MM, could lead to a new understanding of the disease pathogenesis and guide the assessment of treatment options. [source] Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitisINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2005Nurullah AKKOC Abstract HLA-B27 is the major genetic susceptibility factor for ankylosing spondylitis (AS). However, its precise role in the pathogenesis of AS still remains unclear, even though its gene has been cloned and sequenced, and its crystallographic structure has been defined. Arthritogenic peptide and molecular mimicry hypotheses propose mechanisms related to an antigen-presenting function of HLA-B27 to be responsible for disease development. However, peculiar aspects of its immunobiology, such as its misfolding and heavy chain dimerization raise the possibility of involvement of pathogenic mechanisms unrelated to its physiological function. Moreover, HLA-B27 is not a single allele, but a family of 31 different alleles, named HLA-B*2701 to HLA-B*2727. Studies worldwide indicate that the relatively common alleles (subtypes) HLA-B*2705, B*2704, and B*2702 are strongly associated with AS, whereas HLA-B*2706 which is prevalent in South-east Asia and HLA-B*2709 which is prevalent on the Italian island of Sardinia, seem to lack such an association. The distinction between the disease-associated subtypes and those that are not associated, may provide clues to the actual role of HLA-B27 in disease pathogenesis. B*2706 differs from B*2704 by only two residues, and B*2709 differs from B*2705 by only one residue. Moreover, both B*2706 and B*2709 bind an endogenous peptide (derived from vasoactive intestinal peptide type 1 receptor) and also an exogenous peptide (latent membrane protein 2 of Epstein-Barr virus) but in two drastically diverse conformations. These recent X-ray diffraction studies of individual peptides in the context of different HLA-B27 alleles broaden our perception of the possible pathogenetic role of this molecule in the development of AS and related spondyloarthopathies. In summary, the pathogenetic role of HLA-B27 in AS seem to be quite heterogenous, and cannot be explained by a single mechanism, and new ideas have been raised based on the aberrant immunobiologic features of HLA-B27. [source] The Role of c-Jun N-Terminal Kinase (JNK) in Parkinson's DiseaseIUBMB LIFE, Issue 4-5 2003Jun Peng Abstract Given the critical role that the c-Jun N-terminal kinase (JNK) pathway plays in regulating many of the cellular processes which are affected in Parkinson's disease (PD), the possible importance of JNK in disease pathogenesis is being increasingly recognized. Here we review recent findings implicating the JNK signaling pathway in animal models of Parkinson's disease and discuss the relationship between this pathway and the prominent pathological processes observed in the disease state. We suggest that regulation of the JNK signaling pathway may be a central facet in potential treatments for the disease. IUBMB Life, 55: 267-271, 2003 [source] SCN5A Mutation Associated with Cardiac Conduction Defect and Atrial ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 5 2006PÄIVI J. LAITINEN-FORSBLOM Ph.D. Introduction: We aimed at identifying the molecular defect underlying the clinical phenotype of a Finnish family with a cardiac conduction defect and atrial arrhythmias. Methods and Results: A large Finnish family was clinically evaluated (ECG, 24-hour ambulatory ECG, echocardiography). We performed linkage analysis with markers flanking the SCN5A gene and subsequently sequenced the SCN5A gene. Five family members had atrial arrhythmias and intracardiac conduction defects, and due to bradycardia needed a pacemaker when adolescents. No heart failure or sudden cardiac death was observed. Left ventricle dilatation was seen in one individual and three individuals had a slightly enlarged right ventricle. Premature death due to stroke occurred in one subject during the study, and two other members had suffered from stroke at young age. Linkage analysis favored the role of the SCN5A gene in disease pathogenesis, and direct sequencing disclosed D1275N mutation. This alteration was present not only in all six affected individuals, but also in two young individuals lacking clinical symptoms. Conclusions: Cardiac conduction defect and atrial arrhythmias in a large Finnish family appear to result from the SCN5A D1275N mutation. Although no sudden cardiac death was recorded in the family, at least three affected members had encountered brain infarction at the age of 30 or younger. [source] A, aggregation and possible implications in Alzheimer's disease pathogenesisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009Prashant R. Bharadwaj ,,Introduction ,,Amyloid Structure ,,Mechanism of Amyloid aggregation ,,A,: a natively unfolded protein? ,,Ambiguities in synthetic Ab studies ,,Formation of Amyloid plaques ,,Role of Ab in AD Pathogenesis ,,Conclusion Abstract Amyloid , protein (A,) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased A, levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of A, clearance from the brain, unlike familial AD which shows increased A, production. A, aggregation leading to deposition is an essential event in AD. However, the factors involved in A, aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect A, aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized A,. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to A, toxicity. An understanding of A, oligomerization may lead to better strategies to prevent AD. [source] Mucosal tissue transglutaminase expression in celiac diseaseJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2009Vincenzo Villanacci Abstract Tissue transglutaminase (tTG) plays an important role in celiac disease pathogenesis and antibodies to tTG are a diagnostic marker of gluten-sensitive enteropathy. The aim of this study was to investigate the localization of tTG in the duodenal mucosa in control tissues and in different histological stages of celiac disease by using a commercial and a novel set of anti-tTG monoclonal antibodies, to see whether this assessment can be useful for diagnostic purpose. The distribution of tTG was firstly evaluated in 18 untreated celiac patients by using a commercial monoclonal antibody (CUB7402) against tissue transglutaminase enzyme and directed against the loop-core region of the enzyme. Thereafter, in further 30 untreated celiac patients we employed three newly characterized anti-tTG monoclonal antibodies produced against recombinant human-tTG. The epitopes recognized are located in three distinct domains of the protein corresponding to the core, C1 and C2 protein structure. Eleven age- and sex-matched patients with chronic duodenitis acted as controls. All subjects underwent upper endoscopy to obtain biopsy samples from the duodenum. Overall, we found that (i) tTG is equally expressed in CD at different stages of disease; (ii) tTG is expressed, at similar level, in CD and controls with duodenitis. Assessment of tTG level in biopsy samples by immunohistochemical methods is not useful in the clinical diagnostic work-up of CD. [source] African hair length in a school population: a clue to disease pathogenesis?JOURNAL OF COSMETIC DERMATOLOGY, Issue 3 2007FCDerm, N P Khumalo MBChB Summary Background, Anecdotal data suggest that combed natural African hair reaches a length steady state. Easier grooming and anticipated long hair have made relaxers popular. Objectives, These hypotheses were tested in a cross-sectional survey of 1042 school children using a piloted questionnaire and hair length measurements done on four scalp regions. Results, Participants included 45% boys and 55% girls. Girls consider length important for hairstyle choice (P < 0.0001). There was no difference in mean length at 2 to 5 vs. > 5 years (P = 0.3) and at 1 to < 2 vs. 2 to 5 years (P = 0.99), suggesting that a steady state is reached within 1 year after a hair cut for combed natural hair [mean, 5.1 cm (4.3)]. Relaxed hair reached length steady state > 2 years after a haircut [mean, 10.9 cm (3.6)], was longer than natural hair (P < 0.0001), shorter than expected, and significantly shorter on the occiput than the rest of the scalp (P < 0.0001). Conclusions, Persistently short combed natural hair years after a hair cut suggests that breakage eventually equals new growth (i.e., steady state), which is likely to be variable. Relaxed hair, irrespective of last haircut, is also short; chemical damage as a limit to potential lengths needs confirmation. Relatively short occipital relaxed hair could be a clue to disease pathogenesis. [source] Inflammatory bowel disease pathogenesis: therapeutic implicationsJOURNAL OF DIGESTIVE DISEASES, Issue 1 2005Claudio FIOCCHI The pathogenesis of inflammatory bowel disease (IBD) is complex, involving environmental, genetic, microbial, and immune factors. Therefore, treatment should target components that either predispose to or mediate the chronic inflammatory response of IBD. At the moment it is assumed that all components are necessary to have the typical manifestations of IBD but, in reality, it is unclear to what extent each factor contributes to the disease process, and whether some are more important than others. In addition, some factors are not practical targets; for example, environmental factors are poorly defined, too numerous, and require changes that cannot be implemented by the physician or the patient alone. The same is true for genetic factors that are still not amenable to therapeutic manipulations for technical and ethical reasons. This leaves microbial and immune factors as the two categories that can be selected for therapeutic intervention and where all current treatments are focused. The commensal gut flora can be qualitatively or quantitatively modified with antibiotics, probiotics, or diet, and a better characterization of enteric bacteria strains should help greatly in developing more effective therapies. Most current drugs are focused on inhibiting pro-inflammatory molecules produced by immune cells, including biological agents that block specific cytokines such as tumor necrosis factor-alpha. It is anticipated that combination therapies targeting multiple pathogenic components will prove more effective than those blocking single components of IBD pathogenesis. [source] Proteomic identification of biomarkers related to Helicobacter pylori -associated gastroduodenal disease: Challenges and opportunitiesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2008Ming-Shiang Wu Abstract Helicobacter pylori colonize the stomach of over half the world's population. While 80,90% H. pylori -infected individuals have clinically asymptomatic gastritis, 10,15% develop peptic ulcer, and 1,2% gastric malignancies. These variable clinical outcomes have led to an interest in prognostic indicators. The current disease paradigm suggests that host genetics and bacterial virulence both play important roles in modulating the final outcome of H. pylori infection. Elucidation of the interaction between host and bacterium is essential to clarify pathogenesis and to develop new strategies for prevention and treatment. Proteomic technology is a powerful tool for simultaneously monitoring proteins and protein variation on a large scale in biological samples. It has provided an unprecedented opportunity to survey a cell's translational landscape comprehensively, and the results may allow in-depth analyses of host and pathogen interactions. Using this high-throughput platform and taking advantage of complete sequences for both the H. pylori and the human genome in available databases, we have identified several crucial proteins that have pathogenic and prognostic potential. Among them, antibodies to AhpC and GroEs of H. pylori could be utilized for identification of patients who are at high risk of disease complications after H. pylori infection. Evolving proteomic technologies, together with appropriate clinical phenotyping and genotype information should enhance understanding of disease pathogenesis and lead to more precise prediction of variable disease outcomes. It will also facilitate development of biomarkers for diagnosis, treatment, and prevention of H. pylori infection. [source] | ||||||||||||||||||||||||||||||||||||||||||||||