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PubMed1999

The role of muscle weakness in the pathogenesis of osteoarthritis.

To date, very few studies have investigated the role of muscle dysfunction in the pathogenesis of osteoarthritis (OA). Using largely indirect evidence, this article hypothesizes that motor and sensory dysfunction of muscle may be important factors in the pathogenesis of articular damage and are not simply a consequence of joint damage. A new paradigm is constructed to better describe the complex interrelationship between muscle sensorimotor dysfunction, joint damage, and disability in OA. If the hypothesis is correct, because muscle is a relatively plastic tissue, maintaining well-conditioned muscles may delay or prevent the onset of OA, and rehabilitation exercise therapy that reverses muscle sensorimotor dysfunction may ameliorate the effects of OA.

Humans↗
PubMed2003

Pathogenesis of Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a disease characterized by proliferative vascular lesions, which almost invariably contain the KS-associated herpesvirus (KSHV), also called human herpesvirus 8. KSHV is a lymphotrophic and angiotrophic herpesvirus, whose genome encodes several proteins involved in proliferation, antiapoptotic functions, and inflammation. Most KS spindle cells express latent KSHV genes, but a few express lytic genes, which might be involved in angiogenic and paracrine mechanisms that contribute to KS pathogenesis. A number of tissue culture and mouse models have been established, but a comprehensive system that accurately portrays KS pathogenesis still does not exist.

Animals↗
PubMed1996

AIDS-related Kaposi's sarcoma. A template for the translation of molecular pathogenesis into targeted therapeutic approaches.

AIDS-related Kaposi's sarcoma (KS) represents a complex interaction of host and viral factors. There are a number of fundamental questions surrounding the interplay between the disparate factors that can contribute to the pathogenesis and pathophysiology of this disease. Targets such as the enhancement of immune function, inhibition of angiogenic factors or immunostimulatory cytokines, inhibition of viral proteins such as Tat, or hormonal manipulations are now or will in the future become the focus of research to develop innovative anti-KS therapy and prevention measures. Antiviral approaches aimed at HIV or other viruses may potentially target a number of steps in KS pathogenesis. This article reviews diverse modalities--cytotoxic, antiviral, gene-directed, growth factor-targeted, and antiangiogenesis--that singly, or more likely in combination, stand to make an impact on the cure and prevention of AIDS-related KS.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease.

Prior to the identification of the various abnormal proteins deposited as fibrillar aggregates in the Alzheimer's disease (AD) brain, there was tremendous controversy over the importance of the various lesions with respect to primacy in the pathology of AD. Nevertheless, based on analogy to systemic amyloidosis, many investigators believed that the amyloid deposits in AD played a causal role and that characterization of these deposits would hold the key to understanding this complex disease. Indeed, in retrospect, it was the initial biochemical purifications of the approximately 4 kDa amyloid beta-peptide (Abeta) from amyloid deposits in the mid 1980s that launched a new era of AD research (Glenner and Wong, Biochem. Biophys. Res. Commun. 122 (1984) 1121-1135; Wong et al., Proc. Natl. Acad Sci. USA 82 (1985) 8729 8732; and Masters et al., Proc. Natl. Acad Sci. USA 82 (1985) 4245-4249). Subsequent studies of the biology of Abeta together with genetic studies of AD have all supported the hypothesis that altered Abeta metabolism leading to aggregation plays a causal role in AD. Although there remains controversy as to whether Abeta deposited as classic amyloid or a smaller, aggregated, form causes AD, the relevance of studying the amyloid deposits has certainly been proven. Despite the significant advances in our understanding of the role of Abeta in AD pathogenesis, many important aspects of Abeta biology remain a mystery. This review will highlight those aspects of Abeta biology that have led to our increased understanding of the pathogenesis of AD as well as areas which warrant additional study.

Alzheimer Disease↗
PubMed2002

Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson's disease.

Aluminum and zinc have been related to the pathogenesis of Parkinson's disease (PD), the former for its neurotoxicity and the latter for its apparent antioxidant properties. 6-Hydroxydopamine (6-OHDA) is an important neurotoxin putatively involved in the pathogenesis of PD, its neurotoxicity often being related to oxidative stress. The potential effect of these metals on the oxidative stress induced by 6-OHDA autoxidation and the potential of ascorbic acid (AA), cysteine, and glutathione to modify this effect were investigated. Both metals, particularly Al3+, induced a significant reduction in *OH production by 6-OHDA autoxidation. The combined action of AA and a metal caused a significant and sustained increase in *OH generation, particularly with Al3+, while the effect of sulfhydryl reductants was limited to only the first few minutes of the reaction. However, both Al3+ and Zn2+ provoked a decrease in the lipid peroxidation induced by 6-OHDA autoxidation using mitochondrial preparations from rat brain, assessed by TBARS formation. In the presence of AA, only Al3+ induced a significant reduction in lipid peroxidation. After intrastriatal injections of 6-OHDA in rats, tyrosine hydroxylase immunohistochemistry revealed that Al3+ reduces 6-OHDA-induced dopaminergic lesion in the striatum, which corroborates the involvement of lipid peroxidation in 6-OHDA neurotoxicity and appears to discard the participation of this mechanism on PD by Al3+ accumulation. The previously reported antioxidant properties of Zn2+ appear to be related to the induction of Zn2+-containing proteins and not to the metal per se.

Adrenergic Agents↗
PubMed1997

Does oxidative protein damage play a role in the pathogenesis of carbon tetrachloride-induced liver injury in the rat?

Free radicals have been implicated in the pathogenesis of alcohol-induced liver injury in humans and carbon tetrachloride (CCl4)-induced liver injury in rats. The most extensively studied aspect of free radical induced liver injury is lipid peroxidation. Recently it has been found that free radicals can cause oxidative damage to cellular proteins and alter cellular function. One such susceptible protein is the enzyme glutamine synthase (GS). The chemical effects of CCl4 on cell proteins and their biological consequences are not known. Hence, in our study, the effect of CCl4 on liver protein oxidation and GS activity were investigated and compared with lipid peroxidation. A significant increase in liver protein carbonyl content (2-3 fold) and a significant decrease in hepatic GS activity (44-57%) were observed. Damage to proteins was rapid in onset and increased with time. Acute exposure of rats to CCl4 resulted in an increase in hepatic protein carbonyl content and a decrease in hepatic GS within 1 h. In cirrhosis of the liver induced by CCl4, the decrease in hepatic GS activity was accompanied by a significant increase in plasma ammonia levels. We conclude that protein oxidation may play a role in the pathogenesis of CCl4 induced liver injury and that the accumulation of oxidised proteins may be an early indication of CCl4 induced liver damage.

Acute Disease↗
PubMedDate not supplied

The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: inflammatory mediators and endogenous cholecystokinin.

This study was aimed at an assessment of the role of oxygen-derived free radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and CCK, and evaluated the protective effect of the xanthine oxidase inhibitor allopurinol and a novel CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar rats by injecting 2x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. 200 mg x kg(-1) allopurinol 30 min before the first Arg treatment or 50 mg x kg(-1) KSG-504 30 min before and 6, 18 and 36 h after the first Arg injection was administered subcutaneously. Rats were killed at 6, 12, 24 and 48 h following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 h after the Arg injection (30,800 +/- 3,813 versus 6,382 +/- 184 U x L(-1) in the control) and normalized at 48 h. The tissue concentration of MDA was significantly elevated at 24 h, and reached the peak value at 48 h (5.00 +/- 1.75 versus 0.28 +/- 0.05 nM x mg(-1) protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was significantly lower at 12 h after the Arg injection as compared with the controls. Both the TNF-alpha and the IL-6 levels were already elevated significantly at 12 h and peak at 24 h versus the controls (19.1 +/- 7.9 U x mL(-1) and 57.6 +/- 11.2 pg x mL(-1) versus 3.1 +/- 0.8 U x mL(-1) and 15.2 +/- 3.1 pg x mL(-1), respectively). No significant changes in plasma CCK levels were observed. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 +/- 2.257 U x L(-1) at 24 h), prevented the increase in tissue MDA concentration (0.55 +/- 0.09 nM x mg(-1) protein at 48 h) and significantly ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg administration. KSG-504 administration did not exert any beneficial effect on the development of histopathological changes neither modified the serum amylase or cytokine levels. Oxygen-derived free radicals and cytokines are involved, while endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced acute pancreatitis.

Allopurinol↗
PubMed2004

Simple sequence repeats (microsatellites): mutational mechanisms and contributions to bacterial pathogenesis. A meeting review.

This review summarises the presentations and discussions that took place during a European Science Foundation-funded workshop whose purpose was to gain current perspectives on the mutational mechanisms of simple sequence repeats and the contribution of localised hypermutation in such repeats to bacterial pathogenesis. In vitro biophysical and biochemical assays of mutational mechanisms were covered as well as genetic studies in various eukaryotic and prokaryotic organisms. Presentations on bacterial pathogenesis elaborated investigations of the use of repeats for typing of strains, epidemiological investigations of mutation rates and functions of loci whose expression is controlled by simple sequence repeats. This review tabulates current perspectives on the cis- and trans-acting factors for mutation of simple sequence repeats and the orientations of mononucleotide repeats in some bacterial species that utilise repeats for adaptation.

Bacteria↗
PubMed1993

Induction of the release of prostaglandin E2 from polymorphonuclear neutrophil granulocytes by Bacteroides fragilis: its possible role in the pathogenesis of mixed infections.

The presence of anaerobic bacteria, especially of Bacteroides (B.) fragilis, in abdominal abscesses, infected decubitus ulcera, and the infected foot of diabetic patients is well documented. The importance, however, of these microorganisms in the pathogenesis of deep tissue infections has still to be evaluated. Therefore, the aim of this study was to evaluate the potency of B. fragilis as compared to aerobic bacteria widely known for causing inflammation, in inducing the release of prostaglandin E2 from polymorphonuclear granulocytes. Prostaglandin E2 is a potent vasodilator and contributes to edema and erythema, which are part of the inflammatory response. Furthermore, the cAMP-content of the neutrophils was determined after stimulation of the cells with the various bacteria. Of the bacterial species tested, B. fragilis proved to be one of the most potent triggers for prostaglandin E2 release from neutrophils indicating a possible major role of this microorganism in the pathogenesis of mixed infections.

Adult↗
PubMed1990

Hypothesis on the pathogenesis of post-streptococcal glomerulonephritis based on recent clinical and experimental research.

The current theories on the pathogenesis of post streptococcal glomerulonephritis are reviewed. Clinical findings during the last decades have indicated the involvement of an immune mechanism. However, the lack of adequate animal models has hampered a thorough understanding of the development of the disease from the initiating infection to the final glomerulonephritic sequelae. Several facts point to the presence of a special nephritogenic streptococcal factor which is directly or indirectly involved in the pathogenesis. There seems to be a plasminogen activator (PA) with unique properties. Data on animals experiments using streptococci producing this factor as well as on injections of the pure substance are presented and correlated to the finding in post streptococcal glomerulonephritis in man.

Animals↗
PubMed1993

The role of hemolysin(s) in the pathogenesis of Serpulina hyodysenteriae.

Serpulina (Treponema) hyodysenteriae, an anaerobic beta hemolytic spirochaete, is the etiologic agent of swine dysentery. Not much is known at present about the virulence factors of S. hyodysenteriae. However, the hemolysin production of this bacterium is generally accepted to be a virulence factor. To study the exact role of hemolysin production in the pathogenesis of swine dysentery, the gene encoding a hemolysin, tly, was cloned and its nucleotide sequence determined. After inactivation of this gene, the virulence of a tly-minus mutant in mice was tested. The mutant had reduced hemolysis indicating that the tly-encoded hemolysin was not the only hemolysin produced by S. hyodysenteriae. Mice infected with the tly-minus mutant had fewer cecal lesions than mice infected with the wild-type S. hyodysenteriae. It was concluded that the tly-encoded hemolysin might be an important virulence factor, but not the only one. Since it was demonstrated that spirochaetes can be transformed through electroporation, this has made a genetic approach to elucidate the pathogenesis of spirochaetal infections possible.

Animals↗
PubMed1997

The aetiology and pathogenesis of prostate cancer.

The incidence of prostate cancer is increasing, particularly in western countries, but, despite this, its aetiology and pathogenesis remain unclear. Epidemiological studies have suggested a range of possible aetiological factors (e.g. high saturated fat intake, low intake of carotenoids, vasectomy and other sexual factors, high serum androgen levels, and a family history of prostate cancer), although results have been contradictory in many cases. A review of the literature suggests that there may be differences in the importance of these factors in younger (< 60 years) and older patients. In particular, there is growing evidence for the existence of an hereditary form of prostate cancer, with an early age of onset, an independence for dietary and other environmental factors, and an aggressive natural history. There is also increasing evidence to suggest that the pathogenesis of the disease in Japan, with its markedly different incidence rates for clinical disease (as opposed to 'latent' or 'histological' disease), may be different to that in North America. The evidence for a 'two-disease' theory of prostate carcinogenesis is discussed.

Androgens↗
PubMed1995

Role of neutrophils and platelets in the pathogenesis of focal hepatocellular necrosis in endotoxaemia.

To clarify whether neutrophils and platelets are implicated in the pathogenesis of focal hepatocellular necrosis in endotoxaemia, we examined the relationship between the changes in neutrophils and platelets in peripheral blood and the degree of focal hepatocellular necrosis and serum transaminase activity in rats after endotoxin injection. The number of neutrophils in the peripheral blood decreased rapidly during the first hour after endotoxin injection and then increased. This initial decrease might be caused by the adhesion of neutrophils to pulmonary capillary walls, and the subsequent increase might be caused by granulocyte colony-stimulating factor mediated by endotoxin. However, there was no relationship between the degree of focal hepatocellular necrosis and the number of neutrophils sticking to the walls of hepatic sinusoids or the changes in the neutrophil count in the peripheral blood. The number of platelets in the peripheral blood decreased rapidly after endotoxin injection. There was a statistically significant relationship between the number of platelets in the peripheral blood and the level of serum transaminase activity: the fewer the platelets, the more severe was focal hepatocellular necrosis. The present study suggests that rapid and extensive consumption of platelets, rather than neutrophils sticking to the sinusoidal walls, is involved in the pathogenesis of focal hepatocellular necrosis in endotoxaemia.

Animals↗
PubMed1995

Pathogenesis of insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus is strongly associated with certain HLA types and the presence of islet cell-specific autoantibodies. The pathogenesis is a specific loss of pancreatic beta cells. The dissection of IDDM genes is complicated by the low recurrence rate of the disease among first-degree relatives. HLA-DQ2 and 8 are closest to IDDM with a marked synergistic effect of DQ2/8 heterozygotes. The associations with other HLA genes are often explained by linkage disequilibrium. Genetic factors on other chromosomes which influence the pathogenesis are still to be fully identified but candidates are on chromosomes 11 (insulin gene polymorphisms) and 7 (TCR gene polymorphisms). The autoreactivity against the GAD65 isoform is pronounced both before and at the clinical onset of IDDM. GAD65 autoantibodies show the highest predictive value and may represent an initiating autoantigen. Autoantibodies to numerous other beta cell autoantigens are detected at the clinical onset but may represent a secondary response and antigen spreading during a sustained autoimmune attack on the beta cells. The role of T cells in human IDDM is yet to be defined. GAD65 and other islet autoantibodies have a low positive predictive value for IDDM and further investigations are needed to clarify ways to predict IDDM in the general population.

Animals↗
PubMedDate not supplied

Molecular pathogenesis of pancreatic ductal adenocarcinoma and clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer death worldwide. PDAC is also one of the best-studied cancers with regard to molecular pathogenesis. The chief risk factors associated with PDAC are smoking and pancreatitis, in addition genetic predisposition seems to play a major role. This genetic predisposition may in some cases be indirect, for example via the elevated risk of pancreatitis seen in patients with hereditary pancreatitis (HP). The elucidation of the molecular causes of PDAC has enabled the provision of secondary screening for PDAC in conditions such as HP. This review is concerned with the molecular pathogenesis of PDAC and the application of this basic scientific understanding into state-of-the-art clinical practice.

Carcinoma, Pancreatic Ductal↗
PubMed1995

The relevance of apoptosis to AIDS pathogenesis.

Several recent experimental findings support the hypothesis that apoptosis induced by human immune deficiency virus (HIV) is important in the pathogenesis of acquired immune deficiency syndrome (AIDS). Thus, one potential therapeutic strategy against AIDS may be to block the HIV-mediated apoptosis signal transduction pathway. Induction of apoptosis by HIV infection may prove a useful paradigm for the pathogenesis of a wide range of diseases that involve cell depletion and tissue atrophy.

Journal Article↗
PubMed2001

Is immune cell activation the missing link in the pathogenesis of post-diarrhoeal HUS?

Haemolytic uraemic syndrome (HUS), which is caused by Shiga toxin (Stx)-producing Escherichia coli, is the commonest cause of acute renal failure in childhood. It is widely believed that HUS develops following the release of Stx, an AB5 toxin that inhibits protein synthesis and has a direct toxic effect on the kidney endothelium. There remains, however, a mismatch between the current understanding of the pathogenesis of HUS and the evolution of the clinical signs of the disease. Our hypothesis is that Stx-mediated immune cell activation in the gut is the missing link in the pathogenesis of this condition, initiating the characteristic renal pathology of HUS either alone or in synergy with Stx. Validation of this hypothesis could lead to a targeted anti-inflammatory approach aimed at modulating immune cell function in HUS.

Diarrhea↗
PubMed2003

The cellular paradigm of chlamydial pathogenesis.

Diseases caused by Chlamydia are based on intense and chronic inflammation elicited and maintained by reinfection or persistent infection. The traditional view in the field is that disease is mediated by antigen-dependent delayed-type hypersensitivity or autoimmunity. This immunological paradigm has served as the basis for years of chlamydial research but the mechanism or the antigen that causes pathology has yet to be unequivocally revealed. Recent research on responses elicited in Chlamydia-infected cells defines a new direction for our understanding of this microorganism-host interaction and provides the basis for a reassessment of disease mechanisms. Chlamydia-infected non-immune mammalian cells produce proinflammatory chemokines, cytokines, growth factors and other cellular modulators. This cellular response to infection supports an alternative hypothesis for chlamydial pathogenesis: the inflammatory processes of chlamydial pathogenesis are elicited by infected host cells and are necessary and sufficient to account for chronic and intense inflammation and the promotion of cellular proliferation, tissue remodeling and scarring, the ultimate cause of disease sequelae.

Autoimmunity↗