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At least 973 records · Page 54Linked to original sources
PubMed2002

A Yersinia effector and a Pseudomonas avirulence protein define a family of cysteine proteases functioning in bacterial pathogenesis.

A Yersinia effector known as YopT and a Pseudomonas avirulence protein known as AvrPphB define a family of 19 proteins involved in bacterial pathogenesis. We show that both YopT and AvrPphB are cysteine proteases, and their proteolytic activities are dependent upon the invariant C/H/D residues conserved in the entire YopT family. YopT cleaves the posttranslationally modified Rho GTPases near their carboxyl termini, releasing them from the membrane. This leads to the disruption of actin cytoskeleton in host cells. The proteolytic activity of AvrPphB is essential for autoproteolytic cleavage of an AvrPphB precursor as well as for eliciting the hypersensitive response in plants. These findings provide new insights into mechanisms of animal and plant pathogenesis.

Actin Cytoskeleton↗
PubMed2001

Type 1 diabetes: new perspectives on disease pathogenesis and treatment.

As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic complexity of this disease and the challenges associated with its treatment. Many new concepts about the pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate. Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

Adult↗
PubMed2006

HIV/AIDS epidemiology, pathogenesis, prevention, and treatment.

The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most affected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1.

Adolescent↗
PubMed1977

Intrathymic pathogenesis and dual genetic control of myasthenia gravis.

We propose a two-step model for the pathogenesis of myasthenia gravis. In the first step, primitive intrathymic stem-cells are induced by abnormal stimuli to differentiate to (abnormal?) myogenic cells. In the second step, immunocompetent T lymphocytes start an autoimmune reaction against these newly differentiated myogenic cells. The clinical stage is reached when autosensitised effector T lymphocytes leave the thymus and either infiltrate the synaptic spaces of peripheral muscles or participate in the formation of autoantibodies, causing the neuromuscular symptoms. At two points the pathogenesis is under genetic control--the first at the differentiation of the stem-cells to myogenic cells and the second at the immune responsiveness of the lymphocytes to these atypical intrathymic muscle cells.

Animals↗
PubMed1978

Possible role for impaired renal prostaglandin production in pathogenesis of hyporeninaemic hypoaldosteronism.

A 57-year-old woman with hypertension and moderate renal insufficiency had chronic unexplained hyperkalaemia. Metabolic balance studies confirmed a diagnosis of hyporeninaemic hypoaldosteronism. Two observations suggested that impaired renal prostaglandin production contributed to the pathogenesis of the patient's disorder. Baseline renal-prostaglandin synthesis (as determined by urinary excretion of P.G.E and P.G.F) was was substantially depressed when compared with that in nine normal females. Infusion of low doses of P.G.A1 produced a significant increase in serum-aldosterone and urinary potassium excretion; it also led to a dramatic fall in blood-pressure and serum-potassium. It appears from these studies that a defect in renal prostaglandin synthesis has an important role in the pathogenesis of hyporeninaemic hypoaldosteronism.

Adrenal Insufficiency↗
PubMed1989

Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease.

To investigate the pathogenesis of Kawasaki disease, the effects of intravenous gammaglobulin treatment on circulating cytotoxic antibodies against endothelial cells, in-situ endothelial cell activation, and cytokine production and action were examined. Gammaglobulin treatment did not reduce cytotoxic antibody activity against endothelial cells in six patients tested. Expression of endothelial cell activation antigens (endothelial-leucocyte adhesion molecule-1 [ELAM-1] and intercellular adhesion molecule-1) was detected by means of immunoperoxidase staining in skin biopsy samples from five patients before treatment. Samples were obtained immediately after treatment from six patients; there was no endothelial cell activation in four and the two with persistent activation had persistent fever and mucocutaneous symptoms. Peripheral blood mononuclear cells from ten of sixteen acute Kawasaki disease patients spontaneously secreted high levels of interleukin-1 (IL-1). IL-1 secretion remained high in four gammaglobulin-treated patients in whom coronary artery abnormalities developed but fell to normal in six treated patients who had no coronary artery abnormalities. In cell culture, gamma globulin did not inhibit endothelial cell expression of ELAM-1 in response to IL-1 or tumour necrosis factor. The association between improvement of clinical symptoms and the reduction of cytokine secretion and reversal of endothelial cell activation supports a role for immune-mediated injury to cytokine-induced endothelial cell antigens in the pathogenesis of this disorder.

Antigens, Surface↗
PubMed1996

Role of gamma delta T cells in pathogenesis and diagnosis of Behcet's disease.

BACKGROUND: Behcet's disease (BD) is a multisystem disorder of unknown pathogenesis. The diagnosis is based on a set of international clinical criteria. Previous investigations have suggested that immunological cross-reactivity between peptides within streptococcal heat-shock proteins and human peptides might be involved in the pathogenesis of BD. We tested four peptides from mycobacterial heat-shock proteins to see if they specifically stimulated gamma delta T cells from BD patients. We then investigated this response to see whether it could be used as a laboratory test to diagnose BD. METHODS: We used a T-cell proliferative test to assay responses to four mycobacterial 65 kDa heat-shock-protein peptides and to four homologous peptides derived from the sequence of the human 60 kDa heat-shock protein. FINDINGS: We elicited significant gamma delta T-cell responses to the mycobacterial peptides in 25 (76%) of 33 patients with BD, compared with 2 (3.6%) of 55 controls with recurrent oral ulcers, systemic disease, or no disorders. The proportion of BD patients who had false-negative results decreased if the test was done during clinical manifestation of disease activity. There was a correlation between disease activity and T-cell responses. Four homologous peptides from human 60 kDa heat-shock protein also specifically stimulated T cells from patients with BD but with lower stimulation indices. INTERPRETATION: Activation of peripheral-blood mononuclear cells with the four heat-shock-protein peptides elicited significant T-cell proliferative responses by the gamma delta subset of T cells, which may regulate alpha beta T cells. Because these peptides have a high specificity for BD, this assay can be used as a laboratory diagnostic test for BD.

Adult↗
PubMed1999

Recent advances in understanding the pathogenesis of Huntington's disease.

Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder that is characterized by abnormal involuntary movements (chorea), intellectual impairment and selective neuronal loss. The expansion of a polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a length that exceeds 40 repeat units in exon 1 of the gene, HD, correlates with the onset and progression of the disease. The protein encoded by HD, huntingtin, is normally localized in the cytoplasm, whereas the mutant protein is also found in the nucleus, suggesting that its translocation to this site is important for the pathogenesis of HD. Although several proteins that interact with huntingtin have been identified in vitro, the significance of these interactions with the mutant protein in the pathogenesis of HD has yet to be determined. Recent progress in the development of cellular and animal models for the disease have provided invaluable insights and resources for studying the disease mechanisms underlying HD, and will be useful for screening and evaluating possible therapeutic strategies.

Animals↗
PubMed2000

Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations.

Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes simplex virus (HSV) is limited, especially with regard to reactivation and recurrent disease. To further explore the pathogenesis of ACV-resistant HSV-2 viruses, we used the guinea pig model of genital HSV-2 infection to evaluate several ACV-resistant isolates of both thymidine kinase (Tk)-altered and Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-purified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that produced the most severe primary disease and most recurrences, one Tk-deficient virus and one Tk-altered virus, were further evaluated and shown to produce acute and recurrent genital disease similar to that seen with wild-type viruses. Furthermore, the reactivated virus producing recurrent lesions could be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replication following vaginal inoculation with these two ACV-resistant strains. Using the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more common than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HSV strains.

Acyclovir↗
PubMed2001

Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice.

Intranasal infection of BALB/c mice with the WR strain of vaccinia virus leads to pneumonia, profound weight loss, and death. Although the major sites of virus replication are in the lungs and nasal tissue, dissemination of the virus to other visceral organs and brain occurs via the blood. In this report the effects of cidofovir on the pathogenesis of the infection was studied. Mice were infected intranasally with virus followed 1 day later by a single intraperitoneal treatment with cidofovir (100 mg/kg) or placebo. Placebo-treated mice were dead by day 8, whereas all cidofovir-treated animals survived through 21 days. Cidofovir treatment did not prevent profound weight loss from occurring during the acute phase of the infection, but the mice gained weight quickly after the 8th day. Significantly higher arterial oxygen saturation levels, as determined by pulse oximetry, were seen in cidofovir-treated animals compared to placebos on days 4-7. Cidofovir treatment markedly improved lung consolidation scores and prevented lung weights from increasing during the infection. Virus titers in lungs and nasal tissue were high starting from the first day of the infection, whereas the titers in liver, spleen, brain, and blood was low for 3 days then markedly rose between days 4 and 6. Lung and nasal virus titers were reduced 10-30-fold by cidofovir treatment on days 2, 4 and 6. Virus titers in the other tissues and blood at their peak (day 6) were 30- to >1000-fold less than in tissues of placebos. These results illustrate the ability of a single cidofovir treatment to control the pathogenesis of an acute lethal infection in various tissues during the vaccinia virus infection in mice.

Administration, Intranasal↗
PubMed1998

Pathology and pathogenesis of Buerger's disease.

Since Buerger's disease, which is also called 'thromboangiitis obliterans', was proposed in 1908 (Buerger, Am J Med Soc 1908;136:567), more cases have been reported from the United States, Europe, and especially from the Orient. However the pathogenesis of this disease remains unclarified, and its acceptance as a specific disease entity has been disputed (Gore and Burrows, Am J Clin Pathol 1958;29:319; Wessler et al., N Engl J Med 1960;262:1149). We histologically examined the surgically resected arterial specimens from 113 cases, 109 males and four females, clinically diagnosed as Buerger's disease in 1975-1976 and reported the results in 1978 (Kurozumi and Tanaka, Vasc Surg 1978;12:63) and proposed that the term 'Buerger's disease' should be replaced by 'Buerger's syndrome'. We reexamined the above-mentioned cases and will report the pathology and propose the possible pathogenesis of Buerger's disease.

Adult↗
PubMed2003

Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis.

Bacteria inhabit an impressive variety of ecological niches and must adapt constantly to changing environmental conditions. While numerous environmental signals have been examined for their effect on bacteria, the effects of mechanical forces such as shear stress and gravity have only been investigated to a limited extent. However, several important studies have demonstrated a key role for the environmental signals of low shear and/or microgravity in the regulation of bacterial gene expression, physiology, and pathogenesis [Chem. Rec. 1 (2001) 333; Appl. Microbiol. Biotechnol. 54 (2000) 33; Appl. Environ. Microbiol. 63 (1997) 4090; J. Ind. Microbiol. 18 (1997) 22; Curr. Microbiol. 34(4) (1997) 199; Appl. Microbiol. Biotechnol. 56(3-4) (2001) 384; Infect Immun. 68(6) (2000) 3147; Cell 109(7) (2002) 913; Appl. Environ. Microbiol. 68(11) (2002) 5408; Proc. Natl. Acad. Sci. U. S. A. 99(21) (2002) 13807]. The response of bacteria to these environmental signals, which are similar to those encountered during prokaryotic life cycles, may provide insight into bacterial adaptations to physiologically relevant conditions. This review focuses on the current and potential future research trends aimed at understanding the effect of the mechanical forces of low shear and microgravity analogues on different bacterial parameters. In addition, this review also discusses the use of microgravity technology to generate physiologically relevant human tissue models for research in bacterial pathogenesis.

Bacteria↗
PubMed2003

Emerging themes in manganese transport, biochemistry and pathogenesis in bacteria.

Though an essential trace element, manganese is generally accorded little importance in biology other than as a cofactor for some free radical detoxifying enzymes and in the photosynthetic photosystem II. Only a handful of other Mn2+-dependent enzymes are known. Recent data, primarily in bacteria, suggest that Mn2+-dependent processes may have significantly greater physiological importance. Two major classes of prokaryotic Mn2+ uptake systems have now been described, one homologous to eukaryotic Nramp transporters and one a member of the ABC-type ATPase superfamily. Each is highly selective for Mn2+ over Fe2+ or other transition metal divalent cations, and each can accumulate millimolar amounts of intracellular Mn2+ even when environmental Mn2+ is scarce. In Salmonella enterica serovar Typhimurium, simultaneous mutation of both types of transporter results in avirulence, implying that one or more Mn2+-dependent enzymes is essential for pathogenesis. This review summarizes current literature on Mn2+ transport, primarily in the Bacteria but with relevant comparisons to the Archaea and Eukaryota. Mn2+-dependent enzymes are then discussed along with some speculations as to their role(s) in cellular physiology, again primarily in Bacteria. It is of particular interest that most of the enzymes which interconvert phosphoglycerate, pyruvate, and oxaloacetate intermediates are either strictly Mn2+-dependent or highly stimulated by Mn2+. This suggests that Mn2+ may play an important role in central carbon metabolism. Further studies will be required, however, to determine whether these or other actions of Mn2+ within the cell are the relevant factors in pathogenesis.

Bacteria↗
PubMed2000

Hepatitis B infection: pathogenesis and management.

Although hepatitis B is an ancient disease, most of the advances in our knowledge of its epidemiology, prevention, pathogenesis, natural history and treatment were made in the last 30 years. The prospect of global eradication of HBV infection within the next 50 years is technologically possible but implementation of worldwide vaccination against hepatitis B will require significantly more time to overcome the social and economic hurdles. While there is reasonable optimism that HBV infection will be eradicated, there are currently 300 million HBV carriers worldwide who are at risk of dying from liver failure or hepatocellular carcinoma, and there will continue to be new cases of HBV infection for many more years. Thus, HBV infection cannot be considered to be a health problem of the past. The focus of hepatitis B research at the turn of the millenium will be the development of more effective therapies that can be applied to all patients with chronic HBV infection. These treatments need to be effective in inhibiting HBV DNA synthesis and in eliminating ccc DNA. They may involve monotherapy with more potent antiviral agents that do not induce resistance, but are more likely to require a combination of antiviral agents or antiviral and immunomodulatory agents. These treatments must be safe, convenient to administer, and affordable. It is likely that new therapies with increasing efficacy will be available in the next one to two decades and combination therapy will be used widely by 2010. These treatments will induce sustained remission in the majority of patients who can afford them but provision of treatment to all those who need them will be more difficult. Other areas of hepatitis B that need to be addressed are the prevalence of occult HBV infection, the changing epidemiology and clinical significance of HBV variants, in particular the A1896 mutant, and the mechanisms of immune clearance and pathogenesis.

Antibody Formation↗
PubMed1994

The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?

Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy.

Acetaminophen↗
PubMed1987

Hepatic encephalopathy. Application of visual evoked responses to test hypotheses of its pathogenesis in rats.

A previous study of the patterns of visual evoked responses (VERs) in rats was interpreted as providing support for the synergistic neurotoxins hypothesis of the pathogenesis of hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF). In contrast, other studies of the patterns of VERs in rabbits with different encephalopathies were interpreted as providing support for the concept that increased GABA-ergic tone may contribute to the neural inhibition of HE due to FHF. To attempt to resolve the discordant findings in these studies, additional studies of VERs have been undertaken in rats. To induce increased tissue levels of ammonia, mercaptans and fatty acids which are found in HE due to FHF, carefully predetermined doses of urease, dimethyldisulphide and octanoic acid were administered. The (pre-seizure) encephalopathy induced by these three agents was associated with abnormalities of the VER waveform that were fundamentally different from the abnormalities of the VER waveform associated with HE due to thioacetamide-induced FHF. However, the VER waveform in this model of HE due to FHF resembled closely that associated with pentobarbital-induced encephalopathy. These findings are in satisfactory agreement with those in the previous analogous studies in rabbits. They do not provide support for the synergistic neurotoxins hypothesis of the pathogenesis of HE, but are entirely consistent with increased GABA-ergic tone contributing to the neural inhibition of HE due to FHF.

Ammonia↗
PubMed1994

Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis is a common infection of ascitic fluid that develops in cirrhosis. The offending organisms are predominantly of enteric origin. However, the mechanism and route by which bacteria exit from the gut and enter the fluid remain unclear. "Translocation" of bacteria from the gut to extraintestinal sites has been postulated in the pathogenesis of gram-negative sepsis in intensive care unit patients, burn-wound sepsis, and sepsis associated with chemotherapy. Translocation is defined by culture-positivity (with enteric flora) of mesenteric lymph nodes. In this study we assessed the frequency of translocation in a carbon tetrachloride-induced rat model of cirrhosis, ascites, and spontaneous bacterial peritonitis. We determined that translocation was more common in rats with cirrhosis (78.1%) than in normal controls (4.3%) (p < 0.001). Escherichia coli and other gram-negative enteric organisms were cultured. Translocation of enteric bacteria in rats with cirrhosis to extraintestinal sites may be an important early step in the pathogenesis of spontaneous bacterial peritonitis.

Animals↗
PubMed1988

Immune-mediated pathogenesis of Borna disease.

Borna disease is an endemic progressive encephalomyelitis of horses and sheep prevalent in central Europe. A wide variety of animal species, ranging from chickens to primates can be infected experimentally with the causative virus, which is only poorly characterized. Furthermore, BD virus-specific antibodies have been detected in sera and cerebrospinal fluids of psychiatric patients. Our studies on the pathogenesis of BD have shown that-at least in rats-the disease is not caused by the infecting virus itself, but by a virus-induced immunopathological reaction. Thus, after intracerebral infection immunoincompetent rats do not get the disease despite persistent virus replication in cells of the central nervous system. However, after adoptive transfer of immune cells from diseased rats, immunoincompetent rats exhibit full-blown BD. Recently, we have been successful in establishing a virus-specific T cell line of the helper/inducer phenotype (CD4+). This T cell was shown to play an important role in the pathogenesis of BD, suggesting that the disease is caused by a delayed type hypersensitivity reaction.

Animals↗