Enteropathogenic Escherichia coli (EPEC) Tir receptor molecule does not undergo full modification when introduced into host cells by EPEC-independent mechanisms.
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Enteropathogenic Escherichia coli (EPEC), like many other gram-negative pathogens, encodes a type III secretion apparatus dedicated to the release of virulence-associated proteins. One such protein, Tir, is translocated into host cells, where it is modified by the addition of phosphate groups, resulting in a number of species with distinct molecular mass. One phosphorylation event, on tyrosine residue 474 of Tir, does not contribute to shifts in molecular mass but is essential for its actin-nucleating function. The role of the nonphosphotyrosine related modifications is unknown. In this paper, we demonstrate, using three different approaches, that Tir does not encode sufficient information to facilitate its complete modification when introduced into host cells in EPEC-independent mechanisms. Each system revealed that Tir is a substrate for a host kinase whose action results in its partial modification to a form similar to one evident in EPEC-infected host cells. Further Tir modification could not be induced by infecting cells with EPEC, suggesting that Tir must be coexpressed with other EPEC factors to enable its full modification within host cells. One approach used Yersinia spp. to deliver Tir into host cells, and this system revealed that Tir secretion and translocation can occur in the absence of the Tir chaperone molecule, CesT (formerly known as OrfU). CesT was found to be an efficiency factor which was not required, unlike in EPEC, for Tir stability, indicating that it may function to guide Tir to the translocation apparatus or maintain it in a secretion-competent form. (+info)
Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts.
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Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic. (+info)
Fecal impaction following methadone ingestion simulating acute intestinal obstruction,.
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A hitherto unreported clinical entity, namely fecal impaction following methadone ingestion simulating acute intestinal obstruction, is described. Five cases admitted to the Surgical Service of the Beth Israel Medical Center in New York City are discussed. The nature and pathogenesis of the obstruction are analyzed and a suggested method of managing these cases is presented. It is emphasized that with expansion and increasing acceptance of Methadone Maintenance Treatment Programs, the number of such cases will increase. It is thus important that physicians become aware of the existence of this syndrome since involvement in methadone maintenance may be a life-long commitment for persons involved, thus increasing the incidence of the complication. It is also imperative to avoid unnecessary, and possibly harmful surgical intervention in such cases. (+info)
Predicting the severity of intestinal graft-versus-host disease from leukotriene B4 levels after bone marrow transplantation.
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Intestinal graft-versus-host disease (GVHD) produces clinical manifestations and histological changes resembling those of ulcerative colitis and has been treated with drugs which are used for ulcerative colitis. These two conditions also resemble each other with respect to changes of cytokines. Accordingly, we investigated whether the level of leukotriene B4, a risk factor for ulcerative colitis, was also a risk factor or prognostic indicator for intestinal GVHD. The pre-conditioning leukotriene B4 level was significantly related to the grade of intestinal GVHD in 42 patients (P < 0.01). Compared with patients who did not develop severe intestinal GVHD after bone marrow transplantation, those who did had significantly higher interleukin-2 and interferon-gamma levels during the aplastic phase (P <0.01), followed by higher tumor necrosis factor-alpha levels during the recovery phase (P < 0.0001), with significant elevation of tumor necrosis factor-alpha and interferon-gamma occurring in association with exacerbations of intestinal GVHD (P < 0.001). These findings suggest a similarity between the pathogenesis of ulcerative colitis and intestinal GVHD and raise the possibility that leukotriene B4 may be a useful prognostic indicator for intestinal GVHD. (+info)
Glucagon-like peptide 2: a nutrient-responsive gut growth factor.
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Glucagon-like peptide 2 (GLP-2) is a 33-amino acid peptide derived from the tissue-specific, post-translational processing of the proglucagon gene expressed in the intestinal enteroendocrine L-cell. The primary stimulus for GLP-2 secretion is nutrient intake, and involves direct luminal stimulation of the L-cell as well as indirect enteroendocrine and neural mechanisms. The biological activity of GLP-2 in circulation is regulated by the proteolytic cleavage of the N-terminus by dipeptidylpeptidase IV. Several studies have shown that GLP-2 has specific trophic effects on the small and large intestine, which are mediated by stimulation of cell proliferation and inhibition of apoptosis and proteolysis. GLP-2 also has been shown to suppress gastric motility and acid secretion, increase hexose transport activity and suppress food intake, specifically when infused centrally. The actions of GLP-2 are mediated by a G-protein-linked, membrane receptor (GLP-2R) that is localized largely to the gastrointestinal tract, but also is found in the brain. The secretion of GLP-2 and expression of the GLP-2R are present in the late gestation fetus. However, the developing intestine does not become responsive to the trophic effect of GLP-2 until after birth. Based on its efficacy in preventing atrophy and stimulating growth in the neonatal gut, GLP-2 may be a promising therapeutic adjuvant for treatment of infants with compromised gut function. (+info)
Therapeutic options for the treatment of impaired gut function.
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Tissue hypoxia, especially in the splanchnic area, is still considered to be an important cofactor in the pathogenesis of multiple organ failure. Therefore, the specific effects of the various therapeutic interventions on splanchnic perfusion and oxygenation are of particular interest. Restoring and maintaining oxygen transport and tissue oxygenation is the most important step in the supportive treatment of patients with sepsis and impaired gut perfusion. Therefore, supportive treatment should be focused on an adequate volume resuscitation and appropriate use of vasoactive drugs. Adequate volume loading may be the most important step in the treatment of patients with septic shock. An elevated oxygen delivery may be beneficial in some patients, but the increase of oxygen delivery should be guided by the measurement of parameters assessing global and regional oxygenation. Forcing an elevation in oxygen delivery by the use of very high dosages of catecholamines can be harmful. Vasopressors should be used for achieving an adequate perfusion pressure. For norepinephrine, no negative effects on gut perfusion have been demonstrated. Epinephrine and dopamine should be avoided because they seem to redistribute blood flow away from the splanchnic region. There are no convincing data yet to support the routine use of low-dose dopamine or dopexamine to improve an impaired gut perfusion. There is even evidence that low-dose dopamine may reduce the mucosal perfusion in the gut in some patients. It has been suggested that dopexamine can improve splanchnic perfusion, but because these effects remain somewhat controversial, a general recommendation for dopexamine to improve gut perfusion is not justified. (+info)
Congenital microvillous inclusion disease presenting as antenatal bowel obstruction.
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Prenatal ultrasound has led to confidence in the antenatal diagnosis of intestinal obstruction allowing counseling and birth planning. We describe a male infant of a diabetic mother who had an antenatal diagnosis of distal bowel obstruction. This baby was subsequently found not to have bowel obstruction, but a congenital enteropathy - microvillous inclusion disease. The antenatal scans had demonstrated polyhydramnios as well as multiple fluid-filled dilated loops of bowel in the fetal abdomen. To our knowledge, similar prenatal ultrasound findings have not been previously described in this condition. The baby was delivered in a pediatric surgical center and postnatally there was no evidence of bowel obstruction either clinically or on abdominal X-ray. This baby initially fed well, but became collapsed and acidotic on his third day, having lost 26% of his birth weight due to excessive stool loss. The diagnosis of microvillous inclusion disease was made by electron microscopy of a small bowel biopsy. Congenital microvillous inclusion disease is a very rare inherited enteropathy with high mortality and morbidity. This condition, and other enteropathies, should be considered in cases in which antenatally diagnosed bowel obstruction is not confirmed after birth. (+info)
Effect of ectopic expression of rat trefoil factor family 3 (intestinal trefoil factor) in the jejunum of transgenic mice.
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To further examine the function of the trefoil factor family (TFF), the expression of which is up-regulated at sites of injury, we have produced transgenic mice that chronically express rat TFF3 within the jejunum (using a rat fatty acid-binding protein promoter). The expression of rat TFF3 was limited to the villi of the jejunum and had no effect on base-line morphology. Rat TFF3 expression did result, however, in a reduced sensitivity to indomethacin (85 mg/kg subcutaneously), which only caused a 29% reduction in villus height in transgenics versus 51% reduction in controls (p < 0.01). Indomethacin increased initial intestinal epithelial cell proliferation and migration, but the presence of rat TFF3 caused no additional change in proliferation (bromodeoxyuridine), cell migration ([(3)H]thymidine and bromodeoxyuridine), apoptosis (terminal deoxyuridine nucleotidyl nick end labeling), or E-cadherin immunostaining. In vitro studies following changes in resistance of intestinal strips in Ussing chambers (voltage-clamp technique) showed increased base-line resistance in the rat TFF3-expressing region (326 +/- 60 versus 195 +/- 48 ohm.cm(2) in controls, p < 0.05) and reduced the fall in resistance following HCl exposure by about 40% (p < 0.01). Overexpression of TFF3 stabilizes the mucosa against noxious agents, supporting its role in mucosal protection/repair. It may therefore provide a novel approach to the prevention and/or treatment of intestinal ulceration. (+info)