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1.
BACKGROUND AND AIMS: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease. METHODS: Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54. RESULTS: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). CONCLUSIONS: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.  相似文献
2.
BACKGROUND AND AIMS: TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. METHODS: We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. RESULTS: TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). CONCLUSIONS: Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.  相似文献
3.
The adipocyte as an active participant in energy balance and metabolism   总被引:5,自引:0,他引:5  
Badman MK  Flier JS 《Gastroenterology》2007,132(6):2103-2115
Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect.  相似文献
4.
Extracts of salivary glands of the yellow fever mosquito Aedes aegypti inhibit tumour cell-stimulated release of tumour necrosis factor alpha (TNFα) from rat mast cells, but do not inhibit antigen-induced histamine secretion. This inhibitory activity for TNFα is found in salivary glands of female but not in male mosquitoes. This inhibition is not mediated by bacterial contamination (LPS), by calcitonin gene related peptide (CGRP), nerve growth factor (NGF), epidermal growth factor (EGF) or transforming growth factor β (TGFβ). The factor(s) has a molecular weight > 10 kDa and is neutralized by boiling for 10 min or heating at 56°C for 30 min. The modulation of this proinflammatory mediator, TNFα, produced by mast cells in sites of blood feeding may facilitate completion of the blood meal, and as reported for certain vector-transmitted parasites, may enhance infectivity.  相似文献
5.
AIM: To explore the alterations of intestinal mucosa morphology, and the effects of tumor necrosis factor a (TNFα) on enterocyte apoptosis in mice with fulminant hepatic failure (FHF). METHODS: Liver damage was induced by lipopolysaccharide (LPS)/TNF-α in D-galactosamine (GaIN) sensitized BALB/c mice. There were 40 mice in normal saline (NS)-treated group, 40 mice in LPS-treated group, 40 mice in GaIN-treated group, 120 mice in GaIN/ LPS-treated group and 120 mice in GaIN/ TNFα-treated group. Each group was divided into five subgroups of eight mice each. Serum samples and liver, intestinal tissues were respectively obtained at 2, 6,9,12 and 24 h after administration. Anti-TNFa monoclonal antibody was injected intravenously into GaIN/LPS-treated mice. Serum TNFα levels were determined by enzyme linked immunosorbent assays (ELISA). Serum ALT levels were determined using an automatic analyzer. The intestinal tissues were studied under light microscope and electron microscope at 2, 6, 9,12 and 24 h in mice with fulminant hepatic failure, respectively. Enterocyte apoptosis was determined by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) method. The expression of tumor necrosis factor receptor 1 (TNFR1) in intestinal tissue was tested by immunohistochemistry Envision Two Steps. RESULTS: Gut mucosa was morphologically normal at all time points in all groups, but typical apoptotic cells could be seen in all experimental groups under electron microscope. Apoptosis rate of gut mucosal epithelial cells were significantly increased at 6, 9 and 12 h, peaked at 12 h in mice with fulminant hepatic failure. TNFa induced apoptosis of enterocytes in mice with FHF. The integrated OD (IOD) levels of TNFa receptor 1 protein expressed in the intestine of mice with GaIN/LPS and GaIN/ TNFα induced FHF at 2, 6, 9, 12 and 24 h after GaIN/LPS and GaIN/TNFα administration were 169.54±52.62/905.79±111.84,11 350.67±2 133.26/28 160.37±4 601.67, 25 781.00±2 277.75/122 352.30±49 412.40, 5 241.53±3 007.24/ 49 157.93±9 804.88, 7 086.13±1 031.15/3 283.45±127.67, respectively, compared with those in control groups (with NS, LPS and GaIN administration, respectively). IOD level of TNFR1 changed significantly at 6, 9 and 12 h after GaIN/LPS and GalN/TNFa administration. The expression of TNFR1 protein was significantly higher at 9 h after GaIN/LPS and GaIN/TNFα administration than that in control groups. Protein expression of TNFR1 was positively correlated with enterocyte apoptosis. CONCLUSION: TNFα can induce apoptosis of enterocytes in mice with FHF. Anti-TNFα IgG can inhibit this role.  相似文献
6.
BACKGROUND & AIMS: Lymphocytes populate the livers of infants with biliary atresia, but it is unknown whether neonatal lymphocytes regulate pathogenesis of disease. Here, we investigate this question by examining the role of T lymphocytes in the destruction of extrahepatic bile ducts of neonatal mice using an experimental model of biliary atresia. METHODS: Inoculation of neonatal mice with rhesus rotavirus followed by multistaining flow cytometry to quantify expression of interferon-gamma by hepatic lymphocytes, and real-time polymerase chain reaction for mRNA expression of pro-inflammatory cytokines. This was followed by determining the consequences of antibody-mediated depletion of lymphocyte subtypes on the development of biliary obstruction, and coculture and cell transfer experiments to investigate the effector role of lymphocyte subtypes on neonatal biliary disease. RESULTS: Rotavirus infection results in overexpression of interferon-gamma by neonatal hepatic T cells. Among these cells, depletion of CD4(+) cells did not change the course of inflammatory injury and obstruction of neonatal bile ducts. In contrast, loss of CD8(+) cells remarkably suppressed duct injury, prevented luminal obstruction, and restored bile flow. Coculture experiments showed that rotavirus-primed, but not na?ve, CD8(+) cells were cytotoxic to cholangiocytes. In adoptive transfer experiments, we found that primed CD8(+) cells preferentially homed to extrahepatic bile ducts of neonatal mice and invaded their epithelial lining. CONCLUSIONS: Primed neonatal CD8(+) cells can activate a pro-inflammatory program, target diseased and healthy duct epithelium, and drive the phenotypic expression of biliary atresia, thus constituting a potential therapeutic target to halt disease progression.  相似文献
7.
Summary. The mechanisms responsible for hairy-cell (HC) growth both in vitro and in vivo are still unclear. In a recent study we showed that monocytes/macrophages induce HC proliferation in vitro . The purpose of the present paper is to examine the specificity of this accessory cell effect and to establish the mechanism(s) involved.
We demonstrate that the effect is not confined to monocytes/macrophages but is also potentially seen with a range of other cell types. However, at low accessory cell:HC ratios (< 1:20) only human umbilical vein endothelial cells (HUVEC) and macrophages induce HC proliferation. We suggest that these observations are of pathophysiological significance in relation to the close association frequently observed between HCs and endothelial cells/macrophages in the liver and spleen of patients with hairy-cell leukaemia (HCL).
Regarding the mechanisms of the accessory cell effect, we show that both soluble factors and cell contact are important. A blocking anti-TNFα antibody abrogated the HC proliferation induced by HUVEC supernatant. indicating the involvement of this cytokine. Interaction of HCs with HUVEC via CD11b and 11c leucocyte integrins was shown to be important in the contact effect.
Out demonstration of the involvement of both cytokines and cell contact in HC proliferation is in accord with what is already known about the control of B-cell growth and differentiation. More specifically, our results suggest that TNFα and interaction with endothelial cells/macrophages via leucocyte integrins are involved in the proliferation of late B-cells of the maturational stage represented by HCs.  相似文献
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10.
Tumour necrosis factorα has been implicated in protective immune responses to a number of parasitic helminths. However, the final effector mechanisms resulting in death or expulsion of the parasite are unclear. Here we suggest that, by employing phylogenetically conserved mechanisms, the mammalian immune system is able to interfere with helminth development directly and that the protective effects of TNFα in helminth infections may operate via the induction of parasite apoptosis.  相似文献
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