Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR-Hdac3-deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR-Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.     

Platelet reactivity in type 2 diabetes mellitus: a comparative analysis with survivors of myocardial infarction and the role of glycaemic control

Patients with type 2 diabetes mellitus exhibit considerable platelet dysfunction, though this is poorly characterized in patients with diabetes taking aspirin for the primary prevention of cardiovascular events. We sought to compare platelet function in this patient population with that of a high-risk group of non-diabetic subjects with a history of previous myocardial infarction (MI), and to assess whether glycaemic control impacts on platelet function. Methods: Platelet aggregation was measured in response to incremental concentrations of five platelet agonists using light transmission aggregometry. All patients were taking aspirin, and aspirin insensitivity was defined as ≥ 20% arachidonic acid (AA) mediated aggregation. Patients with diabetes were divided according to glycaemic control (HbA(1c)): optimal ≤ 6.5, good 6.6-7.4 and suboptimal ≥ 7.5%. Results: In total, 85 patients with type 2 diabetes and 35 non-diabetic patients with previous MI were recruited. Compared to MI patients, diabetes patients had increased aggregation in response to multiple concentrations of epinephrine, collagen, adenosine diphosphate and AA. Aspirin insensitivity was more common in type 2 diabetes (15% vs. 0%, p=0.037). Platelet aggregation was increased in response to several agonists patients with suboptimal glycaemic control compared to patients with optimal control. Aspirin insensitivity was also more common in patients with suboptimal glycaemic control compared to those with good or optimal control (26.0% vs. 8.3% vs. 4%, p=0.04). Conclusion: Patients with type 2 diabetes mellitus, without proven vascular disease, exhibit platelet dysfunction and have increased platelet aggregation and aspirin insensitivity compared to non-diabetic patients with previous MI. Platelet dysfunction in diabetes is more severe in patients with suboptimal glycaemic control.     

Genetic markers may predict disease behavior in patients with ulcerative colitis

BACKGROUND & AIMS: Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. METHODS: HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. CONCLUSIONS: Genetic markers may predict disease behavior in ulcerative colitis. (Gastroenterology 1997 Jun;112(6):1845-53)     

Swim stress reduces chronic pain in mice through an opioid mechanism

Chronic nociception has been studied in male mice by means of the formalin test in which forelimb motor behaviour is scored after subcutaneous formalin injection. The rating remained above 2.0 for 30 min after the injection (scale range 0-3). The magnitude of the nociception has been compared with that reported in other animal types. Mice are more sensitive than rats, cats and monkeys. The stress of a swim of 3 min has been found to reduce nociception by up to 25%. This analgesia is wholly opioid in nature, being abolished by a moderate dose of naloxone (1 mg/kg).     

Predictors of survival after liver transplantation for hepatocellular carcinoma associated with Hepatitis C.

The efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) is not well defined. This study examines the variables that may determine the outcome of OLT for HCC in HCV patients. From 1990 to 1999, 463 OLTs were performed for HCV cirrhosis. Of these patients, 67 with concurrent HCC were included in the study. Univariate and multivariate analyses considered the following variables: gender, pTNM stage, tumor size, number of nodules, vascular invasion, incidental tumors, adjuvant chemotherapy, preoperative chemoembolization, alpha-fetoprotein (AFP) tumor marker, lobar distribution, and histological grade. Overall OLT survival of HCV patients diagnosed with concomitant HCC was significantly lower when compared to patients who underwent OLT for HCV alone at 1, 3, and 5 years (75%, 71%, and 55% versus 84%, 76%, and 75%, respectively; P < 0.01). Overall survival of patients with stage I HCC was significantly better than patients with stage II, III, or IV (P < .05). Eleven of 67 patients developed tumor recurrence. Sites of recurrence included transplanted liver (5), lung (5), and bone (1). Twenty-four of 67 patients (36%) died during the follow-up time. Causes of deaths included recurrent HCC in 8 of 24 patients (12%) and recurrent HCV in 3 of 24 patients (4.5%), whereas 13 (19.5%) patients died from causes that were unrelated to HCV or HCC. Both univariate and multivariate analysis demonstrated that pTNM status (I versus II, III, and IV; P < .05) was a reliable prognostic indicator for patient survival. Presence of vascular invasion (P = .0001) and advanced pTNM staging (P = .038) increased risk of recurrence. Multivariate analysis showed that pretransplant chemoembolization and adjuvant chemotherapy reduced risk of death after OLT in HCC recipients. In conclusion, this study demonstrates the effectiveness of OLT for patients with HCC in a large cohort of chronic HCV patients. Advanced tumor stage, and particularly vascular invasion, are poor prognostic indicators for tumor recurrence. Early pTNM stage, adjuvant chemotherapy, and preoperative chemoembolization were associated with positive outcomes for patients who underwent OLT for concomitant HCV and HCC.