1,453 research outputs found
The Employee Retirement Income Security Act Preempts State Law Causes of Action against ERISA-Regulated Benefit Plans: \u3cem\u3eAetna Health, Inc. v. Davila\u3c/em\u3e
The Supreme Court of the United States held that ERISA preempts a Texas state law allowing claims against ERISA-regulated employee benefit plans for denial of coverage.
Aetna Health Inc., v. Davila, 124 S. Ct. 2488 (2004
Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype
Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures
Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-Ξ± (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKΞ±/Ξ² phosphorylation and subsequent NF-ΞΊB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects
Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent
Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1
Π’Π΅ΠΎΡΠ΅ΡΠΈΠΊΠΎ-ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ»ΠΎΠ³ΡΡΠ½Ρ ΠΎΡΠ½ΠΎΠ²ΠΈ ΡΠΎΠ·ΡΠΌΡΠ½Π½Ρ ΠΌΠ΅Ρ Π°Π½ΡΠ·ΠΌΡ ΠΏΡΠ°Π²ΠΎΠ²ΠΎΠ³ΠΎ ΡΠ΅Π³ΡΠ»ΡΠ²Π°Π½Π½Ρ
ΠΠ΅ΡΠΎΡ ΡΡΡΡ ΡΡΠ°ΡΡΡ Ρ Π°Π½Π°Π»ΡΠ· Π½Π°ΠΏΡΡΠΌΡΠ² Π½Π°ΡΠΊΠΎΠ²ΠΈΡ
Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Ρ, ΡΠΎ Ρ ΡΠ²ΠΎΡΠΉ ΡΠ΄Π½ΠΎΡΡΡ ΡΠΎΡΠΌΡΡΡΡ ΡΠ΅ΠΎΡΡΡ ΠΌΠ΅Ρ
Π°Π½ΡΠ·ΠΌΡ ΠΏΡΠ°Π²ΠΎΠ²ΠΎΠ³ΠΎ ΡΠ΅Π³ΡΠ»ΡΠ²Π°Π½Π½Ρ (ΠΠΠ ), ΡΠΎΠ·ΠΊΡΠΈΡΡΡ ΡΠ΅ΠΎΡΠ΅ΡΠΈΠΊΠΎΠΌΠ΅ΡΠΎΠ΄ΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΈΡ
ΠΏΡΠΎΠ±Π»Π΅ΠΌ, ΡΠΊΡ ΠΌΠ°ΡΡΡ ΠΌΡΡΡΠ΅ ΠΏΡΠΈ ΠΎΡΠΌΠΈΡΠ»Π΅Π½Π½Ρ ΠΠΠ , Π²ΠΈΠ·Π½Π°ΡΠ΅Π½Π½Ρ ΡΠ° ΡΠΈΡΡΠ΅ΠΌΠ°ΡΠΈΠ·Π°ΡΡΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΈΡ
ΠΏΡΠ΄Ρ
ΠΎΠ΄ΡΠ² Π΄ΠΎ ΡΠΎΠ·ΡΠΌΡΠ½Π½Ρ ΠΠΠ
CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies
BACKGROUND: Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L--an established marker and mediator of cardiovascular disease--induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo. METHODOLOGY/PRINCIPAL FINDINGS: WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels. CONCLUSION: We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease
Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand
Introduction
Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma.
Aims
To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines.
Results
Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both.
Conclusions
1) Both primary and malignant cholangiocytes are relatively resistant to Fasβmediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes
A SNP in 5β² untranslated region of CD40 gene is associated with an increased risk of ischemic stroke in a Chinese population: a case-control study
Acute phase of aortic dissection: a pilot study on CD40L, MPO, and MMP-1, -2, 9 and TIMP-1 circulating levels in elderly patients
Cardiometabolic risk factors and quality of life in severely obese children and adolescents in the Netherlands
BACKGROUND: The prevalence of severe obesity in children and adolescents is increasing. However, little is known about cardiometabolic risk factors and quality of life of children with severe obesity.Therefore, the aim of this study was to assess the demographic characteristics and the prevalence of cardiometabolic risk factors and quality of life in severely obese children and adolescents undergoing intensive inpatient treatment for obesity. METHODS: Data were collected between August 2009 and April 2011 on 16 children (8-13y) and 64 adolescents (13-19y) with severe obesity (SDS-BMI >= 3.0 or SDS-BMI >= 2.3 and comorbidity) participating in an RCT evaluating two intensive inpatient treatment programs for obesity. Demographic, anthropometric, clinical characteristics and two components of the EuroQol for the assessment of quality of life are described. RESULTS: Eighty percent of participants in this study had at least one cardiometabolic risk factor in addition to severe obesity. Low HDL-cholesterol and hypertension were most prevalent (65.0% respectively 31.2%). The highest significant correlations were found between SDS-BMI and SDS-waist circumference, fasting plasma insulin and HOMA-IR (correlation coefficients respectively 0.80, 0.49, and 0.48). With regard to quality of life, the mean utility score of the participants was 0.79 on a scale of 0.0 to 1.0 on the EuroQol questionnaire and their mean individual valuation was 69.1 on a scale of 0 to100. CONCLUSION: Cardiometabolic risk factors are already highly prevalent in this group of severely obese children and adolescents. The score of 69.1 found for quality of life in this study suggests that participants experience important limitations in their quality of life. However, quality of life is not associated with the prevalence of cardiometabolic risk factors. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009)
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