201 research outputs found
Modulation of nitric oxide synthase activity in macrophages
L-Arginine is converted to the highly reactive and unstable nitric oxide (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS). NO decomposes into other nitrogen oxides such as nitrite
(NO2-) and nitrate (NO2-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO−). Activated rodent macrophages are capable of expressing an inducible form of this enzyme (iNOS) in response to appropriate stimuli, i.e., lipopolysaccharide (LPS) and interferon-γ (IFNγ). Other cytokines can modulate the induction of NO biosynthesis in macrophages. NO is a major effector molecule of the anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthesizing pathway has been demonstrated in human monocytes and other cells, but its role in host defence seems to be accessory. A delicate functional balance between microbial stimuli, host-derived cytokines and hormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulation of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage
Surprising findings following a Belgian food contamination with polychlorobiphenyls and dioxins.
We found that 12.1% of Belgian export meat samples from chicken or pork, unrelated to the PCB/dioxin crisis from 1999, contained more than 50 ng polychlorinated biphenyls (PCBs)/g fat and that 6.5% of samples contain more than 20 ng/g fat for the sum of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and its metabolites. Part of this background contamination stems from imported animal feed ingredients (fish flour and grains), sometimes contaminated by recent use of DDT, as can be deduced from the ratio between DDT and its main metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE). However, after comparing PCB concentrations in fish flour and grains with those found in meat, we suggest that the high concentrations stem from recycled fat. This is the first paper describing background concentrations of PCBs in animal meat from Belgium
Oxidized Lipoproteins Suppress Nitric Oxide Synthase in Macrophages: Study of Glucocorticoid Receptor Involvement
Activated cholesterol-laden macrophages in atherosclerotic lesions
are believed to influence the progression of this disease. The
induction of nitric oxide synthase (iNOS) activity was investigated
in control and cholesterol-laden J774 macrophages, obtained by
pre-incubation with oxidized or acetylated low density lipoproteins
(oxLDL, acLDL). Loading with oxLDL caused a small induction of NOS
activity in unstimulated cells, as indicated by nitrite and
citrulline accumulation in the supernatant. However, it suppressed
the iNOS activity resulting from stimulation of the cells with
lipopolysaccharide with or without interferon-γ. AcLDL had no
inhibitory effect, indicating that cholesterol accumulation as such
was not responsible. Since the induction of NOS in macrophages is
inhibited by glucocorticoids, the possibility that a
glucocorticoid-like factor, formed during oxidation of LDL, may
cause the inhibition, was investigated. However, addition of the
glucocorticoid receptor antagonist mifepristone did not prevent the
oxLDL-dependent NOS inhibition, indicating that the glucocorticoid
receptor is not involved in the suppressive effect of oxLDL
Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial
Introduction: To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed.Methods: Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety.Results: There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial.Conclusions: The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.Trial Registration: www.clinicaltrials.gov: NCTNCT00511186. © 2012 Pickkers et al.; licensee BioMed Central Ltd
Ricardo flies Ryanair: Strategic human resource management and competitive advantage in a Single European Aviation Market
How and why are some firms, such as Ryanair, able to consistently record industry-leading profitability that sustains a competitive advantage over their rivals? HRM plays a critical role in four widely recognised profit-generating mechanisms, albeit not always in ways predicted by mainstream strategic HRM. Studies of HRMperformance grounded in the resource-based view (RBV) of the firm invariably focus on the human resources already controlled by the firm – specifically, resources that are rare, inimitable, non-substitutable and can be exploited through organisation (RINO) – rather than strategic factor markets (SFMs) where firms acquire their human resources. In doing so, these studies overlook the industrial relations and wider institutional context that might variously promote, permit or preclude particular HR policies and practices. It is only when different profit-generating mechanisms, either in isolation or combination, are activated under the auspicious conditions of a particular time and place that HRM contributes to sustained competitive advantage
Clinical pharmacology of exogenously administered alkaline phosphatase
Purpose: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). Methods: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg-124 h-1) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. Results: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. Conclusions: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis
Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia
Relapse is a major problem in acute myeloid leukemia (AML) and adversely impacts survival.
In this phase II study, we investigated the effect of vaccination with dendritic cells (DCs)
electroporated with Wilms’ tumor 1 (WT1) mRNA as post-remission treatment in 30 AML
patients at very high risk of relapse. There was a demonstrable anti-leukemic response in 13
patients. Nine patients achieved molecular remission as demonstrated by normalization
of WT1 transcript levels, 5 of which are sustained after a median follow-up of 109.4 months.
Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was
higher in responders than in non-responders (53.8% vs. 25.0%; P=0.01). In patients
receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse
reduction rate of 25% and the 5-year relapse-free survival was higher in responders than in
non-responders (50% vs. 7.7%; P65 years who received DCs
in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared to 51.7% and 18% in
the Swedish Acute Leukemia Registry (SALR). Long-term clinical response was correlated
with increased circulating frequencies of poly-epitope WT1-specific CD8+ T-cells. Long-term
OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed type hypersensitivity-infiltrating CD8+ T-lymphocytes. In conclusion, vaccination of
AML patients with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or
delay relapse after standard chemotherapy, translating into improved OS rates, which are
correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered
at www.clinicaltrials.gov as #NCT00965224
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