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

Anthropogenic and naturally-occurring organobromine compounds in fish oil dietary supplements

Fish oil dietary supplements (FODS) are recommended to increase the intake of polyunsaturated fatty acids (PUFAs), renowned for their beneficial effects on human health. However, FODS also contain anthropogenic contaminants, such as polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs). Sixty-nine (n = 69) PUFA-enriched FODS from 37 producers were collected in 2006 and then analyzed for their levels of organobrominated compounds. Levels of the sum of tri- to hepta-BDEs (BDEs 28, 47, 49, 66, 85, 99, 100, 153, 154, and 183) were typically below 5 ng/g oil, while only a few had higher values of up to 44 ng/g oil. Several peaks in the chromatograms were identified as methoxylated PBDEs (MeO-PBDEs) and polybrominated hexahydroxanthene derivatives (PBHDs). These two groups of compounds have been suggested to be produced by marine organisms (e.g., algae and sponges) and have also been reported in marine samples, such as fish and marine mammals. Median concentrations of MeO-PBDEs and PBHDs (6.2 and 5.3 ng/g oil, respectively) were higher than median concentrations of PBDEs (0.6 ng/g oil), and their maximum values were 1670 and 200 ng/g oil, respectively. FODS are intended to be consumed on a daily basis, and the median daily intakes of MeO-PBDEs and PBHDs from FODS were 3 and 6 times higher than the median intake of PBDEs (3 ng/day). Consumption of FODS does not appear to substantially increase the total dietary intake of PBDEs since the median daily intake from FODS was 8 and 16 times lower than the intake from either fish consumption alone or from total diet. These findings indicate that FODS might be a suitable alternative to fish consumption for certain segments of the population for which fish consumption advices have been issued. The present study also strongly supports the need for not only the inclusion of new anthropogenic contaminants (e.g., PBDEs) but also of naturally occurring compounds in monitoring schemes of marine products destined for human consumption

Delirium prediction in the intensive care unit: comparison of two delirium prediction models

Contains fulltext : 191587.pdf (publisher's version ) (Open Access

Evaluation of a screening system for obesogenic compounds: screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect.

&lt;p&gt;Recently the environmental obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor &amp;gamma; (PPAR&amp;gamma;) dependency of the positive compounds was evaluated using PPAR&amp;gamma; activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPAR&amp;gamma; activation was associated with adipogenesis for parabens, phthalates and BPA, however not required for obesogenic effects induced by Tonalide, indicating the role of other obesogenic mechanisms for this compound.&lt;/p&gt;</p

Oxidatively modified proteins in bronchoalveolar lavage fluid of patients with ARDS and patients at-risk for ARDS.

Oxidative stress in acute respiratory distress syndrome (ARDS) is considered as an important pathophysiological mechanism in acute impairment of lung function. The present study investigated whether a pulmonary oxidant-antioxidant imbalance is indicated by substantial oxidative modification of proteins in bronchoalveolar lavage (BAL) fluid. Oxidatively modified proteins in BAL fluid, as measured by the reduction of protein carbonyl groups with tritiated borohydride, were studied in control subjects, patients with clinically established ARDS, and patients considered at-risk for ARDS because they had had coronary bypass surgery. Subsets of these at-risk patients were pretreated either with methylprednisolone or N-acetylcysteine. The carbonyl content of BAL fluid proteins was greatly increased in ARDS patients (5.0+/-13 nmol carbonyl x mL(-1) BAL fluid; mean+/-SEM; p=0.0004; n=10) and moderately increased in the untreated patients at-risk for ARDS (1.3+/-0.2 nmol x mL(-1); p=0.027; n=19) compared with controls (0.8+/-0.2 nmol x mL(-1); n=12). The two other at-risk groups pretreated either with methylprednisolone or N-acetylcysteine showed carbonyl values that were statistically not different from the controls (1.2+/-0.2 nmol x mL(-1); p=0.13; n=13, and 1.1+/-0.3 nmol x mL(-1); p=0.40; n=8, respectively). These results show that oxidatively modified proteins clearly accumulated in bronchoalveolar lavage fluid of acute respiratory distress syndrome patients, and to a minor extent in untreated at-risk patients. These data suggest a severe oxidant-antioxidant imbalance in acute respiratory distress syndrome

Nitric oxide metabolites in nasal lavage fluid of patients with house dust mite allergy

Background - The role of nitric oxide in the early and late phase of the allergic process was investigated in patients with allergic rhinitis against house dust mite and the effect of fluticasone propionate aqueous nasal spray was determined. Methods - Production of nitric oxide (measured as nitrite + nitrate) in vivo in nasal mucosa was examined in 24 patients with rhinitis allergic to the house dust mite. In a double blind placebo controlled crossover study fluticasone propionate 200 μg aqueous nasal spray was administered twice daily for two weeks. In response to provocation with house dust mite extract (after four basal nasal lavages) nasal lavages were performed every hour for 9.5 hours by washing the nose with saline. In addition, a similar lavage protocol was performed in healthy volunteers with or without challenge with phosphate buffered saline. Results - Nitric oxide is present in nasal lavage fluid in detectable amounts (range 10-50 μM), the level gradually increasing with time in both patients and controls after a decrease during the four basal lavages. Treatment with fluticasone propionate aqueous nasal spray did not affect initial basal production of nitric oxide nor production following provocation with house dust mite extract. Conclusions - Production of nitric oxide in nasal mucosa determined in sequential nasal washings is not affected by therapeutic doses of intranasal steroids