Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study

Contains fulltext : 98009.pdf (publisher's version ) (Open Access)INTRODUCTION: Anemia is a frequently encountered problem during inflammation. Hepcidin is an interleukin-6 (IL-6)-induced key modulator of inflammation-associated anemia. Human sepsis is a prototypical inflammatory syndrome, often complicated by the development of anemia. However, the association between inflammation, hepcidin release and anemia has not been demonstrated in this group of patients. Therefore, we explored the association between hepcidin and sepsis-associated anemia. METHODS: 92 consecutive patients were enrolled after presentation on the emergency ward of a university hospital with sepsis, indicated by the presence of a proven or suspected infection and >/= 2 extended systemic inflammatory response syndrome (SIRS) criteria. Blood was drawn at day 1, 2 and 3 after admission for the measurement of IL-6 and hepcidin-25. IL-6 levels were correlated with hepcidin concentrations. Hemoglobin levels and data of blood transfusions during 14 days after hospitalisation were retrieved and the rate of hemoglobin decrease was correlated to hepcidin levels. RESULTS: 53 men and 39 women with a mean age of 53.3 +/- 1.8 yrs were included. Hepcidin levels were highest at admission (median[IQR]): 17.9[10.1 to 28.4]nmol/l and decreased to normal levels in most patients within 3 days (9.5[3.4 to 17.9]nmol/l). Hepcidin levels increased with the number of extended SIRS criteria (P = 0.0005). Highest IL-6 levels were measured at admission (125.0[46.3 to 330.0]pg/ml) and log-transformed IL-6 levels significantly correlated with hepcidin levels at admission (r = 0.28, P = 0.015), day 2 (r = 0.51, P < 0.0001) and day 3 (r = 0.46, P < 0.0001). Twelve patients received one or more blood transfusions during the first 2 weeks of admission, not related to active bleeding. These patients had borderline significant higher hepcidin level at admission compared to non-transfused patients (26.9[17.2 to 53.9] vs 17.9[9.9 to 28.8]nmol/l, P = 0.052). IL-6 concentrations did not differ between both groups. Correlation analyses showed significant associations between hepcidin levels on day 2 and 3 and the rate of decrease in hemoglobin (Spearman's r ranging from -0.32, P = 0.03 to -0.37, P = 0.016, respectively). CONCLUSIONS: These data suggest that hepcidin-25 may be an important modulator of anemia in septic patients with systemic inflammation

Extended preservation and effect of nitric oxide production in liver transplantation

Liver transplantation (Ltx) has become a routine procedure for patients with end-stage liver disease. Despite ongoing progress on short- and long-term graft survival, primary dysfunction (PDF) remains a major problem. PDF is significantly associated with the duration of cold ischemia- and, possibly, with reperfusion-related injury. Nitric oxide (NO) has many physiological functions and plays an important role in modulating tissue injury. However, the mechanism of NO action in ischemia/reperfusion injury after Ltx is thus far unknown. In this study we investigated the role of inducable NO synthase (iNOS) in the liver after preservation with UW solution using the orthotopic Ltx model in the rat. Male Brown Norway rats were used for the Ltx procedure. After donor hepatectomy, livers were stored on ice-cold UW solution for 24 or 40 h and subsequently transplanted. A control group consisted of rats with Ltx after less than 1 h storage. Posttransplant blood samples were taken at 48 h to determine standard parameters for liver injury (aspartate transaminase, lactate dehydrogenase). Liver biopsies were obtained for detection of expression of iNOS (western blot) 24 and 48 h posttransplant. We observed that a preservation time of 24 h in UW solution presents no problem for graft survival after Ltx in rats with some brain function and in healthy animals. After 40 h preservation, liver damage is obvious and graft survival reduced, indicating the limits of cold storage may be within reach. With longer preservation times, more NOs was detected in liver tissue. This finding suggests that NO has a role in ischemia/reperfusion-related injury. Current intervention with NOS inhibitors will reveal whether NO has a negative or a positive effect on graft survival after Ltx.</p

A non-canonical NRPS is involved in the synthesis of fungisporin and related hydrophobic cyclic tetrapeptides in Penicillium chrysogenum.

The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain

Hofstadter butterflies of carbon nanotubes: Pseudofractality of the magnetoelectronic spectrum

The electronic spectrum of a two-dimensional square lattice in a perpendicular magnetic field has become known as the Hofstadter butterfly [Hofstadter, Phys. Rev. B 14, 2239 (1976).]. We have calculated quasi-one-dimensional analogs of the Hofstadter butterfly for carbon nanotubes (CNTs). For the case of single-wall CNTs, it is straightforward to implement magnetic fields parallel to the tube axis by means of zone folding in the graphene reciprocal lattice. We have also studied perpendicular magnetic fields which, in contrast to the parallel case, lead to a much richer, pseudofractal spectrum. Moreover, we have investigated magnetic fields piercing double-wall CNTs and found strong signatures of interwall interaction in the resulting Hofstadter butterfly spectrum, which can be understood with the help of a minimal model. Ubiquitous to all perpendicular magnetic field spectra is the presence of cusp catastrophes at specific values of energy and magnetic field. Resolving the density of states along the tube circumference allows recognition of the snake states already predicted for nonuniform magnetic fields in the two-dimensional electron gas. An analytic model of the magnetic spectrum of electrons on a cylindrical surface is used to explain some of the results.Comment: 14 pages, 12 figures update to published versio

Nature of complex singularities for the 2D Euler equation

A detailed study of complex-space singularities of the two-dimensional incompressible Euler equation is performed in the short-time asymptotic r\'egime when such singularities are very far from the real domain; this allows an exact recursive determination of arbitrarily many spatial Fourier coefficients. Using high-precision arithmetic we find that the Fourier coefficients of the stream function are given over more than two decades of wavenumbers by \hat F(\k) = C(\theta) k^{-\alpha} \ue ^ {-k \delta(\theta)}, where \k = k(\cos \theta, \sin \theta). The prefactor exponent $\alpha$, typically between 5/2 and 8/3, is determined with an accuracy better than 0.01. It depends on the initial condition but not on $\theta$. The vorticity diverges as $s^{-\beta}$, where $\alpha+\beta= 7/2$ and $s$ is the distance to the (complex) singular manifold. This new type of non-universal singularity is permitted by the strong reduction of nonlinearity (depletion) which is associated to incompressibility. Spectral calculations show that the scaling reported above persists well beyond the time of validity of the short-time asymptotics. A simple model in which the vorticity is treated as a passive scalar is shown analytically to have universal singularities with exponent $\alpha =5/2$.Comment: 22 pages, 24 figures, published version; a version of the paper with higher-quality figures is available at http://www.obs-nice.fr/etc7/euler.pd

Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer

Contains fulltext : 172498.pdf (publisher's version ) (Open Access)BACKGROUND: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored. METHODS: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK. RESULTS: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) microg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure. CONCLUSION: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL. GOV NUMBER: NCT01118065

Of fingers, toes and penises

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62765/1/390029a0.pd

Cardiovascular dynamics in ischemic cardiomyopathy during exercise

Cardiac Dysfunction and Arrhythmia