Hepcidin is elevated in mice injected with Mycoplasma arthritidis

Mycoplasma arthritidis causes arthritis in specific mouse strains. M. arthritidis mitogen (MAM), a superantigen produced by M. arthritidis, activates T cells by forming a complex between the major histocompatability complex II on antigen presenting cells and the T cell receptor on CD4+ T lymphocytes. The MAM superantigen is also known to interact with Toll-like receptors (TLR) 2 and 4. Hepcidin, an iron regulator protein, is upregulated by TLR4, IL-6, and IL-1. In this study, we evaluated serum hepcidin, transferrin saturation, ferritin, IL-6, IL-1, and hemoglobin levels in M. arthritidis injected C3H/HeJ (TLR2+/+, TLR4-/-) mice and C3H/HeSnJ (TLR2+/+, TLR4+/+) mice over a 21 day period. C3H/HeJ mice have a defective TLR4 and an inability to produce IL-6. We also measured arthritis severity in these mice and the amount of hepcidin transcripts produced by the liver and spleen. C3H/HeJ mice developed a more severe arthritis than that of C3H/HeSnJ mice. Both mice had an increase in serum hepcidin within three days after infection. Hepcidin levels were greater in C3H/HeJ mice despite a nonfunctioning TLR4 and low serum levels of IL-6. Splenic hepcidin production in C3H/HeJ mice was delayed compared to C3H/HeSnJ mice. Unlike C3H/HeSnJ mice, C3H/HeJ mice did not develop a significant rise in serum IL-6 levels but did develop a significant increase in IL-1β during the first ten days after injection. Both mice had an increase in serum ferritin but a decrease in serum transferrin saturation. In conclusion, serum hepcidin regulation in C3H/HeJ mice does not appear to be solely dependent upon TLR4 or IL-6

Medium effects in high energy heavy-ion collisions

The change of hadron properties in dense matter based on various theoretical approaches are reviewed. Incorporating these medium effects in the relativistic transport model, which treats consistently the change of hadron masses and energies in dense matter via the scalar and vector fields, heavy-ion collisions at energies available from SIS/GSI, AGS/BNL, and SPS/CERN are studied. This model is seen to provide satisfactory explanations for the observed enhancement of kaon, antikaon, and antiproton yields as well as soft pions in the transverse direction from the SIS experiments. In the AGS heavy-ion experiments, it can account for the enhanced $K^+/\pi^+$ ratio, the difference in the slope parameters of the $K^+$ and $K^-$ transverse kinetic energy spectra, and the lower apparent temperature of antiprotons than that of protons. This model also provides possible explanations for the observed enhancement of low-mass dileptons, phi mesons, and antilambdas in heavy-ion collisions at SPS energies. Furthermore, the change of hadron properties in hot dense matter leads to new signatures of the quark-gluon plasma to hadronic matter transition in future ultrarelativistic heavy-ion collisions at RHIC/BNL.Comment: RevTeX, 65 pages, including 25 postscript figures, invited topical review for Journal of Physics G: Nuclear and Particle Physic

Novel Use of Surveillance Data to Detect HIV-Infected Persons with Sustained High Viral Load and Durable Virologic Suppression in New York City

Background: Monitoring of the uptake and efficacy of ART in a population often relies on cross-sectional data, providing limited information that could be used to design specific targeted intervention programs. Using repeated measures of viral load (VL) surveillance data, we aimed to estimate and characterize the proportion of persons living with HIV/AIDS (PLWHA) in New York City (NYC) with sustained high VL (SHVL) and durably suppressed VL (DSVL). Methods/Principal Findings: Retrospective cohort study of all persons reported to the NYC HIV Surveillance Registry who were alive and $12 years old by the end of 2005 and who had$2 VL tests in 2006 and 2007. SHVL and DSVL were defined as PLWHA with 2 consecutive VLs $100,000 copies/mL and PLWHA with all VLs #400 copies/mL, respectively. Logistic regression models using generalized estimating equations were used to model the association between SHVL and covariates. There were 56,836 PLWHA, of whom 7 % had SHVL and 38 % had DSVL. Compared to those without SHVL, persons with SHVL were more likely to be younger, black and have injection drug use (IDU) risk. PLWHA with SHVL were more likely to die by 2007 and be younger by nearly ten years, on average. Conclusions/Significance: Nearly 60 % of PLWHA in 2005 had multiple VLs, of whom almost 40 % had DSVL, suggesting successful ART uptake. A small proportion had SHVL, representing groups known to have suboptimal engagement in care. This group should be targeted for additional outreach to reduce morbidity and secondary transmission. Measures based o

Tumor Necrosis Factor α Inhibits Expression of the Iron Regulating Hormone Hepcidin in Murine Models of Innate Colitis

Background: Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD). Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models. Methodology/Principal Findings: Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation—dextran sulfate sodium (DSS)-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC) mice. The role of tumor necrosis factor (TNF) $\alpha$ was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNF$\alpha$. Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNF$\alpha$ inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNF$\alpha$ neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNF$\alpha$-dependent decrease in Smad1 protein but not mRNA. Conclusions/Significance: TNF$\alpha$ inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNF$\alpha$ may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated

Mass Spectrometry Analysis of Hepcidin Peptides in Experimental Mouse Models

The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1) and its paralogue Hepcidin-2 (Hep-2) at the peptide level. To this purpose, fourier transform ion cyclotron resonance (FTICR) and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF) MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i) 3 mouse strains (C57Bl/6; DBA/2 and BABL/c) upon stimulation with intravenous iron and LPS, ii) homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X) mutated mice and double affected mice, and iii) mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics

Fluctuations In ``BR-Scaled'' Chiral Lagrangians

We develop arguments for "mapping" the effective chiral Lagrangian whose parameters are given by "BR scaling" to a Landau Fermi-liquid fixed-point theory for nuclear matter in describing fluctuations in various flavor (e.g., strangeness) directions. We use for this purpose the effective Lagrangian used by Furnstahl, Tang and Serot that incorporates the trace anomaly of QCD in terms of a light-quark (quarkonium) degree of freedom with the heavy (gluonium) degree of freedom integrated out. The large anomalous dimension $d_{an}\approx 5/3$ for the scalar field found by Furnstahl et al to be needed for a correct description of nuclear matter is interpreted as an indication for a strong-coupling regime and the ground state given by the BR-scaled parameters is suggested as the background around which fluctuations can be rendered weak so that mean-field approximation is reliable. We construct a simple model with BR scaled parameters that provides a satisfactory description of the properties of matter at normal nuclear matter density. Given this, fluctuations around the BR scaled background are dominated by tree diagrams. Our reasoning relies heavily on recent developments in the study of nucleon and kaon properties in normal and dense nuclear matter, e.g., nucleon and kaon flows in heavy-ion processes, kaonic atoms, and kaon condensation in dense compact-star matter.Comment: 33 pages, Latex, 5 Postscript figure