Global Transcriptional Response to Hfe Deficiency and Dietary Iron Overload in Mouse Liver and Duodenum

Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina™ arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q-RT-PCR) was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe−/− mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe−/− mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes

Effects of iron loading on muscle: genome-wide mRNA expression profiling in the mouse

Background Hereditary hemochromatosis (HH) encompasses genetic disorders of iron overload characterized by deficient expression or function of the iron-regulatory hormone hepcidin. Mutations in 5 genes have been linked to this disease: HFE, TFR2 (encoding transferrin receptor 2), HAMP (encoding hepcidin), SLC40A1 (encoding ferroportin) and HJV (encoding hemojuvelin). Hepcidin inhibits iron export from cells into plasma. Hemojuvelin, an upstream regulator of hepcidin expression, is expressed in mice mainly in the heart and skeletal muscle. It has been suggested that soluble hemojuvelin shed by the muscle might reach the liver to influence hepcidin expression. Heart muscle is one of the target tissues affected by iron overload, with resultant cardiomyopathy in some HH patients. Therefore, we investigated the effect of iron overload on gene expression in skeletal muscle and heart using Illumina™ arrays containing over 47,000 probes. The most apparent changes in gene expression were confirmed using real-time RT-PCR. Results Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Conclusion Microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes.BioMed Central Open acces

Real time simulation using position sensing

An interactive exercise system including exercise equipment having a resistance system, a speed sensor, a controller that varies the resistance setting of the exercise equipment, and a playback device for playing pre-recorded video and audio. The controller, operating in conjunction with speed information from the speed sensor and terrain information from media table files, dynamically varies the resistance setting of the exercise equipment in order to simulate varying degrees of difficulty while the playback device concurrently plays back the video and audio to create the simulation that the user is exercising in a natural setting such as a real-world exercise course

Expression of iron-related genes in human brain and brain tumors

<p>Abstract</p> <p>Background</p> <p>Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (<it>HAMP</it>), HFE, neogenin (<it>NEO1</it>), transferrin receptor 1 (<it>TFRC</it>), transferrin receptor 2 (<it>TFR2</it>), and hemojuvelin (<it>HFE2</it>) in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines.</p> <p>Results</p> <p>Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens.</p> <p>Conclusion</p> <p>These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.</p

HST STIS spectroscopy of the triple nucleus of M31: two nested disks in Keplerian rotation around a Supermassive Black Hole

We present HST spectroscopy of the nucleus of M31 obtained with STIS. Spectra taken around the CaT lines at 8500 see only the red giants in the double bright- ness peaks P1 and P2. In contrast, spectra taken at 3600-5100 A are sensitive to the tiny blue nucleus embedded in P2, the lower surface brightness red nucleus. P2 has a K-type spectrum, but the embedded blue nucleus has an A-type spectrum with strong Balmer absorption lines. Given the small likelihood for stellar collisions, a 200 Myr old starburst appears to be the most plausible origin of the blue nucleus. In stellar population, size, and velocity dispersion, the blue nucleus is so different from P1 and P2 that we call it P3. The line-of-sight velocity distributions of the red stars in P1+P2 strengthen the support for Tremaine s eccentric disk model. The kinematics of P3 is consistent with a circular stellar disk in Keplerian rotation around a super-massive black hole with M_bh = 1.4 x 10^8 M_sun. The P3 and the P1+P2 disks rotate in the same sense and are almost coplanar. The observed velocity dispersion of P3 is due to blurred rotation and has a maximum value of sigma = 1183+-201 km/s. The observed peak rotation velocity of P3 is V = 618+-81 km/s at radius 0.05" = 0.19 pc corresponding to a circular rotation velocity at this radius of ~1700 km/s. Any dark star cluster alternative to a black hole must have a half-mass radius <= 0.03" = 0.11 pc. We show that this excludes clusters of brown dwarfs or dead stars on astrophysical grounds.Comment: Astrophysical Journal, Sep 20, 2005, 21 pages including 20 figure

Peginterferon Alfa-2a and Ribavirin for 16 or 24 Weeks in HCV Genotype 2 or 3

Background Patients infected with hepatitis C virus (HCV) genotype 2 or 3 have sustained virologic response rates of approximately 80% after receiving treatment with peginterferon and ribavirin for 24 weeks. We conducted a large, randomized, multinational, noninferiority trial to determine whether similar efficacy could be achieved with only 16 weeks of treatment with peginterferon alfa-2a and ribavirin. Methods We randomly assigned 1469 patients with HCV genotype 2 or 3 to receive 180 μg of peginterferon alfa-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks. A sustained virologic response was defined as an undetectable serum HCV RNA level (milliliter) 24 weeks after the end of treatment. Results The study failed to demonstrate that the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks (62% vs. 70%; odds ratio for 16 weeks vs. 24 weeks, 0.67; 95% confidence interval, 0.54 to 0.84; P Conclusions Treatment with peginterferon and ribavirin for 16 weeks in patients infected with HCV genotype 2 or 3 results in a lower overall sustained virologic response rate than treatment with the standard 24-week regimen. (ClinicalTrials.gov number, NCT00077636.

Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

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A global view of hepatitis C: Physician knowledge, opinions, and perceived barriers to care

Chronic infection with the hepatitis C virus (HCV) is a leading cause of global morbidity and mortality. While recent advances in antiviral therapy have led to significant improvements in treatment response rates, only a minority of infected patients is treated. Multiple barriers may impede the delivery of HCV therapy

Economic Value of Dengue Vaccine in Thailand

With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1× per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of$60 and cost-effective [< 3× per capita GDP ($12,868)] up to a total vaccination cost of$200. When the total vaccine series was $1.50, many scenarios were cost saving

Structure and variability of the Denmark Strait Overflow: Model and observations

We report on a combined modeling and observational effort to understand the Denmark Strait Overflow (DSO). Four cruises over the course of 3 years mapped hydrographic properties and velocity fields with high spatial resolution. The observations reveal the mean path of the dense water, as well as the presence of strong barotropic flows, energetic variability, and strong bottom friction and entrainment. A regional sigma coordinate numerical model of interbasin exchange using realistic bottom topography and an overflow forced only by an upstream reservoir of dense fluid is compared with the observations and used to further investigate these processes. The model successfully reproduces the volume transport of dense water at the sill, as well as the 1000-m descent of the dense water in the first 200 km from the sill and the intense eddies generated at 1–3 day intervals. Hydraulic control of the mean flow is indicated by a region supercritical to long gravity waves in the dense layer located approximately 100 km downstream of the sill in both model and observations. In addition, despite the differences in surface forcing, both model and observations exhibit similar transitions from mostly barotropic flow at the sill to a bottom-trapped baroclinic flow downstream, indicating the dominant role of the overflow in determining the full water column dynamics