Association of single nucleotide polymorphisms in microRNAs with susceptibility to hepatitis B virus infection and HBV-related liver complications: A study in a Saudi Arabian population.

The aim of this study was to evaluate the association of 10 SNPs in different microRNAs (miRNAs) with susceptibility to hepatitis B virus (HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma (HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV-cleared subject and cirrhosis+HCC. Samples were analysed for 10 SNPs in microRNAs using either PCR-based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV-induced liver complications. SNPs in miRNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their miRNAs, and thus, further investigation to fully explore their therapeutic potential is warranted.

Hepatitis C virus genotype 1: how genetic variability of the core protein affects the response to pegylated-interferon and ribavirin therapy.

Hepatitis C virus subgenotypes 1a and 1b are found worldwide and cause 60% of all hepatitis C cases. It has been reported recently that viral genetic variations have a critical impact on the patient treatment outcome. In particular, polymorphisms of the HCV core protein have been linked to poor treatment response. However, most of these studies were conducted on Asian populations, Japanese in particular who are infected with HCV subgenotype 1b. Hence, we aimed in this study to examine the core protein polymorphisms in Saudi patients who are infected with chronic HCV genotype 1 (1a and 1b subtypes) and its association with treatment outcome. Direct sequencing of full-length core protein and data mining analyses were utilized. Results have shown that the response to treatment is dependent on subgenotypes. Indeed, HCV-1b showed different point mutations that are associated with treatment outcome where the point mutations at positions 70 (Arg(70) Gln) and 75 (Thr(75) Ala) in HCV-1b are significantly associated with PEG-IFN/RBV treatment response. In contrast, HCV-1a showed no significant association between core protein mutations and response to treatment. In addition, analyses of HCV-1a core protein sequences revealed a highly conserved region especially in the responder group. This study provides a new insight in the genetic variability of full-length core protein in HCV genotype 1 in Saudi infected patients.

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B.

Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20,000 IU/mL vs. ≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg-negative patients in four groups: Group I (n = 55): HBV DNA ≥20,000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20,000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20,000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20,000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut-off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I-IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut-off 20,000 vs. 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088-0.868; P = 0.0276) and milder (A0-1) necroinflammatory grade (OR, 0.135; CI: 0.063-0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20,000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51% vs. 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg-negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut-offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.

Gamma-ray flares from the Crab Nebula.

A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (10(15) electron volts) electrons in a region smaller than 1.4 × 10(-2) parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.

Gamma-ray emission concurrent with the nova in the symbiotic binary V407 Cygni.

Novae are thermonuclear explosions on a white dwarf surface fueled by mass accreted from a companion star. Current physical models posit that shocked expanding gas from the nova shell can produce x-ray emission, but emission at higher energies has not been widely expected. Here, we report the Fermi Large Area Telescope detection of variable gamma-ray emission (0.1 to 10 billion electron volts) from the recently detected optical nova of the symbiotic star V407 Cygni. We propose that the material of the nova shell interacts with the dense ambient medium of the red giant primary and that particles can be accelerated effectively to produce pi(0) decay gamma-rays from proton-proton interactions. Emission involving inverse Compton scattering of the red giant radiation is also considered and is not ruled out.

Clinical outcomes for Saudi and Egyptian patients receiving deceased donor liver transplantation in China.

Long waiting list times in liver transplant programs in Saudi Arabia and unavailability of deceased donor transplantation in Egypt have led several patients to seek transplantation in China. All patients who received transplants in China and followed in three centers from January 2003-January 2007 were included. All patients' charts were reviewed. Mortality and morbidity were compared to those transplanted in King Faisal Specialist Hospital & Research Centre (KFSH&RC) during the same period. Seventy-four adult patients were included (46 Saudi nationals; 28 Egyptians). One-year and 3-year cumulative patient survival rates were 83% and 62%, respectively compared to 92% and 84% in KFSH&RC. One-year and 3-year cumulative graft survival rates were 81% and 59%, respectively compared to 90% and 84% in KFSH&RC. Compared to KFSH&RC, the incidence of complications was significantly higher especially biliary complications, sepsis, metastasis and acquired HBV infection posttransplant. Requirements of postoperative interventions and hospital admissions were also significantly greater. Our data show high mortality and morbidity rates in Saudi and Egyptian patients receiving transplants in China. This could be related to more liberal selection criteria, use of donation after cardiac death (DCD) donors or possibly more limited posttransplant care.

Spectrum of the isotropic diffuse gamma-ray emission derived from first-year Fermi Large Area Telescope data.

We report on the first Fermi Large Area Telescope (LAT) measurements of the so-called "extragalactic" diffuse gamma-ray emission (EGB). This component of the diffuse gamma-ray emission is generally considered to have an isotropic or nearly isotropic distribution on the sky with diverse contributions discussed in the literature. The derivation of the EGB is based on detailed modeling of the bright foreground diffuse Galactic gamma-ray emission, the detected LAT sources, and the solar gamma-ray emission. We find the spectrum of the EGB is consistent with a power law with a differential spectral index gamma = 2.41 +/- 0.05 and intensity I(>100 MeV) = (1.03 +/- 0.17) x 10(-5) cm(-2) s(-1) sr(-1), where the error is systematics dominated. Our EGB spectrum is featureless, less intense, and softer than that derived from EGRET data.

Fermi large area telescope search for photon lines from 30 to 200 GeV and dark matter implications.

Dark matter (DM) particle annihilation or decay can produce monochromatic gamma rays readily distinguishable from astrophysical sources. gamma-ray line limits from 30 to 200 GeV obtained from 11 months of Fermi Large Area Space Telescope data from 20-300 GeV are presented using a selection based on requirements for a gamma-ray line analysis, and integrated over most of the sky. We obtain gamma-ray line flux upper limits in the range 0.6-4.5x10{-9} cm{-2} s{-1}, and give corresponding DM annihilation cross-section and decay lifetime limits. Theoretical implications are briefly discussed.

Fermi gamma-ray imaging of a radio galaxy.

The Fermi Gamma-ray Space Telescope has detected the gamma-ray glow emanating from the giant radio lobes of the radio galaxy Centaurus A. The resolved gamma-ray image shows the lobes clearly separated from the central active source. In contrast to all other active galaxies detected so far in high-energy gamma-rays, the lobe flux constitutes a considerable portion (greater than one-half) of the total source emission. The gamma-ray emission from the lobes is interpreted as inverse Compton-scattered relic radiation from the cosmic microwave background, with additional contribution at higher energies from the infrared-to-optical extragalactic background light. These measurements provide gamma-ray constraints on the magnetic field and particle energy content in radio galaxy lobes, as well as a promising method to probe the cosmic relic photon fields.

Gamma-ray emission from the shell of supernova remnant W44 revealed by the Fermi LAT.

Recent observations of supernova remnants (SNRs) hint that they accelerate cosmic rays to energies close to ~10(15) electron volts. However, the nature of the particles that produce the emission remains ambiguous. We report observations of SNR W44 with the Fermi Large Area Telescope at energies between 2 x 10(8) electron volts and 3 x10(11) electron volts. The detection of a source with a morphology corresponding to the SNR shell implies that the emission is produced by particles accelerated there. The gamma-ray spectrum is well modeled with emission from protons and nuclei. Its steepening above approximately 10(9) electron volts provides a probe with which to study how particle acceleration responds to environmental effects such as shock propagation in dense clouds and how accelerated particles are released into interstellar space.

Modulated high-energy gamma-ray emission from the microquasar Cygnus X-3.

Microquasars are accreting black holes or neutron stars in binary systems with associated relativistic jets. Despite their frequent outburst activity, they have never been unambiguously detected emitting high-energy gamma rays. The Fermi Large Area Telescope (LAT) has detected a variable high-energy source coinciding with the position of the x-ray binary and microquasar Cygnus X-3. Its identification with Cygnus X-3 is secured by the detection of its orbital period in gamma rays, as well as the correlation of the LAT flux with radio emission from the relativistic jets of Cygnus X-3. The gamma-ray emission probably originates from within the binary system, opening new areas in which to study the formation of relativistic jets.

A limit on the variation of the speed of light arising from quantum gravity effects.

A cornerstone of Einstein's special relativity is Lorentz invariance-the postulate that all observers measure exactly the same speed of light in vacuum, independent of photon-energy. While special relativity assumes that there is no fundamental length-scale associated with such invariance, there is a fundamental scale (the Planck scale, l(Planck) approximately 1.62 x 10(-33) cm or E(Planck) = M(Planck)c(2) approximately 1.22 x 10(19) GeV), at which quantum effects are expected to strongly affect the nature of space-time. There is great interest in the (not yet validated) idea that Lorentz invariance might break near the Planck scale. A key test of such violation of Lorentz invariance is a possible variation of photon speed with energy. Even a tiny variation in photon speed, when accumulated over cosmological light-travel times, may be revealed by observing sharp features in gamma-ray burst (GRB) light-curves. Here we report the detection of emission up to approximately 31 GeV from the distant and short GRB 090510. We find no evidence for the violation of Lorentz invariance, and place a lower limit of 1.2E(Planck) on the scale of a linear energy dependence (or an inverse wavelength dependence), subject to reasonable assumptions about the emission (equivalently we have an upper limit of l(Planck)/1.2 on the length scale of the effect). Our results disfavour quantum-gravity theories in which the quantum nature of space-time on a very small scale linearly alters the speed of light.

Detection of high-energy gamma-ray emission from the globular cluster 47 Tucanae with Fermi.

We report the detection of gamma-ray emissions above 200 megaelectron volts at a significance level of 17sigma from the globular cluster 47 Tucanae, using data obtained with the Large Area Telescope onboard the Fermi Gamma-ray Space Telescope. Globular clusters are expected to emit gamma rays because of the large populations of millisecond pulsars that they contain. The spectral shape of 47 Tucanae is consistent with gamma-ray emission from a population of millisecond pulsars. The observed gamma-ray luminosity implies an upper limit of 60 millisecond pulsars present in 47 Tucanae.

Detection of 16 gamma-ray pulsars through blind frequency searches using the Fermi LAT.

Pulsars are rapidly rotating, highly magnetized neutron stars emitting radiation across the electromagnetic spectrum. Although there are more than 1800 known radio pulsars, until recently only seven were observed to pulse in gamma rays, and these were all discovered at other wavelengths. The Fermi Large Area Telescope (LAT) makes it possible to pinpoint neutron stars through their gamma-ray pulsations. We report the detection of 16 gamma-ray pulsars in blind frequency searches using the LAT. Most of these pulsars are coincident with previously unidentified gamma-ray sources, and many are associated with supernova remnants. Direct detection of gamma-ray pulsars enables studies of emission mechanisms, population statistics, and the energetics of pulsar wind nebulae and supernova remnants.

A population of gamma-ray millisecond pulsars seen with the Fermi Large Area Telescope.

Pulsars are born with subsecond spin periods and slow by electromagnetic braking for several tens of millions of years, when detectable radiation ceases. A second life can occur for neutron stars in binary systems. They can acquire mass and angular momentum from their companions, to be spun up to millisecond periods and begin radiating again. We searched Fermi Large Area Telescope data for pulsations from all known millisecond pulsars (MSPs) outside of globular clusters, using rotation parameters from radio telescopes. Strong gamma-ray pulsations were detected for eight MSPs. The gamma-ray pulse profiles and spectral properties resemble those of young gamma-ray pulsars. The basic emission mechanism seems to be the same for MSPs and young pulsars, with the emission originating in regions far from the neutron star surface.

Measurement of the cosmic ray e+ +e- spectrum from 20 GeV to 1 TeV with the Fermi Large Area Telescope.

Designed as a high-sensitivity gamma-ray observatory, the Fermi Large Area Telescope is also an electron detector with a large acceptance exceeding 2 m;{2} sr at 300 GeV. Building on the gamma-ray analysis, we have developed an efficient electron detection strategy which provides sufficient background rejection for measurement of the steeply falling electron spectrum up to 1 TeV. Our high precision data show that the electron spectrum falls with energy as E-3.0 and does not exhibit prominent spectral features. Interpretations in terms of a conventional diffusive model as well as a potential local extra component are briefly discussed.

Fermi observations of high-energy gamma-ray emission from GRB 080916C.

Gamma-ray bursts (GRBs) are highly energetic explosions signaling the death of massive stars in distant galaxies. The Gamma-ray Burst Monitor and Large Area Telescope onboard the Fermi Observatory together record GRBs over a broad energy range spanning about 7 decades of gammaray energy. In September 2008, Fermi observed the exceptionally luminous GRB 080916C, with the largest apparent energy release yet measured. The high-energy gamma rays are observed to start later and persist longer than the lower energy photons. A simple spectral form fits the entire GRB spectrum, providing strong constraints on emission models. The known distance of the burst enables placing lower limits on the bulk Lorentz factor of the outflow and on the quantum gravity mass.

Fermi large area telescope measurements of the diffuse gamma-ray emission at intermediate galactic latitudes.

The diffuse galactic gamma-ray emission is produced by cosmic rays (CRs) interacting with the interstellar gas and radiation field. Measurements by the Energetic Gamma-Ray Experiment Telescope (EGRET) instrument on the Compton Gamma-Ray Observatory indicated excess gamma-ray emission greater, > or approximately equal to 1 GeV relative to diffuse galactic gamma-ray emission models consistent with directly measured CR spectra (the so-called "EGRET GeV excess"). The Large Area Telescope (LAT) instrument on the Fermi Gamma-Ray Space Telescope has measured the diffuse gamma-ray emission with improved sensitivity and resolution compared to EGRET. We report on LAT measurements for energies 100 MeV to 10 GeV and galactic latitudes 10 degrees < or = |b| < or = 20 degrees. The LAT spectrum for this region of the sky is well reproduced by a diffuse galactic gamma-ray emission model that is consistent with local CR spectra and inconsistent with the EGRET GeV excess.

Discovery of localized regions of excess 10-TeV cosmic rays.

The 7 year data set of the Milagro TeV observatory contains 2.2 x 10(11) events of which most are due to hadronic cosmic rays. These data are searched for evidence of intermediate scale structure. Excess emission on angular scales of approximately 10 degrees has been found in two localized regions of unknown origin with greater than 12sigma significance. Both regions are inconsistent with pure gamma-ray emission with high confidence. One of the regions has a different energy spectrum than the isotropic cosmic-ray flux at a level of 4.6sigma, and it is consistent with hard spectrum protons with an exponential cutoff, with the most significant excess at approximately 10 TeV. Potential causes of these excesses are explored, but no compelling explanations are found.

The Fermi Gamma-Ray Space Telescope discovers the pulsar in the young galactic supernova remnant CTA 1.

Energetic young pulsars and expanding blast waves [supernova remnants (SNRs)] are the most visible remains after massive stars, ending their lives, explode in core-collapse supernovae. The Fermi Gamma-Ray Space Telescope has unveiled a radio quiet pulsar located near the center of the compact synchrotron nebula inside the supernova remnant CTA 1. The pulsar, discovered through its gamma-ray pulsations, has a period of 316.86 milliseconds and a period derivative of 3.614 x 10(-13) seconds per second. Its characteristic age of 10(4) years is comparable to that estimated for the SNR. We speculate that most unidentified Galactic gamma-ray sources associated with star-forming regions and SNRs are such young pulsars.