Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis.

Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (\u3e 60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients a parts per thousand yen60 years old (median 66; range 60-74) had a significantly higher BuCL versus those \u3c 60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p \u3e 0.34). Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients

Discovery of the Binary Pulsar PSR B1259-63 in Very-High-Energy Gamma Rays around Periastron with H.E.S.S

We report the discovery of very-high-energy (VHE) gamma-ray emission of the binary system PSR B1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the H.E.S.S. experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a gamma-ray signal from the binary system was detected with a total significance above 13 sigma. The flux was found to vary significantly on timescales of days which makes PSR B1259-63 the first variable galactic source of VHE gamma-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F_0(E/1 TeV)^-Gamma with a photon index Gamma = 2.7+-0.2_stat+-0.2_sys and flux normalisation F_0 = (1.3+-0.1_stat+-0.3_sys) 10^-12 TeV^-1 cm^-2 s^-1. This detection of VHE gamma-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE gamma-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.Comment: 10 pages, 8 figures, accepted in Astronomy and Astrophysics on 2 June 2005, replace: document unchanged, replaced author field in astro-ph entry - authors are all members of the H.E.S.S. collaboration and three additional authors (99+3, see document

First detection of a VHE gamma-ray spectral maximum from a Cosmic source: H.E.S.S. discovery of the Vela X nebula

The Vela supernova remnant (SNR) is a complex region containing a number of sources of non-thermal radiation. The inner section of this SNR, within 2 degrees of the pulsar PSR B0833-45, has been observed by the H.E.S.S. gamma-ray atmospheric Cherenkov detector in 2004 and 2005. A strong signal is seen from an extended region to the south of the pulsar, within an integration region of radius 0.8 deg. around the position (RA = 08h 35m 00s, dec = -45 deg. 36' J2000.0). The excess coincides with a region of hard X-ray emission seen by the ROSAT and ASCA satellites. The observed energy spectrum of the source between 550 GeV and 65 TeV is well fit by a power law function with photon index = 1.45 +/- 0.09(stat) +/- 0.2(sys) and an exponential cutoff at an energy of 13.8 +/- 2.3(stat) +/- 4.1(sys) TeV. The integral flux above 1 TeV is (1.28 +/- 0.17 (stat) +/- 0.38(sys)) x 10^{-11} cm^{-2} s^{-1}. This result is the first clear measurement of a peak in the spectral energy distribution from a VHE gamma-ray source, likely related to inverse Compton emission. A fit of an Inverse Compton model to the H.E.S.S. spectral energy distribution gives a total energy in non-thermal electrons of ~2 x 10^{45} erg between 5 TeV and 100 TeV, assuming a distance of 290 parsec to the pulsar. The best fit electron power law index is 2.0, with a spectral break at 67 TeV.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and Astrophysics letter

Observations of Mkn 421 in 2004 with H.E.S.S. at large zenith angles

Mkn 421 was observed during a high flux state for nine nights in April and May 2004 with the fully operational High Energy Stereoscopic System (H.E.S.S.) in Namibia. The observations were carried out at zenith angles of 60$^\circ$--65$^\circ$, which result in an average energy threshold of 1.5 TeV and a collection area reaching 2~km$^2$ at 10~TeV. Roughly 7000 photons from Mkn~421 were accumulated with an average gamma-ray rate of 8 photons/min. The overall significance of the detection exceeds 100 standard deviations. The light-curve of integrated fluxes above 2~TeV shows changes of the diurnal flux up to a factor of 4.3. For nights of high flux, intra-night variability is detected with a decay time of less than 1 hour. The time averaged energy spectrum is curved and is well described by a power-law with a photon index \egamm and an exponential cutoff at \ecut~TeV and an average integral flux above 2~TeV of 3 Crab flux units. Significant variations of the spectral shape are detected with a spectral hardening as the flux increases. Contemporaneous multi-wavelength observations at lower energies (X-rays and gamma-rays above $\approx 300$~GeV) indicate smaller relative variability amplitudes than seen above 2~TeV during high flux state observed in April 2004.Comment: 5 pages, 4 figures, published in A&

Very high energy gamma rays from the direction of Sagittarius A*.

We report the detection of a point-like source of very high energy (VHE) -rays coincident within 1' of Sgr A *, obtained with the HESS array of Cherenkov telescopes. The -rays exhibit a power-law energy spectrum with a spectral index of and a flux above the 165 GeV threshold of m -2 s -1. The measured flux and spectrum differ substantially from recent results reported in particular by the CANGAROO collaboration

A possible association of the new VHE gamma-ray source HESS J1825--137 with the pulsar wind nebula G18.0--0.7

We report on a possible association of the recently discovered very high-energy $\gamma$-ray source HESS J1825--137 with the pulsar wind nebula (commonly referred to as G 18.0--0.7) of the $2.1\times 10^{4}$ year old Vela-like pulsar PSR B1823--13. HESS J1825--137 was detected with a significance of 8.1 $\sigma$ in the Galactic Plane survey conducted with the H.E.S.S. instrument in 2004. The centroid position of HESS J1825--137 is offset by 11\arcmin south of the pulsar position. \emph{XMM-Newton} observations have revealed X-ray synchrotron emission of an asymmetric pulsar wind nebula extending to the south of the pulsar. We argue that the observed morphology and TeV spectral index suggest that HESS J1825--137 and G 18.0--0.7 may be associated: the lifetime of TeV emitting electrons is expected to be longer compared to the {\it XMM-Newton} X-ray emitting electrons, resulting in electrons from earlier epochs (when the spin-down power was larger) contributing to the present TeV flux. These electrons are expected to be synchrotron cooled, which explains the observed photon index of $\sim 2.4$, and the longer lifetime of TeV emitting electrons naturally explains why the TeV nebula is larger than the X-ray size. Finally, supernova remnant expansion into an inhomogeneous medium is expected to create reverse shocks interacting at different times with the pulsar wind nebula, resulting in the offset X-ray and TeV $\gamma$-ray morphology.Comment: 5 pages, 3 figures, to appear in Astronomy and Astrophysics Letter

H.E.S.S. observations of gamma-ray bursts in 2003-2007

Very-high-energy (VHE; >~100 GeV) gamma-rays are expected from gamma-ray bursts (GRBs) in some scenarios. Exploring this photon energy regime is necessary for understanding the energetics and properties of GRBs. GRBs have been one of the prime targets for the H.E.S.S. experiment, which makes use of four Imaging Atmospheric Cherenkov Telescopes (IACTs) to detect VHE gamma-rays. Dedicated observations of 32 GRB positions were made in the years 2003-2007 and a search for VHE gamma-ray counterparts of these GRBs was made. Depending on the visibility and observing conditions, the observations mostly start minutes to hours after the burst and typically last two hours. Results from observations of 22 GRB positions are presented and evidence of a VHE signal was found neither in observations of any individual GRBs, nor from stacking data from subsets of GRBs with higher expected VHE flux according to a model-independent ranking scheme. Upper limits for the VHE gamma-ray flux from the GRB positions were derived. For those GRBs with measured redshifts, differential upper limits at the energy threshold after correcting for absorption due to extra-galactic background light are also presented.Comment: 9 pages, 4 tables, 3 figure