Novel renal replacement strategies for the elimination of serum free light chains in patients with kappa light chain nephropathy

Multiple myeloma (MM) is a malignancy with excessive production of monoclonal proteins. At disease presentation 30% of MM patients have significant renal impairment which may progress to renal failure requiring dialysis. Besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood, however the efficacy was poor with older techniques. We report about a highly efficient method to eliminate serum free light chain (sFLC) using a newly designed protein leaking membrane in patients suffering from sFLC induced acute renal failure. The protein leaking membrane (HCO 1100) is characterized by increased pore size facilitating elimination of middle molecules such as sFLC kappa (22.5 kD). The HCO 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures (high flux hemodialysis, hemodiafiltration and plasma exchange). Hemodiafiltration with the protein leaking membrane HCO 1100 was superior to all other extracorporeal replacement strategies in eliminating sFLC-kappa from circulating blood. A median blood reduction rate of 40.8% (range 13.9% - 66.4%) was achieved during hemodiafiltration. The corresponding peak clearance rate was 25 ml/min. Importantly, the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis. Extracorporeal elimination strategies with the protein leaking membrane HCO 1100 may be a promising adjuvant treatment strategy for patients with sFLC nephropathy requiring dialysis. Hemodiafiltration and to lesser extend also hemodialysis with the HCO 1100 hemofilter are able to eliminate substantial amounts of sFLC kappa in MM patients

Dual-frequency VLBI study of Centaurus A on sub-parsec scales

Centaurus A is the closest active galactic nucleus. High resolution imaging using Very Long Baseline Interferometry (VLBI) enables us to study the spectral and kinematic behavior of the radio jet-counterjet system on sub-parsec scales, providing essential information for jet emission and formation models. Our aim is to study the structure and spectral shape of the emission from the central-parsec region of Cen A. As a target of the Southern Hemisphere VLBI monitoring program TANAMI (Tracking Active Galactic Nuclei with Milliarcsecond Interferometry), VLBI observations of Cen A are made regularly at 8.4 and 22.3 GHz with the Australian Long Baseline Array (LBA) and associated telescopes in Antarctica, Chile, and South Africa. The first dual-frequency images of this source are presented along with the resulting spectral index map. An angular resolution of 0.4 mas x 0.7 mas is achieved at 8.4 GHz, corresponding to a linear scale of less than 0.013 pc. Hence, we obtain the highest resolution VLBI image of Cen A, comparable to previous space-VLBI observations. By combining with the 22.3 GHz image, which has been taken without contributing transoceanic baselines at somewhat lower resolution, we present the corresponding dual-frequency spectral index distribution along the sub-parsec scale jet revealing the putative emission regions for recently detected gamma-rays from the core region by Fermi/LAT. We resolve the innermost structure of the milliarcsecond scale jet and counterjet system of Cen A into discrete components. The simultaneous observations at two frequencies provide the highest resolved spectral index map of an AGN jet allowing us to identify multiple possible sites as the origin of the high energy emission.Comment: 5 pages, 3 figures (1 color); A&A, accepte

Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)

BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-κB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT 1-receptor antibodies or from pharmacologic blockade of AT 1 receptors

Ultra-High Energy Cosmic Ray production in the polar cap regions of black hole magnetospheres

We develop a model of ultra-high energy cosmic ray (UHECR) production via acceleration in a rotation-induced electric field in vacuum gaps in the magnetospheres of supermassive black holes (BH). We show that if the poloidal magnetic field near the BH horizon is misaligned with the BH rotation axis, charged particles, which initially spiral into the BH hole along the equatorial plane, penetrate into the regions above the BH "polar caps" and are ejected with high energies to infinity. We show that in such a model acceleration of protons near a BH of typical mass 3e8 solar masses is possible only if the magnetic field is almost aligned with the BH rotation axis. We find that the power of anisotropic electromagnetic emission from an UHECR source near a supermassive BH should be at least 10-100 times larger then UHECR power of the source. This implies that if the number of UHECR sources within the 100 Mpc sphere is ~100, the power of electromagnetic emission which accompanies proton acceleration in each source, $10^{42-43}$ erg/s, is comparable to the typical luminosities of active galactic nuclei (AGN) in the local Universe. We also explore the acceleration of heavy nuclei, for which the constraints on the electromagnetic luminosity and on the alignment of magnetic field in the gap are relaxed

Recovery of release cloud from laser shock-loaded graphite and hydrocarbon targets: in search of diamonds

This work presents first insights into the dynamics of free-surface release clouds from dynamically compressed polystyrene and pyrolytic graphite at pressures up to 200 GPa, where they transform into diamond or lonsdaleite, respectively. These ejecta clouds are released into either vacuum or various types of catcher systems, and are monitored with high-speed recordings (frame rates up to 10 MHz). Molecular dynamics simulations are used to give insights to the rate of diamond preservation throughout the free expansion and the catcher impact process, highlighting the challenges of diamond retrieval. Raman spectroscopy data show graphitic signatures on a catcher plate confirming that the shock-compressed PS is transformed. First electron microscopy analyses of solid catcher plates yield an outstanding number of different spherical-like objects in the size range between ten(s) up to hundreds of nanometres, which are one type of two potential diamond candidates identified. The origin of some objects can unambiguously be assigned, while the history of others remains speculative

High energy radiation from Centaurus A

We calculate for the nearest active galactic nucleus (AGN), Centaurus A, the flux of high energy cosmic rays and of accompanying secondary photons and neutrinos expected from hadronic interactions in the source. We use as two basic models for the generation of ultrahigh energy cosmic rays (UHECR) shock acceleration in the radio jet and acceleration in the regular electromagnetic field close to the core of the AGN. While scattering on photons dominates in scenarios with acceleration close to the core, scattering on gas becomes more important if acceleration takes place along the jet. Normalizing the UHECR flux from Centaurus A to the observations of the Auger experiment, the neutrino flux may be marginally observable in a 1 km$^3$ neutrino telescope, if a steep UHECR flux \d N/\d E\propto E^{-\alpha} with $\alpha=2.7$ extends down to $10^{17}$ eV. The associated photon flux is close to or exceeds the observational data of atmospheric Cherenkov and $\gamma$-ray telescopes for \alpha\gsim 2. In particular, we find that already present data favour either a softer UHECR injection spectrum than $\alpha=2.7$ for Centaurus A or a lower UHECR flux than expected from the normalization to the Auger observations.Comment: 12 pages, 6 figures; v2: revised version to appear in a special issue of New Journal for Physic

Ndel1 Promotes Axon Regeneration via Intermediate Filaments

Failure of axons to regenerate following acute or chronic neuronal injury is attributed to both the inhibitory glial environment and deficient intrinsic ability to re-grow. However, the underlying mechanisms of the latter remain unclear. In this study, we have investigated the role of the mammalian homologue of aspergillus nidulans NudE, Ndel1, emergently viewed as an integrator of the cytoskeleton, in axon regeneration. Ndel1 was synthesized de novo and upregulated in crushed and transected sciatic nerve axons, and, upon injury, was strongly associated with neuronal form of the intermediate filament (IF) Vimentin while dissociating from the mature neuronal IF (Neurofilament) light chain NF-L. Consistent with a role for Ndel1 in the conditioning lesion-induced neurite outgrowth of Dorsal Root Ganglion (DRG) neurons, the long lasting in vivo formation of the neuronal Ndel1/Vimentin complex was associated with robust axon regeneration. Furthermore, local silencing of Ndel1 in transected axons by siRNA severely reduced the extent of regeneration in vivo. Thus, Ndel1 promotes axonal regeneration; activating this endogenous repair mechanism may enhance neuroregeneration during acute and chronic axonal degeneration