Different Aspects of Classical Pathway Overactivation in Patients With C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown. Here, we investigated the CP convertase activity in patients with C3G and IC-MPGN. Using a refined two-step hemolytic assay, we measured the stability of CP convertases directly in the serum of 52 patients and 17 healthy controls. In four patients, CP convertase activity was prolonged compared to healthy controls, i.e. the enzymatic complex was stabilized. In three patients (2 C3G, 1 IC-MPGN) the convertase stabilization was caused by immunoglobulins, indicating the presence of autoantibodies named C4 nephritic factors (C4NeFs). Importantly, the assay also enabled detection of non-immunoglobulin-mediated stabilization of the CP convertase in one patient with C3G. Prolonged CP convertase activity coincided with C3NeF activity in all patients and for up to 70 months of observation. Crucially, experiments with C3-depleted serum showed that C4NeFs stabilized the CP C3 convertase (C4bC2a), that does not contain C3NeF epitopes. All patients with prolonged CP convertase activity showed clear signs of complement activation, i.e. lowered C3 and C5 levels and elevated levels of C3d, C3bc, C3bBbP, and C5b-9. In conclusion, this work provides new insights into the diverse aspects and (non-)immunoglobulin nature of factors causing CP convertase overactivity in C3G/IC-MPGN.</p

The Effect of Statins and Other Cardiovascular Medication on Ischemia-Reperfusion Damage in a Human DIEP Flap Model: Theoretical and Epidemiological Considerations

Background. Statins and other cardiovascular medication possess antioxidant capacity. It was examined whether chronic use of these medications protects from the development of ischemia-reperfusion (I/R) related complications after DIEP (Deep Inferior Epigastric Perforator Free Flap) surgery. This paper contains a literature study on the antioxidant working mechanisms of these drugs. Methods. Medical information of 134 DIEP patients (173 flaps) was studied from their medical files. Patient and operative characteristics were registered, as well as I/R related complications. Results. Of the group that didnot use statins, 16.3% developed complications versus 30.8% amongst patients that did use these drugs (P = 0.29). Amongst patients that chronically use other cardiovascular medication, 26.8% developed I/R related complications versus 14.4% of the patients without medication (P = 0.10). Conclusions. Chronic use of statins or other cardiovascular medication didnot decrease the occurrence of I/R related complications after DIEP surgery. Therefore, research should be aimed at evaluating short-term pre-treatment with statins

Transmembrane Domain Single-Nucleotide Polymorphisms Impair Expression and Transport Activity of ABC Transporter ABCG2

To study the function and expression of nine naturally occurring single-nucleotide polymorphisms (G406R, F431L, S441N, P480L, F489L, M515R, L525R, A528T and T542A) that are predicted to reside in the transmembrane regions of the ABC transporter ABCG2. The transport activity of the variants was tested in inside-out membrane vesicles from Sf9 insect and human derived HEK293 cells overexpressing ABCG2. Lucifer Yellow and estrone sulfate were used as probe substrates of activity. The expression levels and cellular localization of the variants was compared to the wild-type ABCG2 by western blotting and immunofluorescence microscopy. All studied variants of ABCG2 displayed markedly decreased transport in both Sf9-ABCG2 and HEK293-ABCG2 vesicles. Impaired transport could be explained for some variants by altered expression levels and cellular localization. Moreover, the destructive effect on transport activity of variants G406R, P480L, M515R and T542A is, to our knowledge, reported for the first time. These results indicate that the transmembrane region of ABCG2 is sensitive to amino acid substitution and that patients harboring these ABCG2 variant forms could suffer from unexpected pharmacokinetic events of ABCG2 substrate drugs or have an increased risk for diseases such as gout where ABCG2 is implicated.Peer reviewe

The role of habit in compulsivity.

Compulsivity has been recently characterized as a manifestation of an imbalance between the brain׳s goal-directed and habit-learning systems. Habits are perhaps the most fundamental building block of animal learning, and it is therefore unsurprising that there are multiple ways in which the development and execution of habits can be promoted/discouraged. Delineating these neurocognitive routes may be critical to understanding if and how habits contribute to the many faces of compulsivity observed across a range of psychiatric disorders. In this review, we distinguish the contribution of excessive stimulus-response habit learning from that of deficient goal-directed control over action and response inhibition, and discuss the role of stress and anxiety as likely contributors to the transition from goal-directed action to habit. To this end, behavioural, pharmacological, neurobiological and clinical evidence are synthesised and a hypothesis is formulated to capture how habits fit into a model of compulsivity as a trans-diagnostic psychiatric trait.CM Gillan is supported by a Sir Henry Wellcome Postdoctoral Fellowship (101521/Z/12/Z).This is the final version of the article. It was first available from Elsevier via https://doi.org/10.1016/j.euroneuro.2015.12.03

A Massive White Dwarf Companion to the Eccentric Binary Pulsar System PSR B2303+46

Pulsars in close, eccentric binary systems are usually assumed to have another neutron star as a companion. These double neutron star binaries have proven to be the best laboratories for experimental General Relativity and are the most secure candidates for gravitational wave interferometers. We present deep B, V, and R images of the field containing the eccentric binary pulsar system PSR B2303+46. We find a faint, blue object (B=26.60+/-0.09; (B-R)_0=-0.4+/-0.2) coincident with the timing position. We suggest this object is the optical counterpart to the PSR B2303+46 system. The counterpart is too bright to reflect emission from the pulsar or a neutron star companion. Most likely, the companion of PSR B2303+46 is not a neutron star but a massive white dwarf. We show that the observations are consistent with a hot white dwarf companion (T_eff>~5*10^4 K) with cooling age equal the characteristic age of the pulsar (t_cool~30 Myr) and mass within the range set by timing observations and the Chandrasekhar mass (1.2<M_C<1.4 M_sun). Given the eccentric orbit, the white dwarf must have formed before the neutron star, from what was originally the more massive star in the binary. Due to mass transfer, the originally less massive star could become sufficiently massive to end its life in a supernova explosion and form the radio pulsar. We constrain the mass of the pulsar to be in the range 1.24<M_psr<1.44 M_sun.Comment: Revised version, with only very small changes. 6 pages, 1 figure, uses aas4pp2.sty, psfig.sty. Accepted for publication in Astrophysical Journal Letter

The Temperature and Cooling Age of the White-Dwarf Companion to the Millisecond Pulsar PSR B1855+09

We report on Keck and {\em Hubble Space Telescope} observations of the binary millisecond pulsar PSR B1855+09. We detect its white-dwarf companion and measure \mv=25.90\pm0.12 and \mi=24.19\pm0.11 (Vega system). From the reddening-corrected color, (\mv-\mi)_0=1.06\pm0.21, we infer a temperature \Teff=4800\pm800 K. The white-dwarf mass is known accurately from measurements of the Shapiro delay of the pulsar signal, \Mcomp=0.258^{+0.028}_{-0.016} \Msun. Hence, given a cooling model, one can use the measured temperature to determine the cooling age. The main uncertainty in the cooling models for such low-mass white dwarfs is the amount of residual nuclear burning, which is set by the thickness of the hydrogen layer surrounding the helium core. From the properties of similar systems, it has been inferred that helium white dwarfs form with thick hydrogen layers, with mass \simgt3\times10^{-3} \Msun, which leads to significant additional heating. This is consistent with expectations from simple evolutionary models of the preceding binary evolution. For PSR B1855+09, though, such models lead to a cooling age of $\sim10$Gyr, which is twice the spin-down age of the pulsar. It could be that the spin-down age were incorrect, which would call the standard vacuum dipole braking model into question. For two other pulsar companions, however, ages well over 10 Gyr are inferred, indicating that the problem may lie with the cooling models. There is no age discrepancy for models in which the white dwarfs are formed with thinner hydrogen layers (\simlt3\times10^{-4} \Msun).Comment: 7 pages, 1 figure, aas4pp2.sty. Accepted for publication in ApJ

Graph analysis of the anatomical network organization of the hippocampal formation and parahippocampal region in the rat

Graph theory was used to analyze the anatomical network of the rat hippocampal formation and the parahippocampal region (van Strien et al., Nat Rev Neurosci 10(4):272–282, 2009). For this analysis, the full network was decomposed along the three anatomical axes, resulting in three networks that describe the connectivity within the rostrocaudal, dorsoventral and laminar dimensions. The rostrocaudal network had a connection density of 12 % and a path length of 2.4. The dorsoventral network had a high cluster coefficient (0.53), a relatively high path length (1.62) and a rich club was identified. The modularity analysis revealed three modules in the dorsoventral network. The laminar network contained most information. The laminar dimension revealed a network with high clustering coefficient (0.47), a relatively high path length (2.11) and four significantly increased characteristic network building blocks (structural motifs). Thirteen rich club nodes were identified, almost all of them situated in the parahippocampal region. Six connector hubs were detected and all of them were located in the entorhinal cortex. Three large modules were revealed, indicating a close relationship between the perirhinal and postrhinal cortex as well as between the lateral and medial entorhinal cortex. These results confirmed the central position of the entorhinal cortex in the (para)hippocampal network and this possibly explains why pathology in this region has such profound impact on cognitive function, as seen in several brain diseases. The results also have implications for the idea of strict separation of the “spatial” and the “non-spatial” information stream into the hippocampus. This two-stream memory model suggests that the information influx from, respectively, the postrhinal–medial entorhinal cortex and the perirhinal–lateral entorhinal cortex is separate, but the current analysis shows that this apparent separation is not determined by anatomical constraints

SN 2005hj: Evidence for Two Classes of Normal-Bright SNe Ia and Implications for Cosmology

HET Optical spectra covering the evolution from about 6 days before to about 5 weeks after maximum light and the ROTSE-IIIb unfiltered light curve of the "Branch-normal" Type Ia Supernova SN 2005hj are presented. The host galaxy shows HII region lines at redshift of z=0.0574, which puts the peak unfiltered absolute magnitude at a somewhat over-luminous -19.6. The spectra show weak and narrow SiII lines, and for a period of at least 10 days beginning around maximum light these profiles do not change in width or depth and they indicate a constant expansion velocity of ~10,600 km/s. We analyzed the observations based on detailed radiation dynamical models in the literature. Whereas delayed detonation and deflagration models have been used to explain the majority of SNe Ia, they do not predict a long velocity plateau in the SiII minimum with an unvarying line profile. Pulsating delayed detonations and merger scenarios form shell-like density structures with properties mostly related to the mass of the shell, M_shell, and we discuss how these models may explain the observed SiII line evolution; however, these models are based on spherical calculations and other possibilities may exist. SN 2005hj is consistent with respect to the onset, duration, and velocity of the plateau, the peak luminosity and, within the uncertainties, with the intrinsic colors for models with M_shell=0.2 M_sun. Our analysis suggests a distinct class of events hidden within the Branch-normal SNe Ia. If the predicted relations between observables are confirmed, they may provide a way to separate these two groups. We discuss the implications of two distinct progenitor classes on cosmological studies employing SNe Ia, including possible differences in the peak luminosity to light curve width relation.Comment: ApJ accepted, 31 page

Surface Hydrogen Modeling of Super Soft X-ray Sources: Are They Supernova Ia Progenitors?

Nova explosions occur on the white dwarf (WD) component of a Cataclysmic Variable stellar system which is accreting matter lost by a companion. A Type Ia supernova explosion is thought to result when a WD, in a similar binary configuration, grows in mass to the Chandrasekhar Limit. Here, we present calculations of accretion of Solar matter, at a variety of mass accretion rates, onto hot ($2.3 \times 10^{5}$K), luminous (30L$_\odot$), massive (1.25M$_\odot$, 1.35M$_\odot$) Carbon-Oxygen WDs. In contrast to our nova simulations where the WD has a low initial luminosity and a thermonuclear runaway (TNR) occurs and ejects material, these simulations do not eject material (or only a small fraction of the accreted material) and the WD grows in mass. A hydrogen TNR does not occur because hydrogen fuses to helium in the surface layers, and we call this process Surface Hydrogen Burning (SHB). As the helium layer grows in mass, it gradually fuses either to carbon and oxygen or to more massive nuclei depending on the WD mass and mass accretion rate. If such a WD were to explode in a SN Ia event, therefore, it would show neither hydrogen nor helium in its spectrum as is observed. Moreover, the luminosities and effective temperatures of our simulations agree with the observations of some of the Super Soft X-ray Binary Sources and, therefore, our results strengthen previous speculation that some of them (CAL 83 and CAL 87 for example) are probably progenitors of SN Ia explosions. Finally, we have achieved SHB for values of the mass accretion rate that almost span the observed values of the Cataclysmic Variables.Comment: Accepted by APJL, 4 pages, 1 figure, LaTex (uses emulateapj.sty

Loss of Productivity Due to Neck/Shoulder Symptoms and Hand/Arm Symptoms: Results from the PROMO-Study

Introduction: The objective of the present study is to describe the extent of productivity loss among computer workers with neck/shoulder symptoms and hand/arm symptoms, and to examine associations between pain intensity, various physical and psychosocial factors and productivity loss in computer workers with neck/shoulder and hand/arm symptoms. Methods: A cross-sectional design was used. The study population consisted of 654 computer workers with neck/shoulder or hand/arm symptoms from five different companies. Descriptive statistics were used to describe the occurrence of self-reported productivity loss. Logistic regression analyses were used to examine the associations. Results: In 26% of all the cases reporting symptoms, productivity loss was involved, the most often in cases reporting both symptoms (36%). Productivity loss involved sickness absence in 11% of the arm/hand cases, 32% of the neck/shoulder cases and 43% of the cases reporting both symptoms. The multivariate analyses showed statistically significant odds ratios for pain intensity (OR: 1.26; CI: 1.12-1.41), for high effort/no low reward (OR: 2.26; CI: 1.24-4.12), for high effort/low reward (OR: 1.95; CI: 1.09-3.50), and for low job satisfaction (OR: 3.10; CI: 1.44-6.67). Physical activity in leisure time, full-time work and overcommitment were not associated with productivity loss. Conclusion: In most computer workers with neck/shoulder symptoms or hand/arm symptoms productivity loss derives from a decreased performance at work and not from sickness absence. Favorable psychosocial work characteristics might prevent productivity loss in symptomatic workers. © 2007 Springer Science+Business Media, LLC