New limits on a cosmological constant from statistics of gravitational lensing

We present new limits on cosmological parameters from the statistics of gravitational lensing, based on the recently revised knowledge of the luminosity function and internal dynamics of E/S0 galaxies that are essential in lensing high-redshift QSOs. We find that the lens models using updated Schechter parameters for such galaxies, derived from the recent redshift surveys combined with morphological classification, are found to give smaller lensing probabilities than earlier calculated. Inconsistent adoption of these parameters from a mixture of various galaxy surveys gives rise to systematic biases in the results. We also show that less compact dwarf-type galaxies which largely dominate the faint part of the Schechter-form luminosity function contribute little to lensing probabilities, so that earlier lens models overestimate incidents of small separation lenses. Applications of the lens models to the existing lens surveys indicate that reproduction of both the lensing probability of optical sources and the image separations of optical and radio lenses is significantly improved in the revised lens models. The likelihood analyses allow us to conclude that a flat universe with Omega=0.3(+0.2-0.1) and Omega+Lambda=1 is most preferable, and a matter-dominated flat universe with Lambda=0 is ruled out at 98 % confidence level. These new limits are unaffected by inclusion of uncertainties in the lens properties.Comment: 30 pages, 9 ps figures, AASTeX, ApJ in pres

Early post-metamorphic, Carboniferous blastoid reveals the evolution and development of the digestive system in echinoderms

Inferring the development of the earliest echinoderms is critical to uncovering the evolutionary assembly of the phylum-level body plan but has long proven problematic because early ontogenetic stages are rarely preserved as fossils. Here, we use synchrotron tomography to describe a new early post-metamorphic blastoid echinoderm from the Carboniferous (approx. 323 Ma) of China. The resulting three-dimensional reconstruction reveals a U-shaped tubular structure in the fossil interior, which is interpreted as the digestive tract. Comparisons with the developing gut of modern crinoids demonstrate that crinoids are an imperfect analogue for many extinct groups. Furthermore, consideration of our findings in a phylogenetic context allows us to reconstruct the evolution and development of the digestive system in echinoderms more broadly; there was a transition from a straight to a simple curved gut early in the phylum's evolution, but additional loops and coils of the digestive tract (as seen in crinoids) were not acquired until much later

Shear and Ellipticity in Gravitational Lenses

Galaxies modeled as singular isothermal ellipsoids with an axis ratio distribution similar to the observed axis ratio distribution of E and S0 galaxies are statistically consistent with both the observed numbers of two-image and four-image lenses and the inferred ellipticities of individual lenses. However, no four-image lens is well fit by the model (typical $\chi^2/N_{dof} \sim 20$), the axis ratio of the model can be significantly different from that of the observed lens galaxy, and the major axes of the model and the galaxy may be slightly misaligned. We found that models with a second, independent, external shear axis could fit the data well (typical $\chi^2/N_{dof} \sim 1$), while adding the same number of extra parameters to the radial mass distribution does not produce such a dramatic improvement in the fit. An independent shear axis can be produced by misalignments between the luminous galaxy and its dark matter halo, or by external shear perturbations due to galaxies and clusters correlated with the primary lens or along the line of sight. We estimate that the external shear perturbations have no significant effect on the expected numbers of two-image and four-image lenses, but that they can be important perturbations in individual lens models. However, the amplitudes of the external shears required to produce the good fits are larger than our estimates for typical external shear perturbations (10-15% shear instead of 1-3% shear) suggesting that the origin of the extra angular structure must be intrinsic to the primary lens galaxy in most cases.Comment: 38 pages, 9 figures, submitted to Ap

Determining the Hubble Constant from the Gravitational Lens PG 1115+080

For the quadruple gravitational lens PG 1115+080, we combine recent measurements of the time delays with new lens models to determine the Hubble constant H_0. We explore the effects of systematic uncertainties in the lens models on the estimates of H_0, and we discuss how the uncertainties can be reduced by future observations. We find that the lens cannot be fit by an isolated lens galaxy, but that it can be well fit by including a perturbation from the nearby group of galaxies. To understand the full range of systematic uncertainties it is crucial to use an ellipsoidal galaxy and to let the group position vary. In this case, the existing constraints cannot break degeneracies in the models with respect to the profiles of the galaxy and group and to the position of the group. Combining the known time delays with a range of lens models incorporating most of the plausible systematic effects yields H_0 = 51_{-13}^{+14} km s^{-1} Mpc^{-1}. The constraints on the lens models, and hence on H_0, can be improved by reducing the standard errors in the lens galaxy position from 50 mas to \sim10 mas, reducing the uncertainties in the time delays to \sim0.5 days, and constraining the lens mass distribution using HST photometry and the fundamental plane. In particular, the time delay ratio r_{ABC} = \Delta\tau_{AC} / \Delta\tau_{BA} may provide the best constraint on the mass profile of the galaxy.Comment: revised to use the updated time delays of Bar-Kana astro-ph/9701068; 30 pages, 7 Postscript figures, to appear in Ap

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m2 over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administratio

Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults

<p>Abstract</p> <p>Background</p> <p>The relationships among serum bilirubin concentration, kidney function and proteinuria have yet to be fully elucidated, nor have these relationships been investigated in Korean adults.</p> <p>Method</p> <p>We retrospectively reviewed the medical records of Korean adults who were evaluated at Kosin University Gospel Hospital (Busan, Republic of Korea) during a five-year period from January 2005 to December 2009. We evaluated the relationships among serum bilirubin concentration, estimated glomerular filtration rate (eGFR) and 24-hour urinary protein excretion in a sample of 1363 Korean adults aged 18 years or older.</p> <p>Results</p> <p>The values of eGFR <60 mL/min/1.73 m²and 24-hour urine albumin ≥150 mg/day were observed in 26.1% (n = 356) and 40.5% (n = 553) of subjects, respectively. Fasting glucose levels ≥126 mg/dL were observed in 44.9% (n = 612) of the total sample. After adjustment for potential confounding factors including demographic characteristics, comorbidities and other laboratory measures, total serum bilirubin was positively associated with eGFR and negatively associated with proteinuria both in the whole cohort and in a subgroup of diabetic individuals.</p> <p>Conclusions</p> <p>To our knowledge, this is the first hospital-based study specifically aimed at examining the relationships among serum total bilirubin concentration, 24-hour urine protein and kidney function in Korean adults. We demonstrated that serum total bilirubin concentration was negatively correlated with 24-hour urine protein and positively correlated with eGFR in Korean non-diabetic and diabetic adults.</p

Erythrocyte and Porcine Intestinal Glycosphingolipids Recognized by F4 Fimbriae of Enterotoxigenic Escherichia coli

Enterotoxigenic F4-fimbriated Escherichia coli is associated with diarrheal disease in neonatal and postweaning pigs. The F4 fimbriae mediate attachment of the bacteria to the pig intestinal epithelium, enabling an efficient delivery of diarrhea-inducing enterotoxins to the target epithelial cells. There are three variants of F4 fimbriae designated F4ab, F4ac and F4ad, respectively, having different antigenic and adhesive properties. In the present study, the binding of isolated F4ab, F4ac and F4ad fimbriae, and F4ab/ac/ad-fimbriated E. coli, to glycosphingolipids from erythrocytes and from porcine small intestinal epithelium was examined, in order to get a comprehensive view of the F4-binding glycosphingolipids involved in F4-mediated hemagglutination and adhesion to the epithelial cells of porcine intestine. Specific interactions between the F4ab, F4ac and F4ad fimbriae and both acid and non-acid glycosphingolipids were obtained, and after isolation of binding-active glycosphingolipids and characterization by mass spectrometry and proton NMR, distinct carbohydrate binding patterns were defined for each fimbrial subtype. Two novel glycosphingolipids were isolated from chicken erythrocytes, and characterized as GalNAcα3GalNAcß3Galß4Glcß1Cer and GalNAcα3GalNAcß3Galß4GlcNAcß3Galß4Glcß1Cer. These two compounds, and lactosylceramide (Galß4Glcß1Cer) with phytosphingosine and hydroxy fatty acid, were recognized by all three variants of F4 fimbriae. No binding of the F4ad fimbriae or F4ad-fimbriated E. coli to the porcine intestinal glycosphingolipids occurred. However, for F4ab and F4ac two distinct binding patterns were observed. The F4ac fimbriae and the F4ac-expressing E. coli selectively bound to galactosylceramide (Galß1Cer) with sphingosine and hydroxy 24:0 fatty acid, while the porcine intestinal glycosphingolipids recognized by F4ab fimbriae and the F4ab-fimbriated bacteria were characterized as galactosylceramide, sulfatide (SO3-3Galß1Cer), sulf-lactosylceramide (SO3-3Galß4Glcß1Cer), and globotriaosylceramide (Galα4Galß4Glcß1Cer) with phytosphingosine and hydroxy 24:0 fatty acid. Finally, the F4ad fimbriae and the F4ad-fimbriated E. coli, but not the F4ab or F4ac subtypes, bound to reference gangliotriaosylceramide (GalNAcß4Galß4Glcß1Cer), gangliotetraosylceramide (Galß3GalNAcß4Galß4Glcß1Cer), isoglobotriaosylceramide (Galα3Galß4Glcß1Cer), and neolactotetraosylceramide (Galß4GlcNAcß3Galß4Glcß1Cer)

Sulfatide Recognition by Colonization Factor Antigen CS6 from Enterotoxigenic Escherichia coli

The first step in the pathogenesis of enterotoxigenic Escherichia coli (ETEC) infections is adhesion of the bacterium to the small intestinal epithelium. Adhesion of ETEC is mediated by a number of antigenically distinct colonization factors, and among these, one of the most commonly detected is the non-fimbrial adhesin coli surface antigen 6 (CS6). The potential carbohydrate recognition by CS6 was investigated by binding of recombinant CS6-expressing E. coli and purified CS6 protein to a large number of variant glycosphingolipids separated on thin-layer chromatograms. Thereby, a highly specific binding of the CS6-expressing E. coli, and the purified CS6 protein, to sulfatide (SO3-3Galβ1Cer) was obtained. The binding of the CS6 protein and CS6-expressing bacteria to sulfatide was inhibited by dextran sulfate, but not by dextran, heparin, galactose 4-sulfate or galactose 6-sulfate. When using recombinantly expressed and purified CssA and CssB subunits of the CS6 complex, sulfatide binding was obtained with the CssB subunit, demonstrating that the glycosphingolipid binding capacity of CS6 resides within this subunit. CS6-binding sulfatide was present in the small intestine of species susceptible to CS6-mediated infection, e.g. humans and rabbits, but lacking in species not affected by CS6 ETEC, e.g. mice. The ability of CS6-expressing ETEC to adhere to sulfatide in target small intestinal epithelium may thus contribute to virulence

Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t1/2 ∼1 h), or a slow, zero-order release rate (t1/2 ∼ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies

A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443