Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient.

Novel characterization of bEnd.3 cells that express lymphatic vessel endothelial hyaluronan receptor-1.

Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-alpha), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the bEnd.3 cell line is derived from murine endothelioma, we further examined human tissues of endothelioma and identified lymphatic vessels in the tumor samples which express both LYVE-1 and podoplanin. Moreover, a significantly higher number of lymphatic vessels were detected in the endothelioma samples compared with normal control. Taken together, this study not only redefines bEnd.3 cells for vascular research, but also indicates a broader category of human diseases that are associated with lymphatics, such as endothelioma.

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes.

AIMS/HYPOTHESIS: The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. METHODS: Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10⁻8 mol/l) and/or the UII receptor antagonist, SB-657510 (10⁻8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg kg⁻¹ day⁻¹; n = 20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. RESULTS: In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. CONCLUSIONS/INTERPRETATION: This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

Pressure prediction model for compression garment design.

Based on the application of Laplace's law to compression garments, an equation for predicting garment pressure, incorporating the body circumference, the cross-sectional area of fabric, applied strain (as a function of reduction factor), and its corresponding Young's modulus, is developed. Design procedures are presented to predict garment pressure using the aforementioned parameters for clinical applications. Compression garments have been widely used in treating burning scars. Fabricating a compression garment with a required pressure is important in the healing process. A systematic and scientific design method can enable the occupational therapist and compression garments' manufacturer to custom-make a compression garment with a specific pressure. The objectives of this study are 1) to develop a pressure prediction model incorporating different design factors to estimate the pressure exerted by the compression garments before fabrication; and 2) to propose more design procedures in clinical applications. Three kinds of fabrics cut at different bias angles were tested under uniaxial tension, as were samples made in a double-layered structure. Sets of nonlinear force-extension data were obtained for calculating the predicted pressure. Using the value at 0° bias angle as reference, the Young's modulus can vary by as much as 29% for fabric type P11117, 43% for fabric type PN2170, and even 360% for fabric type AP85120 at a reduction factor of 20%. When comparing the predicted pressure calculated from the single-layered and double-layered fabrics, the double-layered construction provides a larger range of target pressure at a particular strain. The anisotropic and nonlinear behaviors of the fabrics have thus been determined. Compression garments can be methodically designed by the proposed analytical pressure prediction model.

Anomalous compressibility of ferropericlase throughout the iron spin cross-over.

The thermoelastic properties of ferropericlase Mg(1-x)Fe(x)O (x = 0.1875) throughout the iron high-to-low spin cross-over have been investigated by first principles at Earth's lower mantle conditions. This cross-over has important consequences for elasticity such as an anomalous bulk modulus (K(S)) reduction. At room temperature the anomaly is somewhat sharp in pressure but broadens with increasing temperature. Along a typical geotherm it occurs across most of the lower mantle with a more significant K(S) reduction at approximately 1,400-1,600 km depth. This anomaly might also cause a reduction in the effective activation energy for diffusion creep and lead to a viscosity minimum in the mid-lower mantle, in apparent agreement with results from inversion of data related with mantle convection and postglacial rebound.

Improvements in phosphate control with short daily in-center hemodialysis.

BACKGROUND: Hyperphosphatemia is an independent risk factor for mortality in hemodialysis (HD) patients. The relative importance of HD frequency and duration for phosphate removal is not clear. Short daily hemodialysis (SDHD) is a form of HD which offers increased treatment frequency. SDHD studies have not been shown to normalize serum phosphate. METHODS: Twenty-one patients were converted from conventional thrice weekly HD (CHD, 4 h/session) to SDHD (2 - 3.75 h/session, 5 - 6 sessions per week). The primary endpoint was the change in predialysis serum phosphate levels after conversion from CHD to SDHD. Changes in serum calcium levels, phosphate binder and vitamin D analogue usage, and serum parathyroid hormone (PTH) levels were measured as secondary endpoints. RESULTS: Mean duration of SDHD was 17.7 +/- 1.9 months. Mean treatment time was 2.63 +/- 0.10 h, and mean frequency was 5.3 +/- 0.1 sessions per week. Predialysis serum phosphate decreased from 1.99 +/- 0.12 mM at three months pre conversion to 1.27 +/- 0.10 mM at six months post conversion to SDHD (p = 0.002). Serum phosphate remained stable between six and 12 months post conversion (1.27 +/- 0.10 mM to 1.38 +/- 0.14 mM, p = 0.8). When patients were grouped according to SDHD sessional frequency (five sessions/week versus six sessions/week) and compared, no significant differences were found in predialysis serum phosphate levels at six or 12 months post conversion. There were no changes in serum calcium. Overall phosphate binder usage did not change pre and post conversion to SDHD. Serum PTH tended to decrease after one year of SDHD (44.2 +/- 13.4 pM to 21.4 +/- 5.9 pM, p = 0.07). CONCLUSION: Conversion to SDHD significantly decreased serum phosphate. There may be a minimum hemodialysis duration below which increases in frequency are not able to compensate to achieve normal phosphate levels. Future studies are necessary to better characterize the relationship between HD duration and frequency with respect to phosphate removal.

Expression and function of A1 adenosine receptors in the rat hippocampus following transient forebrain ischemia.

We investigated how transient cerebral ischemia affects the gene expression, immunoreactive protein levels, and the function of the A1 subtype of adenosine receptor in the rat hippocampus at different times following reperfusion. A1 receptor mRNA levels were altered significantly in different hippocampal subfields as early as 6 h following insult. However, these changes in mRNA levels were not paralleled at the protein level, as western blotting with A1 receptor-specific antibodies revealed that hippocampal A1 adenosine receptor prevalence did not differ from sham control at either 6 or 24 h following insult. The lack of change in A1 receptor prevalence was consistent with functional examinations, as only marginal changes were observed in the ability of A1 receptors to attenuate excitatory post-synaptic potentials in the CA1 subfield at 24 h following reperfusion. These data illustrate that although the mRNA expression levels of the A1 adenosine receptor are altered by transient cerebral ischemia, the immunoreactive prevalence and function of this receptor are maintained in the post-ischemic hippocampus at times preceding the death of the vulnerable neurons.

The initiation of subduction: criticality by addition of water?

Subduction is a major process of plate tectonics; however, its initiation is not understood. We used high-resolution (less than 1 kilometer) finite-element models based on rheological data of the lithosphere to investigate the role played by water on initiating subduction. A solid-fluid thermomechanical instability is needed to drive a cold, stiff, and negatively buoyant lithosphere into the mantle. This instability can be triggered slowly by sedimentary loading over a time span of 100 million years. Our results indicate that subduction can proceed by a double feedback mechanism (thermoelastic and thermal-rheological) promoted by lubrication due to water.

Phosphatidylinositol 3,4,5-trisphosphate directs association of Src homology 2-containing signaling proteins with gelsolin.

Podosomes are adhesion structures in osteoclasts and are structurally related to focal adhesions mediating cell motility during bone resorption. Here we show that gelsolin coprecipitates some of the focal adhesion-associated proteins such as c-Src, phosphoinositide 3-kinase (PI3K), p130(Cas), focal adhesion kinase, integrin alpha(v)beta(3), vinculin, talin, and paxillin. These proteins were inducibly tyrosine-phosphorylated in response to integrin activation by osteopontin. Previous studies have defined unique biochemical properties of gelsolin related to phosphatidylinositol 3,4,5-trisphosphate in osteoclast podosomes, and here we demonstrate phosphatidylinositol 3,4,5-trisphosphate/gelsolin function in mediating organization of the podosome signaling complex. Overlay and GST pull-down assays demonstrated strong phosphatidylinositol 3,4,5-trisphosphate-PI3K interactions based on the Src homology 2 domains of PI3K. Furthermore, lipid extraction of lysates from activated osteoclasts eliminated interaction between gelsolin, c-Src, PI3K, and focal adhesion kinase despite equal amounts of gelsolin in both the lipid-extracted and unextracted experiment. The cytoplasmic protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of alpha(v)beta(3)-regulated phosphorylation of PTP-PEST. We conclude that gelsolin plays a key role in recruitment of signaling proteins to the plasma membrane through phospholipid-protein interactions and by regulation of their phosphorylation status through its association with PTP-PEST. Because both gelsolin deficiency and PI3K inhibition impair bone resorption, we conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein interactions are critical for osteoclast function.

Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection.

The selection events shaping T cell development in the thymus represent the outcome of TCR-driven intracellular signaling cascades evoked by Ag receptor interaction with cognate ligand. In view of data indicating TCR-evoked thymocyte proliferation to be negatively modulated by the SHP-1 tyrosine phosphatase, a potential role for SHP-1 in regulating selection processes was investigated by analysis of T cell development in H-Y TCR transgenic mice rendered SHP-1 deficient by introduction of the viable motheaten mutation or a dominant negative SHP-1-encoding transgene. Characterization of thymocyte and peripheral T cell populations in H-Y TCR-viable motheaten mice revealed TCR-evoked proliferation as well as the positive and negative selection of H-Y-specific thymocytes to be enhanced in these mice, thus implicating SHP-1 in the negative regulation of each of these processes. T cell selection processes were also augmented in H-Y TCR mice carrying a transgene driving lymphoid-restricted expression of a catalytically inert, dominant-negative form of SHP-1. SHP-1-negative effects on thymocyte TCR signaling were not influenced by co-cross-linking of the CD28 costimulatory and/or CTLA-4 inhibitory receptors and appear, accordingly, to be realized independently of these comodulators. These observations indicate that SHP-1 raises the signaling threshold required for both positive and negative selection and reveal the inhibitory effects of SHP-1 on TCR signaling to be cell autonomous. The demonstrated capacity for SHP-1 to inhibit TCR-evoked proliferation and selection indicate SHP-1 modulatory effects on the magnitude of TCR-generated signal to be a key factor in determining the cellular consequences of TCR-ligand interaction.

Plumes and waves in two-dimensional turbulent thermal convection.

We have conducted a high-resolution, two-dimensional direct numerical simulation of Rayleigh-Bénard convection with stress-free and periodic boundary conditions at a Rayleigh (Ra) number of 10(8) and Prandtl (Pr) number of unity. An aspect-ratio three box has been considered. A single cell has been used as the initial condition. First, the flow develops into time-dependent convection with a strong asymmetry and highly convoluted thermal plumes delineating a large-scale circulation. Smaller thermal plumes detach from the boundary layer and extend over the entire cell, creating a local inversion of the temperature gradient adjacent to the boundary layers. Then the conditions leading to the formation of internal waves are fulfilled, as the local Richardson number decreases sufficiently small to cross the linear threshold of Ri=0.25. Together with the strong shear, convective rolls with a Kelvin-Helmholtz wavelike character are produced. The secondary boundary layer itself becomes unstable and produces smaller plumes. At later times, the large-scale circulation is destroyed and the internal waves disappear. A Reynolds number, based on the global scale, of Re=500, is attained at this stage. Only isolated thermal plumes and vortices are present. Thus, internal waves can be generated at finite Prandtl number fluids for sufficiently high Ra in the presence of a large-scale circulation. Spectral analysis reveals that the kinetic energy decays with a logarithmic slope of -3, while the logarithmic slope of the thermal variance has a value of around -5 / 3.

Generation of a primitive erythroid cell line and promotion of its growth by basic fibroblast growth factor.

An immortalized cell line representing the primitive erythroid (EryP) lineage was established from in vitro-differentiated progeny (embryoid bodies [EBs]) of embryonic stem (ES) cells using a retroviral insertional mutation, and has been termed EB-PE for embryoid body-derived primitive erythroid. Even though EB-PE cells are immortalized, they show characteristics of normal EryP cells, such as gene expression and growth factor dependency. In addition, EB-PE cells can differentiate further in culture. Investigation of growth factor requirements of EB-PE cells showed that basic fibroblast growth factor (bFGF) and erythropoietin (Epo) play unique roles in EB-PE proliferation and differentiation. While bFGF was a strong mitogen, Epo was required for both proliferation and differentiation. The unique proliferative response to bFGF coincided with upregulation of its receptor, fibroblast growth factor receptor (fgfr-1), and downregulation of erythropoietin receptor (EpoR) gene expression. Studies of primary EryP cells derived from early EBs, when tested in a colony-formation assay, also provided evidence for the mitogenic role of bFGF in concert with Epo.

Feeding premature infants after hospital discharge.

Supplying adequate nutrition to premature infants is an ongoing challenge. Common medical conditions that premature infants develop and therapies given to them can increase their nutritional requirements or interfere with the delivery of nutrients. This article outlines factors to consider when prescribing appropriate diet and nutritional supplements at hospital discharge.

Catalytic mechanism and DNA substrate recognition of Escherichia coli MutY protein.

Escherichia coli MutY protein cleaves A/G- or a/7,8-dihydro-8-oxo-guanine (A/GO)-containing DNA on the A-strand by N-glycosylase and apurinic/apyrimidinic endonuclease or lyase activities. In this paper, we show that MutY can be trapped in a stable covalent enzyme-DNA intermediate in the presence of sodium borohydride, a new finding that supports the grouping of MutY in that class of DNA glycosylases that possess concomitant apurinic/apyrimidinic lyase activity. To potentially help determine the substrate recognition site of MutY, mutant proteins were constructed. MutY proteins with a Gly116 --> Ala (G116A) or Asp (G116D) mutation had reduced binding affinities for both A/G- and A/GO-containing DNA substrates. The catalytic parameters, however, were differentially affected. While A/G- and A/GO-containing DNA were cleaved by MutY with specificity constants (kcat/Km) of 10 and 3.3 min-1 microM-1, respectively, MutY(G116D) cleaved these DNAs 2, 300- and 9-fold less efficiently. The catalytic activities of MutY(G116A) with A/G- and A/GO-containing DNA were about the same as that of wild-type MutY. Both MutY(G116A) and MutY(G116D) could be trapped in covalent intermediates with A/GO-containing DNA, but with lower efficiencies than the wild-type enzyme in the presence of sodium borohydride. MutY(G116A) also formed a covalent intermediate with A/G-containing DNA, but MutY(G116D) did not. Since Gly116 of MutY lies in a region that is highly conserved among several DNA glycosylases, it is likely this conserved region is in the proximity of the substrate binding and/or catalytic sites.

Viscous dissipation in three-dimensional convection with temperature-dependent viscosity.

Numerical simulations of three-dimensional convection with temperature-dependent viscosity and viscous heating at realistic Rayleigh numbers for Earth's mantle reveal that, in the strongly time-dependent regime, very intense localized heating takes place along the top portion of descending cold sheets and also at locations where the ascending plume heads impinge at the surface. For a viscosity contrast of 100, these localized heat sources exceed the internal heating due to the radioactive decay of chondritic materials by more than an order of magnitude. The horizontally averaged viscous dissipation is concentrated in the top of the convecting layer and has a magnitude comparable with that of radioactive heating.

Implications for mantle dynamics from the high melting temperature of perovskite.

Recent studies have implied that (Mg, Fe)SiO(3)-perovskite, a likely dominant mineral phase in the lower mantle, may have a high melting temperature. The implications of these findings for the dynamics of the lower mantle were investigated with the use of numerical convection models. The results showed that low homologous temperatures (0.3 to 0.5) would prevail in the modeled lower mantle, regardless of the effective Rayleigh number and internal heating rates. High-temperature ductile creep is possible under relatively cold conditions. In models with low rates of internal heating, local maxima of viscosity developed in the mid-lower mantle that were similar to those obtained from inversion of geoid, topography, and plate velocities.

Three-dimensional instabilities of mantle convection with multiple phase transitions.

The effects of multiple phase transitions on mantle convection are investigated by numerical simulations that are based on three-dimensional models. These simulations show that cold sheets of mantle material collide at junctions, merge, and form a strong downflow that is stopped temporarily by the transition zone. The accumulated cold material gives rise to a strong gravitational instability that causes the cold mass to sink rapidly into the lower mantle. This process promotes a massive exchange between the lower and upper mantles and triggers a global instability in the adjacent plume system. This mechanism may be cyclic in nature and may be linked to the generation of superplumes.

Intraocular lymphoma developing in a patient with Vogt-Koyanagi-Harada syndrome.

A 59-year-old Oriental male with chronic uveitis associated with vitiligo, poliosis, tinnitus and sunset glow fundus was diagnosed as having chronic Vogt-Koyanagi-Harada syndrome. He was treated successfully with steroids (systemic and sub-Tenon's) for two years, but then developed intractable vitritis and visual loss that worsened with the addition of azathioprine. A vitreous biopsy showed large B-cell lymphoma; a mass was also apparent in the subretinal space in the operated eye. Evaluation of the central nervous system was negative for lymphoma. Combined radiation treatment and chemotherapy resulted in dramatic resolution of the intraocular tumor. The possible role of immunosuppression in the development and progression of this tumor is discussed.

Development of diapiric structures in the upper mantle due to phase transitions.

Solid-state phase transitions in time-dependent mantle convection can induce diapiric flows in the upper mantle. When a deep mantle plume rises toward phase boundaries in the upper mantle, the changes in the local thermal buoyancy, local heat capacity, and latent heat associated with the phase change at a depth of 670 kilometers tend to pinch off the plume head from the feeding stem and form a diapir. This mechanism may explain episodic hot spot volcanism. The nature of the multiple phase boundaries at the boundary between the upper and lower mantle may control the fate of deep mantle plumes, allowing hot plumes to go through and retarding the tepid ones.