Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.

AIM: To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients. METHODS: Prospective randomized 2-way cross over study; T2DM patients with (micro)albuminuria and/or hypertension underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) at baseline, after one month of enalapril (20mgqd), and after one month of candesartan (16mgqd). Each BOLD-MRI was performed before and after the administration of furosemide. The mean R2* (=1/T2*) values in the medulla and cortex were calculated, a low R2* indicating high tissue oxygenation. RESULTS: Twelve patients (mean age: 60±11 years, eGFR: 62±22ml/min/1.73m(2)) completed the study. Neither chronic enalapril nor candesartan intake modified renal cortical or medullary R2* levels. Furosemide significantly decreased cortical and medullary R2* levels suggesting a transient increase in renal oxygenation. Medullary R2* levels correlated positively with urinary sodium excretion and systemic blood pressure, suggesting lower renal oxygenation at higher dietary sodium intake and blood pressure; cortical R2* levels correlated positively with glycemia and HbA1c. CONCLUSION: RAS blockade does not seem to increase renal tissue oxygenation in T2DM hypertensive patients. The response to furosemide and the association with 24h urinary sodium excretion emphasize the crucial role of renal sodium handling as one of the main determinants of renal tissue oxygenation.

Extensor carpi ulnaris accessory tendinous slips (ECUATS): MRI features at 3.0T and correlation with tendinosis : 49

Purpose: To assess the visibility and the features of ECUATS on 3.0-T MRI studies, and evaluate their correlation with tendinosis. Methods and materials: Our retrospective study was approved by IRB, with waiver of informed consent. Fifty wrist MRI and 48 MR arthrographies from 98 patients (55 males, 43 females, mean age 42.3 years) performed between January and November 2009 on 3.0-T units were reviewed. Images (transverse T1, T2, FS Gd T1 and VIBE) were independently analyzed by two radiologists, and a consensus reached with a third reader in case of disagreement. The visibility of ECUATS was assessed on each available transverse sequence. When present, ECUATS' origins, diameters and insertions were noted. ECU tendinosis was also evaluated. Inter-rater agreement was assessed using Cohen's Kappa coefficient. Results: ECUATS observed prevalence was 23.5% (23/98). ECUATS were more frequently noted on the VIBE sequence, with a good inter-rater agreement (Kappa = 0.72). Origins were noted in 95.7% of cases: 3 were at the level of, and 20 distal to ECU subsheath. Insertions were seen in 43.5%: 2 were on 5th metacarpal bone, 8 on extensor apparatus of 5th finger. ECUATS mean shortest and longest diameters were 0.54 and 0.85 mm respectively. ECU tendinosis was statistically more frequently noted in patients with ECUATS (p <0.05). Conclusion: ECUATS are readily visible on 3.0-T MRI studies, especially on transverse GRE VIBE images. ECU tendinosis is more frequently noted in patients bearing ECUATS.

Fine structural variations of alphabeta TCRs selected by vaccination with natural versus altered self-antigen in melanoma patients

Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26-35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3 composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.

Structural, metamorphic and geochronological relations between the Zanskar Shear Zone and the Miyar Shear Zone (NW Indian Himalaya): Evidence for two distinct tectonic structures and implications for the evolution of the High Himalayan Crystalline of Zanskar

The geologic structures and metamorphic zonation of the northwestern Indian Himalaya contrast significantly with those in the central and eastern parts of the range, where the high-grade metamorphic rocks of the High Himalayan Crystalline (HHC) thrust southward over the weakly metamorphosed sediments of the Lesser Himalaya along the Main Central Thrust (MCT). Indeed, the hanging wall of the MCT in the NW Himalaya mainly consists of the greenschist facies metasediments of the Chamba zone, whereas HHC high-grade rocks are exposed more internally in the range as a large-scale dome called the Gianbul dome. This Gianbul dome is bounded by two oppositely directed shear zones, the NE-dipping Zanskar Shear Zone (ZSZ) on the northern flank and the SW-dipping Miyar Shear Zone (MSZ) on the southern limb. Current models for the emplacement of the HHC in NW India as a dome structure differ mainly in terms of the roles played by both the ZSZ and the MSZ during the tectonothermal evolution of the HHC. In both the channel flow model and wedge extrusion model, the ZSZ acts as a backstop normal fault along which the high-grade metamorphic rocks of the HHC of Zanskar are exhumed. In contrast, the recently proposed tectonic wedging model argues that the ZSZ and the MSZ correspond to one single detachment system that operates as a subhorizontal backthrust off of the MCT. Thus, the kinematic evolution of the two shear zones, the ZSZ and the MSZ, and their structural, metamorphic and chronological relations appear to be diagnostic features for discriminating the different models. In this paper, structural, metamorphic and geochronological data demonstrate that the MSZ and the ZSZ experienced two distinct kinematic evolutions. As such, the data presented in this paper rule out the hypothesis that the MSZ and the ZSZ constitute one single detachment system, as postulated by the tectonic wedging model. Structural, metamorphic and geochronological data are used to present an alternative tectonic model for the large-scale doming in the NW Indian Himalaya involving early NE-directed tectonics, weakness in the upper crust, reduced erosion at the orogenic front and rapid exhumation along both the ZSZ and the MSZ.

Historical logging, productivity, and structural characteristics of boreal coniferous forests in Norway

Abstract

Oligonucleotide-polyethylenimine complexes targeting retinal cells: structural analysis and application to anti-TGFbeta-2 therapy.

PURPOSE: The aim of this study was to characterize oligonucleotide-polyethylenimine (ODN/PEI) complex preparation for potential transfection of retinal cells in vitro and in vivo. METHODS: The effect of medium preparation [HEPES-buffered saline (HBS), water] on particle size and morphology was evaluated. Cultured Lewis rat retinal Müller glial (RMG) cells were transfected using fluorescein isothiocyanate (FITC)-ODN/PEI complexes specifically directed at transforming growth factor beta (TGFbeta)-2. Efficacy of transfection was evaluated using confocal microscopy, and regulation of gene expression was assayed using quantitative real-time RT-PCR and ELISA assay. One, 24, and 72 h after injection of FITC-ODN/PEI complexes into the vitreous of rat eyes, their distribution was analyzed on eye sections. RESULTS: Complexes prepared in HBS were smaller than complexes prepared in pure water and presented a core-shell structure. These particles showed a high cellular internalization efficacy, along with a significant and specific down-regulation of TGFbeta-2 expression and production in RMG cells, correlating with specific inhibition of cell growth at 72 h. In vivo, complexes efficiently transfect retinal cells and follow a transretinal migration at 24 h. After 72 h, ODN seems to preferentially target RMG cells without inducing any detectable toxicity. CONCLUSIONS: Specific down-regulation of TGFbeta-2 expression using ODN/PEI complexes may have potential interest for the treatment of retinal diseases associated with glial proliferation.

T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension.

This article introduces a new interface for T-Coffee, a consistency-based multiple sequence alignment program. This interface provides an easy and intuitive access to the most popular functionality of the package. These include the default T-Coffee mode for protein and nucleic acid sequences, the M-Coffee mode that allows combining the output of any other aligners, and template-based modes of T-Coffee that deliver high accuracy alignments while using structural or homology derived templates. These three available template modes are Expresso for the alignment of protein with a known 3D-Structure, R-Coffee to align RNA sequences with conserved secondary structures and PSI-Coffee to accurately align distantly related sequences using homology extension. The new server benefits from recent improvements of the T-Coffee algorithm and can align up to 150 sequences as long as 10,000 residues and is available from both http://www.tcoffee.org and its main mirror http://tcoffee.crg.cat.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Long-term monitoring of post-stroke plasticity after transient cerebral ischemia in mice using in vivo and ex vivo diffusion tensor MRI.

WE USED A MURINE MODEL OF TRANSIENT FOCAL CEREBRAL ISCHEMIA TO STUDY: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus.Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.

Mixed spectral-structural classification of very high resolution images with summation kernels

In this paper, mixed spectral-structural kernel machines are proposed for the classification of very-high resolution images. The simultaneous use of multispectral and structural features (computed using morphological filters) allows a significant increase in classification accuracy of remote sensing images. Subsequently, weighted summation kernel support vector machines are proposed and applied in order to take into account the multiscale nature of the scene considered. Such classifiers use the Mercer property of kernel matrices to compute a new kernel matrix accounting simultaneously for two scale parameters. Tests on a Zurich QuickBird image show the relevance of the proposed method : using the mixed spectral-structural features, the classification accuracy increases of about 5%, achieving a Kappa index of 0.97. The multikernel approach proposed provide an overall accuracy of 98.90% with related Kappa index of 0.985.

In vivo Structural Imaging of the Cerebellum, the Contribution of Ultra-High Fields.

This review covers some of the contributions to date from cerebellar imaging studies performed at ultra-high magnetic fields. A short overview of the general advantages and drawbacks of the use of such high field systems for imaging is given. One of the biggest advantages of imaging at high magnetic fields is the improved spatial resolution, achievable thanks to the increased available signal-to-noise ratio. This high spatial resolution better matches the dimensions of the cerebellar substructures, allowing a better definition of such structures in the images. The implications of the use of high field systems is discussed for several imaging sequences and image contrast mechanisms. This review covers studies which were performed in vivo in both rodents and humans, with a special focus on studies that were directed towards the observation of the different cerebellar layers.

Delayed contrast-enhanced MRI of the coronary artery wall in takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) is a rare form of chronic inflammatory granulomatous arteritis of the aorta and its major branches. Late gadolinium enhancement (LGE) with magnetic resonance imaging (MRI) has demonstrated its value for the detection of vessel wall alterations in TA. The aim of this study was to assess LGE of the coronary artery wall in patients with TA compared to patients with stable CAD. METHODS: We enrolled 9 patients (8 female, average age 46±13 years) with proven TA. In the CAD group 9 patients participated (8 male, average age 65±10 years). Studies were performed on a commercial 3T whole-body MR imaging system (Achieva; Philips, Best, The Netherlands) using a 3D inversion prepared navigator gated spoiled gradient-echo sequence, which was repeated 34-45 minutes after low-dose gadolinium administration. RESULTS: No coronary vessel wall enhancement was observed prior to contrast in either group. Post contrast, coronary LGE on IR scans was detected in 28 of 50 segments (56%) seen on T2-Prep scans in TA and in 25 of 57 segments (44%) in CAD patients. LGE quantitative assessment of coronary artery vessel wall CNR post contrast revealed no significant differences between the two groups (CNR in TA: 6.0±2.4 and 7.3±2.5 in CAD; p = 0.474). CONCLUSION: Our findings suggest that LGE of the coronary artery wall seems to be common in patients with TA and similarly pronounced as in CAD patients. The observed coronary LGE seems to be rather unspecific, and differentiation between coronary vessel wall fibrosis and inflammation still remains unclear.