In uncontrolled clinical studies, ursodeoxycholic acid (UDCA) had a beneficial effect on nonalcoholic steatohepatitis (NASH). However, a large controlled trial using UDCA (13‐15 mg/kg/day) was unable ...to confirm these results. Accordingly, a randomized, placebo‐controlled study was initiated with a high dose of UDCA (23‐28 mg/kg/day). The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score (NAS). With the modified Brunt score, 185 patients with histologically proven NASH were randomized intention to treat (ITT), and 147 were treated per protocol (PP). With the NAS, 137 patients were confirmed to have NASH, 48 had borderline NASH, and 1 did not have NASH. The treatment time was 18 months. At entry, the treatment groups were comparable. A second biopsy sample was obtained from 139 of 185 patients (NAS: 107/137). The primary criterion for evaluation was a change in the liver histology; the secondary criteria were single histological variables and liver biochemistry. Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score (P = 0.881) or NAS (P = 0.355). Only lobular inflammation improved significantly (P for the modified Brunt score = 0.011, P for NAS = 0.005). In subgroup analyses, significant improvements in lobular inflammation were also observed in males, younger patients up to 50 years of age, slightly overweight patients, and patients with hypertension and an increased histology score. The fibrosis score did not change (P for ITT = 0.133, P for PP = 0.140). With the exception of γ‐glutamyl transferase, UDCA did not improve laboratory data. Conclusion: High‐dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo. Hepatology 2010
Abstract
Aerosol levels influence the wavelength dependent transmission properties of the atmosphere. Variations in aerosol levels therefore affect the amount of Cherenkov light from air-showers that ...can reach an atmospheric Cherenkov detector. As the amount of detected Cherenkov light is directly related to a primary shower particle’s energy, deviations between actual and assumed atmospheric transmission properties yield errors in reconstructed particle energies as well as energy axes of instrument response functions. In this work, a scheme is presented to assess this influence and potentially reduce related errors in the air-shower reconstruction. The proposed scheme relies on estimations or measurements of the aerosol optical depth and atmospheric density profile which are then used in radiative transfer simulations to generate atmospheric transmission profiles. As the scheme furthermore uses detector specific quantum efficiencies and generalised shower evolution models, it does not rely on detailed Monte Carlo simulations for the different atmospheric conditions but only on the transmission profile which the initial shower reconstruction algorithm is based on. The approach is derived and presented on the example of the H.E.S.S. experiment which employs imaging atmospheric Cherenkov telescopes in the Khomas Highland of Namibia to detect gamma rays in the GeV to TeV energy range.
microRNAs (miRNAs) are endogenous, noncoding approximately 22-nucleotide RNA molecules that have recently emerged as fundamental, post-transcriptional regulators of cognate target gene expression. ...Many mammalian miRNAs are expressed in a tissue-specific manner, a phenomenon that has so far been attributed to transcriptional regulation. We here show by Northern blots and in situ hybridization experiments that the expression of mammalian miRNAs can be regulated at the post-transcriptional level. In particular, miR-138 is spatially restricted to distinct cell types, while its precursor, pre-miR-138-2, is ubiquitously expressed throughout all tissues analyzed. Furthermore, pre-miR-138-2 is exported from the nucleus to the cytoplasm, suggesting that cleavage of this pre-miRNA by Dicer is restricted to certain tissues and cell types. Thus, differential processing of pre-miRNAs might be an alternative mechanism to control miRNA function.
A number of previous investigations implied that there is a relationship between the high voltage electrical losses incurred by corona and the optical energy observed by solar-blind ultraviolet ...cameras. Furthermore, these previous investigations proved that the optical energy detected is influenced by a number of radiometric parameters such as distance and atmospheric conditions, as well as the electrical test configuration. In addition this presents the results of a study to determine the influence of a specific solar-blind ultraviolet camera's spectral bandwidth on the camera's optical measurements. This shows how to uniquely overcome limitations of a particular camera's processing output such that the spectral transfer of the camera can be measured. The aim of this paper is to stimulate and provide additional insight into the electrical losses on dielectric insulators, including the relation of the optical energy observed by solar-blind ultraviolet cameras.
A crucial step in the RNA interference (RNAi) pathway involves the assembly of RISC, the RNA‐induced silencing complex. RISC initially recognizes a double‐stranded short interfering RNA (siRNA), but ...only one strand is finally retained in the functional ribonucleoprotein complex. The non‐incorporated strand, or ‘passenger’ strand, is removed during the assembly process and most probably degraded thereafter. In this report, we show that the passenger strand is cleaved during the course of RISC assembly following the same rules established for the siRNA‐guided cleavage of a target RNA. Chemical modifications impairing the cleavage of the passenger strand also impair the cleavage of a target RNA in vitro as well as the silencing of a reporter gene in vivo, suggesting that passenger strand removal is facilitated by its cleavage during RISC assembly. Interestingly, target RNA cleavage can be rescued if an otherwise non‐cleavable passenger strand shows a nick at the scissile phosphodiester bond, which further indicates that the cleavage event per se is not essential.
Aims Application of antibodies against cardiac troponin I (cTnI-Ab) can induce dilation and dysfunction of the heart in mice. Recently, we demonstrated that immunization with cTnI induces ...inflammation and fibrosis in myocardium of mice. Others have shown that auto-antibodies to cTnI are present in patients with acute coronary syndrome, but little is known about the clinical relevance of detected cTnI-Ab. Methods and results First, anti-cTnI and anti-cTnT antibody titres were measured in sera from 272 patients with dilated- (DCM) and 185 with ischaemic- (ICM) cardiomyopathy. Secondly, 108 patients with acute myocardial infarction (AMI) were included for a follow-up study. Heart characteristics were determined by magnetic resonance imaging 4 days and 6–9 months after AMI. Altogether in 7.0% of patients with DCM and in 9.2% with ICM, an anti-cTnI IgG antibody titre ≥1:160 was measured. In contrast, only in 1.7% of patients with DCM and in 0.5% with ICM, an anti-cTnT IgG antibody titre ≥1:160 was detected. Ten out of 108 patients included in the follow-up study were tested positive for cTnI-Ab with IgG Ab titres ≥1:160. TnI-Ab negative patients showed a significant increase in left ventricular ejection fraction (LVEF) and stroke volume 6–9 months after AMI. In contrast, there was no significant increase in LVEF and stroke volume in TnI-Ab positive patients. Conclusion We demonstrate for the first time that the prevalence of cTnI-Abs in patients with AMI has an impact on the improvement of the LVEF over a study period of 6–9 months.
The microRNA pathway has been implicated in the regulation of synaptic protein synthesis and ultimately in dendritic spine morphogenesis, a phenomenon associated with long-lasting forms of memory. ...However, the particular microRNAs (miRNAs) involved are largely unknown. Here we identify specific miRNAs that function at synapses to control dendritic spine structure by performing a functional screen. One of the identified miRNAs, miR-138, is highly enriched in the brain, localized within dendrites and negatively regulates the size of dendritic spines in rat hippocampal neurons. miR-138 controls the expression of acyl protein thioesterase 1 (APT1), an enzyme regulating the palmitoylation status of proteins that are known to function at the synapse, including the alpha(13) subunits of G proteins (Galpha(13)). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized Galpha(13) both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of Galpha(13) might be an important downstream event of miR-138 function. Our results uncover a previously unknown miRNA-dependent mechanism in neurons and demonstrate a previously unrecognized complexity of miRNA-dependent control of dendritic spine morphogenesis.
Abstract
Background
Fibroblast activation protein (FAP) plays an important role in cardiac wound healing and remodelling. Although initially developed as a theranostic ligand for metastasized cancer, ...FAPI tracers have recently been used to study cardiac remodelling following myocardial infarction in small animal models. Aim of our analysis was to evaluate the activity of fibroblast activation protein via (FAPI) PET-CT scans in human hearts.
Methods
FAPI-PET-CT scans of 229 patients of two consecutive cohorts (initial cohort: n=185; confirmatory cohort: n=44) suffering from metastasized cancer were analysed using a 17-segment model of the left ventricle. Patient characteristics included age, sex, cancer entity, body mass index, renal function, thyroid stimulating hormone, cardiovascular risk factors, previous radiation to the chest, chemotherapies received, and current cardiac medication. Multivariate regression models were created using data from the initial cohort by selecting variables according to Akaike's information criterion in a step-down approach. Linear regression models were used for signal prediction to find potential outliers with unexpectedly high signal intensities. The created models were subsequently evaluated in the confirmatory cohort for reproducibility.
Results
Signal intensity were significantly higher in patients with overweight, diabetes and following radiation to the chest. Our prediction model performed well in both cohorts. A focal enrichment pattern was more frequently observed in patients with known cardiovascular risk factors.
Conclusions
FAPI-PET-CT scans represent a new imaging modality to potentially investigate active cardiac remodelling. High signal intensities are associated with cardiovascular risk factors and metabolic disease. Furthermore, high cardiac FAPI signal intensities are suggestive of an underlying cardiac disease.
Funding Acknowledgement
Type of funding source: None
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