Inter-Pregnancy Weight Change and the Risk of Recurrent Pregnancy Complications

Funding: Funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS, Theme 7: Diet and Health). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript. Data Availability: All relevant data are owned by the Aberdeen Maternity and Neonatal Databank. Interested parties may request access to the data by following the instructions at http://www.abdn.ac.uk/iahs/research/obsgynae/amnd/access.php.

Co-morbidity burden in Parkinson’s disease : Comparison with controls and its influence on prognosis

Open Access funded by Parkinson's UK Financial support: This study was funded by Parkinson’s UK, the Scottish Chief Scientist Office, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The funders had no involvement in the study. We acknowledge funding for the PINE study from Parkinson’s UK (G-0502, G-0914 G-1302), the Scottish Chief Scientist Office (CAF/12/05), the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, NHS Grampian endowments and SPRING. We thank the patients and controls for their participation and the research staff who collected data and supported the study database.

Cytokine-mediated enhancement of epidermal growth factor receptor expression provides an immunological approach to the therapy of pancreatic cancer

The increased expression of epidermal growth factor receptor induced by tumor necrosis factor α renders pancreatic cancer cells more susceptible to antibody-dependent cellular cytotoxicity by a mAb specific for this receptor. Laboratory studies with athymic mice bearing xenografts of human pancreatic cancer cells demonstrated a cytokine-induced ability of the mAb to cause significant tumor regression. In a phase I/II clinical trial, 26 patients with unresectable pancreatic cancer were enrolled into three cohorts receiving variable amounts of the antibody together with a constant amount of tumor necrosis factor α. With increasing doses of antibody, the growth of the primary tumor was significantly inhibited. This was reflected by a longer median survival, with one complete remission lasting for 3 years obtained with the highest dose of antibody employed. Thus, a combination of the cytokine, tumor necrosis factor α, with a mAb to the epidermal growth factor receptor offers a potentially useful approach for the treatment of pancreatic cancer.

Cell-Adhesive Responses to Tenascin-C Splice Variants Involve Formation of Fascin Microspikes

Tenascin-C is an adhesion-modulating matrix glycoprotein that has multiple effects on cell behavior. Tenascin-C transcripts are expressed in motile cells and at sites of tissue modeling during development, and alternative splicing generates variants that encode different numbers of fibronectin type III repeats. We have examined the in vivo expression and cell adhesive properties of two full-length recombinant tenascin-C proteins: TN-190, which contains the eight constant fibronectin type III repeats, and TN-ADC, which contains the additional AD2, AD1, and C repeats. In situ hybridization with probes specific for the AD2, AD1, and C repeats shows that these splice variants are expressed at sites of active tissue modeling and fibronectin expression in the developing avian feather bud and sternum. Transcripts incorporating the AD2, AD1, and C repeats are present in embryonic day 10 wing bud but not in embryonic day 10 lung. By using a panel of nine cell lines in attachment assays, we have found that C2C12, G8, and S27 myoblastic cells undergo concentration-dependent adhesion to both variants, organize actin microspikes that contain the actin-bundling protein fascin, and do not assemble focal contacts. On a molar basis, TN-ADC is more active than TN-190 in promoting cell attachment and irregular cell spreading. The addition of either TN-190 or TN-ADC in solution to C2C12, COS-7, or MG-63 cells adherent on fibronectin decreases cell attachment and results in decreased organization of actin microfilament bundles, with formation of cortical membrane ruffles and retention of residual points of substratum contact that contain filamentous actin and fascin. These data establish a biochemical similarity in the processes of cell adhesion to tenascin-C and thrombospondin-1, also an “antiadhesive” matrix component, and also demonstrate that both the adhesive and adhesion-modulating properties of tenascin-C involve similar biochemical events in the cortical cytoskeleton. In addition to these generic properties, TN-ADC is less active in adhesion modulation than TN-190. The coordinated expression of different tenascin-C transcripts during development may, therefore, provide appropriate microenvironments for regulated changes in cell shape, adhesion, and movement.

Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein

The identification of the neutralization domains of hepatitis C virus (HCV) is essential for the development of an effective vaccine. Here, we show that the hypervariable region 1 (HVR1) of the envelope 2 (E2) protein is a critical neutralization domain of HCV. Neutralization of HCV in vitro was attempted with a rabbit hyperimmune serum raised against a homologous synthetic peptide derived from the HVR1 of the E2 protein, and the residual infectivity was evaluated by inoculation of HCV-seronegative chimpanzees. The source of HCV was plasma obtained from a patient (H) during the acute phase of posttransfusion non-A, non-B hepatitis, which had been titered for infectivity in chimpanzees. The anti-HVR1 antiserum induced protection against homologous HCV infection in chimpanzees, but not against the emergence of neutralization escape mutants that were found to be already present in the complex viral quasispecies of the inoculum. The finding that HVR1 can elicit protective immunity opens new perspectives for the development of effective preventive strategies. However, the identification of the most variable region of HCV as a critical neutralization domain poses a major challenge for the development of a broadly reactive vaccine against HCV.

Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-γ gene and protein expression in lupus T cells

In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-γ). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-γ genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-γ gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-γ production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.

Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to βadrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein–kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein–kinin system could be involved in the development or progression of cardiovascular diseases.

Patterning of the mammalian cochlea

The mammalian cochlea is sophisticated in its function and highly organized in its structure. Although the anatomy of this sense organ has been well documented, the molecular mechanisms underlying its development have remained elusive. Information generated from mutant and knockout mice in recent years has increased our understanding of cochlear development and physiology. This article discusses factors important for the development of the inner ear and summarizes cochlear phenotypes of mutant and knockout mice, particularly Otx and Otx2. We also present data on gross development of the mouse cochlea.

4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ

The estrogen-related receptors (ERRα, ERRβ, and ERRγ) form a family of orphan nuclear receptors that share significant amino acid identity with the estrogen receptors, but for which physiologic roles remain largely unknown. By using a peptide sensor assay, we have identified the stilbenes diethylstilbestrol (DES), tamoxifen (TAM), and 4-hydroxytamoxifen (4-OHT) as high-affinity ligands for ERRγ. In direct binding assays, 4-OHT had a Kd value of 35 nM, and both DES and TAM displaced radiolabeled 4-OHT with Ki values of 870 nM. In cell-based assays, 4-OHT binding caused a dissociation of the complex between ERRγ and the steroid receptor coactivator-1, and led to an inhibition of the constitutive transcriptional activity of ERRγ. ERRα did not bind 4-OHT, but replacing a single amino acid predicted to be in the ERRα ligand-binding pocket with the corresponding ERRγ residue allowed high-affinity 4-OHT binding. These results demonstrate the existence of high-affinity ligands for the ERR family of orphan receptors, and identify 4-OHT as a molecule that can regulate the transcriptional activity of ERRγ.

A quasi-elastic aquifer deformational behavior: Madrid aquifer case study

The purpose of this paper is to analyze the quasi-elastic deformational behavior that has been induced by groundwater withdrawal of the Tertiary detrital aquifer of Madrid (Spain). The spatial and temporal evolution of ground surface displacement was estimated by processing two datasets of radar satellite images (SAR) using Persistent Scatterer Interferometry (PSI). The first SAR dataset was acquired between April 1992 and November 2000 by ERS-1 and ERS-2 satellites, and the second one by the ENVISAT satellite between August 2002 and September 2010. The spatial distribution of PSI measurements reveals that the magnitude of the displacement increases gradually towards the center of the well field area, where approximately 80 mm of maximum cumulated displacement is registered. The correlation analysis made between displacement and piezometric time series provides a correlation coefficient greater than 85% for all the wells. The elastic and inelastic components of measured displacements were separated, observing that the elastic component is, on average, more than 4 times the inelastic component for the studied period. Moreover, the hysteresis loops on the stress–strain plots indicate that the response is in the elastic range. These results demonstrate the quasi-elastic behavior of the aquifer. During the aquifer recovery phase ground surface uplift almost recovers from the subsidence experienced during the preceding extraction phase. Taking into account this unique aquifer system, a one dimensional elastic model was calibrated in the period 1997–2000. Subsequently, the model was used to predict the ground surface movements during the period 1992–2010. Modeled displacements were validated with PSI displacement measurements, exhibiting an error of 13% on average, related with the inelastic component of deformation occurring as a long-term trend in low permeability fine-grained units. This result further demonstrates the quasi-elastic deformational behavior of this unique aquifer system.

Subsidence activity maps derived from DInSAR data: Orihuela case study

A new methodology is proposed to produce subsidence activity maps based on the geostatistical analysis of persistent scatterer interferometry (PSI) data. PSI displacement measurements are interpolated based on conditional Sequential Gaussian Simulation (SGS) to calculate multiple equiprobable realizations of subsidence. The result from this process is a series of interpolated subsidence values, with an estimation of the spatial variability and a confidence level on the interpolation. These maps complement the PSI displacement map, improving the identification of wide subsiding areas at a regional scale. At a local scale, they can be used to identify buildings susceptible to suffer subsidence related damages. In order to do so, it is necessary to calculate the maximum differential settlement and the maximum angular distortion for each building of the study area. Based on PSI-derived parameters those buildings in which the serviceability limit state has been exceeded, and where in situ forensic analysis should be made, can be automatically identified. This methodology has been tested in the city of Orihuela (SE Spain) for the study of historical buildings damaged during the last two decades by subsidence due to aquifer overexploitation. The qualitative evaluation of the results from the methodology carried out in buildings where damages have been reported shows a success rate of 100%.

Twenty-year advanced DInSAR analysis of severe land subsidence: The Alto Guadalentín Basin (Spain) case study

A twenty-year period of severe land subsidence evolution in the Alto Guadalentín Basin (southeast Spain) is monitored using multi-sensor SAR images, processed by advanced differential interferometric synthetic aperture radar (DInSAR) techniques. The SAR images used in this study consist of four datasets acquired by ERS-1/2, ENVISAT, ALOS and COSMO-SkyMed satellites between 1992 and 2012. The integration of ground surface displacement maps retrieved for different time periods allows us to quantify up to 2.50 m of cumulated displacements that occurred between 1992 and 2012 in the Alto Guadalentín Basin. DInSAR results were locally compared with global positioning system (GPS) data available for two continuous stations located in the study area, demonstrating the high consistency of local vertical motion measurements between the two different surveying techniques. An average absolute error of 4.6 ± 4 mm for the ALOS data and of 4.8 ± 3.5 mm for the COSMO-SkyMed data confirmed the reliability of the analysis. The spatial analysis of DInSAR ground surface displacement reveals a direct correlation with the thickness of the compressible alluvial deposits. Detected ground subsidence in the past 20 years is most likely a consequence of a 100–200 m groundwater level drop that has persisted since the 1970s due to the overexploitation of the Alto Guadalentín aquifer system. The negative gradient of the pore pressure is responsible for the extremely slow consolidation of a very thick (> 100 m) layer of fine-grained silt and clay layers with low vertical hydraulic permeability (approximately 50 mm/h) wherein the maximum settlement has still not been reached.

Application of multi-sensor advanced DInSAR analysis to severe land subsidence recognition: Alto Guadalentín Basin (Spain)

Multi-sensor advanced DInSAR analyses have been performed and compared with two GPS station measurements, in order to evaluate the land subsidence evolution in a 20-year period, in the Alto Guadalentín Basin where the highest rate of man-induced subsidence (> 10 cm yr−1) of Europe had been detected. The control mechanisms have been examined comparing the advanced DInSAR data with conditioning and triggering factors (i.e. isobaths of Plio-Quaternary deposits, soft soil thickness and piezometric level).