Allelic depletion of grem1 attenuates diabetic kidney disease.

OBJECTIVE: Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy. RESEARCH DESIGN AND METHODS: Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1(+/-)) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes. RESULTS: A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1(+/-) mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1(+/-) and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1(+/-) mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type but not in grem1(+/-) kidneys. Levels of pSmad1/5/8 decreased in wild-type but not in grem1(+/-) diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1. CONCLUSIONS: These data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.

Increasing incidence of Barrett's oesophagus: a population-based study

Oesophageal adenocarcinoma, a highly fatal cancer, has risen in incidence in Western societies, but it is unclear whether this is due to increasing incidence of its pre-cursor condition, Barrett's oesophagus (BO) or whether the proportion of BO patients undergoing malignant progression has increased in the face of unchanged BO incidence. Data from population-based studies of BO incidence is limited, with equivocal results to date difficult to distinguish from changes in endoscopic practices. The aim of this study was to assess population trends in Barrett's oesophagus (BO) diagnoses in relation to endoscopy and biopsy rates over a 13 year period. The Northern Ireland Barrett's oesophagus Register (NIBR) is a population-based register of all 9,329 adults diagnosed with columnar epithelium of the oesophagus in Northern Ireland between 1993 and 2005, of whom 58.3% were male. European age-standardised annual BO incidence rates were calculated per 100,000 of the population, per 100 endoscopies and per 100 endoscopies including an oesophageal biopsy. Average annual BO incidence rates rose by 159% during the study period, increasing from 23.9/100,000 during 1993-1997 to 62.0/100,000 during 2002-2005. This elevation far exceeded corresponding increases in rates of endoscopies and oesophageal biopsies being conducted. BO incidence increased most markedly in individuals aged <60 years, and most notably amongst males aged <40 years. This study points towards a true increase in the incidence of BO which would appear to be most marked in young males. These findings have significant implications for future rates of oesophageal adenocarcinoma and surveillance programmes. © 2011 Springer Science+Business Media B.V.

Activation of GPVI by collagen is regulated by alpha(2)beta(1) and secondary mediators

We have compared the roles of adenosine diphosphate (ADP), thromboxanes and the integrin alpha(2)beta(1) in the activation of washed platelets by collagen in the presence of the alpha(IIb)beta3 antagonist lotrafiban. The stimulation of protein tyrosine phosphorylation by a collagen suspension is markedly delayed in the presence of the above inhibitors but shows substantial recovery with time. In comparison, activation of phospholipase C (PLC), Ca2+ elevation and dense granule secretion are more severely suppressed by the above inhibitors. blockade has a slightly greater inhibitory effect on all of the above responses than a combination of ADP receptor antagonists and cyclooxygenase inhibitor. Platelets exposed to a collagen monolayer show robust elevation of Ca2+ that is delayed in the presence of the above inhibitors and which is accompanied by of-granule secretion. These results demonstrate that secondary mediators and alpha(2)beta(1) modulate collagen-induced intracellular signaling but have negligible effect on GPVI signaling induced by the specific agonist convulxin. This work supports the postulate that the major role of of alpha(2)beta(1) is to increase the avidity of collagen for the platelet surface and by doing so enhance activation of GPVI. Therefore we propose an important role of secondary mediators in collagen-induced signaling is the indirect regulation of GPVI signaling via activation of alpha(2)beta(1).

Monitoring and population estimation of the European badger (Meles meles) in Northern Ireland

The estimation of animal abundance has a central role in wildlife management and research, including the role of badgers Meles meles in bovine tuberculosis transmission to cattle. This is the first study to examine temporal change in the badger population of Northern Ireland over amedium- to long-term time frame of 14-18 years by repeating a national survey first conducted during 1990-1993. A total of 212 1-km2 squares were surveyed during 2007-2008 and the number, type and activity of setts therein recorded. Badgers were widespread with 75% of squares containing at least one sett. The mean density of activemain setts,which was equivalent to badger social group density, was 0.56 (95%CI: 0.46-0.67) active main setts per km2 during 2007-2008. Social group density varied significantly among landclass groups and counties. The total number of social groups was estimated at 7,600 (95%CI: 6,200-9,000) and, not withstanding probable sources of error in estimating social group size, the total abundance of badgers was estimated to be 34,100 (95% CI: 26,200-42,000). There was no significant change in the badger population from that recorded during 1990-1993. A resource selection model provided a relative probability of sett construction at a spatial scale of 25m. Sett locations were negatively associated with elevation and positively associated with slope, aspect, soil sand content, the presence of cover, and the area of improved grassland and arable agriculture within 300 m.

Improved detection of acute myocardial infarction in patients with chest pain and significant left main stem coronary stenosis.

Background: Non-invasive diagnosis of acute myocardial infarction (AMI) associated with significant left main stem (LMS) stenosis remains challenging.

Methods: Consecutive patients presenting with acute ischaemic-type chest pain from 2000 to 2010 were analysed. Entry criteria: 12-lead ECG and Body Surface Potential Map (BSPM) at presentation, cardiac troponin T (cTnT) =12?h and coronary angiography during admission. cTnT =0.03?µg/l defined AMI. ECG abnormalities assessed: STEMI by Minnesota criteria; ST elevation (STE) aVR =0.5?mm; ST depression (STD) =0.5?mm in =2 contiguous leads (CL); T-wave inversion (TWI) =1?mm in =2 CL. BSPM STE was =2?mm in anterior, =1?mm in lateral, inferior, right ventricular or high right anterior and =0.5?mm in posterior territories. Significant LMS stenosis was =70%.

Results: Enrolled were 2810 patients (aged 60?±?12 years; 71% male). Of these, 116 (4.1%) had significant LMS stenosis with AMI occurring in 92 (79%). STEMI by Minnesota criteria occurred in 13 (11%) (sensitivity 12%, specificity 92%), STE in lead aVR in 23 (20%) (sensitivity 23%, specificity 92%), TWI in 38 (33%) (sensitivity 34%, specificity 71%) and STD in 51 (44%) (sensitivity 49%, specificity 75%). BSPM STE occurred in 85 (73%): sensitivity 88%, specificity 83%, positive predictive value 95% and negative predictive value 65%. Of those with AMI, 74% had STE in either the high right anterior or right ventricular territories not identified by the 12-lead ECG. C-Statistic for AMI diagnosis using BSPM STE was 0.800 (P?<?0.001).

Conclusion: In patients with significant LMS stenosis presenting with chest pain, BSPM STE has improved sensitivity (88%), with specificity 83%, over 12-lead ECG in the diagnosis of AMI.

Hydraulic Subsurface Measurements and Hydrodynamic Modeling as Indicators for Groundwater Flow Systems in the Rotondo Granite, Central Alps (Switzerland)

Regional groundwater flow in high mountainous terrain is governed by a multitude of factors such as geology, topography, recharge conditions, structural elements such as fracturation and regional fault zones as well as man-made underground structures. By means of a numerical groundwater flow model, we consider the impact of deep underground tunnels and of an idealized major fault zone on the groundwater flow systems within the fractured Rotondo granite. The position of the free groundwater table as response to the above subsurface structures and, in particular, with regard to the influence of spatial distributed groundwater recharge rates is addressed. The model results show significant unsaturated zones below the mountain ridges in the study area with a thickness of up to several hundred metres. The subsurface galleries are shown to have a strong effect on the head distribution in the model domain, causing locally a reversal of natural head gradients. With respect to the position of the catchment areas to the tunnel and the corresponding type of recharge source for the tunnel inflows (i.e. glaciers or recent precipitation), as well as water table elevation, the influence of spatial distributed recharge rates is compared to uniform recharge rates. Water table elevations below the well exposed high-relief mountain ridges are observed to be more sensitive to changes in groundwater recharge rates and permeability than below ridges with less topographic relief. In the conceptual framework of the numerical simulations, the model fault zone has less influence on the groundwater table position, but more importantly acts as fast flow path for recharge from glaciated areas towards the subsurface galleries. This is in agreement with a previous study, where the imprint of glacial recharge was observed in the environmental isotope composition of groundwater sampled in the subsurface galleries. Copyright © 2012 John Wiley & Sons, Ltd.

Extreme events and the morphodynamics of gravel-dominated coastal barriers: Strengthening uncertain ground

The long-term morphodynamic ordering of gravel-dominated coastal systems (GDCS), many of which serve as coastal defences in northwest Europe, is dominated by extreme events that generate barrier crest overflow. An understanding of this morphodynamic ordering is fraught with several unresolved difficulties. These are related to the twin problems of the inadequacy of pertinent morphodynamic parameterisation and of obtaining data from modern shores enabling such parameterisation. Major uncertainties concern the timing of over-crest flow in terms of return period of extreme elevation; the intensity and structure of the overflow field; antecedent beachface characteristics in response to storms; the rate of relative sea-level change; tidal stage control; and barrier resistance to forcing, itself determined by a number of unknowns including barrier form and size, sediment size and mosaics, and barrier resilience. While generalised extreme value modelling may provide a means of characterising overwashing return-period and its variability, exceptional tsunami events are outside the scope of such modelling. The characterisation of GDCS morphodynamics in terms of the forcing extreme events will necessitate integrating some or all of these parameters into a single model.

Effect of accelerated rehabilitation on function after ankle sprain: randomised controlled trial

Objective: To compare an accelerated intervention incorporating early therapeutic exercise after acute ankle sprains with a standard protection, rest, ice, compression, and elevation intervention.

Design: Randomised controlled trial with blinded outcome assessor.

Setting: Accident and emergency department and university based sports injury clinic.

Participants: 101 patients with an acute grade 1 or 2 ankle sprain.

Interventions: Participants were randomised to an accelerated intervention with early therapeutic exercise (exercise group) or a standard protection, rest, ice, compression, and elevation intervention (standard group).

Main outcome measures: The primary outcome was subjective ankle function (lower extremity functional scale). Secondary outcomes were pain at rest and on activity, swelling, and physical activity at baseline and at one, two, three, and four weeks after injury. Ankle function and rate of reinjury were assessed at 16 weeks.

Results: An overall treatment effect was in favour of the exercise group (P=0.0077); this was significant at both week 1 (baseline adjusted difference in treatment 5.28, 98.75% confidence interval 0.31 to 10.26; P=0.008) and week 2 (4.92, 0.27 to 9.57; P=0.0083). Activity level was significantly higher in the exercise group as measured by time spent walking (1.2 hours, 95% confidence interval 0.9 to 1.4 v 1.6, 1.3 to 1.9), step count (5621 steps, 95% confidence interval 4399 to 6843 v 7886, 6357 to 9416), and time spent in light intensity activity (53 minutes, 95% confidence interval 44 to 60 v 76, 58 to 95). The groups did not differ at any other time point for pain at rest, pain on activity, or swelling. The reinjury rate was 4% (two in each group).

Conclusion: An accelerated exercise protocol during the first week after ankle sprain improved ankle function; the group receiving this intervention was more active during that week than the group receiving standard care.

Expression of C5a receptor in mouse brain: Role in signal transduction and neurodegeneration

In this study we explored the potential role of the complement derived anaphylatoxin C5a and the expression of its receptor in mouse brain. Using in situ hybridization, we found that C5a receptor messenger RNA is expressed in mouse brain. In response to intraventricular kainic acid injection, there was marked increase in the C5a receptor messenger RNA expression, particularly in hippocampal formation and cerebral cortex. C5a ligand-binding autoradiography confirmed the functional expression and elevation of the C5a receptor post-lesioning. The expression of Cia receptor messenger RNA in brain was confirmed by northern blot hybridization of total RNA from neuronal and glial cells in vitiro. Based on these findings we explored the role of C5a in mechanisms of signal transduction in brain cells. Treatment of primary cultures of mouse astrocytes with human recombinant C5a resulted in the activation of mitogen-activated extracellular signal-regulated protein kinase. This response appeared to be mediated by the C5a receptor since astrocyte cultures derived from C5a receptor knockout mice were not responsive to the treatment. Understanding the regulation of C5a receptor in brain and mechanisms by which pro-inflammatory C5a modulates specific signal transduction pathways in brain cells is crucial to studies of inflammatory mechanisms in neurodegeneration. (C) 1998 IBRO. Published by Elsevier Science Ltd.

RP-LC with fluorescence detection of amino acids in rat brain synaptosomes

For the first time, a simple and validated reversed-phase liquid chromatography (RP-LC) with fluorescence detection has been developed for the simultaneous analysis of glutamate (Glu), ?-aminobutyric acid (GABA), glycine (Gly) and taurine (Tau) in Wistar and tremor rats brain synaptosomes. The samples were separated on a C18 analytical column with gradient elution of methanol and 0.1 mol L-1 potassium acetate at a flow rate of 1 mL min-1. Total run time was approximately 25 min. All calibration curves exhibited good linearity (r 2 > 0.999) within test ranges. The reproducibility was estimated by intra-and inter-day assays and RSD values were less than 2.48%. The recoveries were between 96.32 and 105.21%. The method was successfully applied to the quantification of amino acids in Wistar and tremor rats brain synaptosomes. Through this developed protocol, the levels of Glu in hippocampal and prefrontal cortical synaptosomes of tremor rats were both significantly elevated than those of adult Wistar rats whereas significantly decreased concentrations of GABA and Gly were observed in the hippocampal region of tremor rats without evident difference in the prefrontal cortex between experimental and control groups. In addition, our studies also showed a marked elevation of Tau in tremor rats hippocampal synaptosomes although there was no pronounced difference in the prefrontal cortical region of Wistar and tremor rats.

Isolation basin records of late Quaternary sea-level change, central mainland British Columbia, Canada.

Isolation basin records from the Seymour-Belize Inlet Complex, a remote area of central mainland British Columbia, Canada are used to constrain post-glacial sea-level changes and provide a preliminary basis for testing geophysical model predictions of relative sea-level (RSL) change. Sedimentological and diatom data from three low-lying (<4 m elevation) basins record falling RSLs in late-glacial times and isolation from the sea by ~11,800–11,200 14C BP. A subsequent RSL rise during the early Holocene (~8000 14C BP) breached the 2.13 m sill of the lowest basin (Woods Lake), but the two more elevated basins (sill elevations of ~3.6 m) remained isolated. At ~2400 14C BP, RSL stood at 1.49 ± 0.34 m above present MTL. Falling RSLs in the late Holocene led to the final emergence of the Woods Lake basin by 1604 ± 36 14C BP. Model predictions generated using the ICE-5G model partnered with a small number of different Earth viscosity models generally show poor agreement with the observational data, indicating that the ice model and/or Earth models considered can be improved upon. The best data-model fits were achieved with relatively low values of upper mantle viscosity (5 × 1019 Pa s), which is consistent with previous modelling results from the region. The RSL data align more closely with observational records from the southeast of the region (eastern Vancouver Island, central Strait of Georgia), than the immediate north (Bella Bella–Bella Coola and Prince Rupert-Kitimat) and areas to the north-west (Queen Charlotte Sound, Hecate Strait), underlining the complexity of the regional response to glacio-isostatic recovery.

Prevalence of Adverse Childhood Experiences in a University Population: Associations with Use of Social Services

This paper is part of a series published by the Multiple Adverse Childhood Experiences research group based at QUB. First-year undergraduates took part in an online survey, self-reporting on Adverse Childhood Experiences (ACE) and measures of social service contact. The 10-item ACE questionnaire measures abuse, neglect and household dysfunction (current sample ?????????The study achieved a response rate of 18.6%. (N=765; 552 (72.7%) females and 212 (27.2%) males; 21.8% reporting having been educated at a ‘Protestant’ school, 42% reporting having been educated at a ‘Catholic’ school and 20.4% reporting previous school religious affiliation as ‘other’). Despite obvious non-response bias, ACE scores for this student population are comparable with college-educated populations in the US. Current respondents with previous social service contact are over twenty three times more likely than peers to have experienced multiple adversities. Findings support the hypothesis that social service contact, alone, acts as a proxy indicator for the presence of multiple adverse childhood experiences, with no significant elevation in ACE scores for those going through court proceedings or subject to child protection registration. This study supports current concerns by policy makers to target those children experiencing multiple adversities.

Distribution and pattern of moraines in Far NE Russia reveal former glacial extent

Here we present a series of six maps illustrating the distribution of end moraines in Far NE Russia. The maps are the first to systematically document the distribution of moraines across this region from the Verkhoyansk Mountains at the westernmost limit of our study area to the Chukchi Peninsula in the NE and to Kamchatka in the south, covering almost 4 million km2. Moraines were identified and mapped from analysis of satellite images and digital elevation model data. A total of 2173 moraines are identified, and we highlight some 197 more speculative features (perhaps moraines) that require further investigation. The distribution of moraines indicates that much of the region, now largely ice-free, was formerly occupied by glaciers centred upon the region’s uplands and that glacier outlets were typically < 200 km in length. The maps demonstrate the usefulness of remote sensing to derive an improved understanding of the glacial history of this vast and isolated region, and we present them to stimulate further work and act as a systematic framework for targeted geochronometric dating.

Late Quaternary glaciations in Far NE Russia; combining moraines, topography and chronology to assess regional and global glaciation synchrony

During various periods of Late Quaternary glaciation, small ice-sheets, -caps, -fields and valley glaciers, occupied the mountains and uplands of Far NE Russia (including the Verkhoyansk, Suntar-Khayata, and Chersky Mountains; the KolymaeAnyuy and Koryak Highlands; and much of the Kamchatka and Chukchi
Peninsulas). Here, the margins of former glaciers across this region are constrained through the comprehensive mapping of moraines from remote sensing data (Landsat 7 ETM+ satellite images; ASTER Global Digital Elevation Model (GDEM2); and Viewfinder Panorama DEM data). A total of 8414 moraines
are mapped, and this record is integrated with a series of published age-estimates (n = 25), considered to chronologically-constrain former ice-margin positions. Geomorphological and chronological data are compiled in a Geographic Information System (GIS) to produce ‘best estimate’ reconstructions of ice extent during the global Last Glacial Maximum (gLGM) and, to a lesser degree, during earlier phases of glaciation. The data reveal that much of Far NE Russia (~1,092,427 km2) preserves a glaciated landscape (i.e. is bounded by moraines), but there is no evidence of former ice masses having extended more than 270 km beyond mountain centres (suggesting that, during the Late Quaternary, the region has not been occupied by extensive ice sheets). During the gLGM, specifically, glaciers occupied ~253,000 km2, and rarely extended more than 50 km in length. During earlier (pre-gLGM) periods, glaciers were more extensive, though the timing of former glaciation, and the maximum Quaternary extent, appears to have been asynchronous across the region, and out-of-phase with ice-extent maxima elsewhere in the Northern Hemisphere. This glacial history is partly explained through consideration of climatic-forcing
(particularly moisture-availability, solar insolation and albedo), though topographic-controls upon the former extent and dynamics of glaciers are also considered, as are topographic-controls upon moraine deposition and preservation. Ultimately, our ability to understand the glacial and climatic history of this region is restricted when the geomorphological-record alone is considered, particularly as directly-dated glacial deposits are few, and topographic and climatic controls upon the moraine record are difficult to
distinguish.

An updated moraine map of Far NE Russia

Barr and Clark published a series of maps depicting the distribution of end moraines across Far NE Russia. These
moraines outlined the former distribution and dimensions of glaciers, and were identified through the analysis of
Landsat ETM+ satellite images (15- and 30-m resolution). Now, a number of freely available digital elevation
model (DEM) datasets are available, which cover the entire 4 million km2 of Far NE Russia. These include
the 30-m resolution ASTER GDEM and the 90-m resolution Viewfinder Panorama DEM. Here we use these
datasets, in conjunction with Landsat ETM+ images, to complete the process of systematically and
comprehensively mapping end moraines. With the aid of the DEMs described above, here we present a total
dataset of 8414 moraines, which almost quadruples the inventory of Barr and Clark. This increase in the
number of moraines is considered to reflect the utility of the DEMs for mapping glacial landforms. In terms of
moraine distribution, the Barr and Clark map and the one presented here are comparable, with moraines found
to cluster in highland regions and upon adjacent lowlands, attesting to the former occupation of the region by
mountain-centred ice masses. This record is considered to reflect palaeoclimatic and topographic controls upon
the extent and dynamics of palaeoglaciers, as well as spatial variability in moraine preservation.