Vascular assessment of liver disease - towards a new frontier in MRI

Complex haemodynamic phenomena underpin the pathophysiology of chronic liver disease. Non-invasive MRI-based assessment of hepatic vascular parameters therefore has the potential to yield meaningful biomarkers for chronic liver disease. In this review, we provide an overview of vascular sequelae of chronic liver disease amenable to imaging evaluation and describe the current supportive evidence, strengths and the limitations of MRI methodologies, including dynamic contrast-enhanced, dynamic hepatocyte-specific contrast-enhanced, phase-contrast, arterial spin labelling and MR elastography in the assessment of hepatic vascular parameters. We review the broader challenges of quantitative hepatic vascular MRI, including the difficulties of motion artefact, complex post-processing, long acquisition times, validation and limitations of pharmacokinetic models, alongside the potential solutions that will shape the future of MRI and deliver this new frontier to the patient bedside

Great Expectations: Voluntary Sports Clubs and Their Role in Delivering National Policy for English Sport

“The original publication is available at www.springerlink.com”. Copyright International Society for Third-Sector Research and The Johns Hopkins University. DOI: 10.1007/s11266-009-9095-yVoluntary sports clubs (VSCs) account for about a quarter of all volunteering in England. The volunteers work in a mutual aid, self-production, self-consumption system whose main purpose is identifying and nurturing high-level performers. But the new HMG/Sport England strategies leading to London 2012 expects volunteers to make a major contribution to sustaining and extending participation. The study utilized six focus group sessions with a total of 36 officials and members of 36 clubs across the six counties of Eastern England to assess whether and to what extent government policy objectives can be delivered through the voluntary sector. The study focused on the perceptions and attitudes of club members about being expected to serve public policy and the current pressures they and their clubs face. The results lead the authors to question the appropriateness, sensitivity, and feasibility of current sport policy, particularly the emphasis on VSCs as policy implementers.Peer reviewe

Estimation of contrast agent bolus arrival delays for improved reproducibility of liver DCE MRI

Delays between contrast agent (CA) arrival at the site of vascular input function (VIF) sampling and the tissue of interest affect dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling. We investigate effects of altering VIF CA bolus arrival delays on liver DCE MRI perfusion parameters, propose an alternative approach to estimating delays and evaluate reproducibility. Thirteen healthy volunteers (28.7  ±  1.9 years, seven males) underwent liver DCE MRI using dual-input single compartment modelling, with reproducibility (n  =  9) measured at 7 days. Effects of VIF CA bolus arrival delays were assessed for arterial and portal venous input functions. Delays were pre-estimated using linear regression, with restricted free modelling around the pre-estimated delay. Perfusion parameters and 7 days reproducibility were compared using this method, freely modelled delays and no delays using one-way ANOVA. Reproducibility was assessed using Bland–Altman analysis of agreement. Maximum percent change relative to parameters obtained using zero delays, were  −31% for portal venous (PV) perfusion, +43% for total liver blood flow (TLBF), +3247% for hepatic arterial (HA) fraction, +150% for mean transit time and  −10% for distribution volume. Differences were demonstrated between the 3 methods for PV perfusion (p  =  0.0085) and HA fraction (p  <  0.0001), but not other parameters. Improved mean differences and Bland–Altman 95% Limits-of-Agreement for reproducibility of PV perfusion (9.3 ml/min/100 g, ±506.1 ml/min/100 g) and TLBF (43.8 ml/min/100 g, ±586.7 ml/min/100 g) were demonstrated using pre-estimated delays with constrained free modelling. CA bolus arrival delays cause profound differences in liver DCE MRI quantification. Pre-estimation of delays with constrained free modelling improved 7 days reproducibility of perfusion parameters in volunteers

Substrate-dependent activation of the Vibrio cholerae vexAB RND efflux system requires vexR

Vibrio cholerae encodes six resistance-nodulation-division (RND) efflux systems which function in antimicrobial resistance, virulence factor production, and intestinal colonization. Among the six RND efflux systems, VexAB exhibited broad substrate specificity and played a predominant role in intrinsic antimicrobial resistance. The VexAB system was encoded in an apparent three gene operon that included vexR; which encodes an uncharacterized TetR family regulator. In this work we examined the role of vexR in vexRAB expression. We found that VexR bound to the vexRAB promoter and vexR deletion resulted in decreased vexRAB expression and increased susceptibility to VexAB antimicrobial substrates. Sub-strate-dependent induction of vexRAB was dependent on vexR and episomal vexR expression provided a growth advantage in the presence of the VexAB substrate deoxycholate. The expression of vexRAB increased, in a vexR-dependent manner, in response to the loss of RND efflux activity. This suggested that VexAB may function to export intracellular metabolites. Support for this hypothesis was provided by data showing that vexRAB was upregulated in several metabolic mutants including tryptophan biosynthetic mutants that were predicted to accumulate indole. In addition, vexRAB was found to be upregulated in response to exogenous indole and to contribute to indole resistance. The collective results indicate that vexR is required for vexRAB expression in response to VexAB substrates and that the VexAB RND efflux system modulates the intracellular levels of metabolites that could otherwise accumulate to toxic levels

Pattern scaling using ClimGen: monthly-resolution future climate scenarios including changes in the variability of precipitation

Development, testing and example applications of the pattern-scaling approach for generating future climate change projections are reported here, with a focus on a particular software application called “ClimGen”. A number of innovations have been implemented, including using exponential and logistic functions of global-mean temperature to represent changes in local precipitation and cloud cover, and interpolation from climate model grids to a finer grid while taking into account land-sea contrasts in the climate change patterns. Of particular significance is a new approach for incorporating changes in the inter-annual variability of monthly precipitation simulated by climate models. This is achieved by diagnosing simulated changes in the shape of the gamma distribution of monthly precipitation totals, applying the pattern-scaling approach to estimate changes in the shape parameter under a future scenario, and then perturbing sequences of observed precipitation anomalies so that their distribution changes according to the projected change in the shape parameter. The approach cannot represent changes to the structure of climate timeseries (e.g. changed autocorrelation or teleconnection patterns) were they to occur, but is shown here to be more successful at representing changes in low precipitation extremes than previous pattern-scaling methods

The effect of intervertebral cartilage on neutral posture and range of motion in the necks of sauropod dinosaurs

The necks of sauropod dinosaurs were a key factor in their evolution. The habitual posture and range of motion of these necks has been controversial, and computer-aided studies have argued for an obligatory sub-horizontal pose. However, such studies are compromised by their failure to take into account the important role of intervertebral cartilage. This cartilage takes very different forms in different animals. Mammals and crocodilians have intervertebral discs, while birds have synovial joints in their necks. The form and thickness of cartilage varies significantly even among closely related taxa. We cannot yet tell whether the neck joints of sauropods more closely resembled those of birds or mammals. Inspection of CT scans showed cartilage:bone ratios of 4.5% for Sauroposeidon and about 20% and 15% for two juvenile Apatosaurus individuals. In extant animals, this ratio varied from 2.59% for the rhea to 24% for a juvenile giraffe. It is not yet possible to disentangle ontogenetic and taxonomic signals, but mammal cartilage is generally three times as thick as that of birds. Our most detailed work, on a turkey, yielded a cartilage:bone ratio of 4.56%. Articular cartilage also added 11% to the length of the turkey's zygapophyseal facets. Simple image manipulation suggests that incorporating 4.56% of neck cartilage into an intervertebral joint of a turkey raises neutral posture by 15°. If this were also true of sauropods, the true neutral pose of the neck would be much higher than has been depicted. An additional 11% of zygapophyseal facet length translates to 11% more range of motion at each joint. More precise quantitative results must await detailed modelling. In summary, including cartilage in our models of sauropod necks shows that they were longer, more elevated and more flexible than previously recognised

Pits and fissures: Relative space contribution in fissures from sealants, prophylaxis pastes and organic remnants

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Previous studies by the authors have looked at the nature of the fissure system of human permanent molars and premolars, and has provided evidence for the presence of a prismless layer of enamel. It was noted during these studies that the fissure spaces were often occupied by material other than the fissure sealant. The aim of this study was to define these materials and to look at the percentage contribution of each to the sealed fissure space. MethodS: A sample of teeth, both molars and premolars, were sealed with an unfilled fissure sealant after prophylaxis with a coloured prophylaxis paste. In one group, the crown of the tooth was removed by dissolution in hydrochloric acid following placement of the sealant. This revealed a negative image of the fissure system and its contents. The second group of teeth was sectioned following sealing, and the contents of the fissure space were analyzed. Results: The negative image of the fissure system displayed the fissure contents by colour and the sectioned teeth were able to be computer analyzed to establish the relative contribution of sealant, prophylaxis paste and organic material to the fissure space. Conclusions: Sealant contribution was in the range of 14- 96 per cent, prophylaxis paste from 0-50 per cent and organic remnants 0-55 per cent. The presence of these last two components could contribute to sealant loss

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Use of Caval Subtraction 2D Phase-Contrast MR Imaging to Measure Total Liver and Hepatic Arterial Blood Flow: Preclinical Validation and Initial Clinical Translation

Purpose To validate caval subtraction two-dimensional (2D) phase-contrast magnetic resonance (MR) imaging measurements of total liver blood flow (TLBF) and hepatic arterial fraction in an animal model and evaluate consistency and reproducibility in humans. Materials and Methods Approval from the institutional ethical committee for animal care and research ethics was obtained. Fifteen Sprague-Dawley rats underwent 2D phase-contrast MR imaging of the portal vein (PV) and infrahepatic and suprahepatic inferior vena cava (IVC). TLBF and hepatic arterial flow were estimated by subtracting infrahepatic from suprahepatic IVC flow and PV flow from estimated TLBF, respectively. Direct PV transit-time ultrasonography (US) and fluorescent microsphere measurements of hepatic arterial fraction were the standards of reference. Thereafter, consistency of caval subtraction phase-contrast MR imaging-derived TLBF and hepatic arterial flow was assessed in 13 volunteers (mean age, 28.3 years ± 1.4) against directly measured phase-contrast MR imaging PV and proper hepatic arterial inflow; reproducibility was measured after 7 days. Bland-Altman analysis of agreement and coefficient of variation comparisons were undertaken. Results There was good agreement between PV flow measured with phase-contrast MR imaging and that measured with transit-time US (mean difference, -3.5 mL/min/100 g; 95% limits of agreement [LOA], ±61.3 mL/min/100 g). Hepatic arterial fraction obtained with caval subtraction agreed well with those with fluorescent microspheres (mean difference, 4.2%; 95% LOA, ±20.5%). Good consistency was demonstrated between TLBF in humans measured with caval subtraction and direct inflow phase-contrast MR imaging (mean difference, -1.3 mL/min/100 g; 95% LOA, ±23.1 mL/min/100 g). TLBF reproducibility at 7 days was similar between the two methods (95% LOA, ±31.6 mL/min/100 g vs ±29.6 mL/min/100 g). Conclusion Caval subtraction phase-contrast MR imaging is a simple and clinically viable method for measuring TLBF and hepatic arterial flow. Online supplemental material is available for this article

Negotiating professional and social voices in research principles and practice

This paper draws on work conducted for a qualitative interview based study which explores the gendered racialised and professional identifications of health and social care professionals. Participants for the project were drawn from the professional executive committees of recently formed Primary Care Trusts. The paper discusses how the feminist psychosocial methodological approach developed for the project is theoretically, practically and ethically useful in exploring the voices of those in positions of relative power in relation to both health and social care services and the social relations of gender and ethnicity. The approach draws on psychodynamic accounts of (defended) subjectivity and the feminist work of Carol Gilligan on a voice-centred relational methodology. Coupling the feminist with the psychosocial facilitates an emphasis on voice and dialogic communication between participant and researcher not always captured in psychosocial approaches which tend towards favouring the interviewer as ‘good listener’. This emphasis on dialogue is important in research contexts where prior and ongoing relationships with professional participants make it difficult and indeed undesirable for researchers to maintain silence