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Background and Aims: The prevalence of chronic liver disease in adults exceeds 30% in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare burden. Breath is a rich sampling matrix that offers non-invasive solutions suitable for early-stage detection and disease monitoring. Having previously investigated targeted analysis of a single biomarker, here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical use. Methods: To identify candidate biomarkers we compared 46 breath samples from cirrhosis patients and 42 from controls. Collection and analysis used Breath Biopsy OMNITM, maximizing signal and contrast to background to provide high confidence biomarker detection based upon gas chromatography mass spectrometry (GC-MS). Blank samples were also analyzed to provide detailed information on background volatile organic compounds (VOCs) levels. Results: A set of 29 breath VOCs differed significantly between cirrhosis and controls. A classification model based on these VOCs had an area under the curve (AUC) of 0.95 +/- 0.04 in cross-validated test sets. The seven best performing VOCs were sufficient to maximize classification performance. A subset of 11 VOCs was correlated with blood metrics of liver function (bilirubin, albumin, prothrombin time) and separated patients by cirrhosis severity using principal component analysis. Conclusions: A set of seven VOCs consisting of previously reported and novel candidates show promise as a panel for liver disease detection and monitoring, showing correlation to disease severity and serum biomarkers at late stage.

INTRODUCTION: Liver cirrhosis and its complication — hepatocellular carcinoma (HCC) — have been associated with increased exhaled limonene. It is currently unclear whether this increase is more strongly associated with the presence of HCC or with the severity of liver dysfunction. METHODS: We compared the exhaled breath of 40 controls, 32 cirrhotic patients, and 12 cirrhotic patients with HCC using the Breath Biopsy platform. Breath samples were analyzed by thermal desorption–gas chromatography–mass spectrometry. Limonene levels were compared between the groups and correlated to bilirubin, albumin, prothrombin time international normalized ratio, and alanine aminotransferase. RESULTS: Breath limonene concentration was significantly elevated in subjects with cirrhosis-induced HCC (M: 82.1 ng/L, interquartile range [IQR]: 16.33–199.32 ng/L) and cirrhosis (M: 32.6 ng/L, IQR: 6.55–123.07 ng/L) compared with controls (M: 6.2 ng/L, IQR: 2.62–9.57 ng/L) (P value = 0.0005 and 0.0001, respectively) with no significant difference between 2 diseased groups (P value = 0.37). Levels of exhaled limonene correlated with serum bilirubin (R2 = 0.25, P value = 0.0016, r = 0.51), albumin (R2 = 0.58, P value = 5.3e-8, r = −0.76), and international normalized ratio (R2 = 0.29, P value = 0.0003, r = 0.51), but not with alanine aminotransferase (R2 = 0.01, P value = 0.36, r = 0.19). DISCUSSION: Exhaled limonene levels are primarily affected by the presence of cirrhosis through reduced liver functional capacity, as indicated by limonene correlation with blood metrics of impaired hepatic clearance and protein synthesis capacity, without further alterations observed in subjects with HCC. This suggests that exhaled limonene is a potential non-invasive marker of liver metabolic capacity (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A388).

Background Obtaining a CCT (Certificate of Completion of Training) in Hepatology requires 24 months of dedicated Hepatology training. The non-academic pathway includes an advanced training program (ATP) year which is nationally competitive (17 posts) and often geographically challenging. Shape of Training will enforce a reduction in Gastroenterology training to 4 years requiring trainees to make earlier and more restrictive career decisions (e.g. dropping colonoscopy), and demands training program designers to provide sufficient timely training opportunities while meeting workforce requirements. Of note, the number of Hepatologists nationally is insufficient. With respect to Hepatology training, we sought to gauge the opinions of ST3/4 Gastroenterology trainees to help inform program design. Methodology Quantitative and qualitative data was collected using anonymised questionnaires which were completed by trainees attending the BSG-led ‘Introduction to Gastroenterology Day 2019’ with subsequent framework analysis of qualitative data. Results 44 trainees completed the questionnaire and 32 (73%) are considering a career in Hepatology (5 ‘definitely’, 17 ‘probably’, 10 ‘maybe’). Reasons include: positive clinical experiences, Hepatology patients and disease pathogenesis, and personal circumstances (mainly geographical). 5/32 (16%) aim to work in a Level 3 centre, 15/32 (47%) in a level 2 centre, 3/32 (9%) in a district general hospital (DGH) with the remainder undecided. Of note (considering the whole dataset), 5/44 (11%) are unsure if there is a transplant centre in their deanery. 10/32 (31%) would be able to move and 7/32 (22%) would want to move for an ATP. 16/32 (50%) trainees considering Hepatology favour current national allocation, regarding it as a fair process. The remaining 16/32 (50%) favour local allocation largely due to availability of level 2/3 centres in their deanery. Of the 22 trainees who are ‘probably’ or ‘definitely’ considering Hepatology, 12/22 (55%) are willing to drop colonoscopy training (including 4/5 (80%) who are ‘definitely’ considering Hepatology). Discussion Our results suggest that a significant proportion of early trainees are interested in a career in Hepatology providing reassurance regarding any potential increase in ATPs. Furthermore, outcomes regarding dropping colonoscopy (as necessitated by a shorter training program) are reassuring. Trainees are less interested in DGH Hepatology which is concerning as this is where the need is (Lancet Commission 2019). National ATP allocation is generally supported but would benefit from greater post coverage geographically. Providing trainees with salient information early- ideally prior to commencing specialty training- will facilitate decision making (including choosing or moving deaneries) to permit successful career planning.

Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterized. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either intraperitoneal injections of carbon tetrachloride (CCl4) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for 1 year (mouse). Elastin synthesis, deposition, and degradation were investigated by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blotting, and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl4 model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl4 in MMP-12−/− mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12−/− mice compared with WT. Conclusion: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies. (HEPATOLOGY 2012;55:1965–1975)

Liver fibrosis and its end stage, cirrhosis, represent the final common pathway of virtually all chronic liver diseases. As our understanding of the pathogenesis of liver fibrosis has progressed, it has become evident that the liver provides a useful generic model of inflammation and repair, demonstrating interplay between the epithelial, inflammatory, myofibroblast and extracellular matrix components of the mammalian wound healing response. In this review, the paradigm that liver fibrosis is a potentially reversible process-demonstrating both fibrosis (scarring) and resolution with remodeling and restitution of normal or near-normal tissue architecture-will be explored. The remarkable progress in unraveling the complexities of liver fibrosis has been due to developments in technologies including the isolation of discrete liver cell populations which have facilitated studies of their behavior in tissue culture and in vivo. More recently, animal models that mimic chronic liver diseases have been established. These models are tractable and can be applied in gene knockout and transgenic mice. This article will highlight recent studies that reveal key mechanisms mediating the regression of liver fibrosis which have derived from the use of such complementary animal and human model systems and describe how our greater understanding of this dynamic process is likely to inform the development of directed and effective anti-fibrotic approaches.

Several million tonnes of old electrical/electronic equipment, albeit no more than 1% of the total waste stream, are discarded every year in the European Union (EU). In 1998/9 the EU introduced a draft Directive, the WEEE (Waste from Electrical and Electronic Equipment) Directive, to tackle this increasing waste-disposal problem, although there is, as yet, little evidence to suggest it has any serious environmental impact. The content and implementation timetable of the Directive and the technological and economic challenges facing industry in implementing it are discussed in this article.

Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner.We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.

Portal hypertension is the main cause of complications in patients with cirrhosis. However, evaluating the development and progression of portal hypertension represents a challenge for clinicians. There has been considerable focus on the potential role of noninvasive markers of portal hypertension that could be used to stratify patients with respect to the stage of portal hypertension and to monitor disease progression or treatment response in a longitudinal manner without having to undertake repeated invasive assessment. The pathogenesis of portal hypertension is increasingly understood and emerging knowledge of the vascular processes that underpin portal hypertension has paved the way for exploring novel biomarkers of vascular injury, angiogenesis, and endothelial dysfunction. In this paper we focus on the pathogenesis of portal hypertension and potential non-invasive biomarkers with particular emphasis on serum analytes.

Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter–diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C hi monocytes, a common origin with profibrotic Ly-6C hi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C lo subset, compared with Ly-6C hi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

The rise of green consumerism led to a proliferation of products claiming to be environmentally friendly, however consumers often found the statements given in support of these claims confusing. 'Ecolabels' are intended to help consumers recognise products which have been manufactured and which perform their intended function in an environmentally friendly way. This article gives an overview of the current position regarding ecolabelling within the Member States of the European Union (EU) and proposals for strengthening the EU Ecolable Regulations.

Introduction Hepatorenal syndrome (HRS) is a feared complication of cirrhosis characterised by intense renal vasoconstriction. The pathophysiology remains unclear, pharmacotherapy is limited and mortality is high. We investigated vascular responsiveness and the pathogenesis of renal vasoconstriction in models of advanced rat cirrhosis. Additionally,we determined the mechanism of action of the vasoactive peptide relaxin (RLN), previously shown to increase renal blood flow (RBF) in experimental cirrhosis (Snowdon V et al ., BSG 2013). Methods We induced cirrhosis,reduced RBF and renal dysfunction in male SD rats by carbon tetrachloride (16 wk) or bile duct ligation (4 wk). Arteries from renal (renal, segmental, interlobar) and splanchnic circulation were isolated for functional assessment using wire myography. qPCR array for vasoactive signalling genes,western blot for eNOS signalling proteins and NOS activity assay were undertaken in cirrhotic and control kidneys. Markers of oxidative stress and inflammatory cytokines were measured in serum by ELISA. We studied the effects of s.c. infusion of recombinant human RLN(seralaxin;72 h, 4 µg/h) on these parameters. Doppler USS measured changes in cardiac output (CO) and renal arterial resistive index (RRI) in response to i.v. RLN (4 µg). Kidney endothelial morphology was assessed by electron microscopy, H+E and PAS stained kidney by light microscopy. Results In renal arteries from control and cirrhotic rats endothelial vasodilatation was eNOS-dependent. In cirrhotic rats endothelium-dependent relaxation (acetylcholine; 10–9–3 × 10–5 M) was dramatically reduced (p Conclusion Renal vascular endothelial dysfunction characterises experimental cirrhosis, through a reduction in renal eNOS activity. This impairment may contribute to the renal vasoconstriction seen in cirrhosis and is a promising target for therapeutic modulation. RLN treatment restored renal endothelial vasodilatation. The potential for recombinant forms of RLN as a haemodynamic modulator in human cirrhosis and HRS merits investigation in translational studies. Disclosure of Interest None Declared.

The ninth systematic review (Snowdon and Stewart-Brown 1997) from the NHS Centre for Reviews and Dissemination concludes that the lack of good evidence about the effectiveness of preschool vision screening justifies the withdrawal of the programme. The authors are concerned about the ethical correctness of inviting very young children to an implicitly beneficial examination when there is little to justify the intervention. The following article discusses the issues associated with vision screening of children aged three and four years old.

To undertake a systematic review of the effectiveness of preschool vision screening. To provide evidence on which decisions about the future provision of this service can be made. To indicate areas for further research.The Centre for Reviews and Dissemination guidelines for systematic reviews were used. The research questions were formulated using the Wilson and Jungner criteria for evaluating screening programmes. They concerned prevalence, natural history, disability, treatment and screening in relation to three target conditions: amblyopia, refractive errors and squints which are not cosmetically obvious. Studies were considered for inclusion according to pre-determined criteria for the age group studied, the outcomes measured and the study design. The following types of study design were considered: cross-sectional studies of prevalence, cohort studies of natural history, any type of study (e.g., cross-sectional surveys, case-series, qualitative studies) of disability attributable to a target condition, controlled trials, observational studies and audits of screening programmes, and prospective controlled trials of treatment.The following electronic databases were searched: Biological Abstracts, CINAHL, Embase, ERIC, IAC Health Periodicals, IAPV, Medline, Psychlit, Science Citation Index, System for Information on Grey Literature in Europe, DHSS-Data, Faculty of Public Health Medicine Database of Dissertations, Index of Scientific and Technical Proceedings, Dissertation Abstracts, Index of Theses, NHS Research Register, Public Health Information Sharing Database. A limited amount of handsearching was undertaken. Reference lists were scanned to identify other relevant studies, and requests for unpublished data were made to people working in the field.Data was extracted by the first author and then checked by the second.Quantitative analysis was undertaken where possible. Qualitative analysis was performed where studies were too heterogeneous for the data to be combined, or for research questions that were not suitable for quantitative synthesis.The electronic search yielded over 5000 references, and over 500 abstracts were downloaded from the databases for further scrutiny. A total of 85 studies were included in the main analysis.No studies were found with the primary aim of establishing the prevalence of visual defects in preschool children. Data from studies of screening programmes report a range of yields for all the target conditions combined of 2.4-6.1%. NATURAL HISTORY: No studies designed with the intention of documenting the natural history of the target conditions in children aged 3 or 4 years were found. Other studies that provide some natural history data suggest that mild degrees of amblyopia may resolve spontaneously. In the absence of information about natural history it is impossible to estimate the effect of treatment from studies without a control group that was not treated. DISABILITY: A total of 21 studies exploring disability in relation to the target conditions were included. The literature provides a reasonable basis for generating plausible hypotheses about the ways in which the target conditions might disable people, but is insufficient to draw any firm conclusions about their impact on quality of life. The research to date is not sufficient to determine appropriate outcomes for controlled trials of treatment.Five randomised controlled trials of treatment and six prospective controlleld trials without randomisation were found. No studies compared treatment with no treatment. Most of the studies were methodologically flawed.(ABSTRACT TRUNCATED)

Introduction Hepatorenal syndrome (HRS) is a feared complication of cirrhosis with a high mortality rate and limited treatment options. The hallmark features of HRS are profound renal vasoconstriction, resulting in a functional renal failure but with normal kidney histology. The peptide hormone relaxin (RLN) mediates maternal haemodynamic adaptations to pregnancy, including increased renal blood flow (RBF) and glomerular filtration rate (GFR). We hypothesised that RLN could beneficially modulate RBF in cirrhosis and HRS. Methods Cirrhosis, with reduced RBF, was induced in rats by 16 weeks of intraperitoneal (i.p.) carbon tetrachloride (CCl4) and decompensated biliary cirrhosis by 3 weeks bile duct ligation (BDL). We measured the effect of acute intravenous (i.v.) and extended (72 hr) subcutaneous (s.c.) RLN on systemic haemodynamics, RBF, GFR and organ histology. Subgroups of rats were co-treated with the nitric oxide (NO) synthase inhibitor L-NAME. Blood oxygen dependent-magnetic resonance imaging (BOLD-MRI) was used to quantify changes in renal oxygenation. Tissue expression and distribution of RLN receptor (RXFP1) was determined by qPCR and immunofluorescence. Expression of vasoconstrictor genes was quantified by qPCR array. Results RXFP1 was detected on glomerular podocytes, renal pericytes, and endothelial cells of the renal, segmental and interlobar arteries of cirrhotic rats. In CCl4 cirrhosis, acute i.v. RLN (4µg) induced a 50% increase in RBF after 60 minutes ( p n = 6). BOLD-MRI showed increased tissue oxygenation at the same timepoint in renal cortex and medulla. Extended s.c. RLN increased RBF by 54% in CCl4 ( p n = 8) and 57% in BDL ( p n = 5) and increased GFR by 138% in CCl4 ( p n = 8) and 103% in BDL ( p n = 5). Mean arterial pressure was unaffected by RLN. L-NAME (250mg/L) orally (p.o.) abrogated the effect of RLN on RBF and GFR. The relative expression of vasoconstrictor genes in the kidney was markedly reduced by RLN treatment. Conclusion RLN increases RBF in experimental cirrhosis. Crucially, RLN also improves renal function and oxygenation but does not induce systemic hypotension even in decompensated disease. The effects of RLN are mediated via augmentation of NO and downregulation of vasoconstrictor genes known to be important in the pathogenesis of HRS. RLN has potential as a treatment for HRS and further translational studies are warranted. Disclosure of Interest None Declared.

Background Hepatorenal syndrome is a feared complication of cirrhosis, with a high mortality rate and limited treatment options. The hallmarks of the disorder are functional renal failure, normal kidney histological findings, and profound renal vasoconstriction. The hormone relaxin mediates haemodynamic adaptations to pregnancy including increased renal blood flow and glomerular filtration rate (GFR). We hypothesised that relaxin could be used to modulate renal blood flow in cirrhosis.

Background Hepatorenal syndrome is a feared complication of cirrhosis, with a high mortality rate and limited treatment options. The hallmarks of the disorder are functional renal failure, normal kidney histological findings, and profound renal vasoconstriction. The hormone relaxin mediates haemodynamic adaptations to pregnancy including increased renal blood flow and glomerular filtration rate (GFR). We hypothesised that relaxin could be used to modulate renal blood flow in cirrhosis. Methods Cirrhosis was induced in male rats by 16 weeks of carbon tetrachloride (intraperitoneally) and decompensated biliary cirrhosis by bile duct ligation. The effect of acute intravenous or extended (72 h) subcutaneous relaxin versus placebo was determined by analysis of systemic haemodynamics, renal blood flow, GFR, and organ histology. The effect of co-treatment with L-NG-nitroarginine methyl ester (L-NAME) was measured in subgroups of relaxin or placebo treated rats. Blood oxygen dependent-MRI (BOLD-MRI) was used to non-invasively detect changes to renal oxygenation. Hepatic and renal expression of RXFP1 (relaxin receptor) was determined by IHC and quantitative PCR (qPCR). A qPCR array was used to quantify changes in renal vasodilator/vasoconstrictor gene expression in response to relaxin. Findings RXFP1 was detected in glomerular podocytes, renal pericytes, and renal, segmental, and interlobar arteries of cirrhotic rats. In carbon tetrachloride (CCl 4 ) induced cirrhosis, acute intravenous relaxin (4 μg) induced a 50% increase in renal blood flow after 60 min (p 4 (p 4 (p vs placebo, n=8) and 70% in bile duct ligated animals (p vs placebo, n=3). Mean arterial pressure was unaffected by relaxin. L-NAME (250 mg/L) orally abrogated the effect of relaxin on renal blood flow and GFR. Relative expression of vasoconstrictor genes in kidney was markedly reduced by relaxin treatment. Interpretation Relaxin increases renal blood flow in experimental models of cirrhosis. Crucially, relaxin also improves renal function and oxygenation and does not induce systemic hypotension even in advanced disease. These effects are modulated via augmentation of nitric oxide and downregulation of vasoconstrictors, pivotal in the pathogenesis of hepatorenal syndrome. Relaxin has potential as a novel therapy for hepatorenal syndrome, and further translational studies are warranted. Funding Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative.

Introduction We have previously reported that the multifunctional hormone relaxin (RLX) downregulated the activation state and contractility of hepatic myofibroblasts and reduced portal hypertension (PHT) in cirrhotic rats (Fallowfield J et al BASL 2010). RLX has been shown to induce a range of haemodynamic effects in different organs and species, largely through effects on nitric oxide (NO). In cirrhosis, there is hepatic NO deficiency and hyporesponsiveness. We postulated that the effects of RLX on PHT were, at least in part, mediated by activation of the NO pathway. Methods Cirrhosis and PHT was induced in age-matched male Sprague-Dawley rats by 8 weeks biweekly i.p. CCl4, before randomisation to the following groups: (1) recombinant human H2-relaxin (H2-RLX) s.c. for 72 h; (2) placebo s.c. for 72 h; (3) H2-RLX s.c. + L-NAME p.o. for 72 h; (4) placebo s.c. + L-NAME p.o. for 72 h; n =5–10/group. NO levels in serum were determined by quantitative immunoassay for total nitrite and hepatic NO bioavailability by cGMP immunoassay. Relative levels of Ser 473 phosphorylated Akt (p-Akt) and Ser 1179 phosphorylated eNOS (p-eNOS) protein in whole liver extracts were quantified by Western blotting. Rho-kinase activity was assessed by phosphorylation of the endogenous Rho-kinase substrate moesin (Thr 558 ). Portal pressure (PP) and mean arterial pressure (MAP) were measured under general anaesthesia by direct cannulation. Results Rats treated with CCl4 for 8 weeks developed micronodular cirrhosis, splenomegaly and PHT. There was no difference in mean serum nitrite levels between H2-RLX and placebo treated rats. However, H2-RLX increased hepatic cGMP production (p Conclusion A reduction in NO bioavailability is considered to be a major factor increasing intrahepatic vascular tone in cirrhosis. Our data indicate that H2-RLX was capable of stimulating intrinsic (but not systemic) NO generation in fibrotic liver by activating the Akt/eNOS/cGMP pathway. Furthermore, inhibition of this axis with L-NAME ablated the portal hypotensive effect of H2-RLX, suggesting that it could represent a novel liver-specific NO donor in cirrhotic PHT. Competing interests None declared.

What should policy makers do with systematic reviews that fail to find evidence of effectiveness for interventions currently provided in the NHS? Is no evidence of effectiveness sufficient evidence of no effectiveness? The systematic review process has made great progress in minimising the influence of personal bias in the selection and critical appraisal of evidence. By bringing together in one place and critically appraising all the relevant studies, these reviews can show the fragility of the evidence on which some current practice is based. Policy makers in the NHS take the results of these reviews seriously and expect to be able to act on their findings. But clinicians argue that it is wrong to close down a service, which might be doing good, just because the research evidence of effectiveness is poor. The review of pre-school vision screening commissioned by the NHS Health Technology Assessment Programme1 raises this dilemma and presents policy makers with a difficult decision. This report’s most startling finding was that the reviewers could not identify any robust studies showing that amblyopia (the main target condition of pre-school vision screening programmes2) causes any problems to children or adults. One researcher who tried to find performance differences between amblyopic students (as opposed to people blinded in one eye in adulthood or blindfolded in one eye for the purpose of an experiment) and students with monocular refractive errors was not able to document disabilities that he considered likely to affect everyday life.3 Health professionals have always assumed that reduced vision in one eye must cause problems, and in occupational health services health professionals have been responsible for the development of policies that exclude people …

The neutralization of He+ at grazing incidence from a Ni(111) surface leads to excited states. The light emission from the 3d3D and 3d1D states is studied as a function of the beam energy and angular parameters. The observed circular polarization dependence on the crystallographic surface directions is interpreted in terms of the Brillouin zone of the solid.

In situ Auger sputter depth profiles of saturation implants of 3 keV N2+ in silicon at room temperature exhibit a sharp peak in the nitrogen concentration in the outermost layers, followed by a monotonic decrease. No broad plateau was observed. The energy of the Auger line corresponding to the Si(2p) core electron excitation, monitored throughout the profiling, exhibits a chemical shift of up to 7 eV at the surface peak concentration. Inert gas ion post-bombardment of unsaturated implants significantly modifies the profile, and supports the suggestion that the surface peak arises through radiation enhanced diffusion of implanted atoms.