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Peatlands are globally important stores of soil carbon (C) formed over millennial timescales but are at risk of destabilization by human and climate disturbance. Pools are ubiquitous features of many peatlands and can contain very high concentrations of C mobilized in dissolved and particulate organic form and as the greenhouses gases carbon dioxide (CO 2 ) and methane (CH 4 ). The radiocarbon content ( 14 C) of these aquatic C forms tells us whether pool C is generated by contemporary primary production or from destabilized C released from deep peat layers where it was previously stored for millennia. We present novel 14 C and stable C (δ 13 C) isotope data from 97 aquatic samples across six peatland pool locations in the United Kingdom with a focus on dissolved and particulate organic C and dissolved CO 2 . Our observations cover two distinct pool types: natural peatland pools and those formed by ditch blocking efforts to rewet peatlands (restoration pools). The pools were dominated by contemporary C, with the majority of C (~50%-75%) in all forms being younger than 300 years old. Both pool types readily transform and decompose organic C in the water column and emit CO 2 to the atmosphere, though mixing with the atmosphere and subsequent CO 2 emissions was more evident in natural pools. Our results show little evidence of destabilization of deep, old C in natural or restoration pools, despite the presence of substantial millennial-aged C in the surrounding peat. One possible exception is CH 4 ebullition (bubbling), with our observations showing that millennial-aged C can be emitted from peatland pools via this pathway. Our results suggest that restoration pools formed by ditch blocking are effective at preventing the release of deep, old C from rewetted peatlands via aquatic export., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Peatlands of the central Congo Basin have accumulated carbon over millennia. They currently store some 29 billion tonnes of carbon in peat. However, our understanding of the controls on peat carbon accumulation and loss and the vulnerability of this stored carbon to climate change is in its infancy. Here we present a new model of tropical peatland development, DigiBog_Congo, that we use to simulate peat carbon accumulation and loss in a rain-fed interfluvial peatland that began forming ~20,000 calendar years Before Present (cal. yr BP, where 'present' is 1950 CE). Overall, the simulated age-depth curve is in good agreement with palaeoenvironmental reconstructions derived from a peat core at the same location as our model simulation. We find two key controls on long-term peat accumulation: water at the peat surface (surface wetness) and the very slow anoxic decay of recalcitrant material. Our main simulation shows that between the Late Glacial and early Holocene there were several multidecadal periods where net peat and carbon gain alternated with net loss. Later, a climatic dry phase beginning ~5200 cal. yr BP caused the peatland to become a long-term carbon source from ~3975 to 900 cal. yr BP. Peat as old as ~7000 cal. yr BP was decomposed before the peatland's surface became wetter again, suggesting that changes in rainfall alone were sufficient to cause a catastrophic loss of peat carbon lasting thousands of years. During this time, 6.4 m of the column of peat was lost, resulting in 57% of the simulated carbon stock being released. Our study provides an approach to understanding the future impact of climate change and potential land-use change on this vulnerable store of carbon., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Tropical peatlands are carbon-dense ecosystems because they accumulate partially-decomposed plant material. A substantial fraction of this organic matter may derive from fine root production (FRP). However, few FRP estimates exist for tropical peatlands, with none from the world's largest peatland complex in the central Congo Basin. Here we report on FRP using repeat photographs of roots from in situ transparent tubes (minirhizotrons), measured to 1 m depth over three one-month periods (spanning dry to wet seasons), in a palm-dominated peat swamp forest, a hardwood-dominated peat swamp forest, and a terra firme forest. We find FRP of 2.6 ± 0.3 Mg C ha -1  yr -1 , 1.9 ± 0.5 Mg C ha -1  yr -1 , and 1.7 ± 0.1 Mg C ha -1  yr -1 in the three ecosystem types respectively (mean ± standard error; no significant ecosystem type differences). These estimates fall within the published FRP range worldwide. Furthermore, our hardwood peat swamp estimate is similar to the only other FRP study in tropical peatlands, also hardwood-dominated, from Micronesia. We also found that FRP decreased with depth and was the highest during the dry season. Overall, we show that minirhizotrons can be used as a low-disturbance method to estimate FRP in tropical forests and peatlands., (© 2023. The Author(s).)

The forested swamps of the central Congo Basin store approximately 30 billion metric tonnes of carbon in peat 1,2 . Little is known about the vulnerability of these carbon stocks. Here we investigate this vulnerability using peat cores from a large interfluvial basin in the Republic of the Congo and palaeoenvironmental methods. We find that peat accumulation began at least at 17,500 calibrated years before present (cal. yr BP; taken as AD 1950). Our data show that the peat that accumulated between around 7,500 to around 2,000 cal. yr BP is much more decomposed compared with older and younger peat. Hydrogen isotopes of plant waxes indicate a drying trend, starting at approximately 5,000 cal. yr BP and culminating at approximately 2,000 cal. yr BP, coeval with a decline in dominant swamp forest taxa. The data imply that the drying climate probably resulted in a regional drop in the water table, which triggered peat decomposition, including the loss of peat carbon accumulated prior to the onset of the drier conditions. After approximately 2,000 cal. yr BP, our data show that the drying trend ceased, hydrologic conditions stabilized and peat accumulation resumed. This reversible accumulation-loss-accumulation pattern is consistent with other peat cores across the region, indicating that the carbon stocks of the central Congo peatlands may lie close to a climatically driven drought threshold. Further research should quantify the combination of peatland threshold behaviour and droughts driven by anthropogenic carbon emissions that may trigger this positive carbon cycle feedback in the Earth system., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Tropical peatlands are among the most carbon-dense ecosystems on Earth, and their water storage dynamics strongly control these carbon stocks. The hydrological functioning of tropical peatlands differs from that of northern peatlands, which has not yet been accounted for in global land surface models (LSMs). Here, we integrated tropical peat-specific hydrology modules into a global LSM for the first time, by utilizing the peatland-specific model structure adaptation (PEATCLSM) of the NASA Catchment Land Surface Model (CLSM). We developed literature-based parameter sets for natural (PEATCLSM Trop,Nat ) and drained (PEATCLSM Trop,Drain ) tropical peatlands. Simulations with PEATCLSM Trop,Nat were compared against those with the default CLSM version and the northern version of PEATCLSM (PEATCLSM North,Nat ) with tropical vegetation input. All simulations were forced with global meteorological reanalysis input data for the major tropical peatland regions in Central and South America, the Congo Basin, and Southeast Asia. The evaluation against a unique and extensive data set of in situ water level and eddy covariance-derived evapotranspiration showed an overall improvement in bias and correlation compared to the default CLSM version. Over Southeast Asia, an additional simulation with PEATCLSM Trop,Drain was run to address the large fraction of drained tropical peatlands in this region. PEATCLSM Trop,Drain outperformed CLSM, PEATCLSM North,Nat , and PEATCLSM Trop,Nat over drained sites. Despite the overall improvements of PEATCLSM Trop,Nat over CLSM, there are strong differences in performance between the three study regions. We attribute these performance differences to regional differences in accuracy of meteorological forcing data, and differences in peatland hydrologic response that are not yet captured by our model., (© 2022 The Authors. Journal of Advances in Modeling Earth Systems published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Background: Liver transplantation (LT) for alcohol-related liver disease has historically been reserved for patients who have been six months abstinent. Given the increasing incidence of alcohol-related hepatitis (AH) and dismal survival in patients who fail medical therapy, transplant centers are extending their acceptance criteria for patients with less than 6 months of sobriety. We sought to determine the barriers for listing., Methods: We conducted a retrospective chart review of all inpatient LT referrals for a diagnosis of AH between September 2019 and December 2020. LT evaluations were performed by a multidisciplinary team. Descriptive statistics were reported using mean and standard deviation (SD) or percentage where appropriate., Results: During our study period, 82 patients were evaluated for LT. Of these 82 patients, 62 were declined for liver transplantation. The mean (SD) age of the 62-patient cohort was 44 years (10.7), and most patients were men. The mean (SD) number of reasons for denial was 2 (0.97). Four patients had medical contraindications for transplant. Twenty-seven (44%) and 35 (56%) patients lacked insight and were at risk of alcohol relapse, respectively. Forty-three (69%) and fourteen (22.5%) patients had insufficient social support and an inability to maintain a therapeutic relationship with the transplant team, respectively., Conclusion: Patients are more likely denied for psychosocial factors than medical comorbidities. The majority were due to lack of insight, insufficient social support, and inability to maintain a therapeutic relationship with the transplant team. Resources should be allocated to address these issues., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V.)

Mangroves are among the world's most carbon-dense ecosystems, but have suffered extensive deforestation, prompting reforestation projects. The effects of mangrove reforestation on belowground carbon dynamics are poorly understood. In particular, we do not know how fine root production develops following mangrove reforestation, despite fine root production being a major carbon sink and an important control of mangrove soil accretion. Using minirhizotrons, we investigated fine root production and its depth variation along a chronosequence of mature Vietnamese mangroves. Our results showed that fine root production decreases strongly with stand age in the uppermost 32 cm of our soil profiles. In younger mangrove stands, fine root production declines with depth, possibly due to a vertical gradient in soil nutrient availability; while root production in the oldest stand is low at all depths and exhibits no clear vertical pattern. A major fraction of fine root production occurs deeper than 30 cm, depths that are commonly omitted from calculations of mangrove carbon budgets. Younger mangroves may accrue shallow soil organic matter faster than older mangroves. Therefore, root productivity and forest stand age should be accounted for when forecasting mangrove carbon budgets and resistance to sea-level rise., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

The carbon (C) accumulation histories of peatlands are of great interest to scientists, land users and policy makers. Because peatlands contain more than 500 billion tonnes of C, an understanding of the fate of this dynamic store, when subjected to the pressures of land use or climate change, is an important part of climate-change mitigation strategies. Information from peat cores is often used to recreate a peatland's C accumulation history from recent decades to past millennia, so that comparisons between past and current rates can be made. However, these present day observations of peatlands' past C accumulation rates (known as the apparent rate of C accumulation - aCAR) are usually different from the actual uptake or loss of C that occurred at the time (the true C balance). Here we use a simple peatland model and a more detailed ecosystem model to illustrate why aCAR should not be used to compare past and current C accumulation rates. Instead, we propose that data from peat cores are used with existing or new C balance models to produce reliable estimates of how peatland C function has changed over time.

Global peatlands store more carbon than is naturally present in the atmosphere 1,2 . However, many peatlands are under pressure from drainage-based agriculture, plantation development and fire, with the equivalent of around 3 per cent of all anthropogenic greenhouse gases emitted from drained peatland 3-5 . Efforts to curb such emissions are intensifying through the conservation of undrained peatlands and re-wetting of drained systems 6 . Here we report eddy covariance data for carbon dioxide from 16 locations and static chamber measurements for methane from 41 locations in the UK and Ireland. We combine these with published data from sites across all major peatland biomes. We find that the mean annual effective water table depth (WTD e ; that is, the average depth of the aerated peat layer) overrides all other ecosystem- and management-related controls on greenhouse gas fluxes. We estimate that every 10 centimetres of reduction in WTD e could reduce the net warming impact of CO 2 and CH 4 emissions (100-year global warming potentials) by the equivalent of at least 3 tonnes of CO 2 per hectare per year, until WTD e is less than 30 centimetres. Raising water levels further would continue to have a net cooling effect until WTD e is within 10 centimetres of the surface. Our results suggest that greenhouse gas emissions from peatlands drained for agriculture could be greatly reduced without necessarily halting their productive use. Halving WTD e in all drained agricultural peatlands, for example, could reduce emissions by the equivalent of over 1 per cent of global anthropogenic emissions.

Mangroves are among the world's most carbon-dense ecosystems, but they are threatened by rapid climate change and rising sea levels. The accumulation and decomposition of soil organic matter (SOM) are closely tied to mangroves' carbon sink functions and resistance to rising sea levels. However, few studies have investigated the response of mangrove SOM dynamics to likely future environmental conditions. We quantified how mangrove SOM decay is affected by predicted global warming (+4°C), sea level changes (simulated by altering of the inundation duration to 0, 2, and 6 hr/day), and their interaction. Whilst changes in inundation duration between 2 and 6 hr/day did not affect SOM decay, the treatment without inundation led to a 60% increase. A warming of 4°C caused SOM decay to increase by 21%, but longer inundation moderated this temperature-driven increase. Our results indicate that (a) sea level rise is unlikely to decrease the SOM decay rate, suggesting that previous mangrove elevation gain, which has allowed mangroves to persist in areas of sea level rise, might result from changes in root production and/or mineral sedimentation; (b) sea level fall events, predicted to double in frequency and area, will cause periods of intensified SOM decay; (c) changing tidal regimes in mangroves due to sea level rise might attenuate increases in SOM decay caused by global warming. Our results have important implications for forecasting mangrove carbon dynamics and the persistence of mangroves and other coastal wetlands under future scenarios of climate change., (© 2019 John Wiley & Sons Ltd.)

Objectives: The epidemiology, clinical characteristics and outcomes of antimicrobial-associated anaphylaxis remain ill-defined. We sought to examine antimicrobial anaphylaxis with regard to: (i) the frequency of implicated antimicrobials; (ii) attributable mortality; and (iii) referral for definitive allergy assessment., Methods: This was conducted through a national retrospective multicentre cohort study at five Australian tertiary hospitals (January 2010 to December 2015). Cases of antimicrobial anaphylaxis were identified from ICD-10 coding and adverse drug reaction committee databases., Results: There were 293 participants meeting the case definition of antimicrobial anaphylaxis and 310 antimicrobial anaphylaxis episodes. Of 336 implicated antimicrobials, aminopenicillins (62/336, 18.5%) and aminocephalosporins (57/336, 17%) were implicated most frequently. ICU admission occurred in 43/310 (13.9%) episodes; however, attributable mortality was low (3/310, 1%). The rate of anaphylaxis to IV antibiotics was 3.5 (95% CI=2.9-4.3) per 100 000 DDDs and the rate of hospital-acquired anaphylaxis was 1.9 (95% CI=2.1-3.3) per 100 000 occupied bed-days. We observed overall low rates of hospital discharge documentation (222/310, 71.6%) and follow-up by specialist allergy services (73/310, 23.5%), which may compromise medication safety and antimicrobial prescribing in future., Conclusions: This study demonstrated that a high proportion of severe immediate hypersensitivity reactions presenting or acquired in Australian hospitals are secondary to aminopenicillins and aminocephalosporins. Overall rates of hospital-acquired anaphylaxis, predominantly secondary to cephalosporins, are low, and also associated with low inpatient mortality., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Peatlands are globally important stores of carbon (C) that contain a record of how their rates of C accumulation have changed over time. Recently, near-surface peat has been used to assess the effect of current land use practices on C accumulation rates in peatlands. However, the notion that accumulation rates in recently formed peat can be compared to those from older, deeper, peat is mistaken - continued decomposition means that the majority of newly added material will not become part of the long-term C store. Palaeoecologists have known for some time that high apparent C accumulation rates in recently formed peat are an artefact and take steps to account for it. Here we show, using a model, how the artefact arises. We also demonstrate that increased C accumulation rates in near-surface peat cannot be used to infer that a peatland as a whole is accumulating more C - in fact the reverse can be true because deep peat can be modified by events hundreds of years after it was formed. Our findings highlight that care is needed when evaluating recent C addition to peatlands especially because these interpretations could be wrongly used to inform land use policy and decisions.

Background: Fine root production is one of the least well understood components of the carbon cycle in terrestrial ecosystems. Minirhizotrons allow accurate and non-destructive sampling of fine root production. Small and large scale studies across a range of ecosystems are needed to have baseline data on fine root production and further assess the impact of global change upon it; however, the expense and the low adaptability of minirhizotrons prevent such data collection, in worldwide distributed sampling schemes, in low-income countries and in some ecosystems (e.g. tropical forested wetlands)., Results: We present EnRoot, a narrow minirhizotron of 25 mm diameter, that is partially 3D printable. EnRoot is inexpensive (€150), easy to construct (no prior knowledge required) and adapted to a range of ecosystems including tropical forested wetlands (e.g. mangroves, peatlands). We tested EnRoot's accuracy and precision for measuring fine root length and diameter, and it yielded Lin's concordance correlation coefficient values of 0.95 for root diameter and 0.92 for length. As a proof of concept, we tested EnRoot in a mesocosm study, and in the field in a tropical mangrove. EnRoot proved its capacity to capture the development of roots of a legume ( Medicago sativa ) and a mangrove species (seedlings of Rhizophora mangle ) in laboratory mesocosms. EnRoot's field installation was possible in the root-dense tropical mangrove because its narrow diameter allowed it to be installed between larger roots and because it is fully waterproof. EnRoot compares favourably with commercial minirhizotrons, and can image roots as small as 56 µm., Conclusion: EnRoot removes barriers to the extensive use of minirhizotrons by being low-cost, easy to construct and adapted to a wide range of ecosystem. It opens the doors to worldwide distributed minirhizotron studies across an extended range of ecosystems with the potential to fill knowledge gaps surrounding fine root production., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Natural open-water pools are a common feature of northern peatlands and are known to be an important source of atmospheric methane (CH4). Pool environmental variables, particularly water chemistry, vegetation community and physical characteristics, have the potential to exert strong controls on carbon cycling in pools. A total of 66 peatland pools were studied across three regions of the UK (northern Scotland, south-west Scotland, and Northern Ireland). We found that within-region variability of pool water chemistry was low; however, for many pool variables measured there were significant differences between regions. PCA analysis showed that pools in SW Scotland were strongly associated with greater vegetative cover and shallower water depth which is likely to increase dissolved organic carbon (DOC) mineralisation rates, whereas pools in N Scotland were more open and deeper. Pool water DOC, particulate organic carbon and dissolved CH4 concentrations were significantly different between regions. Pools in Northern Ireland had the highest concentrations of DOC (mean=14.5 mg L(-1)) and CH4 (mean=20.6 μg C L(-1)). Chloride and sulphate concentrations were significantly higher in the pools in N Scotland (mean values 26.3 and 2.40 mg L(-1), respectively) than elsewhere, due to a stronger marine influence. The ratio of UV absorbance at 465 nm to absorbance at 665 nm for pools in Northern Ireland indicated that DOC was sourced from poorly humified peat, potentially increasing the bioavailability and mineralisation of organic carbon in pools compared to the pools elsewhere. This study, which specifically aims to address a lack of basic biogeochemical knowledge about pool water chemistry, clearly shows that peatland pools are highly regionally variable. This is likely to be a reflection of significant regional-scale differences in peatland C cycling., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This article provides models and code for numerically simulating muscle-fluid-structure interactions (FSIs). This work was presented as part of the symposium on Leading Students and Faculty to Quantitative Biology through Active Learning at the society-wide meeting of the Society for Integrative and Comparative Biology in 2015. Muscle mechanics and simple mathematical models to describe the forces generated by muscular contractions are introduced in most biomechanics and physiology courses. Often, however, the models are derived for simplifying cases such as isometric or isotonic contractions. In this article, we present a simple model of the force generated through active contraction of muscles. The muscles' forces are then used to drive the motion of flexible structures immersed in a viscous fluid. An example of an elastic band immersed in a fluid is first presented to illustrate a fully-coupled FSI in the absence of any external driving forces. In the second example, we present a valveless tube with model muscles that drive the contraction of the tube. We provide a brief overview of the numerical method used to generate these results. We also include as Supplementary Material a MATLAB code to generate these results. The code was written for flexibility so as to be easily modified to many other biological applications for educational purposes., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Introduction: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke., Methods: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff's-alpha (K-alpha)., Results: Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60-0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K-alpha = 0.33-0.72)., Conclusion: For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best.

Background: Beliefs, cognitions, and behaviors relating to pain can be associated with a range of negative outcomes. In patients, certain beliefs are associated with increased levels of pain and related disability. There are few data, however, showing the extent to which beliefs of patients differ from those of the general population., Objective: This study explored pain beliefs in a large nonclinical population and a chronic low back pain (CLBP) sample using the Pain Beliefs Questionnaire (PBQ) to identify differences in scores and factor structures between and within the samples., Design: This was a cross-sectional study., Methods: The samples comprised patients attending a rehabilitation program and respondents to a workplace survey. Pain beliefs were assessed using the PBQ, which incorporates 2 scales: organic and psychological. Exploratory factor analysis was used to explore variations in factor structure within and between samples. The relationship between the 2 scales also was examined., Results: Patients reported higher organic scores and lower psychological scores than the nonclinical sample. Within the nonclinical sample, those who reported frequent pain scored higher on the organic scale than those who did not. Factor analysis showed variations in relation to the presence of pain. The relationship between scales was stronger in those not reporting frequent pain., Limitations: This was a cross-sectional study; therefore, no causal inferences can be made., Conclusions: Patients experiencing CLBP adopt a more biomedical perspective on pain than nonpatients. The presence of pain is also associated with increased biomedical thinking in a nonclinical sample. However, the impact is not only on the strength of beliefs, but also on the relationship between elements of belief and the underlying belief structure.

Introduction: This study aims to determine the diagnostic accuracy of Primovist-enhanced MRI in the detection of hepatocellular carcinoma (HCC) in cirrhosis, using liver explant histopathology correlation., Methods: Thirty patients underwent a Primovist-enhanced MRI prior to liver transplantation for cirrhosis at the Princess Alexandra Hospital from 2006 to June 2012. Pre-contrast T1, T2 and post-Primovist arterial, portal venous and delayed hepatobiliary phase sequences were routinely obtained. A retrospective audit of MRI reports determined whether HCCs was identified on pre-transplantation imaging. Results were correlated to the explant liver histopathology. Specificity and sensitivity of Primovist in HCC identification in cirrhosis was determined., Results: The time interval between preoperative MRI and transplantation ranged from the day of transplantation to 112 weeks pre-transplantation. Thirty-nine HCCs were identified histologically in explants. Fifteen HCCs were identified on pre-transplant MRI in 11 patients, ranging from 11 to 43 mm, all confirmed on histopathology. Fourteen MRI studies identified no lesion, concordant on histology. Twenty-four either well or moderately differentiated HCCs were identified on histopathology, all of which were less than 17 mm, were not depicted on MRI. No poorly differentiated HCCs were present in the explants. Two regenerative nodules were correctly identified on MRI. This correlated to a sensitivity of 42.5%, specificity of 100% and a positive predictive value of 100% and negative predictive value of 39.5%., Conclusion: Primovist-enhanced MRI is very accurate in the identification of HCC in cirrhosis, especially if the tumour is greater than 17 mm and undifferentiated. However, sensitivity is reduced for well- and moderately differentiated HCC less than 17 mm., (© 2013 The Authors. Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists.)

Sediments can be both a source and a sink of dissolved phosphorus (P) in surface water and shallow groundwater. Using laboratory mesocosms, we studied the influence of flooding with deionized water and simulated river water on P release to solution using sediment columns taken from a riparian wetland. The mesocosm incubation results showed that rather than retaining nutrients, sediments in the riparian zone may be a significant source of P. Concentrations of dissolved P in porewater reached more than 3 mg L(-1) and in surface water over 0.8 mg L(-1) within a month of sediment inundation. The reductive dissolution of P-bearing iron (Fe) oxides was the likely mechanism responsible for P release. Dissolved P to Fe molar ratios in anaerobic samples were approximately 0.45 when columns were flooded with water that simulated the chemistry of the adjacent river. This suggests there was insufficient Fe in the anaerobic samples to precipitate all P if the solutions were oxygenated or transported to an aerobic environment. If the anaerobic wetland solutions were delivered to oxygenated rivers and streams adjacent to the riparian zone, the equilibrium concentration of P in these systems could rise. The timing of P release was inversely related to the nitrate (NO3-) concentration in floodwater. This indicates that in riparian zones receiving low nitrate loads, or where NO3- loads are being progressively reduced, the risk of dissolved P release may increase. These findings present particular challenges for restoration and management in riparian areas.

Mitochondrial F1F0 adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0 ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.

This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

Objectives: An interaction between adenosine A1 receptors and ATP-sensitive potassium channels (KATP) has been hypothesized to mediate preconditioning in several species. Unlike other species tested, KATP blockers and A1 antagonists do not abolish preconditioning in rat hearts. The purpose of this study was to determine if KATP and A1 receptors are pharmacologically linked in rat hearts as they are in other species., Methods: Isolated rat hearts were given 0.03-1.00 microM R-PIA (adenosine A1 receptor agonist) with or without concomitant 0.3 microM glyburide starting 10 min pre-ischemia. After 25 min global ischemia, the hearts were reperfused for 30 min. Rat hearts were also treated with 1-30 microM cromakalim in the presence of 10 microM DPCPX (adenosine A1 antagonist)., Results: R-PIA produced a concentration-dependent bradycardia before ischemia which was blocked by DPCPX. R-PIA increased the time to onset of contracture in a concentration-dependent manner (EC25 = 0.13 microM) and this was unaffected by 0.3 microM glyburide (EC25 = 0.20 microM). This concentration of glyburide completely abolished the protective effects of 10 microM cromakalim. R-PIA also significantly enhanced post-ischemic recovery of function and reduced LDH release, and glyburide did not alter these responses. Cromakalim significantly increased the time to onset of contracture (EC25 = 4.5 microM) and 10 microM DPCPX had no effect on this (EC25 = 5.6 microM). Cromakalim also significantly enhanced post-ischemic recovery of function and reduced LDH release. DPCPX did not alter these cardioprotective effects while glyburide completely abolished the cardioprotective effects of cromakalim., Conclusions: While both cromakalim and R-PIA are cardioprotective in isolated rat hearts, they are not pharmacologically linked, possibly explaining why preconditioning may be different in this species.

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (KATP) opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of KATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

Blockers of ATP-sensitive K+ channels (KATP) abolish preconditioning in several species. Glyburide does not abolish preconditioning in rat hearts, but this may be due to a loss of its activity during ischemia. We determined the effect of a KATP blocker, which is more active during ischemia (sodium 5-hydroxydecanoate, 5-HD), on preconditioning in isolated rat hearts. Rat hearts were subjected to 4 periods of 5 min global ischemia followed by 30 min of global ischemia and reperfusion. Preconditioning significantly enhanced post-ischemic recovery of function and reduced lactate dehydrogenase (LDH) release vs. sham. 5-HD (100 microM) did not abolish preconditioning. Cromakalim (20 microM) was protective in this ischemic model and this was abolished by 5-HD. This is further evidence that KATP opening is not the mechanism of preconditioning in rats.

Endothelium-derived nitric oxide (NO) has recently been reported to be a mediator of ischemic preconditioning in dog hearts. The aim of the present study was to determine the role of NO in ischemic preconditioning in isolated perfused rat hearts. Rat hearts were perfused at either constant pressure (80 mmHg) or constant flow. After aerobic perfusion (37 degrees C) for 10 min, hearts were treated with N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), which is an inhibitor of NO synthase, or vehicle. Ten minutes later, the hearts were preconditioned (4 episodes of 5 min of global ischemia and 5 min of reperfusion) or perfused normally before a 30-min global ischemic period. All hearts were reperfused for 30 min. Coronary flow or perfusion pressure plus heart rate and contractile function were measured continuously. Hearts perfused at constant pressure and treated with 30 microM L-NAME, a concentration that effectively inhibits endogenous NO synthesis, exhibited decreased coronary flow after 10 min, and flow remained decreased throughout the experiment. Ischemic preconditioning before 30 min of global ischemia resulted in a doubling of contractile function and a reduction of lactate dehydrogenase release at the end of the 30-min reperfusion period compared with nonpreconditioned hearts. The protective effect of preconditioning was not different in L-NAME-treated hearts. In addition, inhibition of NO synthase had no effect on the severity of ischemia in nonpreconditioned hearts. Similar results were obtained in preconditioned hearts that were perfused at constant flow, indicating that the flow reductions caused by L-NAME did not influence the results.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The mechanism of the protective effect of ischaemic preconditioning in the myocardium is not yet known. The aim of this study was to test the hypothesis that endogenous myocardial catecholamines may be mediators of preconditioning., Methods: To test whether endogenous catecholamines are involved in preconditioning, experiments were performed in hearts from rats which had been catecholamine depleted with either reserpine or 6-hydroxydopamine. Experiments were also done to determine if noradrenaline can mimic preconditioning., Results: Catecholamine depletion with either reserpine or 6-hydroxydopamine had no effect on preischaemic coronary flow or cardiac function. Ischaemic preconditioning (four episodes of 5 min global ischaemia and 5 min reperfusion) resulted in a significant increase in postischaemic cardiac function and a 50% decrease in lactate dehydrogenase (LDH) release following 30 min ischaemia and 30 min reperfusion compared with non-preconditioned hearts. Reserpine pretreatment did not affect the response to ischaemia or to preconditioning, although LDH release tended to be greater than in normal hearts, especially in the non-preconditioned group. Although 6-hydroxydopamine significantly increased postischaemic cardiac function in the preconditioned group, no other index of ischaemic damage (for example, LDH release, left ventricular end diastolic pressure) was affected. Further studies showed that 10 nmol.min-1 noradrenaline did not affect the severity of ischaemia, indicating that it does not mimic preconditioning., Conclusions: Endogenous catecholamines are not necessary for ischaemic preconditioning in isolated rat hearts and play little or no role in the functional responses to ischaemia.

Cromakalim, an agent that opens ATP-modulated potassium channels, has recently been reported to reduce skeletal muscle contractile force during anoxia in vitro. To determine whether this activity occurs in vivo, cromakalim was tested for its ability to influence muscle function and blood flow in a model of skeletal muscle ischemia. In anesthetized ferrets the muscles of the hindlimb were stimulated electrically via the sciatic nerve and isometric force of contraction was measured. Under normal perfusion conditions, contractile force peaked (324 +/- 33 g) within 1 or 2 min and gradually declined to about 85% of the peak over 20 min. Following this initial period, the abdominal aorta was partially occluded to reduce femoral blood pressure to 35-40 mm Hg, and infusion of cromakalim or vehicle was started. After 60 min of treatment, a second exercise challenge was performed. In the vehicle-treated group, peak force was reduced by 33% (p < 0.05), and over the 20-min stimulation period, the area under the force-time curve (AUC) was 22.8 +/- 2.6% of that seen during the normal flow period. Compared to vehicle, cromakalim infusions of 1.33 or 3.0 micrograms/kg/min reduced mean arterial blood pressure by 7 and 45%, but had no significant effect on either peak force or AUC. Although the higher dose of cromakalim significantly reduced vascular resistance in resting, normally perfused skeletal muscle of the forelimbs, neither dose affected blood flow in the ischemic skeletal muscles of the hindlimb during exercise. These results suggest that cromakalim does not influence skeletal muscle blood flow or function during an acute ischemic insult.

Neutrophils are reported to play an important role in the genesis of tissue damage during reperfusion after periods of ischemia in a variety of organs and may also be involved in loss of tissue function during ischemia. To test this hypothesis, the monoclonal antibody, MoAb 60.3, which prevents the adhesion of ferret neutrophils to cultured human endothelial cells at a concentration of 30 micrograms/ml, was tested in a model of peripheral vascular disease to determine whether it would preserve skeletal muscle function during ischemia. In an anesthetized ferret the muscles of the hindlimb were stimulated electrically to contract isometrically and the force of contraction was measured. Under normal perfusion conditions the contractile force peaked within 1 or 2 min of initiation of stimulation and gradually declined to approximately 80% of peak force after 20 min. When femoral arterial pressure was reduced to 45 mmHg by partial occlusion of the abdominal aorta, peak force was reduced by 25 +/- 7%, and within 5 min the force decayed to approximately 20% of the original peak, resulting in an area under the force-time curve (AUC) of 32 +/- 5% of that seen during the normal flow period. During ischemia after treatment with MoAb 60.3 (2 mg/kg iv), peak force was 94 +/- 3% and AUC was 49 +/- 5% of that observed during the normal flow period, a significant protective effect compared with the untreated control group (P = 0.0294). When the nonneutrophil-directed monoclonal antibody, L6, was tested in this model, no protective effects were evident.(ABSTRACT TRUNCATED AT 250 WORDS)