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Identification of ecosystem services, i.e. the contributions that ecosystems make to human well-being, has proven instrumental in galvanising public and political support for safeguarding biodiversity and its benefits to people. Here we synthesise the global evidence on ecosystem services provided and disrupted by freshwater bivalves, a heterogenous group of >1200 species, including some of the most threatened (in Unionida) and invasive (e.g. Dreissena polymorpha) taxa globally. Our systematic literature review resulted in a data set of 904 records from 69 countries relating to 24 classes of provisioning (N = 189), cultural (N = 491) and regulating (N = 224) services following the Common International Classification of Ecosystem Services (CICES). Prominent ecosystem services included (i) the provisioning of food, materials and medicinal products, (ii) knowledge acquisition (e.g. on water quality, past environments and historical societies), ornamental and other cultural contributions, and (iii) the filtration, sequestration, storage and/or transformation of biological and physico-chemical water properties. About 9% of records provided evidence for the disruption rather than provision of ecosystem services. Synergies and trade-offs of ecosystem services were observed. For instance, water filtration by freshwater bivalves can be beneficial for the cultural service ‘biomonitoring’, while negatively or positively affecting food consumption or human recreation. Our evidence base spanned a total of 91 genera and 191 species, dominated by Unionida (55% of records, 76% of species), Veneroida (21 and 9%, respectively; mainly Corbicula spp.) and Myoida (20 and 4%, respectively; mainly Dreissena spp.). About one third of records, predominantly from Europe and the Americas, related to species that were non-native to the country of study. The majority of records originated from Asia (35%), with available evidence for 23 CICES classes, as well as Europe (29%) and North America (23%), where research was largely focused on ‘biom, MCIU - Ministerio de Ciencia, Innovación y Universidades(CA18239), This study resulted from discussions facilitated by the EU COST Action CA18239. A.Z. was supported by an Anne McLaren Fellowship by the University of Nottingham. A.S.V. acknowledges support from FCT – Portuguese Foun dation for Science and Technology through the program Stimulus for Scientific Employment – Individual Support [contract reference 2020.01175.CEECIND] and Ministerio de Ciencia, Innovaci on y Universidades (Spain) through the 2018 Juan de la Cierva-Formaci on program [contract reference FJC2018-038131-I]. D.C.A. was supported by a Dawson Fellowship from St. Catharine’s College, Cam bridge. E.E. was supported by Portuguese national funds from FCT - Foundation for Science and Technology through projects UIDB/04326/2020, UIDP/04326/2020 and LA/P/0101/2020. [Corrections added on 22 July 2022, after first online publication: Funder details for Eduardo Esteves have been added in this version.]

In the present study, we evaluated the effects of different environments on the filtering rate (FR), mortality, and biodeposition (BD) of the freshwater mussel

There is growing acknowledgement that human���induced change can push ecosystems beyond tipping points, resulting in the dramatic and sudden loss of vital ecosystem services. Invasive non���native species (INNS) are spreading rapidly due to anthropogenic activities and climate change and can drive changes to ecosystem functioning by altering abiotic conditions and restructuring native communities. Shallow lake ecosystems are especially vulnerable to perturbation from INNS as they can exist in two alternative stable states: either clear water with an abundance of vegetation or turbid, unvegetated and dominated by phytoplankton. Through a global meta���analysis of studies observing the effects of INNS on recipient lake ecosystems, we found that certain INNS drive significant changes in the abundance of key taxa and conditions that govern the balance of alternative equilibria in shallow lakes. Invasive fish and crustaceans demonstrated effects likely to lead to early ecosystem collapse to a turbid state and delay ecosystem recovery. Invasive molluscs presented opposite effects, which may delay ecosystem collapse and encourage ecosystem recovery. Our results demonstrate that INNS could significantly alter the tipping points of ecosystem collapse and recovery, and that not all invasive species may initiate system collapse. Our results provide guidance for managers of invaded shallow lake ecosystems, which provide diverse services including sanitation, potable water supply, industrial cooling, aquaculture and recreational resources. Moreover, our approach could be applied to identify key potential drivers of change in other crucial ecosystems which demonstrate alternative equilibria, such as coral reefs and kelp forests.

Antarctica is experiencing significant ecological and environmental change, which may facilitate the establishment of non‐native marine species. Non‐native marine species will interact with other anthropogenic stressors affecting Antarctic ecosystems, such as climate change (warming, ocean acidification) and pollution, with irreversible ramifications for biodiversity and ecosystem services. We review current knowledge of non‐native marine species in the Antarctic region, the physical and physiological factors that resist establishment of non‐native marine species, changes to resistance under climate change, the role of legislation in limiting marine introductions, and the effect of increasing human activity on vectors and pathways of introduction. Evidence of non‐native marine species is limited: just four marine non‐native and one cryptogenic species that were likely introduced anthropogenically have been reported freely living in Antarctic or sub‐Antarctic waters, but no established populations have been reported; an additional six species have been observed in pathways to Antarctica that are potentially at risk of becoming invasive. We present estimates of the intensity of ship activity across fishing, tourism and research sectors: there may be approximately 180 vessels and 500+ voyages in Antarctic waters annually. However, these estimates are necessarily speculative because relevant data are scarce. To facilitate well‐informed policy and management, we make recommendations for future research into the likelihood of marine biological invasions in the Antarctic region., Are there non‐native marine species in Antarctica? With over 500 visits from more than 180 vessels annually and rapidly changing environmental conditions, Antarctica appears to be increasingly vulnerable to impacts from non‐native marine species. We explore factors that influence the likelihood of non‐native marine species establishing in the Antarctic region, present new estimates for human activity, and make recommendations to researchers, environmental managers and policy makers.

Funder: MAVA Foundation; Id: http://dx.doi.org/10.13039/100013324, The crisis generated by the emergence and pandemic spread of COVID‐19 has thrown into the global spotlight the dangers associated with novel diseases, as well as the key role of animals, especially wild animals, as potential sources of pathogens to humans. There is a widespread demand for a new relationship with wild and domestic animals, including suggested bans on hunting, wildlife trade, wet markets or consumption of wild animals. However, such policies risk ignoring essential elements of the problem as well as alienating and increasing hardship for local communities across the world, and might be unachievable at scale. There is thus a need for a more complex package of policy and practical responses. We undertook a solution scan to identify and collate 161 possible options for reducing the risks of further epidemic disease transmission from animals to humans, including potential further SARS‐CoV‐2 transmission (original or variants). We include all categories of animals in our responses (i.e. wildlife, captive, unmanaged/feral and domestic livestock and pets) and focus on pathogens (especially viruses) that, once transmitted from animals to humans, could acquire epidemic potential through high rates of human‐to‐human transmission. This excludes measures to prevent well‐known zoonotic diseases, such as rabies, that cannot readily transmit between humans. We focused solutions on societal measures, excluding the development of vaccines and other preventive therapeutic medicine and veterinary medicine options that are discussed elsewhere. We derived our solutions through reading the scientific literature, NGO position papers, and industry guidelines, collating our own experiences, and consulting experts in different fields. Herein, we review the major zoonotic transmission pathways and present an extensive list of options. The potential solutions are organised according to the key stages of the trade chain and encompass solutions that can be applied at the local, regional and international scales. This is a set of options targeted at practitioners and policy makers to encourage careful examination of possible courses of action, validating their impact and documenting outcomes.

The expansion of Invasive Alien Species (IAS) is a growing concern to the UK water industry because of their diverse impacts on water quality, infrastructure and eradication costs. New regulations reinforcing the industry's responsibilities beyond operational costs, coupled with continued range expansion and establishment of new IAS will increase damages. To tackle IAS effectively, the water industry requires reliable information about which species pose the greatest risk to operations and which areas are most vulnerable to invasion. Here we assess potential biosecurity threats for the 24 water companies in the UK using well-established modelling research techniques such as risk assessment and distribution modelling. Using a consensus approach with environmental managers and water companies, we identified 11 IAS of concern for the UK water industry, including five plants, three crustaceans, two molluscs and one fish. These invaders pose important hazards in terms of water quality, flood protection, human health, integrity of infrastructures, recreational and aesthetic values, amongst others. We used distribution models to predict their potential expansion under current and future 2050 climate scenarios within each of the 24 water companies in the UK. Water companies in the South East of England (Cambridge Water, Anglian Water, Affinity Water and Thames Water) are under the highest risk of invasional meltdown from multiple IAS, both now and under future scenarios. The quagga mussel poses the most serious risk of immediate spread and may exacerbate the impacts of the widespread zebra mussel for the water industry. The information generated in this study can support the prioritization of species and regions at risk, so that funds for prevention and eradication of invasions are well allocated. Ultimately, this study demonstrates that scientific risk assessments, usually restricted to the academic and public sectors, can be extremely useful to guide decision-making by the private sector.

Biosecurity is likely to be seriously compromised by the United Kingdom’s exit from the European Union. Common rules and safeguards, backed by a common judicial system, have for decades protected human, animal and plant health against biological hazards. Even so, ash dieback still threatens 60 million UK trees, and African swine fever has spread to Europe (see I. Capua and M. Monti Nature 566, 326; 2019).

Background The optimal timing of cholecystectomy for patients admitted with acute gallbladder pathology is unclear. Some studies have shown that emergency cholecystectomy during the index admission can reduce length of hospital stay with similar rates of conversion to open surgery, complications and mortality compared with a ‘delayed’ operation following discharge. Others have reported that cholecystectomy during the index acute admission results in higher morbidity, extended length of stay and increased costs. This study examined the cost-effectiveness of emergency versus delayed cholecystectomy for acute benign gallbladder disease. Methods Using data from a prospective population-based cohort study examining the outcomes of cholecystectomy in the UK and Ireland, a model-based cost–utility analysis was conducted from the perspective of the UK National Health Service, with a 1-year time horizon for costs and outcomes. Probabilistic sensitivity analysis was used to investigate the impact of parameter uncertainty on the results obtained from the model. Results Emergency cholecystectomy was found to be less costly (£4570 versus £4720; €5484 versus €5664) and more effective (0·8868 versus 0·8662 QALYs) than delayed cholecystectomy. Probabilistic sensitivity analysis showed that the emergency strategy is more than 60 per cent likely to be cost-effective across willingness-to-pay values for the QALY from £0 to £100 000 (€0–120 000). Conclusion Emergency cholecystectomy is less costly and more effective than delayed cholecystectomy. This approach is likely to be beneficial to patients in terms of improved health outcomes and to the healthcare provider owing to the reduced costs.

Protected areas (PAs) are intended to provide native biodiversity and habitats with a refuge against the impacts of global change, particularly acting as natural filters against biological invasions. In practice, however, it is unknown how effective PAs will be in shielding native species from invasions under projected climate change. Here, we investigate the current and future potential distributions of 100 of the most invasive terrestrial, freshwater, and marine species in Europe. We use this information to evaluate the combined threat posed by climate change and invasions to existing PAs and the most susceptible species they shelter. We found that only a quarter of Europe's marine and terrestrial areas protected over the last 100 years have been colonized by any of the invaders investigated, despite offering climatically suitable conditions for invasion. In addition, hotspots of invasive species and the most susceptible native species to their establishment do not match at large continental scales. Furthermore, the predicted richness of invaders is 11%¿18% significantly lower inside PAs than outside them. Invasive species are rare in long-established national parks and nature reserves, which are actively protected and often located in remote and pristine regions with very low human density. In contrast, the richness of invasive species is high in the more recently designated Natura 2000 sites, which are subject to high human accessibility. This situation may change in the future, since our models anticipate important shifts in species ranges toward the north and east of Europe at unprecedented rates of 14¿55 km/decade, depending on taxonomic group and scenario. This may seriously compromise the conservation of biodiversity and ecosystem services. This study is the first comprehensive assessment of the resistance that PAs provide against biological invasions and climate change on a continental scale and illustrates their strategic value in safeguarding native biodiversity., Research was supported by the Spanish Program of R+D+I (JCI‐2012‐11908, SEV‐2012‐0262, CGL2014‐55145‐R, CGL2015‐65346R, and CGL2009‐7515), Iberdrola Foundation (2014 Energy and Environment Scholarships), the Czech Science Foundation (project no. 14‐36079G, Centre of Excellence PLADIAS), The Czech Academy of Sciences (project RVO 67985939), and the European Community's Seventh Framework Programme FP7/2007‐2013 (grant agreement no. 281422, TEEMBIO). This research contributes to COST Action Alien Challenge (TD1209).

Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice.Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach.Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p 0.001), indication for surgery (p 0.001), ASA (p 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p 0.001), and a score6 identified patients at high risk of conversion (7.1% vs. 1.2%).This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.

Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment-related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma making it an excellent therapeutic target. To evaluate the feasibility of anti-EMMPRIN therapy, an ex-vivo human head and neck cancer model was established using specimens obtained at the time of surgery (n=22). Tumor slices were exposed to varying concentrations of anti-EMMPRIN monoclonal antibody and cetuximab for comparison purposes. Cetuximab is the only monoclonal antibody currently approved for the treatment of head and neck carcinoma. After treatment, tumor slices were assessed by immunohistochemistry and western blot analysis for apoptosis (TUNEL) and EMMPRIN expression. Of the tumor specimens 33% showed a significant reduction in mean ATP levels after treatment with cetuximab compared with untreated controls, whereas 58% of the patients responded to anti-EMMPRIN therapy (P

Human activities such as transport, trade and tourism are likely to influence the spatial distribution of non-native species and yet, Species Distribution Models (SDMs) that aim to predict the future broad scale distribution of invaders often rely on environmental (e.g. climatic) information only. This study investigates if and to what extent do human activities that directly or indirectly influence nature (hereafter the human footprint) affect the global distribution of invasive species in terrestrial, freshwater and marine ecosystems. We selected 72 species including terrestrial plants, terrestrial animals, freshwater and marine invasive species of concern in a focus area located in NW Europe (encompassing Great Britain, France, The Netherlands and Belgium). Species Distribution Models were calibrated with the global occurrence of species and a set of high-resolution (9×9 km) environmental (e.g. topography, climate, geology) layers and human footprint proxies (e.g. the human influence index, population density, road proximity). Our analyses suggest that the global occurrence of a wide range of invaders is primarily limited by climate. Temperature tolerance was the most important factor and explained on average 42% of species distribution. Nevertheless, factors related to the human footprint explained a substantial amount (23% on average) of species distributions. When global models were projected into the focus area, spatial predictions integrating the human footprint featured the highest cumulative risk scores close to transport networks (proxy for invasion pathways) and in habitats with a high human influence index (proxy for propagule pressure). We conclude that human related information–currently available in the form of easily accessible maps and databases—should be routinely implemented into predictive frameworks to inform upon policies to prevent and manage invasions. Otherwise we might be seriously underestimating the species and areas under highest risk of future invasions., The first author would like to thank the constructive comments and advice on the manuscript made by Drs Montserrat Vilà, Juan Pedro González-Varo and Pablo González-Moreno.

Summary Background: We describe 7 years experience of providing anesthesia for children undergoing lithotripsy in a hospital without pediatric inpatient facilities. A pediatric team, including anesthetist, pediatric nurse along with the equipment travel across the city with the patient from the children's hospital. As a high incidence of postoperative vomiting and discomfort was observed, the effect of increasing intraoperative analgesia and the use of antiemetic medication was examined. Methods: From 1998 to 2004, 69 children (49 boys and 20 girls) were anesthetized for 120 procedures: 67 extracorporeal shock wave lithotripsy (ESWL) and 53 endosurgical procedures, consisting of percutaneous nephrolithotomy (29), ureteroscopic laser lithotripsy (17) and percutaneous bladder litholapaxy (7). The mean age was 5.4 years (10 months to 13 years) and weight 23.7 kg (7.1–59 kg). ESWL was performed initially with a Wolf Piezolith 2300, and after 1999, a Dornier Compact Delta. Results: Increased administration of intraoperative analgesia resulted in reduced postoperative analgesia requirements in all the groups, with a significant reduction (P

Whereas avascular necrosis of the scaphoid after a fracture is well-documented, idiopathic avascular necrosis of the scaphoid (Preiser’s disease) is rare. Little is known of the aetiology of the condition and even less about the best course of management. We describe a rare case of bilateral Preiser’s disease. Possible aetiological factors and a summary of the current concepts of management are discussed.

In patients with kidney failure, adequate control of fluid status remains one of the most difficult routine issues to be addressed in the modern style of dialysis. This is primarily due to the lack of quantitative methods for the assessment of fluid status and the reliance on subjective criteria. Fluid is removed from the blood during dialysis treatments using a process called ultrafiltration. The last decade has seen considerable developments in blood volume monitoring (BVM) technology which has enabled responses to ultrafiltration to be continually monitored on an individual basis. This has enabled feedback control of patients' blood volume to be applied with partial success, reducing the number of symptoms. The feedback control algorithms employed have been relatively unsophisticated, using simple proportional control with no attempt to include models of the patient fluid dynamics. This paper describes the development of some prototype fluid kinetic models which may be used in a more advanced control system. Initial results demonstrate the importance of active control processes in the patients' physiological compensatory mechanisms.

We have investigated the basis of the lack of activity of a natural variant human peroxisome proliferator-activated receptor alpha, hPPARalpha6/29. A subcloning approach was used to change the four variant amino acids in the hPPARalpha6/29 sequence, individually and in combination, to those found in an active human PPARalpha. Individual amino acid "back mutations" were unable to confer on hPPARalpha6/29 the ability to be activated by peroxisome proliferators in a transient transfection assay. Although hPPARalpha6/29 was able to bind specifically to DNA in the presence of the retinoid X receptor alpha (RXRalpha), the complete restoration of receptor transcriptional activity required two separate back mutations of the hPPARalpha6/29 sequence, namely amino acid 123 in the DNA binding domain, and amino acid 444 close to the C-terminus. This suggests that sequences in the PPARalpha DNA binding domain influence other receptor functions besides DNA binding.

Limitations to short haemodiaiysis It is now generally accepted that there is a significant risk of underdialysis if the treatment time is shortened towards 4 h or less. To avoid these risks, a return to longer dialysis times has been advocated, despite the increase in cost and inconvenience to the patient. An alternative strategy would be to understand the mechanism of reduced efficiency in short dialysis and specifically correct for it without resorting to long treatments. If it were possible to increase the rate of removal of fluid and solute mass in proportion to the reduction of dialysis time, without increasing the patient's fluid content, blood pressure or solute concentrations, then the short treatment would have equivalent efficacy to the long treatment. There are a number of factors which combine to reduce rate of fluid and solute removal in short dialysis. These include the relatively slow diffusion of middle and large molecular weight solutes, hypotension related to high ultrafiltration rates and the post-dialysis rebound. This paper will consider only the post-dialysis rebound, although it is accepted that other factors need to be considered when prescribing short dialysis. The rate at which solute can be removed from the patient is dependent on the dialyser clearance and on the rate at which solute can be conveyed from all parts of the body into the arterial needle. While the dialyser clearance rate is controllable and relatively easy to measure, the other factors are much more difficult to measure and are generally impossible to modify. For solute to travel from the intracellular compartment (which is the largest body water compartment) to the needle, it must cross the cell membrane, be carried into the central circulation by venous blood flow, be pumped into the aorta by the heart and carried to the needle by the fistula blood flow. Therefore the rate of transfer depends on the intra/extracellular mass transfer coefficient, regional blood flow rates, cardiac output

Purpose: Occlusive iliofemoral venous thrombosis is associated with morbid short- and long-term consequences. Having been disappointed with standard anticoagulant therapy and systemic fibrinolysis, we embarked on an aggressive multidisciplinary regional approach to treat these patients, with the goals of therapy being (1) to eliminate iliofemoral venous thrombus, (2) to provide unobstructed venous drainage from the affected limb, and (3) to prevent recurrent thrombosis. Methods: Twelve consecutive patients were treated for extensive iliofemoral venous thrombosis. Each had thrombus from their infrapopliteal veins through their iliofemoral system, and four had vena caval involvement. The conditions of 11 patients failed to improve when the patients were given anticoagulants, and prior systemic fibrinolysis failed in five patients. The treatment strategy includes catheter-directed thrombolysis with intrathrombus infusion of the plasminogen activator or operative thrombectomy or venous bypass with a permanent 4 mm arteriovenous fistula (AVF). Results: Nine of 12 patients had a good or excellent clinical outcome (mean follow-up 25 months), which correlated with restored unobstructed venous drainage from the affected limb. Seven patients had catheter-directed lytic therapy attempted. In five patients the catheters were appropriately positioned, and lysis was successful. Five of the eight patients who underwent operations had successful procedures. Two of the three patients with poor operative outcomes had residual thrombus in their iliac veins or vena cava after thrombectomy (without bypass). The third patient, in whom anticoagulation was contraindicated, had an initially successful thrombectomy and AVF; however, vena caval thrombosis developed 2 months after operation. No patient had symptomatic pulmonary emboli, and routine posttreatment ventilation/perfusion lung scanning was not performed. Conclusions: An aggressive multidisciplinary regional approach to patients with obliterative iliofemoral venous thrombosis, designed to remove thrombus and provide unobstructed venous drainage, offers substantially better clinical outcome compared with systemic fibrinolysis and standard anticoagulation. Catheter-directed thrombolysis is successful if the catheter is appropriately positioned within the thrombus. Contemporary venous thrombectomy, which includes thrombus removal, completion phlebography, AVF, and cross-pubic bypass when necessary, is associated with high success rates. Failures can be anticipated and avoided in most patients. (J VASC SURG 1994;20:244-54.)

Two new cases of popliteal venous aneurysm are reported and added to the 22 other cases of popliteal venous aneurysm available for review. Both patients were first seen with acute pulmonary embolism and were treated with thrombolytic therapy followed by anticoagulation. Each had recurrent venous thromboembolism before discovery of the popliteal venous aneurysm. One popliteal venous aneurysm was diagnosed with phlebography and the second with venous duplex imaging, confirmed with phlebography. Both were surgically corrected with tangential aneurysmectomy and lateral venorrhaphy. Twenty-four cases of popliteal venous aneurysm are now available for review. Seventy-one percent (17 of 24) presented with pulmonary embolism, 88% (21 of 24) were saccular, and 96% (23 of 24) were located in the proximal popliteal vein. All but two were diagnosed by ascending phlebography. Three patients received no treatment: in two of these the outcome was not documented and the third had occasional pain. Two patients received anticoagulation without subsequent operative repair and both died of recurrent pulmonary emboli. Operative correction resulted in a 75% patency rate with 21% complications, most of which were related to postoperative anticoagulation. No patient who was operated on had subsequent pulmonary embolism, and there were no operative deaths. We suggest that all patients who have pulmonary embolism have lower-extremity venous duplex imaging. All popliteal venous aneurysms should be surgically repaired, inasmuch as nonoperative therapy results in recurrent thromboembolism and an unacceptably high mortality rate. Tangential aneurysmectomy with lateral venorrhaphy is the recommended procedure.

The efficiency of haemodialysis may be limited by recirculation of blood between venous and arterial needles. Recirculation can be detected directly using a saline dilution method but is most commonly calculated from the urea concentrations of simultaneous samples from venous and arterial lines and a peripheral vein (three-sample method). The methods detect markedly different rates of recirculation in similar study populations. To investigate the possibility that the methods detect different phenomena, we performed both tests on 16 haemodialysis patients at various extracorporeal blood flow rates (Qb). The saline dilution method showed no recirculation in any of the patients, whereas the three-sample method indicated recirculation in all patients. The three-sample method indicated a mean recirculation fraction of 12.5% (SD 6.1) and was not influenced by changing Qb, suggesting that it was not detecting fistula recirculation. The three-sample method detects a solute concentration difference between arterial blood and peripheral blood during dialysis. There appears to be a disequilibrium between a central pool, represented by the arterial sample, and a poorly perfused peripheral pool, relatively isolated from the dialysis process, represented by the peripheral venous sample. The three-sample method for detecting recirculation should be abandoned.

Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated.

The purpose of this investigation was to compare intersegmental knee and hip forces for below-knee amputee (BKA) and able-bodied children during standing. Three unilateral BKA children and 10 able-bodied children (7-9 years) were tested on four separate occasions at six month intervals. Three trials of external force and spatial data during standing were collected from each subject for each session. These data were utilised to determine the intersegmental forces at the knees and hips of the children using a static force analysis. Results indicated that in some instances the intersegmental forces for the BKA children were significantly greater than those of the able-bodied children and in other instances significantly lower (p less than 0.05). In all cases, however, the values were substantially less than corresponding values for walking and running. The effects of the forces upon spatial orientations indicated significant differences between the two groups of children. The frontal plane prosthetic knee angle, the sagittal plane prosthetic and non-prosthetic knee angles, and the sagittal plane trunk angle were all greater for the BKA children when compared to able-bodied children. These differences may be the result of the anatomical structure of the amputee and/or the construction of the prosthesis.

The discovery of a second estrogen receptor (ER beta) has significant implications for our understanding of the molecular basis for the diverse actions of estrogen. Here we report the differential activation by natural and xenobiotic estrogens of ER alpha and ER beta when linked to different response elements. Receptor mediated activation of reporter constructs containing either the estrogen response element (ERE) from the vitellogenin (Vit) gene or from the luteinizing hormone beta (LH) gene were examined in transiently transfected Cos-1 cells. ER beta preferentially activated the consensus Vit ERE whereas ER alpha showed greater activation at the divergent LH ERE. This differential activation was observed for a number of ligands including estradiol, estrone, bisphenol A, octylphenol and diethystilbestrol. These findings show that the nature of the ERE, as well as the ratio of ER subtypes in a particular cell/tissue, will influence whether particular estrogen responsive genes are activated in the presence of natural or xenobiotic estrogens.

We have been attempting to elucidate the molecular mechanisms through which peroxisome proliferators exert their pleiotropic effects, with particular emphasis on understanding why humans appear unresponsive to these compounds. There is a wealth of data to implicate the peroxisome proliferator-activated receptor alpha (PPAR alpha) in mediating these effects in rodent species; PPAR alpha is expressed in tissues that show physiological changes in response to PPs, is transcriptionally activated in vitro by a variety of PPs, and it has been recently demonstrated that mice lacking this receptor are refractory to the effects of clofibrate and Wy-14,643, at least in the short term. It is conceivable that differences in PPAR alpha between responsive rodent and unresponsive human subjects may provide the key to understanding the basis of this species variation in response, and with this in mind we have been studying the biology of PPAR alpha in humans and looking at interindividual variation. There is already published evidence, albeit on only two sequences, for structural and functional polymorphism in human PPAR alphas. We have extended these findings, and shown that: There is considerable variation in hPPAR alpha cDNAs obtained from different individuals, both at the gross structural level (lack of a coding exon) and of a more subtle nature (single base changes leading to amino acid substitutions). One such cDNA, the sequence of which differs at only three amino acids from that published, encodes a receptor that is incapable of transcriptional activation by potent PPs. The degree to which hPPAR alpha transcripts are expressed in human livers can vary by up to an order of magnitude between individuals. The tissue-specific expression profile of PPAR alpha in humans is very different from that in rat and mouse. In particular, the human liver contains generally low levels of PPAR alpha in contrast to the responsive rodents, in which potent PPs cause liver tumors. Taken together, these data suggest first that human and rodent PPAR alphas differ according to a number of molecular and biochemical criteria, and secondly that there is a degree of interindividual variation in PPAR alpha structure and function. Studies are ongoing to clarify this further, but human polymorphism may go some way towards explaining the apparent paradox that active PPAR alpha receptors can be isolated from an "unresponsive" species.

We measured the net rates of skeletal muscle glycogen synthesis and glycolysis (conversion of [3-3H]glucose to 3H2O) in healthy overnight-fasted volunteers. Two studies were performed. In study 1, seven subjects participated in two paired infusions under basal conditions of either [2-3H]glucose (H2) or [3-3H]glucose (H3). Total glucose uptake (Rd) and rates of whole body 3H2O formation (3H2O Ra) were measured. With H2, Rd and 3H2O Ra were similar. With H3, 3H2O Ra, equal to glycolysis, was 65% of Rd. In study 2, six different subjects underwent a 3-h, 40 mU.m-2 x min-1 euglycemic insulin clamp. [6,6-2H2]glucose was infused throughout and H3 was infused during the last hour of the study. Open muscle biopsies were obtained at 150 and 180 min. Glycogen synthesis was assessed by three independent means: 1) direct measurement, as 3H disintegrations per minute in isolated muscle glycogen per plasma H3 specific activity; 2) extrapolation from the activity of glycogen synthase assayed in the presence of the concentrations of glucose 6-phosphate and UDP-glucose measured in the biopsy; and 3) the difference between Rd and glycolysis. Despite a wide range in Rd [24.5-58.8 mumol.kg fat-free mass (FFM)-1 x min-1] and glycolysis (14.2-26.1), the three methods yielded similar results of 20.0 +/- 3.9, 22.5 +/- 3.7, and 20.6 +/- 3.7 mumol.kg FFM-1 x min-1 and correlated highly with each other (r2 = 0.92-0.96). Our results (study 1) indicate that the rate of plasma tritiated water formation reflects the intracellular detritiation of tritiated glucose. Under hyperinsulinemic conditions (study 2) the net rate of muscle glycogen synthesis can be accurately estimated from the glycogen synthase activity and from the difference between total glucose uptake and glycolysis. Thus, at high physiological plasma insulin concentrations resulting in submaximal stimulation of muscle glycogen synthesis, the latter can be accurately measured in humans.

Although anticoagulation is the treatment most commonly chosen for patients suffering from deep venous thrombosis (DVT), thrombolytic therapy offers the promise of dissolving the thrombus within the deep venous system, restoring patency and preserving valve function. If this is achieved, the incidence and severity of post-thrombotic syndrome can be reduced. Data from 13 studies comparing anticoagulant therapy with thrombolytic therapy for DVT in 591 patients have shown that, among those treated with heparin, 4% had significant or complete lysis, 14% had partial lysis and 82% failed to improve or worsened. Of those receiving lytic therapy, 45% had significant or complete lysis, 18% had partial lysis and 37% failed to improve or worsened. Long-term follow-up of randomized patients has shown that those with successful lysis had a lower incidence of post-thrombotic syndrome and improved long-term venous function. The failure rate of systemic lytic therapy among patients suffering iliofemoral venous thrombosis is high; therefore, catheter-directed thrombolysis has been adopted with increasing success. Thrombolytic therapy, delivered systemically using catheter-directed techniques, should be considered as an important alternative in the treatment of patients with DVT.

On rare occasions, thoracic injuries require resuscitative efforts including emergent thoracotomy that result in edematous changes to the lungs and heart. Hemodynamic compromise occurs when these organs are placed in their anatomic position and closure of the thoracotomy is attempted. Adaptation of a temporary abdominal closure to a thoracic injury is described.

Objective: Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma. To evaluate the feasibility of anti-CD147 therapy, an ex vivo human head and neck cancer model was established.

Clinical deterioration of patients with chronic venous disease (CVD) has been well described and a standardized classification has been proposed. The progressive hemodynamic deterioration producing these clinical findings is less well appreciated. This study examines and correlates venous hemodynamics with clinical severity in patients with CVD. Two hundred seventy-four extremities from 149 patients with varying degrees of CVD and 56 extremities from 28 symptom-free volunteers were evaluated clinically and hemodynamically. Each limb was assessed for functional venous volume, degree of valvular insufficiency, efficiency of the calf muscle pump, and noninvasive estimate of ambulatory venous pressure. In addition, exercise venous pressures were recorded in 56 extremities from 36 patients and 9 extremities from 6 volunteers. As CVD progresses from class 0 to class 2, venous volume expands, valvular function deteriorates, the calf muscle pump becomes inefficient, and ambulatory venous hypertension develops. However, once extremities develop brawny edema or hyperpigmentation, further deterioration of limb hemodynamics does not occur. Patients with deep venous obstruction have more severe valvular insufficiency, calf muscle pump dysfunction, and ambulatory venous hypertension than have patients without evidence of obstruction. Residual volume fraction offers a reliable noninvasive estimate of ambulatory venous pressure (r = 0.76), although its correlation was significantly better for patients without venous obstruction (r = 0.86) than for those with obstruction (r = 0.40; p0.05). Deterioration in venous hemodynamics parallels clinical severity through class 2. Once brawny edema and hyperpigmentation occur, ulceration develops without additional deterioration of venous hemodynamics.

Gallbladder cancer is the most common malignant tumor of the biliary tract, but its early diagnosis is uncommon. The use of ultrasonography has increased the detection of benign gallbladder tumors, and the premalignant potential of gallbladder adenomas is now undisputed. Adenomyomatosis of the gallbladder has recently been suggested to have malignant potential, and we report a case of adenocarcinoma of the gallbladder occurring in localized adenomyomatosis that was successfully treated by radical curative surgery. The more rigorous use of ultrasonography and a more aggressive approach to "benign" polypoid lesions of the gallbladder may represent the best way of achieving early diagnosis and cure in gallbladder cancer.

Colonic complications are rare in acute pancreatitis. Over the last 9 years at St. Mary's Hospital, London, UK, we have managed severe acute pancreatitis by intensive supportive therapy followed by sub-total pancreatic resection and/or debridement in those who fail to improve. Of the 22 patients who have undergone this form of surgery, nine were found to have colonic involvement in the form of either necrosis or perforation. In addition, one patient presenting at West Middlesex University Hospital, Isleworth, UK, had severe acute pancreatitis and almost total colonic necrosis as an unexpected finding at emergency laparotomy. These ten patients comprised seven men and three women of median age 59 years and with a median of four Ranson criteria. In seven patients, colonic involvement was discovered at the time of pancreatic surgery or laparotomy for pancreatitis and in the remainder it presented between 1 and 3 weeks later as either a faecal fistula (n = 2) or persistent abdominal sepsis (n = 1). The ascending colon was involved in one patient, the splenic flexure and descending colon in one, the transverse colon in three, the splenic flexure alone in four, and one patient had almost total colonic involvement. All patients underwent resection of the involved colon and exteriorization with either a proximal colostomy (n = 7) or ileostomy (n = 3) and a distal mucous fistula. Pathological examination of the resected colons revealed a spectrum of changes from pericolitis through to ischaemic necrosis suggesting at least two possible mechanisms. Six patients died from overwhelming sepsis between 1 day and 4 weeks (median 11 days) after colonic resection. Severe acute pancreatitis must be recognized as a cause of colonic ischaemia and necrosis; this complication is associated with a very poor prognosis despite surgical intervention.

To demonstrate any difference in outcome between patients with carcinoma at various sites within the large bowel, analysis of a large number of patients is necessary. From the Large Bowel Cancer Project, 4292 patients have been evaluated to compare mode of presentation, surgical management, pathological findings and outcome. Carcinoma at the splenic flexure was associated with the highest risk of obstruction (49 per cent); postoperative cardiopulmonary complications (36 per cent); in-hospital mortality (18 per cent); and the lowest age-adjusted 5-year survival (28 per cent), even after curative resection (38 per cent). This survival disadvantage was seen even in those without obstruction. Further, it was not accounted for by differences in age, sex, Dukes' stage or tumour differentiation between the various sites as stratification by these variables failed to alter significance (log rank χ2 = 11·1; d.f. = 4; P < 0·05). Compared with carcinoma of the left colon and rectum, tumours in the right colon were more likely to be poorly differentiated and locally advanced (in terms of fixation and penetration of the bowel wall) but were not associated with a higher risk of either distant spread at presentation or local recurrence. Age-adjusted 5-year survival following curative surgery was higher for the right colon (65 per cent) than the left (59 per cent).

1. It has been shown in vitro that serial measurements of blood water during ultrafiltration accurately reflect changing blood volume. 2. It has been shown that minute changes in blood hydration produce detectable changes in blood viscosity. 3. An ‘in-line’ capillary viscometer has been constructed which can be placed in parallel with an extracorporeal circuit to give a continuous semi-quantitative measure of blood viscosity during ultrafiltration or haemodialysis. By making serial measurements of blood water each ‘viscometer curve’ can be corrected to permit calculation of blood volume provided that the starting blood volume is known. 4. Blood volume changes of less than 1% can be detected in vitro and provided that blood volume changes solely as a result of the removal or influx of water it can be measured continuously to within an accuracy of 4% for volume changes up to 30% irrespective of starting packed cell volume or blood water.

Rectal cysts are uncommon, with a search of the medical literature revealing only 12 reported cases. This is in contrast with postanal and sacrococcygeal dermoids which, although still uncommon, appear to occur more frequently. This paper describes a case involving a dermoid cyst arising in the lateral wall of the rectum and reviews the recorded cases of rectal cysts.

Non-operative management of acute necrotizing pancreatitis carries a mortality of up to 80 per cent. Over the last 6 years we have pursued an aggressive policy of intensive supportive therapy followed by pancreatic resection in those patients with this severe form of the disease. We have managed 15 patients in this way, 14 by subtotal pancreatic resection (usually body and tail of the gland) and one by total pancreatectomy; 7 had early overwhelming multi-system failure with a median of 4 positive prognostic factors whilst 8 were operated on later between 3 and 8 weeks (plus one at 32 weeks) and had varying clinical pictures. Eight patients had ischaemia of the transverse colon which was noted at operation in four, and presented postoperatively in the remainder. Re-operation was necessary in 13 patients to remove further slough or resect ischaemic bowel. Five patients (33 per cent) died between 10 days and 4 weeks postoperatively, death being due to sepsis and multi-system failure in four and a massive retroperitoneal haemorrhage in one. of the ten survivors, four require insulin. Timely excision of necrotic pancreatic tissue combined with intensive supportive therapy may help reduce the high mortality in this condition.

Knowledge of useful fistula flow (UFF), the maximum blood flow available using twin needles within acceptable pressure limits and without recirculation, is essential for the optimal management of patients receiving maintenance hemodialysis or hemofiltration. A technique for the measurement of UFF employing thermal dilution for the detection of recirculation has been developed. Using this technique, 94 studies were carried out in 69 forearm fistulae. UFF exceeded 400 ml/min in 45 fistulae. In these satisfactory fistulae a normal range was defined for basal intrafistula pressures (60 mmHg being the approximate upper limit of normal). Analysis of arterial and venous line pressure recordings with increasing extracorporeal blood flow and knowledge of the presence or absence of recirculation allowed us to define the functional problem in unsatisfactory fistulae. The functional diagnosis was supported in 16 of 24 fistulae by angiography or surgery or both. In all but two of the remainder, satisfactory UFF was obtained by repositioning the patients' needling sites. Fistulae were divided into different clinical groups. Of 35 fistulae which were thought to be clinically acceptable, 7 were found to be unsatisfactory. In 17 fistulae in patients with poor biochemical control, recirculation was detected in 8. Of 11 fistulae reported to produce poor flows on dialysis, 4 had UFF above 400 ml/min. Of 6 fistulae in patients experiencing needling difficulties, 5 had satisfactory UFF. These studies which take only a few minutes and can be carried out immediately preceding a routine dialysis session not only identify unsatisfactory fistulae, but yield valuable diagnostic information in these cases. This has reduced dependence on angiography and has led to more careful selection of patients for surgery.

Despite extensive study of the difference in the cardiovascular response to ultrafiltration in isolation and during haemodialysis, there is still disagreement in the literature as to whether or not there is a difference in the efficiency of plasma refilling between the two procedures. We believe that this results both from the use of inadequate techniques to measure change in blood volume and shortcomings in experimental design. We have employed novel methods in ten patients to study plasma refilling during isolated ultrafiltration and dialytic ultrafiltration. Measurement of blood pressure and heart rate confirmed the inferior cardiovascular tolerance to haemodialysis observed by others. However, no difference in the rate of plasma refilling could be demonstrated. Our observations suggest that the superior tolerance to isolated ultrafiltration is not explained by differences in vascular refilling.

An optical blood hydration monitor for use with extracorporeal haemodialysis circuits is described. Studies in five stable haemodialysis patients demonstrate good correlations between measured blood water, haemoglobin concentration and optical attenuation during ultrafiltration. There are no significant errors introduced as a result of a changing extracorporeal circuit pressure and errors resulting from a changing state of oxygenation of haemoglobin are small. Changes in blood volume effected by ultrafiltration may be deduced if it is assumed that these are due solely to shifts of water into or out of the vascular compartment.

Effect of dialysate composition on intercompartmental fluid shift. Effect of dialysate composition on intercompartmental fluid shift and hemodynamics was studied in 12 patients during 1.5 or 2 hours of hemodialysis without net ultrafiltration, using high (H;Na 154 mmol/liter), normal (N;Na 140 mmol/liter) or low (L:Na 126 mmol/liter) concentration dialysate. H dialysate was associated with a small (0.9%) increase in blood volume, a larger increase in plasma volume and a decrease in erythrocyte volume. L dialysate resulted in a 2.3% decrease in blood volume, a larger decrease in plasma volume and an increase in erythrocyte volume. N dialysate gave results which were intermediately between the other two dialysis conditions. There was no difference in the post-dialysis mean arterial pressure between the groups, although heart rate increased more during H dialysis than during the other two conditions. Change in blood and erythrocyte volume correlated significantly with change in plasma Na concentration and osmolality, but not with change in plasma urea concentration. We conclude that dialysate composition affects the movement of water into and out of the plasma and erythrocytes in a manner that can be accounted for by altered plasma concentrations of osmotically active substances.