Liver preservation with machine perfusion and a newly developed cell-free oxygen carrier solution under subnormothermic conditions.

We describe a new preservation modality combining machine perfusion (MP) at subnormothermic conditions(21 °C) with a new hemoglobin-based oxygen carrier (HBOC) solution. MP (n=6) was compared to cold static preservation (CSP; n=6) in porcine orthotopic liver transplants after 9 h of cold ischemia and 5-day follow-up. Recipients' peripheral blood, serial liver biopsies, preservation solutions and bile specimens were collected before, during and after liver preservation. Clinical laboratorial and histological analyses were performed in addition to mitochondrial functional assays, transcriptomic, metabolomic and inflammatory inflammatory mediator analyses. Compared with CSP, MP animals had: (1) significantly higher survival (100%vs. 33%; p<0.05); (2) superior graft function (p<0.05);(3) eight times higher hepatic O2 delivery than O2 consumption (0.78 mL O2/g/h vs. 0.096 mL O2/g/h) during MP; and (4) significantly greater bile production (MP=378.5 ± 179.7; CS=151.6 ± 116.85). MP downregulated interferon (IFN)-α and IFN-γ in liver tissue. MP allografts cleared lactate, produced urea, sustained gluconeogenesis and produced hydrophilic bile after reperfusion. Enhanced oxygenation under subnormothermic conditions triggers regenerative and cell protective responses resulting in improved allograft function. MP at 21 °C with the HBOC solution significantly improves liver preservation compared to CSP.

Mortality from internal and external radiation exposure in a cohort of male German uranium millers, 1946-2008.

PURPOSE: To examine exposure-response relationships between ionizing radiation and several mortality outcomes in a subgroup of 4,054 men of the German uranium miner cohort study, who worked between 1946 and 1989 in milling facilities, but never underground or in open pit mines. METHODS: Mortality follow-up was from 1946 to 2008, accumulating 158,383 person-years at risk. Cumulative exposure to radon progeny in working level months (WLM) (mean = 8, max = 127), long-lived radionuclides from uranium ore dust in kBqh/m(3) (mean = 3.9, max = 132), external gamma radiation in mSv (mean = 26, max = 667) and silica dust was estimated by a comprehensive job-exposure matrix. Internal Poisson regression models were applied to estimate the linear excess relative risk (ERR) per unit of cumulative exposure. RESULTS: Overall, a total of 457, 717 and 111 deaths occurred from malignant cancer, cardiovascular diseases and non-malignant respiratory diseases, respectively. Uranium ore dust and silica dust were not associated with mortality from any of these disease groups. A statistically significant relationship between cumulative radon exposure and mortality from all cancers (ERR/100 WLM = 1.71; p = 0.02), primarily due to lung cancer (n = 159; ERR/100 WLM = 3.39; p = 0.05), was found. With respect to cumulative external gamma radiation, an excess of mortality of solid cancers (n = 434; ERR/Sv = 1.86; p = 0.06), primarily due to stomach cancer (n = 49, ERR/Sv = 10.0; p = 0.12), was present. CONCLUSION: The present findings show an excess mortality from lung cancer due to radon exposure and from solid cancers due to external gamma radiation in uranium millers that was not statistically significant. Exposure to uranium was not associated with any cause of death, but absorbed organ doses were estimated to be low.

Occupational dust and radiation exposure and mortality from stomach cancer among German uranium miners, 1946-2003.

OBJECTIVES: 'Dusty occupations' and exposure to low-dose radiation have been suggested as potential risk factors for stomach cancer. Data from the German uranium miner cohort study are used to further evaluate this topic. METHODS: The cohort includes 58 677 miners with complete information on occupational exposure to dust, arsenic and radiation dose based on a detailed job-exposure matrix. A total of 592 stomach cancer deaths occurred in the follow-up period from 1946 to 2003. A Poisson regression model stratified by age and calendar year was used to calculate the excess relative risk (ERR) per unit of cumulative exposure to fine dust or from cumulative absorbed dose to stomach from α or low-LET (low linear energy transfer) radiation. For arsenic exposure, a binary quadratic model was applied. RESULTS: After adjustment for each of the three other variables, a statistically non-significant linear relationship was observed for absorbed dose from low-LET radiation (ERR/Gy=0.30, 95% CI -1.26 to 1.87), α radiation (ERR/Gy=22.5, 95% CI -26.5 to 71.5) and fine dust (ERR/dust-year=0.0012, 95% CI -0.0020 to 0.0043). The relationship between stomach cancer and arsenic exposure was non-linear with a 2.1-fold higher RR (95% CI 0.9 to 3.3) in the exposure category above 500 compared with 0 dust-years. CONCLUSION: Positive statistically non-significant relationships between stomach cancer and arsenic dust, fine dust and absorbed dose from α and low-LET radiation were found. Overall, low statistical power due to low doses from radiation and dust are of concern.

Safety of liver resection in the elderly: how important is age?

BACKGROUND: With the aging population, more elderly patients are being considered for hepatic resection. We investigated whether advanced age was associated with higher rate and severity of postoperative complications. METHODS: A total of 75 patients aged ≥70 years (group E) were matched with 75 patients aged <70 years (group Y) by the extent of liver resection and by operative indications. Primary outcome measures were rates and severity of complications. Secondary outcome measures were length of hospital stay and discharge destination. Univariate analysis was also performed to identify variables associated with higher surgical risk. RESULTS: Male-to-female ratio was 43:32 in both groups. Overall complication rates were 44 and 33.3% in group E and Y, respectively (P = 0.241; odds ratio = 1.57; 95% confidence interval [95% CI], 0.81-3.05). There was no mortality in both groups. The only postoperative age-related morbidity was confusion in the elderly. There was no difference in the rates of severe complications (grade ≥3) between group E and group Y (16 vs. 14.7%; P = 0.744; odds ratio = 1.11; 95% CI, 0.46-2.70). Median length of hospital stay were 7 and 6 days, respectively (P = 0.01). Nineteen percent and 1% of patients in group E and group Y were discharge to rehabilitation facilities, respectively (P = 0.001). Univariate analysis showed that preoperative systemic chemotherapy and longer operative time were associated with higher morbidity in the elderly. CONCLUSIONS: Liver resection can be performed in patients aged ≥70 years as safely as in younger patients. Duration and timing of systemic chemotherapy before liver resection should be optimized to minimize postoperative morbidity.

Modelling particle retention in the alveolar-interstitial region of the human lungs.

Better information is available now on long-term particle retention in the human lungs than there was in 1994, when the human respiratory tract model (HRTM) was adopted by the International Commission on Radiological Protection (ICRP). Three recent studies are especially useful because they provide such information for groups of people who inhaled very similar aerosols. For all three the HRTM significantly underestimates lung retention of insoluble material. The purpose of this work was to improve the modelling of long-term retention in the deep lung. A simple physiologically based model developed to predict lung and lymph node particle retention in coal miners was found to represent lung retention in these studies adequately. Instead of the three alveolar-interstitial (AI) compartments in the HRTM, it has an alveolar compartment which clears to the bronchial tree and to a second compartment, representing the interstitium, which clears only to lymph nodes. The main difference from the HRTM AI model is that a significant fraction of the AI deposit is sequestered in the interstitium. To obtain default parameter values for general use, the model was fitted to data from the three recent studies, and also the experimental data used in development of the HRTM to define particle transport from the AI region for the first year after intake. The result of the analysis is that about 40% of the AI deposit of insoluble particles is sequestered in the interstitium and the remaining fraction is cleared to the ciliated airways with a half-time of about 300 days. For some long-lived radionuclides in relatively insoluble form (type S), this increased retention increases the lung dose per unit intake by 50-100% compared to the HRTM value.

ICRP recommendations on radon.

The International Commission on Radiological Protection (ICRP) publishes guidance on protection from radon in homes and workplaces, and dose coefficients for use in assessments of exposure for protection purposes. ICRP Publication 126 recommends an upper reference level for exposures in homes and workplaces of 300 Bq m-3. In general, protection can be optimised using measurements of air concentrations directly, without considering radiation doses. However, dose estimates are required for workers when radon is considered as an occupational exposure (e.g. in mines), and for higher exposures in other workplaces (e.g. offices) when the reference level is exceeded persistently. ICRP Publication 137 recommends a dose coefficient of 3 mSv per mJ h m-3 (approximately 10 mSv per working level month) for most circumstances of exposure in workplaces, equivalent to 6.7 nSv per Bq h m-3 using an equilibrium factor of 0.4. Using this dose coefficient, annual exposure of workers to 300 Bq m-3 corresponds to 4 mSv. For comparison, using the same coefficient for exposures in homes, 300 Bq m-3 corresponds to 14 mSv. If circumstances of occupational exposure warrant more detailed consideration and reliable alternative data are available, site-specific doses can be assessed using methodology provided in ICRP Publication 137.

Miner studies and radiological protection against radon.

Fundamental estimates of radon-associated health risk have been provided by epidemiological studies of miners. In total, approximately 15 studies have been conducted worldwide since the 1960s. These results have contributed directly to radiological protection against radon. The present article summarises the main results, with a focus on analyses of miners exposed more recently, estimates of radon lifetime attributable risk, and interaction between radon and smoking. The potential for the upcoming Pooled Uranium Miner Analysis project to further improve our knowledge is discussed.

Liver transplantation using donation after cardiac death donors: long-term follow-up from a single center.

There is a lack of universally accepted clinical parameters to guide the utilization of donation after cardiac death (DCD) donor livers and it is unclear as to which patients would benefit most from these organs. We reviewed our experience in 141 patients who underwent liver transplantation using DCD allografts from 1993 to 2007. Patient outcomes were analyzed in comparison to a matched cohort of 282 patients who received livers from donation after brain death (DBD) donors. Patient survival was similar, but 1-, 5- and 10-year graft survival was significantly lower in DCD (69%, 56%, 44%) versus DBD (82%, 73%, 63%) subjects (p < 0.0001). Primary nonfunction and biliary complications were more common in DCD patients, accounting for 67% of early graft failures. A donor warm ischemia time >20 min, cold ischemia time >8 h and donor age >60 were associated with poorer DCD outcomes. There was a lack of survival benefit in DCD livers utilized in patients with model for end-stage liver disease (MELD) < or =30 or those not on organ-perfusion support, as graft survival was significantly lower compared to DBD patients. However, DCD and DBD subjects transplanted with MELD >30 or on organ-perfusion support had similar graft survival, suggesting a potentially greater benefit of DCD livers in critically ill patients.

Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA.

The quiescent nature of most peripheral T cells poses an effective limitation to human immunodeficiency virus (HIV) replication and, in particular, to viral integration into the host chromatin. Two HIV proteins, Nef and Tat, increase T cell activity, but a requirement of integration for viral gene expression would preclude a role for these proteins in resting cells. Here, we report that HIV infection leads to selective transcription of the nef and tat genes before integration. This preintegration transcription in quiescent cells leads to increased T cell activation and viral replication.

Dosimetric models used in the Alpha-Risk project to quantify exposure of uranium miners to radon gas and its progeny.

The European project Alpha-Risk aims to quantify the cancer and non-cancer risks associated with multiple chronic radiation exposures by epidemiological studies, organ dose calculation and risk assessment. In the framework of this project, mathematical models have been applied to the organ dosimetry of uranium miners who are internally exposed to radon and its progeny as well as to long-lived radionuclides present in the uranium ore. This paper describes the methodology and the dosimetric models used to calculate the absorbed doses to specific organs arising from exposure to radon and its progeny in the uranium mines. The results of dose calculations are also presented.

Internal dose assessments: uncertainty studies and update of ideas guidelines and databases within CONRAD project.

The work of Task Group 5.1 (uncertainty studies and revision of IDEAS guidelines) and Task Group 5.5 (update of IDEAS databases) of the CONRAD project is described. Scattering factor (SF) values (i.e. measurement uncertainties) have been calculated for different radionuclides and types of monitoring data using real data contained in the IDEAS Internal Contamination Database. Based upon this work and other published values, default SF values are suggested. Uncertainty studies have been carried out using both a Bayesian approach as well as a frequentist (classical) approach. The IDEAS guidelines have been revised in areas relating to the evaluation of an effective AMAD, guidance is given on evaluating wound cases with the NCRP wound model and suggestions made on the number and type of measurements required for dose assessment.

Internal dosimetry: towards harmonisation and coordination of research.

The CONRAD Project is a Coordinated Network for Radiation Dosimetry funded by the European Commission 6th Framework Programme. The activities developed within CONRAD Work Package 5 ('Coordination of Research on Internal Dosimetry') have contributed to improve the harmonisation and reliability in the assessment of internal doses. The tasks carried out included a study of uncertainties and the refinement of the IDEAS Guidelines associated with the evaluation of doses after intakes of radionuclides. The implementation and quality assurance of new biokinetic models for dose assessment and the first attempt to develop a generic dosimetric model for DTPA therapy are important WP5 achievements. Applications of voxel phantoms and Monte Carlo simulations for the assessment of intakes from in vivo measurements were also considered. A Nuclear Emergency Monitoring Network (EUREMON) has been established for the interpretation of monitoring data after accidental or deliberate releases of radionuclides. Finally, WP5 group has worked on the update of the existing IDEAS bibliographic, internal contamination and case evaluation databases. A summary of CONRAD WP5 objectives and results is presented here.

Analysis of T cell responses in liver allograft recipients. Evidence for deletion of donor-specific cytotoxic T cells in the peripheral circulation.

Analysis of cell-mediated lympholysis in long-term liver allograft recipients indicated that there was a donor-specific unresponsiveness that could not be reversed by the addition of rIL-2 and/or mixed lymphocyte culture supernatant or by nonspecific stimulation of the cultures with PHA. Stimulation of recipient cells with semisyngeneic cells having both donor and third-party HLA antigens failed to reveal the presence of cytotoxic T cells (CTL) specific to the donor, whereas the CTL response to third-party antigens remained normal. Removal of B lymphocytes from the responding cell population did not influence the responses. Furthermore, limiting dilution analysis showed that the liver transplant recipients did not have detectable levels of CTL precursors (CTLp) reactive to the donor antigens, whereas their CTLp to third-party antigens remained normal. Donor-specific CTLp were present before and during the early post-transplant period; these cells were eliminated from the peripheral circulation by 10 mo after transplantation. Taken together, these results indicate that there is a deletion of CTLp specific to donor MHC antigens in the peripheral circulation of long-term liver allograft recipients that may account in part for the success of liver transplantation across MHC barriers.

Adult to adult living-related liver transplant: report on an initial experience in Italy.

INTRODUCTION: Living-related liver transplantation has become the treatment of choice for many liver diseases. We present our initial analysis of 53 cases of adult to adult living-related liver transplantation performed in a single institute in Italy. MATERIALS AND METHODS: From January 2002 to September 2006, we performed 53 adult to adult living-related liver transplantations. The donors (age 18-53) all had genetic or emotional relationships; they were all ABO identical or compatible. Recipients (ages 18-68) suffered from cirrhosis secondary to viral etiology (18), hepatocellular carcinoma with viral cirrhosis (24), cystic fibrosis (2), primary biliary cirrhosis (2), hepatocellular carcinoma with non-viral cirrhosis (2), alcoholic cirrhosis (1), ornithine transcarbamylase deficiency (OTC), (1) criptogenic cryptogenic cirrhosis, (1) primary sclerosing cholangitis, (1) biliary atresia and metastatic carcinoid (1). Donor liver resection resulted in 51 right hepatectomies and two left hepatectomies. Graft body weight ratio was always above 0.8%; graft implantation was performed with the piggy back technique and, in 43 cases, with the use of veno-venous bypass. RESULTS: There was neither donor mortality nor need of blood transfusion. Actuarial recipient survival rate at 3 years was 82.66% and graft survival rate was 75.34%. Six patients underwent retransplantation: in four cases due to hepatic artery thrombosis, and in two, due to graft dysfunction. Three patients had one episode each of acute cellular rejection. CONCLUSION: Adult to adult living-related liver transplantation represents a resource to be used in confronting organ shortage, and is a valuable option for decreasing mortality and drop out from the waiting list.

Assessment of intakes and doses to workers followed for 15 years after accidental inhalation of 60CO.

Intakes and doses are assessed for seven workers who accidentally inhaled particles containing Co in the same incident. Comprehensive whole body data to 15 y, and some early urine and fecal data, are available for each individual. The biokinetic and dosimetric models currently recommended by ICRP have been used to assess these cases. It was not possible to obtain good fits to the data using the ICRP models with their default parameter values. However, good fits to all the measurement data were obtained by varying parameter values following a procedure similar to that recommended in recently developed guidelines for assessment of internal doses from monitoring data. It was found that retention in the lungs was much longer than predicted by the ICRP Human Respiratory Tract Model, and so for each case it was necessary to reduce the particle transport clearance of material from the deep lungs. This reduction in lung clearance rates, and the use of specific AMAD values, were the dominating factors in changing assessed doses from those calculated using ICRP default values.

Avoiding biased estimates of dose when nothing is known about the time of intake.

A common problem in internal dosimetry occurs in routine monitoring, when it is required to estimate an intake from a measurement made at the end of a monitoring interval, and the time of intake is unknown. ICRP suggests that it should be assumed that the intake occurred in the middle of the monitoring period. However, it has been shown that this will, in the long-term, lead to biased estimates of a worker's intake and dose. In order to overcome this biasing, the United States Department of Energy (USDOE) recommends a different method based on calculating the intakes for all possible intake times in the interval and then taking an arithmetic average. In a recent paper, it has been shown that both the ICRP and USDOE methods were biased and that the only unbiased estimator of the true intake was obtained by assuming a constant chronic intake throughout the monitoring interval. In all of the analyses carried out to date on this 'Constant Chronic' method, it was assumed that the measurements were exact. In this paper, the effects of assuming either normally or log-normally distributed measurement errors are explored, and the effect on the bias of the intake estimate is investigated.

The autocorrelation coefficient as a tool for assessing goodness of fit between bioassay predictions and measurement data.

Project IDEAS has produced guidelines for internal dose assessment. An integral part of this process is assessing the goodness of fit of biokinetic models to bioassay data. It is recommended that a fit should only be accepted if (a) it is close enough to the data not to be rejected by a chi2 test and (b) if it looks acceptable to 'the eye'. The latter criterion was added to enable the assessor to reject fits which seemed to display some sort of systematic bias. However, there are problems with both of these tests: (a) the chi2 test is dependent on the assumed uncertainties which are often unknown, (b) 'by eye' assessment is subjective. In this paper, another statistic, the autocorrelation coefficient of the residuals, rho, is investigated. The main advantages of the rho statistic are that it is objective, very sensitive to biasing and independent of the assumed errors.

ERIDAS, a computer program for rapid calculation of internal doses from measurements of people in an emergency.

In an emergency involving the deliberate or accidental release of radioactive materials, there could potentially be a large number of people who require monitoring for internal contamination. Doses from these measurements will need to be calculated as quickly as possible. Emergency Response Internal Dose Assessment Software (ERIDAS) has been designed for this purpose.

IMBA Professional Plus: a flexible approach to internal dosimetry.

IMBA (Integrated Modules for Bioassay Analysis) is a suite of software modules that implement the current ICRP biokinetic and dosimetric models for estimation of intakes and doses. The IMBA modules have gone through extensive quality assurance, and are now used for routine formal dose assessment by Approved Dosimetry Services throughout the UK. HPA has continued to develop the IMBA modules. In addition, several projects, sponsored by organisations both in the USA and in Canada, have resulted in the development of customised user-friendly interfaces (IMBA Expert 'editions'). These enable users not only to use the standard ICRP models, but also to change many of the parameter values from ICRP defaults, and to apply sophisticated data handling techniques to internal dose calculations. These include: fitting measurement data with the maximum likelihood method; using multiple chronic and acute intakes; and dealing with different data types, such as urine, faces and whole body simultaneously. These interfaces were improved further as a result of user-feedback, and a general 'off-the-shelf' product, IMBA Professional, was developed and made available in January 2004. A new version, IMBA Professional Plus, was released in April 2005, which is both faster and more powerful than previous software. The aim of this paper is to describe the capabilities of IMBA Professional Plus, and the mathematical methods used.

Evaluation of scattering factor values for internal dose assessment following the IDEAS guidelines: preliminary results.

The IDEAS Guidelines for the assessment of internal doses from monitoring data suggest default measurement uncertainties (i.e. scattering factors, SFs) to be used for different types of monitoring data. However, these default values were mainly based upon expert judgement. In this paper, SF values have been calculated for different radionuclides and types of monitoring data using real data contained in the IDEAS Internal Contamination Database. Results are presented.