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The limited availability of human hepatocytes results in the use of animal cells in most bioartificial liver support devices. In the present work, clinically relevant liver specific metabolic activities were compared in rat, pig and human hepatocytes cultured on liver-derived biomatrix to optimize the expression of differentiated functions. Pig hepatocytes showed higher rates of diazepam metabolism (2.549+/-0.821 microg/h/million cells vs. 0.474+/-0.079 microg/h/million cells rats, p0.005, and vs. 0.704+/-0.171 microg/h/million cells in man, p0.005) and of bilirubin conjugation (21.60116+/-8.433237 micromoles/l/24 h vs. 6.786809+/-2.983758 in man, p0.001 and vs. 9.956538+/-1.781016 micromoles/l/24 h in rats, p0.005). Urea synthesis was similar in pig and in human hepatocytes (150+/-46.3 vs. 144.8+/-21.46 nmoles/h/million cells) and it was lower in rats (84.38+/-35.2; p0.001 vs. man, p0.02 vs. pig). High liver specific metabolic activities in cultured pig hepatocytes further support their use as a substitue for human cells in bioartificial liver devices.

Cathepsin B and cathepsin L--cysteine proteinases--may play an important role in cancer invasion and metastasis. The authors determined tissue antigen concentrations of cathepsins, using the ELISA method, in 25 patients with gastric cancer (17 males, 8 females, mean age 62, range 31-84). They evaluated the possible relationship that these proteinases may have with the presence of metastases, differentiation and histotype. Significantly higher cathepsin B and cathepsin L antigen levels were found: 1. in gastric cancer tissues vs. normal tissues distant from tumors (CATB: p0.05, CATL: p0.005); 2. in diffuse vs. intestinal type cancers (p0.05); 3. in patients with poorly vs. well-differentiated cancers (p0.05); in gastric cancers with vs. without metastasis (p0.05). Their results confirm that cathepsin B and L play an important role in gastric cancer invasion and metastasis. Considering the significantly higher cathepsins detected in cancers with metastasis, a poor differentiation and of diffuse histotype, these proteinases could be useful for identification gastric cancer patients with a poor prognosis.

Liver transplantation, considered today as the most effective treatment for end-stage liver diseases, can not always be performed on every patient affected with a liver disease. Patients with end-stage liver diseases, usually have high bilirubin, encephalopathy and renal failure. In these situations cytokines play an important role in different processes, from apoptosis to regeneration. The aim of this clinical study has been to analyse the action of new artificial liver system, called Molecular Adsorbent Recycling System (MARS) on cytokines metabolism in patients affected with acute on chronic liver failure. The results are intriguing because an increase of IL-6 and a decrease of TNF-alpha observed during MARS treatment. The study confirms the efficacy of MARS therapy in terms of homeostasis of the cytokines network and suggests an usefulness of monitoring their level during liver failure.

BACKGROUND: To evaluate the prognostic accuracy of proadrenomedullin (proADM) in comparison with and in addition to the Multidimensional Prognostic Index (MPI), a validated predictive tool for mortality derived from a comprehensive geriatric assessment (CGA) to predict one-month mortality risk in older patients hospitalized with community-acquired pneumonia (CAP). METHODS: All patients aged 65 years and older, consecutively admitted to an acute geriatric ward with a diagnosis of CAP from February to July 2012. At admission and at discharge they were submitted to a standard CGA in order to calculate MPI. Moreover, plasma samples were taken at baseline and after one, three and five days of hospitalization for the analysis of pro-ADM. RESULTS: Fifty patients (mean age 86.2±7.5 years), with 31 at high risk of mortality (MPI-3) were enrolled. ProADM and MPI, both at admission and at discharge, were significant predictor of mortality. As expected, MPI at admission showed lower predictive accuracy than MPI at discharge (survival C-statistic 0.667 vs. 0.851). The addition of proADM to the MPI at admission significantly increased accuracy in predicting one-month mortality (C-statistics from 0.667 to 0.731, P=0.018 at baseline; from 0.667 to 0.733, P=0.008 at 1 day; from 0.633 to 0.724; P=0.019 at 3 days; from 0.667 to 0.828; P=0.003 at 5 days). Conversely, adding pro-ADM to the MPI at discharge did not significantly improve the model's prognostic accuracy. CONCLUSIONS: ProADM may significantly improve the prognostic accuracy of the MPI at admission in hospitalized elderly patients with CAP. © 2018 EDIZIONI MINERVA MEDICA.

Essentials Prothrombin and partial thromboplastin time (PT/PTT) measure direct oral anticoagulants (DOACs). PT, PTT and specific tests for DOACs were performed on patients treated for atrial fibrillation. Normal PT/PTT don't exclude DOAC activity and their prolongation doesn't confirm DOAC action. The use of PT or PTT to evaluate DOAC activity could cause dangerous misinterpretations. Summary: Background Prothrombin time (PT) and activated partial thromboplastin time (APTT) have been proposed to measure the effect of oral anti-activated factor X (FXa) or anti-activated FII drugs, respectively. Aims To evaluate the relationships and responsiveness of PT and APTT versus direct oral anticoagulant (DOAC) concentrations measured with specific coagulation tests performed with different platforms in four Italian anticoagulation clinics. Methods Six hundred and thirty-five patients with atrial fibrillation participated in the study: 240 were receiving dabigatran, 264 were receiving rivaroxaban, and 131 were receiving apixaban. Blood was taken at trough and peak within the first month (15–25 days) of treatment. PT, APTT, diluted thrombin time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban were determined. Results For dabigatran, the correlation between APTT and dTT ranged from r = 0.80 to r = 0.62. For rivaroxaban, the correlation between the anti-FXa assay and PT ranged from r = 0.91 to r = 0.73. For apixaban, the correlation between the anti-FXa assay and PT was lower than for the two other drugs (r = 0.81 to r = 0.54). Despite the above significant correlations, the responsiveness of PT or APTT was relatively poor. A discrepancy between global testing and DOAC plasma concentrations was shown in a considerable proportion of patients, depending on the platform and drug, with values ranging from 6% to 62%. Conclusions Overall, poor responsiveness of the screening tests to DOAC concentrations was observed. PT and APTT normal values cannot exclude DOAC anticoagulant activity, and PT or APTT prolongation is not always associated with DOAC anticoagulant effect as determined with specific tests.

The Prolong study shows that continuing vitamin K antagonists (VKA) in patients with abnormal D: -dimer (evaluated by a qualitative assay, Clearview Simplify D: -dimer) results in a significant reduction of venous thromboembolism (VTE) recurrence. The present study retrospectively analyzes a subgroup of patients enrolled in the Prolong study with a view to calculate cut-off values for six quantitative D: -dimer methods to predict the risk of VTE recurrence. We measured D: -dimer levels by VIDAS D: -dimer Exclusion (bioMerieux), STA Liatest D: -dimer (DiagnosticaStago), HemosIL D: -dimer and HemosIL D: -dimer HS (Instrumentation Laboratory), Innovance D: -dimer (Siemens) and AutoDimer (Trinity Biotech) in frozen plasma aliquots sampled 30 ± 10 days after VKA cessation in 390 patients enrolled in the Prolong study. During follow-up (562.7 years), 28 patients had recurrent VTE (7.2%, 5.0% person-years). Since D: -dimer levels are positively correlated with age and significantly lower in men, we calculated method-specific cut-off values according to age and gender. The HRs for VTE recurrence calculated using method-specific cut-off values based on age and gender are higher than those using cut-off values indicated by the manufacturers for VTE exclusion in symptomatic outpatients. These data suggest that method-specific cut-off values calculated according to patient age and gender can be more accurate in identifying patients at a higher risk for VTE recurrence. These method-specific cut-off values are being evaluated in the ongoing prospective management multicenter DULCIS study.

FULMINANT HEPATIC FAILURE (FHF) overall survival rate is usually ,20%. At least in certain etiologic categories, however, up to 60% of patients survive without transplantation. Similar figures (1-year survival between 56 and 80%) are currently reported in several series after hepatic grafting. The possibility of an early prediction on which patients have little hope of recovery would be of great help in the correct therapeutic management of the disease by identifying early those patients who need transplantation. When the graft is not available, these patients could be selected for “hazardous” liver assistance procedures, and if the procedure has certain benefits, this is more likely to be recognized if it is applied only to patients with a high probability of dying with conventional treatment alone. On the contrary, in the group of patients with concrete possibilities of spontaneous recovery, liver transplantation may represent a significant overtreatment. At present, however, there is no consensus on the prediction of outcome in FHF. Clinical indicators still remain the most important parameters for assessment of prognosis in patients with FHF. The purpose of the present study was to define a score capable of distinguishing early between patients who will recover with a conservative medical support and those who will not.

Fibrinogen is a strong cardiovascular risk factor in the general population, and increased fibrinogen plasma concentrations have been reported in type 2 diabetic patients. However, the mechanisms leading to hyperfibrinogenemia in type 2 diabetes are not known. It is also not known whether possible alterations of fibrinogen turnover may precede clinical diabetic micro- and macrovascular complications and therefore potentially contribute to their onset. To address these questions, fibrinogen production was determined in six male type 2 diabetic patients without detectable micro- and macrovascular complications (age, 45 ± 4 yr; body mass index, 27 ± 0.9 kg/m2) and in seven nondiabetic matched controls using leucine isotope precursor-product relationships. Plasma glucose (P < 0.001), insulin (P < 0.05), and glucagon concentrations (P < 0.01) were increased in the patients. Diabetic patients also had increased plasma fibrinogen concentration (+∼50%; P < 0.01) and pool (+∼40%; P < 0.01) as well as fractional (+∼35%; P = 0.08) and absolute (+∼100%; P < 0.01) synthetic rates. The plasma glucagon concentration was positively related (P < 0.005 or less) to the fibrinogen concentration as well as to fractional and absolute synthetic rates. Thus, fibrinogen production is markedly enhanced, and this alteration is likely to determine the observed hyperfibrinogenemia in type 2 diabetic patients. Hyperglucagonemia may contribute to the increased fibrinogen production. These findings in normoalbuminuric patients without clinical complications support the hypothesis that increased fibrinogen production and plasma concentrations may precede and possibly contribute to the onset of clinical cardiovascular complications in type 2 diabetes.