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Aims/hypothesis: Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet., Methods: The primary outcome of the study was change in HbA 1c . Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA 1c 48-97 mmol/mol (6.5-11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min -1 (1.73 m) -2 . Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev., Results: Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA 1c (mean ± SEM: -6.2 ± 0.8 mmol/mol (-0.6 ± 0.1%) vs -0.75 ± 1.0 mmol/mol (-0.1 ± 0.1%); p < 0.001). Nine (out of 37) pre-specified secondary outcomes are reported in the present paper, of which five were significantly different between the diets, (p < 0.05); compared with a CD diet, a CRHP diet reduced the secondary outcomes (mean ± SEM or medians [interquartile range]) of fasting plasma glucose (-0.71 ± 0.20 mmol/l vs 0.03 ± 0.23 mmol/l; p < 0.05), postprandial plasma glucose AUC (9.58 ± 0.29 mmol/l × 240 min vs 11.89 ± 0.43 mmol/l × 240 min; p < 0.001) and net AUC (1.25 ± 0.20 mmol/l × 240 min vs 3.10 ± 0.25 mmol/l × 240 min; p < 0.001), hepatic fat content (-2.4% [-7.8% to -1.0%] vs 0.2% [-2.3% to 0.9%]; p < 0.01) and pancreatic fat content (-1.7% [-3.5% to 0.6%] vs 0.5% [-1.0% to 2.0%]; p < 0.05). Changes in other secondary outcomes, i.e. 24 h blood pressure and muscle-, visceral- or subcutaneous adipose tissue, did not differ between diets., Conclusions/interpretation: A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA 1c and hepatic fat content in weight stable individuals with type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT02764021., Funding: The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.

The paper deals with modeling the liver perfusion intended to improve quantitative analysis of the tissue scans provided by the contrast-enhanced computed tomography (CT). For this purpose, we developed a model of dynamic transport of the contrast fluid through the hierarchies of the perfusion trees. Conceptually, computed time-space distributions of the so-called tissue density can be compared with the measured data obtained from CT; such a modeling feedback can be used for model parameter identification. The blood flow is characterized at several scales for which different models are used. Flows in upper hierarchies represented by larger branching vessels are described using simple 1D models based on the Bernoulli equation extended by correction terms to respect the local pressure losses. To describe flows in smaller vessels and in the tissue parenchyma, we propose a 3D continuum model of porous medium defined in terms of hierarchically matched compartments characterized by hydraulic permeabilities. The 1D models corresponding to the portal and hepatic veins are coupled with the 3D model through point sources, or sinks. The contrast fluid saturation is governed by transport equations adapted for the 1D and 3D flow models. The complex perfusion model has been implemented using the finite element and finite volume methods. We report numerical examples computed for anatomically relevant geometries of the liver organ and of the principal vascular trees. The simulated tissue density corresponding to the CT examination output reflects a pathology modeled as a localized permeability deficiency.

This paper reports in vitro effects of individual heavy metals (Cd(2+), Cu(2+) and Hg(2+)), and PAHs, including benzo[a]pyrene(BaP), indeno[1,2,3-cd]pyrene (IP) and fluoranthene (FL), and their mixtures on ethoxyresorufin-O-deethylase (EROD) activities using a plate-reader method. The results showed that all three metals inhibited EROD activity, while BaP/IP significantly induced the enzyme. However, FL alone decreased EROD activity. Moreover, co-treatment with BaP/IP and heavy metals inhibited PAH-induced EROD activities, while combined exposure to FL and heavy metals induced FL-inhibited EROD activities.

Clinical/methodical Issue: Perfusion computed tomography (CT) has its main application in the clinical routine diagnosis of neuroradiological problems., Standard Radiological Methods: Polyphase multi-detector spiral computed tomography is primarily used in liver diagnostics., Methodical Innovations: The use of perfusion CT is also possible for the diagnostics and differentiation of diffuse hepatic diseases., Performance: The differentiation between cirrhosis and cirrhosis-like parenchymal changes is possible. It also helps to detect early stages of malignant tumors., Achievements: However, there are some negative aspects, particularly that of radiation exposure., Practical Recommendations: This paper summarizes the technical basics and possible applications of perfusion CT in cases of diffuse liver disease and weighs up the advantages and disadvantages of the examinations.

For many years the American mink (Neovison vison) has been used in North America (where it originates from) as a sensitive indirect bioindicator in assessing the degree of mercury (Hg) contamination in terrestrial ecosystems. The aim of this paper was the determination of total concentrations of Hg in the liver and kidneys of feral and ranch mink from the Warta Mouth National Park (WMNP) and from farms located in northwestern Poland, for comparison with similar data on American mink from North America. In road-killed feral mink from the WMNP, the mean concentrations were 11.8 and 14.1 mg/kg dry weight in the liver and kidney, respectively. Mean Hg concentrations in feral mink were from 240 to 90 times higher in these two respective tissues than in ranch mink. The feral mink from northwestern Poland had concentrations of hepatic and nephric Hg similar to the highest concentrations that have been recorded over the past several decades in wild American mink from certain areas of Canada and the USA.

Volume segmentation is a relatively slow process and, in certain circumstances, the enormous amount of prior knowledge available is underused. Model-based liver segmentation suffers from the large shape variability of this organ, and from structures of similar appearance that juxtapose the liver. The technique presented in this paper is devoted to combine a statistical analysis of the data with a reconstruction model from sparse information: only the most reliable information in the image is used, and the rest of the liver's shape is inferred from the model and the sparse observation. The resulting process is more efficient than standard segmentation since most of the workload is concentrated on the critical points, but also more robust, since the interpolated volume is consistent with the prior knowledge statistics. The experimental results on liver datasets prove the sparse information model has the same potential as PCA, if not better, to represent the shape of the liver. Furthermore, the performance assessment from measurement statistics on the liver's volume, distance between reconstructed surfaces and ground truth, and inter-observer variability demonstrates the liver is efficiently segmented using sparse information.

In this paper, we propose an original and efficient tree matching algorithm for intra-patient hepatic vascular system registration. Vascular systems are segmented from CT-scan images acquired at different times, and then modeled as trees. The goal of this algorithm is to find common bifurcations (nodes) and vessels (edges) in both trees. Starting from the tree root, edges and nodes are iteratively matched. The algorithm works on a set of match solutions that are updated to keep the best matches thanks to a quality criterion. It is robust against topological modifications due to segmentation failures and against strong deformations. Finally, this algorithm is validated on a large synthetic database containing cases with various deformation and segmentation problems.

The chemotherapeutic agent methotrexate is widely used in tumor therapy for different forms of leukemia and for the therapy of arthritis. Methotrexate is eliminated from systemic blood circulation by the liver and its transport into hepatocytes is therefore described in detail in this paper. Methotrexate uptake is energy- and sodium-dependent. The Km and the Vmax are 23 microM and 36 pmol/mg protein min, respectively. The apparent activation energy (E(app)) of methotrexate uptake (5 microM [3H]methotrexate) is 53.73 kJ/mol, which indicates an energy-dependent carrier-mediated process. Although methotrexate is a folate derivative, folate itself does not inhibit methotrexate uptake, whereas the reduced folates, dihydrofolate and tetrahydrofolate are weak uncompetitive inhibitors. In contrast, the bile acids taurocholate and cholate are effective competitive inhibitors of methotrexate uptake into hepatocytes. Further strong inhibitors are the loop diuretic bumetanide, the mycotoxin ochratoxin A and bromosulfophthalein. Because tumor patients develop drug resistance during methotrexate therapy, the uptake of methotrexate was tested in different hepatoma cell lines. In HepG2-cells and Reuber hepatoma Fao-cells the transport was non-existent or very small. However, the hepatocytoma fusion cell line HPCT-1E3, a hybrid cell line between primary rat hepatocytes and rat Reuber Fao-cells, shows an intermediate transport activity with a threefold increase of the methotrexate uptake. These results indicate the presence of a bile acid sensitive methotrexate carrier in hepatocytes which is absent in dedifferentiated hepatoma cells. The carrier differs from previously described transporters for the uptake of organic anions.

This paper presents a case of asymptomatic membranous obstruction of the inferior vena cava with a rare hemodynamic pattern consisting of large intrahepatic venous connections between the right inframembranous and the middle supramembranous hepatic vein. These remarkably large collaterals obviated significant enlargement of the azygous venous system and the development of a Budd-Chiari syndrome.

The goal of the present study was to optimize technetium-99m labelling of low-density lipoprotein (LDL) and to investigate the in vitro and in vivo properties of the tracer to determine whether its application for quantitative scintigraphy of hepatic LDL receptor activity is feasible. LDL labelled with iodine-125 by the iodine monochloride method was used as a reference tracer. Comparison of different assessments of radiochemical purity [trichloro-acetic acid precipitation (%ppTCA), paper chromatography, size-exclusion chromatography and chloroform-methanol extraction] exhibited %ppTCA to be superior as a parameter of tracer quality. In spite of a high radiochemical purity immediately after labelling, modifications of 99mTc labelling of LDL did not overcome the poor long-term stability of the tracer. Subsequent dialysis in phosphate buffer over about 3 h sufficiently increased the long-term stability in vitro and in vivo. The competitive recognition of dialysed 99mTc-LDL and 125I-LDL with native LDL by high-affinity binding sites was demonstrated in human hepatoma cells (HepG2) and human fibroblasts. Biodistribution data of simultaneously injected 99mTc-LDL and 125I-LDL in New Zealand White rabbits showed a high uptake of both tracers in tissues with high LDL receptor activity, yet 99mTc-LDL uptake exceeded 125I-LDL uptake by two- to sevenfold. In contrast to 125I-LDL, 99mTc-LDL showed a higher unspecific uptake into the bone marrow and the spleen, suggesting an additional uptake mechanism probably via the scavenger pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously reported long term erythroid differentiation of adult bone marrow cells seeded onto adherent cells derived from adult bone marrow. In this paper, we show that the adherent cells obtained from foetal liver do not support the erythroid differentiation of either adult bone marrow cells or foetal liver cells. Adherent layers derived from bone marrow of adult W/Wv mice supported differentiation of adult bone marrow precursors, but foetal liver progenitors only produced erythrocytes for a few weeks and the foetal origin of these red cells was confirmed by haemoglobin typing. The duration and extent of erythropoiesis was generally inversely proportional to the cell dose. Foetal progenitors were as sensitive to erythropoietin as adult cells, but were optimally stimulated at a lower plateau concentration. These results suggest that inhibitory cells present in foetal liver may block erythropoiesis and their growing importance with age may provide an explanation for the arrest of erythropoiesis in the liver at late developmental stages.

This paper describes a rapid method for the identification of salbutamol in liver and urine. Salbutamol is extracted from liver with an acid solution, purified on Baker columns and eluted with methanol. After derivatization, salbutamol is detected on HPTLC plates as a blue spot. Urine samples are directly purified on the C18 columns and then the same procedure is followed as for the liver samples. Using this screening method, salbutamol can be semi-quantitatively determined at the micrograms/kg level.

Cholic acid inhibits the uptake of demethylphalloin (DMP), in a competitive manner. The bile acid increases the Michaelis constant but not Vmax of the inward transport. The inhibition constant Ki for cholate was found to be 8 microM. Cholate competes for the transport system but not for intracellular binding of phallotoxins. Various experimental data presented in this paper exclude an accumulation of phallotoxins in hepatocytes by intracellular binding only. Preincubation of hepatocytes with small concentration of either (3H)-demethylphalloin or (14C)-cholate and subsequent treatment with high concentrations of the non-labelled compounds reduces the intracellular concentration of both radioactive substrates. In accordance with earlier findings the above results suggest a common component needed for the transport of both phallotoxins and cholic acid.

Interactions between bile salts and cellular constituents are of considerable significance in studies on cholestasis. The main points of interest are the effects of the various bile salts on lipid and protein structures. Of primary interest are the interactions with lipids since these can cause disorder in cellular metabolism by eliminating compartmentalization. Conformational changes of proteins can occur through interactions with bile salts. They can involve specific functions. Of special importance here are the enzymes, since these are decisive supportive agents in cellular processes. In this paper, the effect of various bile salts on the activity of key hepatic enzymes was studied. In addition to the kinetic tests for enzyme activity, structural changes of the enzymes were studied as well using electrophoretic techniques. It could be shown that even much lower bile salt concentrations than those which occur in bile can lead to a complete inhibition of activity. The varying sensitivities of different enzymes when they react in the presence of bile salts is striking. According to the degree of hydroxylation, the various bile salts show characteristic differences in inhibitory effect on enzymatic activity. On the basis of the results reported here, it is quite possible that the interaction between bile salts and enzymes is a participating factor in the etiology and pathogenesis of cholestatic hepatic changes.

Antipyrine plasma clearance and rates of metabolite formation were measured on four occasions in eight patients with disseminated nonseminomatous testicular cancer. Antipyrine tests were performed before, during (2X), and after treatment with a combination of cisplatin (P), vinblastin (V), and bleomycin (B). Pretreatment values were compared with a male control group (n = 14) matched for age and body weight. Antipyrine plasma clearance was 20% higher in patients with testicular cancer (first experiment) than in the control group. This difference was mainly due to a 35% higher clearance for production of 3-hydroxymethylantipyrine (HMA), while clearance for production of norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) was not significantly different from the control group. A reduction in CLHMA was observed after complete remission (fourth experiment), indicating that the presence of the tumor may be related to a selective increase of HMA formation. Treatment with the PVB combination resulted in a 30% increase in antipyrine plasma clearance (second and third experiments), whereas the rates of formation of the main metabolites of antipyrine were all increased to the same extent. These accelerating effects of PVB treatment persisted for at least 6 weeks after the start of the last treatment cycle. The data presented in this paper demonstrate that the presence of a testicular tumor and the use of cytostatics can have an accelerating and partially selective effect on oxidative drug-metabolizing enzyme activity in man.

This paper reports a simple model for calculation of maximal scintiphoto contrast caused by a spherical cold or hot lesion located in an arbitrary position inside an organ with uniformly distributed radioactivity. By applying this model, equidetection curves were constructed for cross sections through the liver. Comparison of equidetection curves obtained for different camera views enabled determination of the view to be selected for the best visualization of a given lesion. The minimum size of a cold lesion that can be detected without regard to the location in the liver in 3.0 cm diameter using anterior, right oblique anterior, right lateral, and posterior views. 99mTc is found to be a more suitable radionuclide for liver scintigraphy than 113mIn.

3H-Demethylphalloin (3H-DMP) a cyclopeptide very similar to phalloidin is taken up by isolated hepatocytes in vitro. Hepatocytes prepared from newborn animals are less sensitive to phalloidin. Their uptake of 3H-DMP is about one tenth of that of cells from adult animals. Ascites hepatoma cells, known to be insensitive to phalloidin took up negligible amounts of 3H-DMP. Cells prepared from regenerating livers took up insignificantly lower amounts of the toxin than in hepatocytes from adult animals. Treatment of hepatocytes with low concentrations of trypsin was found to switch off the phalloidin sensitivity in a reversible manner. This inhibition is due to a reduced uptake of 3H-DMP. Pretreatment of animals with CCl4, known to reduce the sensitivity to phalloidin, also decreases the uptake of 3H-DMP in isolated hepatocytes. Various agents, drugs and reagents were found to inhibit the response of isolated hepatocytes to phalloidin. All these compounds (bile acids, rifampicin, silybin, DIDS, glutardialdehyde, bromosulphophthalein, fusidic acid, antamanide, novobiocin) inhibit also the uptake of 3H-DMP in isolated hepatocytes. The results confirm our working hypothesis, presented in several previous papers, that decreased sensitivity to phalloidin is probably due to a reduced or blocked uptake of the toxin.