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Sample records for quantitative liver function

  1. Assessment of liver function in chronic liver diseases and regional function of irradiated liver by means of 99mTc-galactosyl-human serum albumin liver scintigraphy and quantitative spectral analysis.

    PubMed

    Fukui, A; Murase, K; Tsuda, T; Fujii, T; Ikezoe, J

    2000-12-01

    Scintigraphy with 99mTc-diethylenetriamine pentaacetic acid galactosyl human serum albumin (99mTc-GSA) was performed on 102 patients, then the hepatic extraction fraction (HEF), the rate constant for liver uptake of the tracer from the blood (K1) and the hepatic blood flow index (HBFI) were determined by spectral analysis. The HEF, K1 and HBFI values correlated moderately or closely with various indices of hepatic function, and the HEF and K1 values decreased according to the stage of liver dysfunction. The HEF and K1 values linearly and nonlinearly correlated with HH15 and LHL15, respectively. The HEF, K1 and HBFI values for the irradiated portion of 20 patients before and alter irradiation were compared. The HEF value in patients with a cirrhotic liver significantly (p < 0.002) decreased compared with that in patients with a normal liver at a dose of less than 40 Gy, whereas the HBFI value in patients with a normal liver significantly (p < 0.05) decreased compared with that in patients with a cirrhotic liver at a dose of 40 Gy or greater. This method appears to be a simple, non-invasive and useful tool with which to quantitatively evaluate liver function and it also helps clarify changes in regional function of the irradiated liver.

  2. Three-Dimensional Quantitative Evaluation of the Segmental Functional Reserve in the Cirrhotic Liver Using Multi-Modality Imaging

    PubMed Central

    Xiang, Canhong; Chen, Yingmao; Shao, Mingzhe; Li, Can; Huang, Xin; Gong, Lei; Li, Ang; Duan, Weidong; Zhang, Aiqun; Dong, Jiahong

    2016-01-01

    Abstract To quantitatively evaluate the regional functional reserve in the cirrhotic liver and to seek related index that reflects diminished segmental liver function. A 3D system for quantitative evaluation of the liver was used to fuse technetium-99m galactosyl human serum albumin single-photon emission computed tomography and computed tomography images from 20 patients with cirrhotic liver and hepatocellular carcinoma. A set of parameters reflecting liver function including morphological liver volume, functional liver volume, functional liver density (FLD), and the drug absorption rate constant for hepatic cells (GSA-K) was calculated. Differences in FLD and GSA-K in intrahepatic segments were compared in patients with a tumor embolus (Group Y) and those without such an embolus (Group N) in the right portal vein. Differences in FLD and GSA-K in tumor-bearing (T+ group) and tumor-free (T− group) segments in patients with no tumor embolus (Group N) were also compared. Eleven living donor liver transplantation donor served as the control group. The FLD of the liver as a whole was significantly lower in patients with cirrhosis than in the control group (0.53 ± 0.13 vs 0.68 ± 0.10, P = 0.010). The FLD in segments of the right hemiliver was significantly lower than that in segments of the left hemiliver in Group Y (0.31 ± 0.21 vs 0.58 ± 0.12, P = 0.002) but not in Group N (0.60 ± 0.19 vs 0.55 ± 0.13, P = 0.294). FLD was 0.45 ± 0.17 in the T+ group and 0.60 ± 0.08 in the T− group (P = 0.008). Differences in GSA-K in intrahepatic segments were not significant. In the control group, differences in FLD and GSA-K in intrahepatic segments were not significant. The segmental liver functional reserve can be quantitatively calculated. FLD, but not GSA-K, is an index that reflects diminished regional liver function caused by portal flow obstruction or tumor compression. PMID:26945357

  3. Liver Function Tests

    MedlinePlus

    ... Your Liver > Liver Disease Information > Liver Function Tests Liver Function Tests Explore this section to learn more ... including a description and diagnosis. Why is the liver important? The liver is the second largest organ ...

  4. Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging

    PubMed Central

    Georgiou, Leonidas; Penny, Jeffrey; Nicholls, Glynis; Woodhouse, Neil; Blé, François-Xavier; Hubbard Cristinacce, Penny L.; Naish, Josephine H.

    2017-01-01

    individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes. Conclusions This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions. PMID:28002117

  5. Liver Function Tests

    MedlinePlus

    ... food, store energy, and remove poisons. Liver function tests are blood tests that check to see how well your liver ... hepatitis and cirrhosis. You may have liver function tests as part of a regular checkup. Or you ...

  6. Liver function tests

    MedlinePlus

    Liver function tests are common tests that are used to see how well the liver is working. Tests include: ... M, Bowne WB, Bluth MH. Evaluation of liver function. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

  7. [Lidocaine elimination and MEGX formation after oral lidocaine administration--a practicable test for assessment of quantitative liver function].

    PubMed

    Klinker, H; Joeres, R; Bomhard, M; Keller, F; Dorer, J; Zilly, W; Richter, E

    1993-02-01

    Oral load with 200 mg Lidocain was performed in 370 patients with chronic liver disease. The 120- and 240-minute Lidocain plasma concentrations as well as the 30- and 60-minute MEGX plasma concentrations, main metabolite of Lidocain, were measured by means of gas chromatography and with the commercial TDX test from the firm Abbott. No side effects caused by the load were observed and all of the patients resorbed Lidocain. Peak concentrations were found both for Lidocain and for MEGX in the 60-minute tests. Patients with liver cirrhosis of different aetiology showed significantly higher Lidocain plasma concentrations and lower MEGX values than patients with chronic non-cirrhotic liver disease. The differentiation of these two groups of patients was most successful via the determination of the 240-minute Lidocain plasma concentration. Oral load with 200 mg Lidocain has turned out to be a practicable and meaningful test for the estimation of the Cytochrom P450-dependent liver function.

  8. Hepatic (Liver) Function Panel

    MedlinePlus

    ... related side effects. The hepatic function panel evaluates: Alanine aminotransferase (ALT). This enzyme, found in the liver, ... MORE ON THIS TOPIC Mononucleosis Hepatitis Blood Test: Alanine Aminotransferase (ALT, or SGPT) Blood Test: Aspartate Aminotransferase ( ...

  9. Monitoring of Total and Regional Liver Function after SIRT.

    PubMed

    Bennink, Roelof J; Cieslak, Kasia P; van Delden, Otto M; van Lienden, Krijn P; Klümpen, Heinz-Josef; Jansen, Peter L; van Gulik, Thomas M

    2014-01-01

    Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepatocellular carcinoma or metastatic liver cancer. SIRT is usually well tolerated. However, in most patients, SIRT will result in a (temporary) decreased liver function. Occasionally patients develop radioembolization-induced liver disease (REILD). In case of a high tumor burden of the liver, it could be beneficial to perform SIRT in two sessions enabling the primary untreated liver segments to guarantee liver function until function in the treated segments has recovered or functional hypertrophy has occurred. Clinically used liver function tests provide evidence of only one of the many liver functions, though all of them lack the possibility of assessment of segmental (regional) liver function. Hepatobiliary scintigraphy (HBS) has been validated as a tool to assess total and regional liver function in liver surgery. It is also used to assess segmental liver function before and after portal vein embolization. HBS is considered as a valuable quantitative liver function test enabling assessment of segmental liver function recovery after regional intervention and determination of future remnant liver function. We present two cases in which HBS was used to monitor total and regional liver function in a patient after repeated whole liver SIRT complicated with REILD and a patient treated unilaterally without complications.

  10. Portable device for the analysis of liver function: a boon to liver surgery and critical care.

    PubMed

    Mobley, Constance M; Zarrinpar, Ali

    2016-01-01

    Liver biology, liver disease and its management present a myriad of challenges to clinicians. Difficulties arise in determining liver functional capacity, which must be effectively measured in a quantitative reproducible manner. Measurement of indocyanine green (ICG) clearance, an exceptional tool that has been used for decades to assess liver function, has traditionally been cumbersome to perform. New technology now allows for rapid and noninvasive determination of ICG clearance making it clinically accessible. This adds ICG clearance measurement to the armamentarium of physiologic monitors that could be routinely used in the evaluation of patients undergoing liver surgery or in the intensive care setting.

  11. Oral contraceptives and liver function

    PubMed Central

    Hargreaves, Tom

    1969-01-01

    Oral contraceptives can cause liver damage and jaundice but this is very rare in women in the United Kingdom. The drugs are contraindicated where there is a history of recurrent intrahepatic cholestasis of pregnancy and acute or chronic disturbance of liver function which can be congenital or acquired. It is not yet known whether the oestrogenic or progestogenic components of oral contraceptives cause the hepatic abnormalities. The available data suggest that neither oestrogens nor progestogens in low doses impair hepatic excretory processes. The full implications of the continued administration of oestrogens and progestogens for many years on liver proteins are not yet known.

  12. Monitoring Hepatocyte Dysfunction and Biliary Complication After Liver Transplantation Using Quantitative Hepatobiliary Scintigraphy

    PubMed Central

    Zou, Si-Juan; Chen, Dong; Li, Yan-Zhao; Du, Dun-Feng; Chen, Zhi-Shui; Zhu, Xiao-Hua

    2015-01-01

    Abstract The significance of hepatobiliary scintigraphy (HBS) for hepatic graft function assessment was established mostly on retrospective studies and was not widely recognized due to the lack of quantitative data and variation in accuracy. This prospective study was performed to investigate the effectiveness of quantitative HBS for assessing hepatocyte dysfunction and biliary complication in liver transplant recipients. In 57 recipients who had undergone orthotopic liver transplantation, a total of 67 dynamic 99mTc-EHIDA scans were performed and quantitative parameters including the hepatocyte extraction fraction (HEF), time to maximum hepatic radioactivity (Tmax), and time for peak activity to decrease by 50% (T1/2) were calculated. The scintigraphic results based on the 3 parameters were compared against the final diagnosis. A ROC curve analysis was carried out to identify the cutoff value of Tmax for diagnosis of biliary stricture. Correlation between the parameters of postoperative HBS and conventional biochemical liver function indices were also analyzed. Quantitative 99mTc-EHIDA HBS had an overall sensitivity of 94.12% (16/17), specificity of 93.33% (42/45), and diagnostic accuracy of 93.55% (58/62) for detecting hepatocyte dysfunction and biliary complication in liver transplant recipients. The recommended cutoff value of Tmax for diagnosis of post-transplant biliary stricture was set at 15.75 min with a sensitivity of 100.0% and a specificity of 94.0%. The scintigraphic parameters (HEF, Tmax) were statistically significantly associated with the conventional liver function parameters. Quantitative 99mTc-EHIDA HBS offers a noninvasive imaging modality with high sensitivity and specificity to diagnose hepatocyte dysfunction as well as distinguish between patients with or without biliary stricture following liver transplantation. Furthermore, HEF and Tmax values obtained from dynamic HBS show good correlation with conventional liver function parameters

  13. Monitoring Hepatocyte Dysfunction and Biliary Complication After Liver Transplantation Using Quantitative Hepatobiliary Scintigraphy.

    PubMed

    Zou, Si-Juan; Chen, Dong; Li, Yan-Zhao; Du, Dun-Feng; Chen, Zhi-Shui; Zhu, Xiao-Hua

    2015-11-01

    The significance of hepatobiliary scintigraphy (HBS) for hepatic graft function assessment was established mostly on retrospective studies and was not widely recognized due to the lack of quantitative data and variation in accuracy. This prospective study was performed to investigate the effectiveness of quantitative HBS for assessing hepatocyte dysfunction and biliary complication in liver transplant recipients.In 57 recipients who had undergone orthotopic liver transplantation, a total of 67 dynamic Tc-EHIDA scans were performed and quantitative parameters including the hepatocyte extraction fraction (HEF), time to maximum hepatic radioactivity (Tmax), and time for peak activity to decrease by 50% (T1/2) were calculated. The scintigraphic results based on the 3 parameters were compared against the final diagnosis. A ROC curve analysis was carried out to identify the cutoff value of Tmax for diagnosis of biliary stricture. Correlation between the parameters of postoperative HBS and conventional biochemical liver function indices were also analyzed.Quantitative Tc-EHIDA HBS had an overall sensitivity of 94.12% (16/17), specificity of 93.33% (42/45), and diagnostic accuracy of 93.55% (58/62) for detecting hepatocyte dysfunction and biliary complication in liver transplant recipients. The recommended cutoff value of Tmax for diagnosis of post-transplant biliary stricture was set at 15.75 min with a sensitivity of 100.0% and a specificity of 94.0%. The scintigraphic parameters (HEF, Tmax) were statistically significantly associated with the conventional liver function parameters.Quantitative Tc-EHIDA HBS offers a noninvasive imaging modality with high sensitivity and specificity to diagnose hepatocyte dysfunction as well as distinguish between patients with or without biliary stricture following liver transplantation. Furthermore, HEF and Tmax values obtained from dynamic HBS show good correlation with conventional liver function parameters.

  14. Assessment of liver volume variation to evaluate liver function.

    PubMed

    Tong, Cong; Xu, Xinsen; Liu, Chang; Zhang, Tianzheng; Qu, Kai

    2012-12-01

    In order to assess the value of liver volumetry in cirrhosis and acute liver failure (ALF) patients, we explored the correlation between hepatic volume and severity of the hepatic diseases. The clinical data of 48 cirrhosis patients with 60 normal controls and 39 ALF patients were collected. Computed tomography-derived liver volume (CTLV) and body surface area (BSA) of normal controls were calculated to get a regression formula for standard liver volume (SLV) and BSA. Then CTLV and SLV of all patients were calculated and grouped by Child-Turcotte-Pugh classification for cirrhosis patients and assigned according to prognosis of ALF patients for further comparison. It turned out that the mean liver volume of the control group was 1,058 ± 337 cm(3). SLV was correlated with BSA according to the regression formula. The hepatic volume of cirrhosis patients in Child A, B level was not reduced, but in Child C level it was significantly reduced with the lowest liver volume index (CTLV/SLV). Likewise, in the death group of ALF patients, the volume index was significantly lower than that of the survival group. Based on volumetric study, we proposed an ROC (receiver operating characteristic) analysis to predict the prognosis of ALF patients that CTLV/SLV < 83.9% indicates a poor prognosis. In conclusion, the CTLV/SLV ratio, which reflects liver volume variations, correlates well with the liver function and progression of cirrhosis and ALF. It is also a very useful marker for predicting the prognosis of ALF.

  15. In vivo, label-free, three-dimensional quantitative imaging of liver surface using multi-photon microscopy

    SciTech Connect

    Zhuo, Shuangmu E-mail: hanry-yu@nuhs.edu.sg; Yan, Jie; Kang, Yuzhan; Peng, Qiwen; and others

    2014-07-14

    Various structural features on the liver surface reflect functional changes in the liver. The visualization of these surface features with molecular specificity is of particular relevance to understanding the physiology and diseases of the liver. Using multi-photon microscopy (MPM), we have developed a label-free, three-dimensional quantitative and sensitive method to visualize various structural features of liver surface in living rat. MPM could quantitatively image the microstructural features of liver surface with respect to the sinuosity of collagen fiber, the elastic fiber structure, the ratio between elastin and collagen, collagen content, and the metabolic state of the hepatocytes that are correlative with the pathophysiologically induced changes in the regions of interest. This study highlights the potential of this technique as a useful tool for pathophysiological studies and possible diagnosis of the liver diseases with further development.

  16. How predictive quantitative modelling of tissue organisation can inform liver disease pathogenesis.

    PubMed

    Drasdo, Dirk; Hoehme, Stefan; Hengstler, Jan G

    2014-10-01

    From the more than 100 liver diseases described, many of those with high incidence rates manifest themselves by histopathological changes, such as hepatitis, alcoholic liver disease, fatty liver disease, fibrosis, and, in its later stages, cirrhosis, hepatocellular carcinoma, primary biliary cirrhosis and other disorders. Studies of disease pathogeneses are largely based on integrating -omics data pooled from cells at different locations with spatial information from stained liver structures in animal models. Even though this has led to significant insights, the complexity of interactions as well as the involvement of processes at many different time and length scales constrains the possibility to condense disease processes in illustrations, schemes and tables. The combination of modern imaging modalities with image processing and analysis, and mathematical models opens up a promising new approach towards a quantitative understanding of pathologies and of disease processes. This strategy is discussed for two examples, ammonia metabolism after drug-induced acute liver damage, and the recovery of liver mass as well as architecture during the subsequent regeneration process. This interdisciplinary approach permits integration of biological mechanisms and models of processes contributing to disease progression at various scales into mathematical models. These can be used to perform in silico simulations to promote unravelling the relation between architecture and function as below illustrated for liver regeneration, and bridging from the in vitro situation and animal models to humans. In the near future novel mechanisms will usually not be directly elucidated by modelling. However, models will falsify hypotheses and guide towards the most informative experimental design.

  17. Shear wave elastography results correlate with liver fibrosis histology and liver function reserve

    PubMed Central

    Feng, Yan-Hong; Hu, Xiang-Dong; Zhai, Lin; Liu, Ji-Bin; Qiu, Lan-Yan; Zu, Yuan; Liang, Si; Gui, Yu; Qian, Lin-Xue

    2016-01-01

    AIM: To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. METHODS: Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. RESULTS: At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P < 0.001). Specifically, the F4 group had a significantly higher elastic modulus than the F3, F2, and F0 groups (P = 0.002, P = 0.003, and P = 0.006, respectively), and the F3 group also had a significantly higher modulus than the control F0 group (P = 0.039). LSM was negatively associated with plasma MEGX concentrations at 30 min (r = -0.642; P = 0.013) and 60 min (r = -0.651; P = 0.012), time to ½ of the maximum concentration (r = -0.538; P = 0.047), and the area under the curve (r = -0.636; P = 0.014). Multiple comparisons showed identical differences in these three measures

  18. Multiphoton microscopy in defining liver function

    NASA Astrophysics Data System (ADS)

    Thorling, Camilla A.; Crawford, Darrell; Burczynski, Frank J.; Liu, Xin; Liau, Ian; Roberts, Michael S.

    2014-09-01

    Multiphoton microscopy is the preferred method when in vivo deep-tissue imaging is required. This review presents the application of multiphoton microscopy in defining liver function. In particular, multiphoton microscopy is useful in imaging intracellular events, such as mitochondrial depolarization and cellular metabolism in terms of NAD(P)H changes with fluorescence lifetime imaging microscopy. The morphology of hepatocytes can be visualized without exogenously administered fluorescent dyes by utilizing their autofluorescence and second harmonic generation signal of collagen, which is useful in diagnosing liver disease. More specific imaging, such as studying drug transport in normal and diseased livers are achievable, but require exogenously administered fluorescent dyes. If these techniques can be translated into clinical use to assess liver function, it would greatly improve early diagnosis of organ viability, fibrosis, and cancer.

  19. Quantitative imaging of lymph function.

    PubMed

    Sharma, Ruchi; Wang, Wei; Rasmussen, John C; Joshi, Amit; Houston, Jessica P; Adams, Kristen E; Cameron, Arlin; Ke, Shi; Kwon, Sunkuk; Mawad, Michel E; Sevick-Muraca, Eva M

    2007-06-01

    Functional lymphatic imaging was demonstrated in the abdomen and anterior hindlimb of anesthetized, intact Yorkshire swine by using near-infrared (NIR) fluorescence imaging following intradermal administration of 100-200 microl of 32 microM indocyanine green (ICG) and 64 microM hyaluronan NIR imaging conjugate to target the lymph vascular endothelial receptor (LYVE)-1 on the lymph endothelium. NIR fluorescence imaging employed illumination of 780 nm excitation light ( approximately 2 mW/cm(2)) and collection of 830 nm fluorescence generated from the imaging agents. Our results show the ability to image the immediate trafficking of ICG from the plexus, through the vessels and lymphangions, and to the superficial mammary, subiliac, and middle iliac lymph nodes, which were located as deep as 3 cm beneath the tissue surface. "Packets" of ICG-transited lymph vessels of 2-16 cm length propelled at frequencies of 0.5-3.3 pulses/min and velocities of 0.23-0.75 cm/s. Lymph propulsion was independent of respiration rate. In the case of the hyaluronan imaging agent, lymph propulsion was absent as the dye progressed immediately through the plexus and stained the lymph vessels and nodes. Lymph imaging required 5.0 and 11.9 microg of ICG and hyaluronan conjugate, respectively. Our results suggest that microgram quantities of NIR optical imaging agents and their conjugates have a potential to image lymph function in patients suffering from lymph-related disorders.

  20. Cellular Organization of Normal Mouse Liver: A Histological, Quantitative Immunocytochemical, and Fine Structural Analysis

    PubMed Central

    Baratta, Janie L.; Ngo, Anthony; Lopez, Bryan; Kasabwalla, Natasha; Longmuir, Kenneth J.; Robertson, Richard T.

    2009-01-01

    The cellular organization of normal mouse liver was studied using light and electron microscopy and quantitative immunocytochemical techniques. The general histological organization of the mouse liver is similar to livers of other mammalian species, with a lobular organization based on the distributions of portal areas and central venules. The parenchymal hepatocytes were detected with immunocytochemical techniques to recognize albumin or biotin containing cells. The macrophage Kupffer cells were identified with F4-80 immunocytochemistry, Ito stellate cells were identified with GFAP immunocytochemistry, and endothelial cells were labeled with the CD-34 antibody. Kupffer cells were labeled with intravascularly administered fluorescently labeled latex microspheres of both large (0.5 μm) and small (0.03 μm) diameters, while endothelial cells were labeled only with small diameter microspheres. Neither hepatocytes nor Ito stellate cells were labeled by intravascularly administered latex microspheres. The principal fine structural features of hepatocytes and non-parenchymal cells of mouse liver are similar to those reported for rat. Counts of immunocytochemically labeled cells with stained nuclei indicated that hepatocytes constituted approximately 52% of all labeled cells, Kupffer cells about 18%, Ito cells about 8%, and endothelial cells about 22% of all labeled cells. Approximately 35% of the hepatocytes contained two nuclei; none of the Kupffer or Ito cells were double nucleated. The presence of canaliculi and a bile duct system appear similar to that reported for other mammalian species. The cellular organization of the mouse liver is quite similar to that of other mammalian species, confirming that the mouse presents a useful animal model for studies of liver structure and function. PMID:19255771

  1. Liver gender dimorphism--insights from quantitative morphology.

    PubMed

    Marcos, Ricardo; Correia-Gomes, Carla; Miranda, Helena; Carneiro, Fatima

    2015-12-01

    It was shown recently that many genes are differentially expressed in the liver of males and females, thus strengthening the concept of liver gender dimorphism. This dimorphism exists in many pathological scenarios, from regeneration to fibrosis, which has led to the development of gender hepatology. Nevertheless, it is still unknown if gender dimorphism occurs in the structure of the normal liver. In recent years, it has been shown that, compared with male, the female rat liver bears less fibrotic tissue, more Kupffer cells (per volume unit) and has higher hepatocellularity, including binucleated hepatocytes (per volume unit). Our hypothesis is that the human liver also hides a gender dimorphic pattern. Baseline differences in fibrotic tissue would contribute to explain severe liver fibrosis in men. As to the disparity of Kupffer cells, this would clarify the stronger response to post-surgery infections in women, and it could be equated when appraising the higher susceptibility to alcohol. Regarding differences in hepatocytes, they not only justify existing differences in some liver parameters (e.g., transaminases and bilirubin), but they could also account for the higher regenerative potential of the female liver. The structural dimorphism in the human liver would sustain the concept of gender hepatology and, eventually, should be considered in the context of liver transplantation.

  2. Moesin functionality in hypothermic liver preservation injury.

    PubMed

    Tian, Tao; Lindell, Susanne L; Kowalski, Chris; Mangino, Martin J

    2014-08-01

    The objective of this study was to determine how expression and functionality of the cytoskeletal linker protein moesin is involved in hepatic hypothermic preservation injury. Mouse livers were cold stored in University of Wisconsin (UW) solution and reperfused on an isolated perfused liver (IPL) device for one hour. Human hepatocytes (HepG2) and human or murine sinusoidal endothelial cells (SECs) were cold stored and rewarmed to induce hypothermic preservation injury. The cells were transfected with: wild type moesin, an siRNA duplex specific for moesin, and the moesin mutants T558D and T558A. Tissue and cell moesin expression and its binding to actin were determined by Western blot. Liver IPL functional outcomes deteriorated proportional to the length of cold storage, which correlated with moesin disassociation from the actin cytoskeleton. Cell viability (LDH and WST-8) in the cell models progressively declined with increasing preservation time, which also correlated with moesin disassociation. Transfection of a moesin containing plasmid or an siRNA duplex specific for moesin into HepG2 cells resulted in increased and decreased moesin expression, respectively. Overexpression of moesin protected while moesin knock-down potentiated preservation injury in the HepG2 cell model. Hepatocytes expressing the T558A (inactive) and T558D (active) moesin binding mutants demonstrated significantly more and less preservation injury, respectively. Cold storage time dependently caused hepatocyte detachment from the matrix and cell death, which was prevented by the T558D active moesin mutation. In conclusion, moesin is causally involved in hypothermic liver cell preservation injury through control of its active binding molecular functionality.

  3. Integrative Quantitative Proteomics Unveils Proteostasis Imbalance in Human Hepatocellular Carcinoma Developed on Nonfibrotic Livers*

    PubMed Central

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-01-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen®, and AMMP®) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253. PMID:25225353

  4. Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

    PubMed

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-12-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen(®), and AMMP(®)) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253.

  5. Impaired Physical Function Following Pediatric Liver Transplantation

    PubMed Central

    Feldman, Amy G.; Neighbors, Katie; Mukherjee, Shubra; Rak, Melanie; Varni, James W.; Alonso, Estella M.

    2016-01-01

    Objective Investigate the spectrum of physical function of pediatric liver transplant (LT) recipients 12–24 months post-LT. Study design Review data collected through the Functional Outcomes Group, an ancillary study of Studies of Pediatric Liver Transplantation registry. Patients were eligible if they had survived LT by 12–24 months. Children ≥ 8 years and parents completed the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales, which includes 8 questions assessing physical function. Scores were compared to a matched healthy child population (n=1658), and between survivors with optimal versus non-optimal health. Results A total of 263 patients were included. Median age at transplant and survey was 4.8 years (IQR 1.3–11.4) and 5.9 years (IQR 2.6–13.1), respectively. The mean Physical Functioning Score on child and parent reports were 81.2± 17.3 and 77.1± 23.7, respectively. Compared to a matched healthy population, transplant survivors and their parents reported lower physical function scores (p<0.01). 32.9% of patients and 35.0% of parents reported a physical function score <75, which is >1 SD below the mean of a healthy population. Physical Function Scores were significantly higher in survivors with optimal health than those with non-optimal health (p<0.01). There was a significant relationship between Emotional Functioning and Physical Functioning Scores for LT recipients (r=0.69, p<0.001). In multivariate analysis, primary disease, height Z score<−1.64 at long term follow-up (LTF) visit, ≥4 days of hospitalization since LTF visit, and not listed as Status 1 were predictors of poor physical function. Conclusions Pediatric LT recipients 1–2 years post-LT and their parents report lower physical function than a healthy population. Findings suggest practitioners need to routinely assess physical function, and development of rehabilitation programs may be important. PMID:26850789

  6. Photoacoustic molecular imaging for in vivo liver iron quantitation

    NASA Astrophysics Data System (ADS)

    Maccarinelli, Federica; Carmona, Fernando; Regoni, Maria; Arosio, Paolo

    2016-05-01

    A recent study showed that ferritin is a suitable endogenous contrast agent for photoacoustic molecular imaging in cultured mammalian cells. We have therefore tested whether this imaging technique can be used for in vivo quantification of iron in mouse livers. To verify this hypothesis, we used multispectral optoacoustic tomography (MSOT) to image albino CD1 mice before and after experimental iron loading. Postmortem assays showed that the iron treatment caused a 15-fold increase in liver iron and a 40-fold increase in liver ferritin levels, while in vivo longitudinal analysis using MSOT revealed just a 1.6-fold increase in the ferritin/iron photoacoustic signal in the same animals. We conclude that MSOT can monitor changes in ferritin/iron levels in vivo, but its sensitivity is much lower than that of ex vivo iron assays.

  7. Quantitative methods in assessment of neurologic function.

    PubMed

    Potvin, A R; Tourtellotte, W W; Syndulko, K; Potvin, J

    1981-01-01

    Traditionally, neurologists have emphasized qualitative techniques for assessing results of clinical trials. However, in recent years qualitative evaluations have been increasingly augmented by quantitative tests for measuring neurologic functions pertaining to mental state, strength, steadiness, reactions, speed, coordination, sensation, fatigue, gait, station, and simulated activities of daily living. Quantitative tests have long been used by psychologists for evaluating asymptomatic function, assessing human information processing, and predicting proficiency in skilled tasks; however, their methodology has never been directly assessed for validity in a clinical environment. In this report, relevant contributions from the literature on asymptomatic human performance and that on clinical quantitative neurologic function are reviewed and assessed. While emphasis is focused on tests appropriate for evaluating clinical neurologic trials, evaluations of tests for reproducibility, reliability, validity, and examiner training procedures, and for effects of motivation, learning, handedness, age, and sex are also reported and interpreted. Examples of statistical strategies for data analysis, scoring systems, data reduction methods, and data display concepts are presented. Although investigative work still remains to be done, it appears that carefully selected and evaluated tests of sensory and motor function should be an essential factor for evaluating clinical trials in an objective manner.

  8. Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.

    PubMed

    Massafra, Vittoria; Milona, Alexandra; Vos, Harmjan R; Burgering, Boudewijn M T; van Mil, Saskia W C

    2017-01-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing "light" lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing "heavy" lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e., Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e., Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e., Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that fully uncouple metabolic benefit from mitogenic potential.

  9. Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation

    PubMed Central

    Vos, Harmjan R.; Burgering, Boudewijn M. T.; van Mil, Saskia W. C.

    2017-01-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing “light” lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing “heavy” lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e., Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e., Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e., Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that fully uncouple metabolic benefit from mitogenic potential. PMID:28178326

  10. The correlation of contrast-enhanced ultrasound and MRI perfusion quantitative analysis in rabbit VX2 liver cancer.

    PubMed

    Xiang, Zhiming; Liang, Qianwen; Liang, Changhong; Zhong, Guimian

    2014-12-01

    Our objective is to explore the value of liver cancer contrast-enhanced ultrasound (CEUS) and MRI perfusion quantitative analysis in liver cancer and the correlation between these two analysis methods. Rabbit VX2 liver cancer model was established in this study. CEUS was applied. Sono Vue was applied in rabbits by ear vein to dynamically observe and record the blood perfusion and changes in the process of VX2 liver cancer and surrounding tissue. MRI perfusion quantitative analysis was used to analyze the mean enhancement time and change law of maximal slope increasing, which were further compared with the pathological examination results. Quantitative indicators of liver cancer CEUS and MRI perfusion quantitative analysis were compared, and the correlation between them was analyzed by correlation analysis. Rabbit VX2 liver cancer model was successfully established. CEUS showed that time-intensity curve of rabbit VX2 liver cancer showed "fast in, fast out" model while MRI perfusion quantitative analysis showed that quantitative parameter MTE of tumor tissue increased and MSI decreased: the difference was statistically significant (P < 0.01). The diagnostic results of CEUS and MRI perfusion quantitative analysis were not significantly different (P > 0.05). However, the quantitative parameter of them were significantly positively correlated (P < 0.05). CEUS and MRI perfusion quantitative analysis can both dynamically monitor the liver cancer lesion and surrounding liver parenchyma, and the quantitative parameters of them are correlated. The combined application of both is of importance in early diagnosis of liver cancer.

  11. Liver Function Tests Following Open Cardiac Surgery

    PubMed Central

    Sabzi, Feridoun; Faraji, Reza

    2015-01-01

    Introduction: The cardiopulmonary bypass may have multiple systemic effects on the body organs as liver. This prospective study was planned to explore further the incidence and significance of this change. Methods: Two hundred patients with coronary artery bypass grafting (CABG), were randomly selected for the study. Total and indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase were measured preoperatively and at 24, 48 and 72 hours, following coronary artery bypass grafting. Postoperative value of the liver function tests with respect to hypothermia or hypotension were compared by one way analysis of variance for repeated measure and compared with t test. Patient’s characteristics with bilirubin value (≤1.5 mg or >1.5 mg) were compared with t test. Results: A significant increase of total bilirubin, aspartate aminotransferase, and alkaline phosphatase were noted in the third postoperative day. Significant relation was seen between hypotension and alkaline phosphatase, and aspartate aminotransferase change but hypothermia had not affected alanine aminotransferase, total bilirubin and indirect bilirubin change. Pump time, alanine aminotransferase in third postoperative day and direct bilirubin in first and second day of postoperative period had significant relation with pre and post-operative bilirubin change. Conclusion: Transient but not permanent alterations of hepatic enzymes after coronary artery bypass grafting presumably attributed to the decreased hepatic flow, hypoxia, or pump-induced inflammation. PMID:26191391

  12. Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip.

    PubMed

    Du, Yu; Li, Ning; Yang, Hao; Luo, Chunhua; Gong, Yixin; Tong, Chunfang; Gao, Yuxin; Lü, Shouqin; Long, Mian

    2017-02-28

    Physiologically, four major types of hepatic cells - the liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes - reside inside liver sinusoids and interact with flowing peripheral cells under blood flow. It is hard to mimic an in vivo liver sinusoid due to its complex multiple cell-cell interactions, spatiotemporal construction, and mechanical microenvironment. Here we developed an in vitro liver sinusoid chip by integrating the four types of primary murine hepatic cells into two adjacent fluid channels separated by a porous permeable membrane, replicating liver's key structures and configurations. Each type of cells was identified with its respective markers, and the assembled chip presented the liver-specific unique morphology of fenestration. The flow field in the liver chip was quantitatively analyzed by computational fluid dynamics simulations and particle tracking visualization tests. Intriguingly, co-culture and shear flow enhance albumin secretion independently or cooperatively, while shear flow alone enhances HGF production and CYP450 metabolism. Under lipopolysaccharide (LPS) stimulations, the hepatic cell co-culture facilitated neutrophil recruitment in the liver chip. Thus, this 3D-configured in vitro liver chip integrates the two key factors of shear flow and the four types of primary hepatic cells to replicate key structures, hepatic functions, and primary immune responses and provides a new in vitro model to investigate the short-duration hepatic cellular interactions under a microenvironment mimicking the physiology of a liver.

  13. Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic human liver.

    PubMed

    Song, Sunmi; Shackel, Nicholas A; Wang, Xin M; Ajami, Katerina; McCaughan, Geoffrey W; Gorrell, Mark D

    2011-03-01

    Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell-collagen interactions in chronic liver injury.

  14. Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery?

    PubMed Central

    De Gasperi, Andrea; Mazza, Ernestina; Prosperi, Manlio

    2016-01-01

    Indocyanine green (ICG) kinetics (PDR/R15) used to quantitatively assess hepatic function in the perioperative period of major resective surgery and liver transplantation have been the object of an extensive, updated and critical review. New, non invasive bedside monitors (pulse dye densitometry technology) make this opportunity widely available in clinical practice. After having reviewed basic concepts of hepatic clearance, we analysed the most common indications ICG kinetic parameters have nowadays in clinical practice, focusing in particular on the diagnostic and prognostic role of PDR and R15 in the perioperative period of major liver surgery and liver transplantation. As recently pointed out, even if of extreme interest, ICG clearance parameters have still some limitations, to be considered when using these tests. PMID:26981173

  15. Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery?

    PubMed

    De Gasperi, Andrea; Mazza, Ernestina; Prosperi, Manlio

    2016-03-08

    Indocyanine green (ICG) kinetics (PDR/R15) used to quantitatively assess hepatic function in the perioperative period of major resective surgery and liver transplantation have been the object of an extensive, updated and critical review. New, non invasive bedside monitors (pulse dye densitometry technology) make this opportunity widely available in clinical practice. After having reviewed basic concepts of hepatic clearance, we analysed the most common indications ICG kinetic parameters have nowadays in clinical practice, focusing in particular on the diagnostic and prognostic role of PDR and R15 in the perioperative period of major liver surgery and liver transplantation. As recently pointed out, even if of extreme interest, ICG clearance parameters have still some limitations, to be considered when using these tests.

  16. Quantitative evaluation of noise reduction and vesselness filters for liver vessel segmentation on abdominal CTA images

    NASA Astrophysics Data System (ADS)

    Luu, Ha Manh; Klink, Camiel; Moelker, Adriaan; Niessen, Wiro; van Walsum, Theo

    2015-05-01

    Liver vessel segmentation in CTA images is a challenging task, especially in the case of noisy images. This paper investigates whether pre-filtering improves liver vessel segmentation in 3D CTA images. We introduce a quantitative evaluation of several well-known filters based on a proposed liver vessel segmentation method on CTA images. We compare the effect of different diffusion techniques i.e. Regularized Perona-Malik, Hybrid Diffusion with Continuous Switch and Vessel Enhancing Diffusion as well as the vesselness approaches proposed by Sato, Frangi and Erdt. Liver vessel segmentation of the pre-processed images is performed using a histogram-based region grown with local maxima as seed points. Quantitative measurements (sensitivity, specificity and accuracy) are determined based on manual landmarks inside and outside the vessels, followed by T-tests for statistic comparisons on 51 clinical CTA images. The evaluation demonstrates that all the filters make liver vessel segmentation have a significantly higher accuracy than without using a filter (p  <  0.05) Hybrid Diffusion with Continuous Switch achieves the best performance. Compared to the diffusion filters, vesselness filters have a greater sensitivity but less specificity. In addition, the proposed liver vessel segmentation method with pre-filtering is shown to perform robustly on a clinical dataset having a low contrast-to-noise of up to 3 (dB). The results indicate that the pre-filtering step significantly improves liver vessel segmentation on 3D CTA images.

  17. Rapid Quantitative Determination of Squalene in Shark Liver Oils by Raman and IR Spectroscopy.

    PubMed

    Hall, David W; Marshall, Susan N; Gordon, Keith C; Killeen, Daniel P

    2016-01-01

    Squalene is sourced predominantly from shark liver oils and to a lesser extent from plants such as olives. It is used for the production of surfactants, dyes, sunscreen, and cosmetics. The economic value of shark liver oil is directly related to the squalene content, which in turn is highly variable and species-dependent. Presented here is a validated gas chromatography-mass spectrometry analysis method for the quantitation of squalene in shark liver oils, with an accuracy of 99.0 %, precision of 0.23 % (standard deviation), and linearity of >0.999. The method has been used to measure the squalene concentration of 16 commercial shark liver oils. These reference squalene concentrations were related to infrared (IR) and Raman spectra of the same oils using partial least squares regression. The resultant models were suitable for the rapid quantitation of squalene in shark liver oils, with cross-validation r (2) values of >0.98 and root mean square errors of validation of ≤4.3 % w/w. Independent test set validation of these models found mean absolute deviations of the 4.9 and 1.0 % w/w for the IR and Raman models, respectively. Both techniques were more accurate than results obtained by an industrial refractive index analysis method, which is used for rapid, cheap quantitation of squalene in shark liver oils. In particular, the Raman partial least squares regression was suited to quantitative squalene analysis. The intense and highly characteristic Raman bands of squalene made quantitative analysis possible irrespective of the lipid matrix.

  18. Renal Function and Transplantation in Liver Disease.

    PubMed

    Parajuli, Sandesh; Foley, David; Djamali, Arjang; Mandelbrot, Didier

    2015-09-01

    Kidney injury is associated with increased morbidity and mortality in liver transplant recipients. Since the introduction of the model for end-stage liver disease for the allocation of organs for liver transplantation in 2002, the heavy weighting of serum creatinine in the model for end-stage liver disease score has significantly increased the incidence of renal dysfunction seen among patients undergoing liver transplantation. As a result, the frequency of simultaneous liver-kidney (SLK) transplantation compared to liver transplantation alone (LTA) has also increased. The decision to perform SLK rather than LTA is an important one because the benefits to the liver transplant recipient receiving a kidney transplant must be balanced with the benefits of using that organ for a patient with end-stage renal disease. However, predicting whether or not a patient with liver failure has reversible kidney disease, and therefore does not also need a kidney transplant, is difficult. The severity and duration of pretransplant renal dysfunction, hepatitis c, diabetes, and other risk factors for kidney disease are associated with an increased risk of posttransplant end-stage renal disease. However, there are currently no clinical findings that accurately predict renal recovery post liver transplant. As a result, the rate of SLK versus LTA differs significantly between transplant centers. To increase consistency across centers, multiple guidelines have been proposed to guide the decision between SLK and LTA, but their poor predictive value has limited their uniform adoption. Nevertheless, adoption of uniform rules for the allocation of kidneys would reduce the variability between centers in rates of SLK transplant.

  19. EX VIVO STUDY OF QUANTITATIVE ULTRASOUND PARAMETERS IN FATTY RABBIT LIVERS

    PubMed Central

    Ghoshal, Goutam; Lavarello, Roberto J.; Kemmerer, Jeremy P.; Miller, Rita J.; Oelze, Michael L.

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) affects more than 30% of Americans, and with increasing problems of obesity in the United States, NAFLD is poised to become an even more serious medical concern. At present, accurate classification of steatosis (fatty liver) represents a significant challenge. In this study, the use of high-frequency (8 to 25 MHz) quantitative ultrasound (QUS) imaging to quantify fatty liver was explored. QUS is an imaging technique that can be used to quantify properties of tissue giving rise to scattered ultrasound. The changes in the ultrasound properties of livers in rabbits undergoing atherogenic diets of varying durations were investigated using QUS. Rabbits were placed on a special fatty diet for 0, 3, or 6 weeks. The fattiness of the livers was quantified by estimating the total lipid content of the livers. Ultrasonic properties, such as speed of sound, attenuation, and backscatter coefficients, were estimated in ex vivo rabbit liver samples from animals that had been on the diet for varying periods. Two QUS parameters were estimated based on the backscatter coefficient: effective scatterer diameter (ESD) and effective acoustic concentration (EAC), using a spherical Gaussian scattering model. Two parameters were estimated based on the backscattered envelope statistics (the k parameter and the μ parameter) according to the homodyned K distribution. The speed of sound decreased from 1574 to 1565 m/s and the attenuation coefficient increased from 0.71 to 1.27 dB/cm/MHz, respectively, with increasing fat content in the liver. The ESD decreased from 31 to 17 μm and the EAC increased from 38 to 63 dB/cm3 with increasing fat content in the liver. A significant increase in the μ parameter from 0.18 to 0.93 scatterers/mm3 was observed with increasing fat content in the liver samples. The results of this study indicate that QUS parameters are sensitive to fat content in the liver. PMID:23062376

  20. Quantitative characterization of fatty liver disease using x-ray scattering

    NASA Astrophysics Data System (ADS)

    Elsharkawy, Wafaa B.; Elshemey, Wael M.

    2013-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a dynamic condition in which fat abnormally accumulates within the hepatocytes. It is believed to be a marker of risk of later chronic liver diseases, such as liver cirrhosis and carcinoma. The fat content in liver biopsies determines its validity for liver transplantation. Transplantation of livers with severe NAFLD is associated with a high risk of primary non-function. Moreover, NAFLD is recognized as a clinically important feature that influences patient morbidity and mortality after hepatic resection. Unfortunately, there is a lack in a precise, reliable and reproducible method for quantification of NAFLD. This work suggests a method for the quantification of NAFLD. The method is based on the fact that fatty liver tissue would have a characteristic x-ray scattering profile with a relatively intense fat peak at a momentum transfer value of 1.1 nm-1 compared to a soft tissue peak at 1.6 nm-1. The fat content in normal and fatty liver is plotted against three profile characterization parameters (ratio of peak intensities, ratio of area under peaks and ratio of area under fat peak to total profile area) for measured and Monte Carlo simulated x-ray scattering profiles. Results show a high linear dependence (R2>0.9) of the characterization parameters on the liver fat content with a reported high correlation coefficient (>0.9) between measured and simulated data. These results indicate that the current method probably offers reliable quantification of fatty liver disease.

  1. Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver

    PubMed Central

    Sabidó, Eduard; Bosch, Elena

    2016-01-01

    Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients. PMID:26582562

  2. Application of quantitative targeted absolute proteomics to profile protein expression changes of hepatic transporters and metabolizing enzymes during cholic acid-promoted liver regeneration.

    PubMed

    Miura, Takayuki; Tachikawa, Masanori; Ohtsuka, Hideo; Fukase, Koji; Nakayama, Shun; Sakata, Naoaki; Motoi, Fuyuhiko; Naitoh, Takeshi; Katayose, Yu; Uchida, Yasuo; Ohtsuki, Sumio; Terasaki, Tetsuya; Unno, Michiaki

    2017-02-26

    Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study was to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed CA-containing diet for 5 days (CA1) and mice fed CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase of apoptosis. Quantitative targeted absolute proteomics revealed (i) decreases in basolateral bile acid transporters ntcp, oatp1a1, oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters bcrp, mrp6, ent1, oatp2b1, and (ii) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, while the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.

  3. Optimizing global liver function in radiation therapy treatment planning

    NASA Astrophysics Data System (ADS)

    Wu, Victor W.; Epelman, Marina A.; Wang, Hesheng; Romeijn, H. Edwin; Feng, Mary; Cao, Yue; Ten Haken, Randall K.; Matuszak, Martha M.

    2016-09-01

    Liver stereotactic body radiation therapy (SBRT) patients differ in both pre-treatment liver function (e.g. due to degree of cirrhosis and/or prior treatment) and radiosensitivity, leading to high variability in potential liver toxicity with similar doses. This work investigates three treatment planning optimization models that minimize risk of toxicity: two consider both voxel-based pre-treatment liver function and local-function-based radiosensitivity with dose; one considers only dose. Each model optimizes different objective functions (varying in complexity of capturing the influence of dose on liver function) subject to the same dose constraints and are tested on 2D synthesized and 3D clinical cases. The normal-liver-based objective functions are the linearized equivalent uniform dose (\\ell \\text{EUD} ) (conventional ‘\\ell \\text{EUD} model’), the so-called perfusion-weighted \\ell \\text{EUD} (\\text{fEUD} ) (proposed ‘fEUD model’), and post-treatment global liver function (GLF) (proposed ‘GLF model’), predicted by a new liver-perfusion-based dose-response model. The resulting \\ell \\text{EUD} , fEUD, and GLF plans delivering the same target \\ell \\text{EUD} are compared with respect to their post-treatment function and various dose-based metrics. Voxel-based portal venous liver perfusion, used as a measure of local function, is computed using DCE-MRI. In cases used in our experiments, the GLF plan preserves up to 4.6 % ≤ft(7.5 % \\right) more liver function than the fEUD (\\ell \\text{EUD} ) plan does in 2D cases, and up to 4.5 % ≤ft(5.6 % \\right) in 3D cases. The GLF and fEUD plans worsen in \\ell \\text{EUD} of functional liver on average by 1.0 Gy and 0.5 Gy in 2D and 3D cases, respectively. Liver perfusion information can be used during treatment planning to minimize the risk of toxicity by improving expected GLF; the degree of benefit varies with perfusion pattern. Although fEUD model optimization is computationally inexpensive and

  4. Correlation analysis between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis

    PubMed Central

    TANG, NING; ZHANG, YAPING; LIU, ZEYU; FU, TAO; LIANG, QINGHONG; AI, XUEMEI

    2016-01-01

    The aim of the present study was to investigate the correlation between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis. A total of 30 infants with cholestasis and 20 healthy infants were included in the study. Biochemical assays based on the initial rate method and colorimetric assays were conducted to determine the levels of liver function markers in the serum [such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), γ-glutamyl transferase (γ-GT), cholinesterase (CHE) and total bile acids (TBA)] and four serum biomarkers of liver fibrosis were measured using radioimmunoassays [hyaluronic acid (HA), procollagen type III (PCIII), laminin (LN) and collagen type IV (cIV)]. The serum levels of ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01); the serum levels of CHE in the infants with cholestasis were significantly lower compared to the healthy infants (P<0.01). The serum levels of HA, PCIII, and cIV in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01). Correlation analyses between liver function and the four biomarkers of liver fibrosis showed that HA was positively correlated with AST and γ-GT (P<0.05) and negatively correlated with ALT, CHE and TBA (P<0.05). cIV was positively correlated with γ-GT (P<0.05) and negatively correlated with CHE (P<0.05). In conclusion, statistically significant differences were identified for the liver function markers (ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA) and the biomarkers HA, PCIII and cIV of liver fibrosis between infants with cholestasis and healthy infants. Thus, the serum levels of HA, cIV, γ-GT and CHE are sensitive markers for cholestatic liver fibrosis in infants. PMID:27347413

  5. Study on Assessment of Renal Function in Chronic Liver Disease

    PubMed Central

    Das, Nupur; Paria, Baishakhi; Sarkar, Sujoy

    2015-01-01

    Introduction: Renal dysfunction is common in chronic liver disease. The cause of this renal dysfunction is either multi-organ involvement in acute conditions or secondary to advanced liver disease. Objectives: The study was undertaken to assess the renal function in chronic liver diseases and find out the association of alteration of renal function with gradation of liver disease. (assessed by child-pugh criteria) and to find out the association of alteration of renal function among the cases of chronic liver disease of different aetiology. Materials and Methods: This cross-sectional, observational study was undertaken in Department of General Medicine, Calcutta National Medical College & Hospital, Kolkata during March 2012 to July 2013 with 50 admitted patients of chronic liver disease after considering the exclusion criteria. The patients were interviewed with a pre-designed and pre-tested schedule, examined clinically, followed by some laboratory investigations relevant to diagnose the aetiology of chronic liver disease, and to assess the severity of liver and renal dysfunction. Data was analysed by standard statistical method. Results: Eighty six percent of the patients were male and the mean age of study population was 43.58 y, 68% patients suffered from alcoholic liver disease, followed by 14% patients had chronic Hepatitis-B, 10% patients developed acute kidney injury, 20% had hepato renal syndrome and 14% had IgA deposition. The distribution of serum urea and creatinine across the categories of Child Pugh classification tested by Mann-Whitney test and the distribution was statistically significant. Conclusion: The present study has found significant association between severity of liver dysfunction and certain parameters of renal dysfunction. PMID:25954647

  6. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

    PubMed

    Zhang, Zheng; Lin, Hu; Shi, Ming; Xu, Ruonan; Fu, Junliang; Lv, Jiyun; Chen, Liming; Lv, Sa; Li, Yuanyuan; Yu, Shuangjie; Geng, Hua; Jin, Lei; Lau, George K K; Wang, Fu-Sheng

    2012-03-01

    Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

  7. Oral health and liver function in children and adolescents with cirrhosis of the liver

    PubMed Central

    Kowalczyk, Wojciech; Krasuska-Sławińska, Ewa; Dądalski, Maciej; Kostewicz, Krzysztof; Pawłowska, Joanna

    2014-01-01

    Introduction People with cirrhosis of the liver are predisposed to developing oral lesions. The occurrence and type of lesion depend on the degree of liver function impairment and its type, and on the severity and duration of systemic diseases. In children, the age at which the early symptoms of liver disease are experienced is also of great importance. Aim To assess the prevalence of oral pathological lesions in children and adolescents with cirrhosis of the liver, and their correlation with the degree of liver function impairment. Material and methods Clinical and laboratory results of liver function tests (Model of End-Stage Liver Disease/Score of Paediatric End-Stage Liver Disease, Child-Pugh score) were assessed in 35 patients with cirrhosis of the liver. The average age of the patients was 10.7 ±4.74 years. All patients also had their oral cavities examined (mucosa, gingiva – GI, hygiene – PLI, teeth – dmft/dmfs and DMFt/DMFs, DDE Index and Candida spp. presence) and this was then correlated to the degree of liver function impairment. Results According to the Child-Pugh scale, 16 patients were class A and 19 were class B/C. Jaundice during the first 3 years of life occurred in 9 patients. Mucosal lesions were found in 26 out of 35 patients (74%), including 10 out of 16 (63%) in Child-Pugh group A, and 16 out of 19 (84%) in group B/C (NS – non significant). Oral candidiasis occurred more often in class B/C than in class A (47.4% vs. 12.5%; p < 0.05). The GI index (Gingival Index) and PLI index (Dental Plaque Index) did not differ between the groups (A vs. B/C) but correlated in the whole group (R = 0.58) as well as in subgroups A (R = 0.65) and B/C (R = 0.59). Dmft/dmfs and DMFt/DMFs indexes did not differ between groups A and B/C, and neither did the DMFt/DMFs in patients with/without enamel defects. Conclusions Oral mucosal lesions are commonly found in children with cirrhosis of the liver. Advanced liver disease promotes oral candidiasis. Severity

  8. Quantitative Estimation of the Amount of Fibrosis in the Rat Liver Using Fractal Dimension of the Shape of Power Spectrum

    NASA Astrophysics Data System (ADS)

    Kikuchi, Tsuneo; Nakazawa, Toshihiro; Furukawa, Tetsuo; Higuchi, Toshiyuki; Maruyama, Yukio; Sato, Sojun

    1995-05-01

    This paper describes the quantitative measurement of the amount of fibrosis in the rat liver using the fractal dimension of the shape of power spectrum. The shape of the power spectrum of the scattered echo from biotissues is strongly affected by its internal structure. The fractal dimension, which is one of the important parameters of the fractal theory, is useful to express the complexity of shape of figures such as the power spectrum. From in vitro experiments using rat liver, it was found that this method can be used to quantitatively measure the amount of fibrosis in the liver, and has the possibility for use in the diagnosis of human liver cirrhosis.

  9. Biomechanics and functionality of hepatocytes in liver cirrhosis.

    PubMed

    Sun, Shan; Song, Zhenyuan; Cotler, Scott J; Cho, Michael

    2014-06-27

    Cirrhosis is a life-threatening condition that is generally attributed to overproduction of collagen fibers in the extracellular matrix that mechanically stiffens the liver. Chronic liver injury due to causes including viral hepatitis, inherited and metabolic liver diseases and external factors such as alcohol abuse can result in the development of cirrhosis. Progression of cirrhosis leads to hepatocellular dysfunction. While extensive studies to understand the complexity underlying liver fibrosis have led to potential application of anti-fibrotic drugs, no such FDA-approved drugs are currently available. Additional studies of hepatic fibrogenesis and cirrhosis primarily have focused on the extracellular matrix, while hepatocyte biomechanics has received limited attention. The role of hepatocyte biomechanics in liver cirrhosis remains elusive, and how the cell stiffness is correlated with biological functions of hepatocytes is also unknown. In this study, we demonstrate that the biomechanical properties of hepatocytes are correlated with their functions (e.g., glucose metabolism), and that hepatic dysfunction can be restored through modulation of the cellular biomechanics. Furthermore, our results indicate the hepatocyte functionality appears to be regulated through a crosstalk between the Rho and Akt signaling. These novel findings may lead to biomechanical intervention of hepatocytes and the development of innovative tissue engineering for clinical treatment to target liver cells rather than exclusively focusing on the extracellular matrix alone in liver cirrhosis.

  10. Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver.

    PubMed

    Campbell, H A; Pitot, H C; Potter, V R; Laishes, B A

    1982-02-01

    The mathematical science of quantitative stereology has established relationships for the quantitation of elements in three-dimensional space from observations on two-dimensional planes. This report describes the utilization and importance of such mathematical relationships for the quantitative analysis of focal hepatic lesions in terms relative to the volume of the liver. Three examples are utilized to demonstrate the utility of such calculations in the three-dimensional quantitation of hepatic focal lesions. The first is that of a computer-simulated experiment based on defined hypothetical situations. The simulations demonstrate the applicability of the computations described in this report to the evaluation of two-dimensional data from typical animal experiments. The other two examples are taken from actual experiments and involve the transplantation of hepatic cell populations into the liver suitably prepared hosts and the quantitation of altered foci produced by initiation with diethylnitrosamine-partial hepatectomy followed by promotion with phenobarbital. The quantitation of altered foci by means of a two-dimensional analysis (simple enumeration of focal intersections/area of tissue section) is proportional to the quantitation of foci per volume of liver provided that the mean diameter of the foci for each treatment is sufficiently uniform, as exemplified in the text by the transplantation experiment. When such mean diameters are unequal as in the diethylnitrosamine-phenobarbital experiment described herein, quantitation from three-dimensional analysis gives significantly different results as compared with enumeration of focal intersections on two-dimensional areas. These studies clearly demonstrate that the frequency and size of foci intersections viewed on two-dimensional tissue sections do not necessarily reflect the number of size of foci in the three-dimensional tissue. Only by quantitating the number and size of the foci in relation to the three

  11. Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools.

    PubMed

    Wang, Yan; Hou, Jin-Lin

    2016-05-01

    Fibrosis, a common pathogenic pathway of chronic liver disease (CLD), has long been indicated to be significantly and most importantly associated with severe prognosis. Nowadays, with remarkable advances in understanding and/or treatment of major CLDs such as hepatitis C, B, and nonalcoholic fatty liver disease, there is an unprecedented requirement for the diagnosis and assessment of liver fibrosis or cirrhosis in various clinical settings. Among the available approaches, liver biopsy remains the one which possibly provides the most direct and reliable information regarding fibrosis patterns and changes in the parenchyma at different clinical stages and with different etiologies. Thus, many endeavors have been undertaken for developing methodologies based on the strategy of quantitation for the invasive assessment. Here, we analyze the impact of fibrosis assessment on the CLD patient care based on the data of recent clinical studies. We discuss and update the current invasive tools regarding their technological features and potentials for the particular clinical applications. Furthermore, we propose the potential resolutions with application of quantitative invasive tools for some major issues in fibrosis assessment, which appear to be obstacles against the nowadays rapid progress in CLD medicine.

  12. Distribution of Diseases Causing Liver Function Test Abnormality in Children and Natural Recovery Time of the Abnormal Liver Function

    PubMed Central

    2016-01-01

    Although liver function test abnormality is frequently noted in children, there is no report about the distribution of the etiology and natural recovery time of the abnormal liver function. From March 2005 to February 2014, clinical information was retrospectively collected from 559 children who had abnormal liver function and were hospitalized or visited the outpatient clinic at the Jeju National University Hospital. The etiology of abnormal liver function was classified into groups and the natural recovery time of abnormal liver function was analyzed. The etiological groups of 559 patients included ‘nonspecific hepatitis’ in 42 (7.5%), ‘infection’ in 323 (57.8%), ‘rheumatologic and autoimmune’ in 66 (11.8%), ‘nonalcoholic fatty liver disease’ in 57 (10.2%), ‘anatomic’ in 12 (2.1%), ‘toxic’ in 13 (2.1%), ‘metabolic’ in 8 (1.4%), ‘hematologic’ in 7 (1.3%), ‘hemodynamic’ in 4 (0.7%), and ‘others’ in 27 (4.8%). Among the ‘infection’ group (57.8%), the ‘viral infection in the respiratory tract’ subgroup, which had 111 patients (19.8%), was the most common. The natural recovery time of the abnormal liver function was 27 days (median) in ‘nonspecific hepatitis’, 13 days (median) in ‘viral respiratory tract disease’, 16 days (median) in ‘viral gastroenteritis’, 42 days (median) in ‘viral febrile illness”, and 7 days (median) in “Kawasaki disease”. The information on the natural recovery time of abnormal liver function may help the physician to perform good clinical consultation for patients and their parents. PMID:27709857

  13. Quantitative optical imaging of paracetamol-induced metabolism changes in the liver

    NASA Astrophysics Data System (ADS)

    Liang, Xiaowen; Wang, Haolu; Liu, Xin; Roberts, Michael

    2016-12-01

    Paracetamol is the most readily available and widely used painkiller. However, its toxicity remains the most common cause of liver injury. The toxicity of paracetamol has been attributing to its toxic metabolite, which depletes cellular glutathione (GSH) stores and reacts within cells to increase oxidative stress, leading to mitochondrial dysfunction and cell necrosis. Multiphoton microscopy (MPM) and fluorescence lifetime imaging (FLIM) can provide quantitative imaging of biological tissues and organs in vivo and allow direct visualization of cellular events, which were used to monitor cellular metabolism in paracetamol-induced toxicity in this study. To better understand mechanisms of paracetamol induced liver injury, the redox ratio of NADH/FAD in liver cells were detected and quantified by MPM imaging to represent the relative rates of glycolysis and oxidative phosphorylation within cells. Compared to normal liver, average fluorescence lifetime of NADH and redox ratio of NADH/FAD in hepatocytes was significantly decreased after paracetamol overdose for 12 and 24 hrs, reflecting impaired metabolic activity. GSH levels of treatment groups were significantly lower than those of normal livers, with gradually decreasing from periportal to centrilobular zonation. This imaging technique has significant implications for investigating metabolic mechanisms of paracetamol toxicity.

  14. Functions of autophagy in normal and diseased liver

    PubMed Central

    Czaja, Mark J.; Ding, Wen-Xing; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-hsiung James; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao-Ming

    2013-01-01

    Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases. PMID:23774882

  15. Functions of autophagy in normal and diseased liver.

    PubMed

    Czaja, Mark J; Ding, Wen-Xing; Donohue, Terrence M; Friedman, Scott L; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J; Lemoine, Antoinette; Lin, Jiandie D; Ou, Jing-hsiung James; Perlmutter, David H; Randall, Glenn; Ray, Ratna B; Tsung, Allan; Yin, Xiao-Ming

    2013-08-01

    Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases.

  16. Structure, regulation and function of gap junctions in liver

    PubMed Central

    Maes, Michaël; Decrock, Elke; Wang, Nan; Leybaert, Luc; da Silva, Tereza Cristina; Veloso Alves Pereira, Isabel; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2016-01-01

    Gap junctions are a specialized group of cell-to-cell junctions that mediate direct intercellular communication between cells. They arise from the interaction of 2 hemichannels of adjacent cells, which in turn are composed of 6 connexin proteins. In liver, gap junctions are predominantly found in hepatocytes and play critical roles in virtually all phases of the hepatic life cycle, including cell growth, differentiation, liver-specific functionality and cell death. Liver gap junctions are directed through a broad variety of mechanisms ranging from epigenetic control of connexin expression to posttranslational regulation of gap junction activity. This paper reviews established and novel aspects regarding the architecture, control and functional relevance of liver gap junctions. PMID:27001459

  17. A Local and Global Function Model of the Liver

    PubMed Central

    Wang, Hesheng; Feng, Mary; Jackson, Andrew; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2015-01-01

    Purposes To develop a local and global function model in the liver based upon regional and organ function measurements to support individualized adaptive radiation therapy (RT). Methods and Materials A local and global model for liver function was developed to include both functional volume and the effect of functional variation of subunits. Adopting the assumption of parallel architecture in the liver, the global function was composed of a sum of local function probabilities of subunits, varying between 0 and 1. The model was fit to 59 datasets of liver regional and organ function measures from 23 patients obtained prior to, during and 1 month after RT. The local function probabilities of subunits were modeled by a sigmoid function in relating to MRI-derived portal venous perfusion values. The global function was fitted to a logarithm of an indocyanine green retention rate at 15 min (an overall liver function measure). Cross-validation was performed by leave-m-out tests. The model was further evaluated by fitting to the data divided based upon whether the patients had hepatocellular carcinoma (HCC) or not. Results The liver function model showed that 1) a perfusion value of 68.6 ml/(100g·min) yielded a local function probability of 0.5; 2) the probability reached 0.9 at a perfusion value of 98 ml/(100g·min), and 3) at a probability of 0.03 (corresponding perfusion of 38 ml/(100g·min)) or lower, the contribution to global function was lost. Cross-validations showed that the model parameters were stable. The model fitted to the data from the patients with HCC indicated that the same amount of portal venous perfusion was translated into less local function probability than the patients with non-HCC tumors. Conclusions The developed liver function model could provide a means to better assess individual and regional dose responses of hepatic functions, and provide guidance for individualized treatment planning of RT. PMID:26700712

  18. Musculoskeletal Health, Kidney and Liver Function in Retired Jockeys.

    PubMed

    Cullen, S; Donohoe, A; McGoldrick, A; McCaffrey, N; Davenport, C; Byrne, B; Donaghy, C; Tormey, W; Smith, D; Warrington, G

    2015-11-01

    The long-term implications of making-weight daily on musculoskeletal health and functioning of the kidney and liver remain unknown. This study aimed to investigate musculoskeletal health and kidney and liver function in a group of retired jockeys. 28 retired male jockeys (age 50-70 years) provided fasting blood samples for markers of bone metabolism and kidney and liver function. A dual-energy x-ray absorptiometry (DXA) scan was performed for the assessment of bone mineral density (BMD). Established reference ranges were used for interpretation of results. Comparisons were made between retired jockeys based on the professional racing licence held: Flat, National Hunt or Dual. Mean whole-body osteopenia was reported, with no differences between groups. Bone markers, micronutrients, electrolytes and associated hormones, and markers for kidney and liver function were within clinical normative ranges. No differences existed between groups. Results indicate the retired jockeys in this study do not demonstrate compromised bone health or kidney and liver function. However, the retired jockeys may not have undergone chronic weight cycling in the extreme manner evident in present-day jockeys, indicating the next generation of jockeys may face more of a problem. Jockeys should be tracked longitudinally throughout their racing career and beyond.

  19. Autophagy in the liver: functions in health and disease.

    PubMed

    Ueno, Takashi; Komatsu, Masaaki

    2017-03-01

    The concept of macroautophagy was established in 1963, soon after the discovery of lysosomes in rat liver. Over the 50 years since, studies of liver autophagy have produced many important findings. The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced autophagy, which is precisely regulated by concentrations of hormones and amino acids. Liver autophagy provides starved cells with amino acids, glucose and free fatty acids for use in energy production and synthesis of new macromolecules, and also controls the quality and quantity of organelles such as mitochondria. Although the efforts of early investigators contributed markedly to our current knowledge of autophagy, the identification of autophagy-related genes represented a revolutionary breakthrough in our understanding of the physiological roles of autophagy in the liver. A growing body of evidence has shown that liver autophagy contributes to basic hepatic functions, including glycogenolysis, gluconeogenesis and β-oxidation, through selective turnover of specific cargos controlled by a series of transcription factors. In this Review, we outline the history of liver autophagy study, and then describe the roles of autophagy in hepatic metabolism under healthy and disease conditions, including the involvement of autophagy in α1-antitrypsin deficiency, NAFLD, hepatocellular carcinoma and viral hepatitis.

  20. Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C

    PubMed Central

    Zaitoun, A; Al, M; Awad, S; Ukabam, S; Makadisi, S; Record, C

    2001-01-01

    Backgrounds—Hepatic fibrosis is one of the main consequences of liver disease. Both fibrosis and steatosis may be seen in some patients with chronic hepatitis C and alcoholic liver disease (ALD). Aims—To quantitate fibrosis and steatosis by stereological and morphometric techniques in patients with chronic hepatitis C and compare the results with a control group of patients with ALD. In addition, to correlate the quantitative features of fibrosis with the Ishak modified histological score. Materials and methods—Needle liver biopsies from 86 patients with chronic hepatitis C and from 32 patients with alcoholic liver disease (disease controls) were analysed by stereological and morphometric analyses using the Prodit 5.2 system. Haematoxylin and eosin and Picro-Mallory stained sections were used. The area fractions (AA) of fibrosis, steatosis, parenchyma, and other structures (bile duct and central vein areas) were assessed by stereological method. The mean diameters of fat globules were determined by morphometric analysis. Results—Significant differences were found in the AA of fibrosis, including fibrosis within portal tract areas, between chronic hepatitis C patients and those with ALD (mean (SD): 19.14 (10.59) v 15.97 (12.51)). Portal and periportal (zone 1) fibrosis was significantly higher (p = 0.00004) in patients with chronic hepatitis C compared with the control group (mean (SD): 9.04 (6.37) v 3.59 (3.16)). Pericentral fibrosis (zone 3) occurred in both groups but was significantly more pronounced in patients with ALD. These results correlate well with the modified Ishak scoring system. However, in patients with cirrhosis (stage 6) with chronic hepatitis C the AA of fibrosis varied between 20% and 74%. The diameter of fat globules was significantly lower in patients with hepatitis C (p = 0.00002) than the ALD group (mean (SD): 14.44 (3.45) v 18.4 (3.32)). Microglobules were more frequent in patients with chronic hepatitis C than in patients with ALD

  1. Limitation of liver function tests in metastatic carcinoid tumors

    SciTech Connect

    Moinuddin, M.; Dean, P.; Vander Zwaag, R.; Dragutsky, M.

    1987-04-01

    To evaluate the utility of liver function tests (LFT) as indicators of metastatic carcinoid tumors, a retrospective study was performed. The LFT results of 17 patients with carcinoid tumors metastatic to the liver were compared with 17 patients with other malignant tumors. In the noncarcinoid group, 82.4% of the patients had elevated alkaline phosphatase (AP) or gamma glutamyl transpeptidase (GGTP), whereas only 28.6% of carcinoid patients had abnormal enzymes. The medians of all LFT values were significantly higher in noncarcinoid patients than in the carcinoid group, except for glutamic pyruvic transaminase (SGPT). Our data indicate that LFT are helpful in screening for liver metastases in patients with noncarcinoid tumors, but are unreliable in carcinoid tumors. Imaging tests should be used to rule out liver metastases in carcinoid tumors, irrespective of LFT results.

  2. Impaired liver function attenuates liver regeneration and hypertrophy after portal vein embolization

    PubMed Central

    Kageyama, Yumiko; Kokudo, Takashi; Amikura, Katsumi; Miyazaki, Yoshihiro; Takahashi, Amane; Sakamoto, Hirohiko

    2016-01-01

    AIM To clarify the clinical factors associated with liver regeneration after major hepatectomy and the hypertrophic rate after portal vein embolization (PVE). METHODS A total of 63 patients who underwent major hepatectomy and 13 patients who underwent PVE in a tertiary care hospital between January 2012 and August 2015 were included in the analysis. We calculated the remnant liver volume following hepatectomy using contrast-enhanced computed tomography (CT) performed before and approximately 3-6 mo after hepatectomy. Furthermore, we calculated the liver volume using CT performed 2-4 wk after PVE. Preoperative patient characteristics and laboratory data were analyzed to identify factors affecting postoperative liver regeneration or hypertrophy rate following PVE. RESULTS The remnant liver volume/total liver volume ratio negatively correlated with the liver regeneration rate after hepatectomy (ρ = -0.850, P < 0.001). The regeneration rate was significantly lower in patients with an indocyanine green retention rate at 15 min (ICG-R15) of ≥ 20% in the right hepatectomy group but not in the left hepatectomy group. The hypertrophic rate after PVE positively correlated with the regeneration rate after hepatectomy (ρ = 0.648, P = 0.017). In addition, the hypertrophic rate after PVE was significantly lower in patients with an ICG-R15 ≥ 20% and a serum total bilirubin ≥ 1.5 mg/dL. CONCLUSION The regeneration rate after major hepatectomy correlated with hypertrophic rate after PVE. Both of them were attenuated in the presence of impaired liver function. PMID:27729956

  3. Multifeature analysis of an ultrasound quantitative diagnostic index for classifying nonalcoholic fatty liver disease

    PubMed Central

    Liao, Yin-Yin; Yang, Kuen-Cheh; Lee, Ming-Ju; Huang, Kuo-Chin; Chen, Jin-De; Yeh, Chih-Kuang

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome. This study applied an integrated analysis based on texture, backscattering, and attenuation features in ultrasound imaging with the aim of assessing the severity of NAFLD. Ultrasound radiofrequency data obtained from 394 clinical cases were analyzed to extract three texture features (autocorrelation, sum average, and sum variance), the signal-to-noise ratio (SNR), and the slope of the center-frequency downshift (CFDS slope). The texture, SNR, and CFDS slope were combined to produce a quantitative diagnostic index (QDI) that ranged from 0 to 6. We trained the QDI using training data and then applied it to test data to assess its utility. In training data, the areas (AUCs) under the receiver operating characteristic curves for NAFLD and severe NAFLD were 0.81 and 0.84, respectively. In test data, the AUCs were 0.73 and 0.81 for NAFLD and severe NAFLD, respectively. The QDI was able to distinguish severe NAFLD and a normal liver from mild NAFLD, and it was significantly correlated with metabolic factors. This study explored the potential of using the QDI to supply information on different physical characteristics of liver tissues for advancing the ability to grade NAFLD. PMID:27734972

  4. In vivo quantitation of the rat liver's ability to eliminate endotoxin from portal vein blood

    SciTech Connect

    Yamaguchi, Y.; Yamaguchi, K.; Babb, J.L.; Gans, H.

    1982-12-01

    The in vivo uptake of endotoxin by the liver from portal vein blood was assessed during a single passage through the liver. /sup 51/Cr labeled and unlabeled endotoxin were infused in different amounts into the femoral vein of three groups of lead-sensitized rats: a nonoperated, a sham-operated, and a surgically created reversed Eck fistula (REF) group. Whereas in the former two the infused endotoxin encounters the lung as the first filter organ, the liver performs this function in the latter experimental model. The mortality rates observed in control and sham-operated, lead-sensitized rats were found to correlate closely and reproducibly to the degree of endotoxemia. This assay was then applied to determine the amount of endotoxin eliminated by the liver by establishing, in the REF rat, the amounts of endotoxin that escaped hepatic clearance. The capacity of the liver to eliminate endotoxin from portal vein blood during a single passage increases as the portal vein endotoxin level rises; it approaches a maximum, suggesting that endotoxin's interaction with the Kupffer cells conforms to classical saturation kinetics. A Lineweaver-Burk plot prepared from these data indicates that the maximal in vivo capacity of the liver to remove endotoxin from portal vein blood approximates 1.5 micrograms/gm liver/hr. Data obtained with the use of radiolabeled endotoxin corroborate the information obtained with the bioassay technique. Endotoxin eliminated by the Kupffer cells in these quantities is slowly disintegrated; 4 hr after termination of the endotoxin infusion, less than 4% of the radiolabel is found in the urine and none in the bile. These observations indicate that the Kupffer cell's functional capacity to sequester and detoxify endotoxin is extensive and far exceeds the requirements imposed by physiological and most pathological conditions.

  5. Quantitative computed tomography of the liver in juvenile green sea turtles (Chelonia mydas).

    PubMed

    Bonelli, Marília de Albuquerque; de Oliveira, Daniel Capucho; Costa, Lorena Adão Vescovi Séllos; Forattini, Jannine Garcia; Júnior, João Luiz Rossi; Leite, Flaviana Lima Guião; Costa, Fabiano Séllos

    2013-06-01

    Quantitative computed tomography (QCT) is a highly sensitive, applicable technique for determining the x-ray attenuation of organs. This technique reveals great precision in the detection of alterations in the x-ray attenuation of hepatic parenchyma, although the lack of studies establishing normal values limits its application in wild animals. The objective of this study was to establish mean hepatic attenuation values in four healthy juvenile sea turtles (Chelonia mydas) using QCT. Helical computed tomography scans were performed and regions of interest selected in the liver after multi-planar reconstruction images were obtained. The mean attenuation value for the hepatic parenchyma in these four turtles was 60.09 +/- 5.3 standard deviation Hounsfield units. Determining normal x-ray attenuation values of the liver increases knowledge of the computed tomographic anatomy of this species and may be useful in the investigation of hepatic diseases.

  6. Functional tissue engineering of the liver and islets.

    PubMed

    Ohashi, Kazuo; Okano, Teruo

    2014-01-01

    Cell-based therapies by using hepatocytes and islets have recently been evaluated as a new therapeutic modality for patients with many forms of liver diseases and insulin-deficient diabetes mellitus. In most of the recently conducted clinical trials, cells have been delivered into liver vasculatures by infusing them through the portal circulation. More recently, tissue engineering-based approaches have spurred significant interests, using hepatocytes and islets in which small but functional new tissues would be created in vivo. Under circumstances in which a higher level of cell engraftment could be obtained, these approaches could provide therapeutic effects. Considerable efforts have been given to sustaining engineered tissues and maintaining their therapeutic effects. This review highlights several strategies that can achieve a higher level of cell survival for creating new functional liver and islet tissues.

  7. Assessment of thyroid and gonadal function in liver diseases

    PubMed Central

    Kharb, Sandeep; Garg, M. K.; Puri, Pankaj; Brar, Karninder S.; Pandit, Aditi; Srivastava, Sharad

    2015-01-01

    Introduction: Liver is involved with the synthesis of carrier proteins and metabolism of various hormones and liver diseases may, therefore, be associated with various endocrine disturbances. This study was conducted to assess thyroid and gonadal function in subjects with acute hepatitis (AH), chronic liver disease (CLD), and those who had undergone liver transplantation (LT). Materials and Methods: Patients with AH, CLD with Child-Pugh stage A (CLD-1) and Child-Pugh stage B or C (CLD-2), and LT seen at our tertiary level hospital were assessed clinically, biochemically, and for thyroid and gonadal functions besides 25 healthy controls. Results: Thyroid dysfunction and hypogonadism were present in 14 (16%) and 24 (28%) patients with liver diseases respectively. Among thyroid dysfunction, the commonest was sick euthyroid syndrome six (7%), followed by subclinical hypothyroidism in three patients (3.5%), subclinical hyperthyroidism and thyrotoxicosis in two patients each (2.3%) and overt hypothyroidism in one patient. Among patients with LT and AH groups, the only abnormality was significantly lower total T3 compared with healthy controls. The CLD2 group had significantly lower levels of all thyroid hormones compared with controls and CLD1 group. Hypogonadism was commonest in patients with CLD-2 (14; 50%) followed by LT (3; 33%), CLD-1 (4; 20%), and AH (3; 14%). Hypogonadism was predicted by older age, lower levels of serum albumin, total cholesterol, and triglycerides and higher levels of plasma glucose, serum bilirubin, aspartate transaminases, and international normalized ratio. Gonadal functions showed recovery following LT. Conclusions: Thyroid dysfunction and hypogonadism form an important part of the spectrum of acute and CLD, and patients with LT. Deterioration of synthetic functions of liver disease predicts presence of hypogonadism. PMID:25593833

  8. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues.

    PubMed

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health.Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper,we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameter scan provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  9. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues

    NASA Astrophysics Data System (ADS)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health. Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper, we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameters can provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  10. Evidence for regulatory genes on mouse chromosome 7 that affect the quantitative expression of proteins in the fetal and newborn liver.

    PubMed Central

    Giometti, C S; Gemmell, M A; Taylor, J; Tollaksen, S L; Angeletti, R; Gluecksohn-Waelsch, S

    1992-01-01

    A series of deletions around the albino locus on mouse chromosome 7 is believed to include one or more regulatory genes that control the activities of a cluster of liver enzymes. To further characterize the functions of this region of the mouse genome, we have used quantitative two-dimensional electrophoresis to analyze the effects of two of these deletions, c3H and c14CoS, on the expression of liver proteins. More than 400 distinct protein gene products were quantitated in livers from fetal and newborn wild-type homozygous (cch/cch), heterozygous (cch/c3H or cch/c14CoS), and deletion homozygous (c3H/c3H or c14CoS/c14CoS) mice. Livers of fetal and newborn c3H heterozygotes and homozygous wild-type littermates produced qualitatively identical protein patterns after two-dimensional electrophoresis. In livers of c3H homozygous fetuses, however, abnormal amounts (either increased or decreased relative to homozygous wild-type and heterozygous littermates) of 29 proteins were found. Twenty-eight of these 29 protein anomalies were also found in livers of newborn c3H homozygotes. Livers of fetal and newborn mice homozygous for the c14CoS deletion, which overlaps the c3H deletion and produces a similar phenotype, expressed normal amounts of these proteins. One of the 29 proteins (MSN807) has an amino-terminal sequence similar to a 23-kDa translationally controlled protein abundant in mouse erythroleukemia and sarcoma-180 cells. These results suggest that normal chromosome 7 contains genes, located within the region of the c3H but not the c14CoS deletion, that regulate the abundance of specific proteins in the liver. These proteins cannot be related to the phenotypic alterations shared by the c3H and c14CoS deletions. Images PMID:1549608

  11. Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine.

    PubMed

    Chang, C C; Sakashita, N; Ornvold, K; Lee, O; Chang, E T; Dong, R; Lin, S; Lee, C Y; Strom, S C; Kashyap, R; Fung, J J; Farese, R V; Patoiseau, J F; Delhon, A; Chang, T Y

    2000-09-08

    By using specific anti-ACAT-1 antibodies in immunodepletion studies, we previously found that ACAT-1, a 50-kDa protein, plays a major catalytic role in the adult human liver, adrenal glands, macrophages, and kidneys but not in the intestine. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity in the intestine may be largely derived from a different ACAT protein. To test this hypothesis, we produced specific polyclonal anti-ACAT-2 antibodies that quantitatively immunodepleted human ACAT-2, a 46-kDa protein expressed in Chinese hamster ovary cells. In hepatocyte-like HepG2 cells, ACAT-1 comprises 85-90% of the total ACAT activity, with the remainder attributed to ACAT-2. In adult intestines, most of the ACAT activity can be immunodepleted by anti-ACAT-2. ACAT-1 and ACAT-2 do not form hetero-oligomeric complexes. In differentiating intestinal enterocyte-like Caco-2 cells, ACAT-2 protein content increases by 5-10-fold in 6 days, whereas ACAT-1 protein content remains relatively constant. In the small intestine, ACAT-2 is concentrated at the apices of the villi, whereas ACAT-1 is uniformly distributed along the villus-crypt axis. In the human liver, ACAT-1 is present in both fetal and adult hepatocytes. In contrast, ACAT-2 is evident in fetal but not adult hepatocytes. Our results collectively suggest that in humans, ACAT-2 performs significant catalytic roles in the fetal liver and in intestinal enterocytes.

  12. Extraction and quantitation of total cholesterol, dolichol and dolichyl phosphate from mammalian liver

    SciTech Connect

    Crick, D.C.; Carroll, K.K.

    1987-12-01

    A procedure is described for the determination of total cholesterol, dolichol and dolichyl phosphate (Dol-P) in mammalian liver. It is based on extraction of these compounds into diethyl ether after alkaline saponification of the tissue. Extractability is affected by the length of saponification and concentration of potassium hydroxide (KOH) in the saponification mixture. After extraction, total cholesterol and dolichol are quantitated directly by reverse-phase high pressure liquid chromatography (HPLC) on C18. Dol-P requires further purification before quantitation by HPLC, this is accomplished by chromatography on silicic acid. These methods gave recoveries of over 90% for cholesterol and dolichol and about 60% for Dol-P, using (4-/sup 14/C)cholesterol, a polyprenol containing 15 isoprene units, and (1-/sup 14/C)Dol-P as recovery standards. Concentrations of total cholesterol, dolichol and Dol-P in livers from one month-old-CBA mice were found to be 5.7 +/- 0.7 mg/g, 66.3 +/- 1.2 micrograms/g and 3.7 +/- 0.3 micrograms/g, respectively.

  13. Bioreactor Technologies to Support Liver Function In Vitro

    PubMed Central

    Ebrahimkhani, Mohammad R; Neiman, Jaclyn A Shepard; Raredon, Micah Sam B; Hughes, David J; Griffith, Linda G

    2014-01-01

    Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drive efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models. PMID:24607703

  14. Quantitation of rat liver xanthine oxidase by radioimmunoassay. A mechanism for sex-specific differences

    SciTech Connect

    Decker, D.E.; Levinson, D.J.

    1982-03-01

    To further delineate the mechanism responsible for the differences in xanthine oxidase activity in male and female Sprague-Dawley rats, a sensitive and specific radioimmunoassay (RIA) was developed for the measurement of hepatic xanthine oxidase. The RIA could detect as little as 5 mg of liver enzyme. Specificity of the RIA was confirmed by 1) Ouchterlony double immuno-diffusion in which a single precipitin band exhibited xanthine oxidase activity, when crude liver homogenate and an enzyme-specific stain were used; 2) parallelism between purified 125I-labeled xanthine oxidase and serial dilutions of crude liver homogenate; 3) a linear correlation between xanthine oxidase activity and the level of enzyme protein; and 4) a single protein band coincident with purified xanthine oxidase, when an immunoprecipitate prepared from antisera and crude liver homogenate was analyzed on sodium dodecyl sulfate (SDS) polyacrylamide gels. Whether xanthine oxidase activity was assayed in the absence of nicotinamide adenine dinucleotide (NAD+) (oxidase form) or in the presence of NAD+ (dehydrogenase), male values were consistently higher, and both forms of the enzyme correlated significantly with each other. When purified to homogeneity, neither form of the enzyme was appreciably affected by 17 beta-estradiol or testosterone propionate. When the RIA was employed, levels of hepatic xanthine oxidase were significantly greater in male than in female rats. We concluded from these data that increased xanthine oxidase activity in the male corresponds to a greater quantitative complement of xanthine oxidase protein. Furthermore, lower xanthine oxidase activity in the female cannot be explained by immunologically cross-reactive material without enzyme activity nor by a direct sex-steroid enzyme interaction.

  15. Quantitative assay and subcellular distribution of enzymes acting on dolichyl phosphate in rat liver

    PubMed Central

    Ravoet, A; Amar-Costesec, A; Godelaine, D; Beaufay, H

    1981-01-01

    To establish on a quantitative basis the subcellular distribution of the enzymes that glycosylate dolichyl phosphate in rat liver, preliminary kinetic studies on the transfer of mannose, glucose, and N-acetylglucosamine-1-phosphate from the respective (14)C- labeled nucleotide sugars to exogenous dolichyl phosphate were conducted in liver microsomes. Mannosyltransferase, glucosyltransferase, and, to a lesser extent, N- acetylglucosamine-phosphotransferase were found to be very unstable at 37 degrees C in the presence of Triton X-100, which was nevertheless required to disperse the membranes and the lipid acceptor in the aqueous reaction medium. The enzymes became fairly stable in the range of 10-17 degrees C and the reactions then proceeded at a constant velocity for at least 15 min. Conditions under which the reaction products are formed in amount proportional to that of microsomes added are described. For N- acetylglucosaminephosphotransferase it was necessary to supplement the incubation medium with microsomal lipids. Subsequently, liver homogenates were fractionated by differential centrifugation, and the microsome fraction, which contained the bulk of the enzymes glycosylating dolichyl phosphate, was analyzed by isopycnic centrifugation in a sucrose gradient without any previous treatment, or after addition of digitonin. The centrifugation behavior of these enzymes was compared to that of a number of reference enzymes for the endoplasmic reticulum, the golgi complex, the plasma membranes, and mitochondria. It was very simily to that of enzymes of the endoplasmic reticulum, especially glucose-6-phosphatase. Subcellular preparations enriched in golgi complex elements, plasma membranes, outer membranes of mitochondira, or mitoplasts showed for the transferases acting on dolichyl phosphate relative activities similar to that of glucose- 6-phosphatase. It is concluded that glycosylations of dolichyl phosphate into mannose, glucose, and N-acetylglucosamine-1

  16. Splenectomy Improves Hemostatic and Liver Functions in Hepatosplenic Schistosomiasis Mansoni

    PubMed Central

    Leite, Luiz Arthur Calheiros; Pimenta Filho, Adenor Almeida; Ferreira, Rita de Cássia dos Santos; da Fonseca, Caíque Silveira Martins; dos Santos, Bianka Santana; Montenegro, Silvia Maria Lucena; Lopes, Edmundo Pessoa de Almeida; Domingues, Ana Lúcia Coutinho; Owen, James Stuart; Lima, Vera Lucia de Menezes

    2015-01-01

    Background Schistosomiasis mansoni is a chronic liver disease, in which some patients (5–10%) progress to the most severe form, hepatosplenic schistosomiasis. This form is associated with portal hypertension and splenomegaly, and often episodes of gastrointestinal bleeding, even with liver function preserved. Splenectomy is a validated procedure to reduce portal hypertension following digestive bleeding. Here, we evaluate beneficial effects of splenectomy on blood coagulation factors and liver function tests in hepatosplenic schistosomiasis mansoni compared to non-operated patients. Methodology/Principal Findings Forty-five patients who had undergone splenectomy surgery were assessed by laboratory analyses and ultrasound examination and compared to a non-operated group (n = 55). Blood samples were obtained for liver function tests, platelet count and prothrombin time. Coagulation factors (II, VII, VIII, IX and X), protein C and antithrombin IIa, plasminogen activator inhibitor-1 were measured by routine photometric, chromogenic or enzyme-linked immunosorbent assays, while hyperfibrinolysis was defined by plasminogen activator inhibitor-1 levels. Both groups had similar age, gender and pattern of periportal fibrosis. Splenectomized patients showed significant reductions in portal vein diameter, alkaline phosphatase and bilirubin levels compared to non-operated patients, while for coagulation factors there were significant improvement in prothrombin, partial thromboplastin times and higher levels of factor VII, VIII, IX, X, protein C and plasminogen activator inhibitor-1. Conclusion/Significance This study shows that the decrease of flow pressure in portal circulation after splenectomy restores the capacity of hepatocyte synthesis, especially on the factor VII and protein C levels, and these findings suggest that portal hypertension in patients with hepatosplenic schistosomiasis influences liver functioning and the blood coagulation status. PMID:26267788

  17. Quantitative temporal analysis of /sup 99m/Technetium p-isopropyl-iminodiacetic acid (PIPIDA) as a measure of hepatic function in health and disease

    SciTech Connect

    Joshi, S.N.; George, E.A.; Perrillo, R.P.

    1981-01-01

    Excretory liver function was analyzed in 10 healthy volunteers and 28 subjects with acute or chronic liver injury following intravenous administration of /sup 99m/technetium p-isopropyl iminodiacetic acid. Hepatobiliary transit of this agent was quantitated at 5-min intervals for a total of 60 min. Indices of total liver activity, liver cell uptake, liver parenchymal clearance, and bile duct clearance of /sup 99m/technetium p-isopropyl iminodiacetic acid were calculated from time--activity curves over heart, liver, extrahepatic bile ducts, and gallbladder. Seven subjects with acute viral hepatitis, 15 with extrahepatic biliary obstruction, and 6 with intrahepatic cholestasis were evaluated. Compared with healthy volunteers, a significant (p less than 0.0001) reduction in total liver activity and liver parenchymal clearance was demonstrated in all patient groups. Major resolution in all liver-derived indices, particularly total liver activity, occurred during convalescence from hepatitis and after biliary drainage. Nonmeasurable bile duct clearance always indicated a diagnosis of extrahepatic obstruction in cholestatic subjects, and this index normalized in subjects following biliary drainage. Whereas visual assessment of /sup 99m/technetium p-isopropyl iminodiacetic acid scans provided limited, useful information about the functional status of the liver, quantitative temporal analysis proved to be a much more effective technique.

  18. Function of Autophagy in Nonalcoholic Fatty Liver Disease.

    PubMed

    Czaja, Mark J

    2016-05-01

    Autophagy is a lysosomal degradative pathway that functions to promote cell survival by supplying energy in times of stress or by removing damaged organelles and proteins after injury. The involvement of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) was first suggested by the finding that this pathway mediates the breakdown of intracellular lipids in hepatocytes and therefore may regulate the development of hepatic steatosis. Subsequent studies have demonstrated additional critical functions for autophagy in hepatocytes and other hepatic cell types such as macrophages and stellate cells that regulate insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. These findings suggest a number of possible mechanistic roles for autophagy in the development of NAFLD and progression to NASH and its complications. The functions of autophagy in the liver, together with findings of decreased hepatic autophagy in association with conditions that predispose to NAFLD such as obesity and aging, suggest that autophagy may be a novel therapeutic target in this disease.

  19. Structural and functional hepatocyte polarity and liver disease

    PubMed Central

    Gissen, Paul; Arias, Irwin M.

    2015-01-01

    Summary Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases. PMID:26116792

  20. Albumin Binding Function: The Potential Earliest Indicator for Liver Function Damage

    PubMed Central

    Ge, Penglei; Yang, Huayu; Lu, Jingfen; Liao, Wenjun; Du, Shunda; Xu, Yingli; Xu, Haifeng; Lu, Xin; Sang, Xinting; Zhong, Shouxian; Huang, Jiefu

    2016-01-01

    Background. Currently there is no indicator that can evaluate actual liver lesion for early stages of viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and cirrhosis. Aim of this study was to investigate if albumin binding function could better reflect liver function in these liver diseases. Methods. An observational study was performed on 193 patients with early NAFLD, viral hepatitis, and cirrhosis. Cirrhosis patients were separated according to Child-Pugh score into A, B, and C subgroup. Albumin metal ion binding capacity (Ischemia-modified albumin transformed, IMAT) and fatty acid binding capacity (total binding sites, TBS) were detected. Results. Both IMAT and TBS were significantly decreased in patients with NAFLD and early hepatitis. In hepatitis group, they declined prior to changes of liver enzymes. IMAT was significantly higher in cirrhosis Child-Pugh class A group than hepatitis patients and decreased in Child-Pugh class B and class C patients. Both IMAT/albumin and TBS/albumin decreased significantly in hepatitis and NAFLD group patients. Conclusions. This is the first study to discover changes of albumin metal ion and fatty acid binding capacities prior to conventional biomarkers for liver damage in early stage of liver diseases. They may become potential earliest sensitive indicators for liver function evaluation. PMID:28101103

  1. MR Prediction of Liver Function and Pathology Using Gd-EOB-DTPA: Effect of Liver Volume Consideration

    PubMed Central

    Shimamoto, Dai; Nishie, Akihiro; Asayama, Yoshiki; Ushijima, Yasuhiro; Takayama, Yukihisa; Fujita, Nobuhiro; Shirabe, Ken; Hida, Tomoyuki; Kubo, Yuichiro; Honda, Hiroshi

    2015-01-01

    Purpose. To evaluate whether the diagnostic performance of Gd-EOB-DTPA-enhanced MRI in evaluating liver function and pathology is improved by considering liver volume (LV). Methods. This retrospective study included 104 patients who underwent Gd-EOB-DTPA-enhanced MRI before liver surgery. For each patient, using the precontrast and hepatobiliary phase images, we calculated the increase rate of the liver-to-spleen signal intensity ratio (LSR), that is, the “ΔLSR,” and the increase rate of the liver-to-muscle signal intensity ratio (LMR), that is, the “ΔLMR.” ΔLSR × LV and ΔLMR × LV were also calculated. The correlation of each MR parameter with liver function data or liver pathology was assessed. The correlation coefficients were compared between ΔLSR (ΔLMR) and ΔLSR (ΔLMR) × LV. Results. The correlation coefficient between ΔLSR (ΔLMR) × LV and cholinesterase was significantly higher than that between ΔLSR (ΔLMR) and cholinesterase. The correlation coefficient between ΔLSR (ΔLMR) × LV and the degree of fibrosis or necroinflammatory activity was significantly lower than that between ΔLSR (ΔLMR) and the degree of fibrosis or necroinflammatory activity. Conclusion. The inclusion of liver volume may improve Gd-EOB-DTPA-based predictions of liver function, but not in predictions of liver pathology. PMID:26609519

  2. Quantitative analysis of ultrasonic images of fibrotic liver using co-occurrence matrix based on multi-Rayleigh model

    NASA Astrophysics Data System (ADS)

    Isono, Hiroshi; Hirata, Shinnosuke; Hachiya, Hiroyuki

    2015-07-01

    In medical ultrasonic images of liver disease, a texture with a speckle pattern indicates a microscopic structure such as nodules surrounded by fibrous tissues in hepatitis or cirrhosis. We have been applying texture analysis based on a co-occurrence matrix to ultrasonic images of fibrotic liver for quantitative tissue characterization. A co-occurrence matrix consists of the probability distribution of brightness of pixel pairs specified with spatial parameters and gives new information on liver disease. Ultrasonic images of different types of fibrotic liver were simulated and the texture-feature contrast was calculated to quantify the co-occurrence matrices generated from the images. The results show that the contrast converges with a value that can be theoretically estimated using a multi-Rayleigh model of echo signal amplitude distribution. We also found that the contrast value increases as liver fibrosis progresses and fluctuates depending on the size of fibrotic structure.

  3. Microporous membrane-based liver tissue engineering for the reconstruction of three-dimensional functional liver tissues in vitro.

    PubMed

    Kasuya, Junichi; Tanishita, Kazuo

    2012-01-01

    To meet the increasing demand for liver tissue engineering, various three-dimensional (3D) liver cell culture techniques have been developed. Nevertheless, conventional liver cell culture techniques involving the suspending cells in extracellular matrix (ECM) components and the seeding of cells into 3D biodegradable scaffolds have an intrinsic shortcoming, low cell-scaffold ratios. We have developed a microporous membrane-based liver cell culture technique. Cell behaviors and tissue organization can be controlled by membrane geometry, and cell-dense thick tissues can be reconstructed by layering cells cultured on biodegradable microporous membranes. Applications extend from liver parenchymal cell monoculture to multi-cell type cultures for the reconstruction of 3D functional liver tissue. This review focuses on the expanding role for microporous membranes in liver tissue engineering, primarily from our research.

  4. A novel cause for abnormal liver function tests in pregnancy and the puerperium: non-alcoholic fatty liver disease.

    PubMed

    Page, L M; Girling, J C

    2011-11-01

    Non-alcoholic fatty liver disease (NAFLD) is the commonest liver disease in the western world, but has never been reported in pregnancy before. We suggest that NAFLD should also be considered as a cause for abnormal liver function tests during pregnancy. As NAFLD is driven by insulin resistance, it is biologically plausible that pregnancy may reveal previously subclinical disease. Obstetricians have a vital role in optimising maternal health during and after pregnancy and therefore we need to include NAFLD in the differential diagnosis for abnormal liver function tests and recommend lifestyle modifications that may prevent progression to cirrhosis and hepatocellular carcinoma.

  5. Quantitative assessment of fibrinogen cross-linking by epsilon aminocaproic acid in patients with end-stage liver disease.

    PubMed

    Quach, Thien; Tippens, Melissa; Szlam, Fania; Van Dyke, Rebecca; Levy, Jerrold H; Csete, Marie

    2004-01-01

    Analysis of the effectiveness of antifibrinolytic therapy for liver transplant recipients is hampered by lack of quantitative assays for assessing drug effects. We adapted chemical engineering tools used in polymerization studies to quantify fibrinogen cross-linking by plasma from liver transplant patients obtained before and after epsilon aminocaproic acid (EACA) therapy. A target fluorescein isothiocyanate-fibrinogen (FITC-fibrinogen) molecule was constructed; it fluoresces in a quantifiable pattern when in solution, and undergoes cross-linking in the presence of plasmin inhibitors. Cross-linking quenches the fluorescent signal, and the quenching is a quantifiable endpoint. Thus fluorescence from this reporter molecule can be used to assess functional improvement in fibrinogen cross-linking as a result of antifibrinolytic therapies, and it is sensitive to picomolar amounts of plasmin inhibitors and activators. Cross-linking of FITC-fibrinogen by patient plasma, before and after EACA therapy, was assessed using fluorescence spectrometry. Fluorescence patterns from FITC-fibrinogen indicated no significant cross-linking of the target fibrinogen as a consequence of EACA in posttreatment plasma. When the fibrinogen-FITC target was assayed without plasma in the presence of EACA at concentrations that bracket therapeutic levels (100 and 400 microg/ml), significant fluorescence quenching (target FITC-fibrinogen cross-linking) was achieved. These results suggest that fibrinogen-FITC fluorescence is sensitive enough to detect EACA activity in clinically relevant ranges, but that EACA given in usual doses is insufficient to promote fibrinogen cross-linking in patients with end-stage liver disease.

  6. Atherosclerosis and Liver Function Tests in Coronary Angiography Patients

    PubMed Central

    Doganer, YC; Rohrer, JE; Aydogan, U; Agerter, DC; Cayci, T; Barcin, C

    2015-01-01

    ABSTRACT Objective: Elevated aminotransferase levels indicating liver function, even in the normal range, have attracted great concern as potential novel markers of cardiovascular risk assessment. We hypothesized the possibility that liver function test variations in the normal range might be meaningfully associated to coronary artery disease (CAD). Method: Eighty-eight patients were randomly selected from those who underwent coronary angiography from June 2010 to June 2011 after applying to the outpatient cardiology clinic in Gulhane Military Medical Academy. According to the results of angiographies, patients were classified into three groups as normal, non-critical (< 50% involvement in coronaries), and critical (≥ 50% involvement in coronaries). In addition to angiographic intervention, measurements of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, albumin and the other serum parameters were performed in all patients. Results: The patient groups of CAD were balanced (28 critical cases, 30 non-critical cases and 30 normal cases). Mean age was 51.93 ± 9.3 (range 32–65) years and 19.3 per cent (n = 17) were females. Multiple linear regression analysis of all three liver function tests explained a significant portion of the variance, but adjusted r-squares were small (AST = 0.174, ALT = 0.242, albumin = 0.124). Albumin was significantly higher for patients with critical CAD than for patients with no CAD (beta = 3.205, p = 0.002). Non-critical CAD was not significantly different from no CAD for any of the dependent variables. Mean AST was significantly higher for patients taking aspirin (beta = 0.218, p = 0.049), as was mean ALT (beta = 0.264, p = 0.015). Conclusion: Alanine aminotransferase and AST may not be associated with angiographically determined coronary atherosclerosis. Albumin may be more sensitive to demonstrate the burden of atherosclerosis. These results indicate that the association between the liver

  7. Quantitative comparison of transient elastography (TE), shear wave elastography (SWE) and liver biopsy results of patients with chronic liver disease.

    PubMed

    Kim, Hyun-Jin; Lee, Hae-Kag; Cho, Jae-Hwan; Yang, Han-Jun

    2015-08-01

    [Purpose] The purpose of this study was to carry out a comparitive analysis of hepatic fibrosis results of the liver hardness of patients with chronic liver disease as measured by elastography (TE), shear wave elastography (SWE), and liver biopsy. [Subjects and Methods] This study was a retrospective analysis of 304 patients who underwent SWE and TE before and after liver biopsy, taken from among patients who had been checked for liver fibrosis by liver biopsy between August 2013 and August 2014. We used receiver operating characteristic (ROC) curve to prove the diagnostic significance of liver stiffness, and then analyzed the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SWE and TE, as well as the kappa index through cross-analysis of SWE, TE, and liver biopsy. [Results] For liver hardness, the sensitivity of SWE was 84.39%, the specificity of SWE was 97.92%, the accuracy of SWE was 87.33%, the positive predictive value of SWE was 99.32%, and the negative predictive value of SWE was 63.51%. The sensitivity of TE was 94.80%, the specificity of TE was 77.08%, the accuracy of TE was 90.95%, the positive predictive value of TE was 93.97%, and the negative predictive value of TE was 80.43%. [Conclusion] It is our opinion that SWE and TE are non-invasive methods that are more effective than the invasive methods used for diagnosing liver hardness. Invasive methods cover only a section of liver tissue, and are more likely to cause side effects during biopsy.

  8. Basic investigation on acoustic velocity change imaging method for quantitative assessment of fat content in human liver

    NASA Astrophysics Data System (ADS)

    Mano, Kazune; Tanigawa, Shohei; Hori, Makoto; Yokota, Daiki; Wada, Kenji; Matsunaka, Toshiyuki; Morikawa, Hiroyasu; Horinaka, Hiromichi

    2016-07-01

    Fatty liver is a disease caused by the excess accumulation of fat in the human liver. The early diagnosis of fatty liver is very important, because fatty liver is the major marker linked to metabolic syndrome. We already proposed the ultrasonic velocity change imaging method to diagnose fatty liver by using the fact that the temperature dependence of ultrasonic velocity is different in water and in fat. For the diagonosis of a fatty liver stage, we attempted a feasibility study of the quantitative assessment of the fat content in the human liver using our ultrasonic velocity change imaging method. Experimental results showed that the fat content in the tissue mimic phantom containing lard was determined by its ultrasonic velocity change in the flat temperature region formed by a circular warming ultrasonic transducer with an acoustic lens having an appropriate focal length. By considering the results of our simulation using a thermal diffusion equation, we determined whether this method could be applied to fatty liver assessment under the condition that the tissue had the thermal relaxation effect caused by blood flow.

  9. Redox Control of Liver Function in Health and Disease

    PubMed Central

    Marí, Montserrat; Colell, Anna; Morales, Albert; von Montfort, Claudia; Garcia-Ruiz, Carmen

    2010-01-01

    Abstract Reactive oxygen species (ROS), a heterogeneous population of biologically active intermediates, are generated as by-products of the aerobic metabolism and exhibit a dual role in biology. When produced in controlled conditions and in limited quantities, ROS may function as signaling intermediates, contributing to critical cellular functions such as proliferation, differentiation, and cell survival. However, ROS overgeneration and, particularly, the formation of specific reactive species, inflicts cell death and tissue damage by targeting vital cellular components such as DNA, lipids, and proteins, thus arising as key players in disease pathogenesis. Given the predominant role of hepatocytes in biotransformation and metabolism of xenobiotics, ROS production constitutes an important burden in liver physiology and pathophysiology and hence in the progression of liver diseases. Despite the recognized role of ROS in disease pathogenesis, the efficacy of antioxidants as therapeutics has been limited. A better understanding of the mechanisms, nature, and location of ROS generation, as well as the optimization of cellular defense strategies, may pave the way for a brighter future for antioxidants and ROS scavengers in the therapy of liver diseases. Antioxid. Redox Signal. 12, 1295—1331. PMID:19803748

  10. Quantitation of human MAO A and B in liver, intestine and placenta: Reassessment of activity

    SciTech Connect

    Riley, L.A.

    1989-01-01

    Monoamine oxidases (MAO) oxidize a variety of exogenous and endogenous amines including neurotransmitters such as serotonin, dopamine and norepinephrine as well as the potent dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). The two forms of MAO (A and B) differ in molecular weight and inhibitor selectivity, and are differentially expressed in the nervous system and many other tissues. Although some substrates are preferentially oxidized by one form of MAO, substrates that can be oxidized by only one MAO form have not been reported. How well each MAO oxidizes various substrates has not been thoroughly characterized because of difficulties in separating and quantitating MAO A and B active sites. By immunoblotting SDS-polyacrylamide gels of mitochondrial extracts with monoclonal antibodies specific for each form of MAO, MAO B protein was detected in intestine and placenta, tissues that have been reported to contain MAO A activity. An improved procedure was developed for quantitating the ratio and amounts of MAO A and B active sites, using the ligand ({sup 3}H)-pargyline to label MAO and specific monoclonal antibodies to separate MAO A from B. Data from liver, placenta and platelets were used to re-evaluate the molecular activity of both MAO A and B for six commonly studied substrates.

  11. Functional state of rat liver RNA polymerase IA and IB.

    PubMed

    Zoncheddu, A; Accomando, R; Pertica, M; Orunesu, M

    1979-01-01

    Phosphocellulose chromatography has been employed to characterize RNA polymerase I present in two different functional states in rat liver cells. The actively transcribing enzyme solubilized from nuclei appears to belong both to the IA and IB classes, whereas the non-transcribing enzyme present in the cytoplasmic fraction has been found to belong only to the IA class. Indirect and direct evidence indicates, however, that in isolated nuclei only the IB form is to be regarded as the physiological form of the enzyme, the IA form arising as a procedural artefact during the extraction process. It may, therefore, be concluded that rat liver IA and IB RNA polymerase are to be strictly regarded as the non-transcribing and transcribing form of the enzyme, respectively.

  12. Overnight salivary caffeine clearance: a liver function test suitable for routine use.

    PubMed

    Jost, G; Wahlländer, A; von Mandach, U; Preisig, R

    1987-01-01

    The feasibility of measuring caffeine clearance from saliva (SCl) was assessed in ambulatory patients with liver disease and in a control group, and the results were compared with quantitative liver function tests. For this purpose, the subjects were given 280 mg caffeine p.o. in decaffeinated coffee powder between noon and 4 p.m., and caffeine concentrations were measured in saliva (using an enzyme immunoassay) before bedtime and upon arising. In the cirrhotics (n = 29), SCl was 0.58 +/- S.D. 0.45 ml per min X kg, thus being reduced to approximately one-third of drug-free, nonsmoking controls (1.53 +/- 0.46, n = 18); although patients with noncirrhotic liver disease showed intermediate values (0.95 +/- 0.47), their reduction in SCl was significant (p less than 0.001). SCl was correlated with indocyanine green fractional clearance, galactose elimination capacity and aminopyrine breath test; however, the closest relationship (Rs = 0.80) was observed with the aminopyrine breath test. It is suggested that the measurement of SCl represents a noninvasive and innocuous procedure for quantifying hepatic microsomal function, and is suitable for routine use. Since a.m. saliva concentrations of caffeine are highly correlated (Rs = -0.94) with SCl, further simplification of the test to a single-point measurement appears possible.

  13. Warmer ambient temperatures depress liver function in a mammalian herbivore

    PubMed Central

    Kurnath, Patrice; Dearing, M. Denise

    2013-01-01

    Diet selection in mammalian herbivores is thought to be mainly influenced by intrinsic factors such as nutrients and plant secondary compounds, yet extrinsic factors like ambient temperature may also play a role. In particular, warmer ambient temperatures could enhance the toxicity of plant defence compounds through decreased liver metabolism of herbivores. Temperature-dependent toxicity has been documented in pharmacology and agriculture science but not in wild mammalian herbivores. Here, we investigated how ambient temperature affects liver metabolism in the desert woodrat, Neotoma lepida. Woodrats (n = 21) were acclimated for 30 days to two ambient temperatures (cool = 21°C, warm = 29°C). In a second experiment, the temperature exposure was reduced to 3.5 h. After temperature treatments, animals were given a hypnotic agent and clearance time of the agent was estimated from the duration of the hypnotic state. The average clearance time of the agent in the long acclimation experiment was 45% longer for animals acclimated to 29°C compared with 21°C. Similarly, after the short exposure experiment, woodrats at 29°C had clearance times 26% longer compared with 21°C. Our results are consistent with the hypothesis that liver function is reduced at warmer environmental temperatures and may provide a physiological mechanism through which climate change affects herbivorous mammals. PMID:24046878

  14. Development of quantitative neuropsychological tests for diagnosis of subclinical hepatic encephalopathy in liver cirrhosis patients and establishment of diagnostic criteria-multicenter collaborative study in Japanese.

    PubMed

    Kato, Akinobu; Kato, Motoichiro; Ishii, Hiromasa; Ichimiya, Yosuke; Suzuki, Kazuyuki; Kawasaki, Hironaka; Yamamoto, Shin-Ichiro; Kumashiro, Ryukichi; Yamamoto, Kyosuke; Kawamura, Naohiro; Hayashi, Naoaki; Matsuzaki, Shohei; Terano, Akira; Okita, Kiwamu; Watanabe, Akiharu

    2004-10-01

    At present, there are no generally accepted diagnostic criteria or methods for subclinical hepatic encephalopathy (SHE) associated with liver cirrhosis. We therefore developed an easily conducted computer-aided quantitative neuropsychiatric function test system for use in routine medical practice. We established normal values in healthy Japanese subjects and determined differences between healthy persons and liver cirrhosis patients without clinical encephalopathy in a multi-center clinical trial. The test system consists of eight tests: number connection tests A and B, a figure position test, a digit symbol test, a block design test, and reaction time tests A, B and C. The test results were affected by age, but not by gender or facility. No learning effect was noted. The results were therefore reported by 5-year quartile ranges and differences were evaluated between 542 healthy subjects and 292 cirrhotic patients. When the cut-off value was set at the 10th/90th percentile of the results in healthy subjects, the results of each of the 8 tests were abnormal in about 25% of cirrhotic patients, and at least 1 of the 8 tests gave values greater than the 10th/90th percentile cut-off value in 58.2% of the 292 liver cirrhosis patients. SHE patients were thought to be included in these 58.2% of patients. The developed test makes it possible to quantitatively assess neuropsychiatric function, and the results obtained can be used as a basis for the diagnosis of SHE.

  15. Liver reserve function assessment by acoustic radiation force impulse imaging

    PubMed Central

    Sun, Xiao-Lan; Liang, Li-Wei; Cao, Hui; Men, Qiong; Hou, Ke-Zhu; Chen, Zhen; Zhao, Ya-E

    2015-01-01

    AIM: To evaluate the utility of liver reserve function by acoustic radiation force impulse (ARFI) imaging in patients with liver tumors. METHODS: Seventy-six patients with liver tumors were enrolled in this study. Serum biochemical indexes, such as aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin (ALB), total bilirubin (T-Bil), and other indicators were observed. Liver stiffness (LS) was measured by ARFI imaging, measurements were repeated 10 times, and the average value of the results was taken as the final LS value. Indocyanine green (ICG) retention was performed, and ICG-K and ICG-R15 were recorded. Child-Pugh (CP) scores were carried out based on patient’s preoperative biochemical tests and physical condition. Correlations among CP scores, ICG-R15, ICG-K and LS values were observed and analyzed using either the Pearson correlation coefficient or the Spearman rank correlation coefficient. Kruskal-Wallis test was used to compare LS values of CP scores, and the receiver-operator characteristic (ROC) curve was used to analyze liver reserve function assessment accuracy. RESULTS: LS in the ICG-R15 10%-20% group was significantly higher than in the ICG-R15 < 10% group; and the difference was statistically significant (2.19 ± 0.27 vs 1.59 ± 0.32, P < 0.01). LS in the ICG-R15 > 20% group was significantly higher than in the ICG-R15 < 10% group; and the difference was statistically significant (2.92 ± 0.29 vs 1.59 ± 0.32, P < 0.01). The LS value in patients with CP class A was lower than in patients with CP class B (1.57 ± 0.34 vs 1.86 ± 0.27, P < 0.05), while the LS value in patients with CP class B was lower than in patients with CP class C (1.86 ± 0.27 vs 2.47 ± 0.33, P < 0.01). LS was positively correlated with ICG-R15 (r = 0.617, P < 0.01) and CP score (r = 0.772, P < 0.01). Meanwhile, LS was negatively correlated with ICG-K (r = -0.673, P < 0.01). AST, ALT and T-Bil were positively correlated with LS, while ALB was negatively

  16. Controlled therapy by imaging of functional structures of intact liver

    NASA Astrophysics Data System (ADS)

    Wang, W.; Zhuang, Feng Y.; Ruan, G.; Kakihana, Yasuyuki; Krug, A.; Kessler, Manfred D.

    2000-04-01

    Ligustrazine, a Chinese herb medicine has been used to treat the diseases of cardiovascular and cerebral vascular diseases in China by Chinese traditional physicians or many years. Recently, results showed that ligustrazine is a powerful hepatic vasodilator. It can greatly change the blood supply of the tissues. Due to micro-optical tissue sensor developed recently it became possible to image functional structures of tissue on the level of intact blood capillaries. In our experiment we used the Oxyscan in order to study the effect of Ligustrazine on the oxygen supply of rat liver.

  17. Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis

    PubMed Central

    Liao, Ming-Feng; Yen, Su-Chen; Chun-Yen, Lin; Rong-Kuo, Lyu

    2013-01-01

    Interferon β-1a is a widely used immunomodulation treatment for multiple sclerosis. Liver function impairment is a common side effect and usually develops in the first 6 months after interferon use. Here, we describe 2 multiple sclerosis patients who developed delayed liver function impairment 5 years after receiving interferon β-1a treatment. Their liver function recovered after discontinuing interferon use, and further detailed hepatological evaluations excluded other etiologies of liver function impairment. Our case reports illustrate that liver function impairment induced by interferon β-1a can be delayed for 5 years after starting treatment and, probably, this is an idiosyncratic reaction. Regular liver function monitoring in multiple sclerosis patients who receive interferon β is necessary even after the first 6 months of treatment, especially in those patients with concomitant use of other liver-toxic medications. PMID:23904853

  18. Quantitative Evaluation of Scintillation Camera Imaging Characteristics of Isotopes Used in Liver Radioembolization

    PubMed Central

    Elschot, Mattijs; Nijsen, Johannes Franciscus Wilhelmus; Dam, Alida Johanna; de Jong, Hugo Wilhelmus Antonius Maria

    2011-01-01

    Background Scintillation camera imaging is used for treatment planning and post-treatment dosimetry in liver radioembolization (RE). In yttrium-90 (90Y) RE, scintigraphic images of technetium-99m (99mTc) are used for treatment planning, while 90Y Bremsstrahlung images are used for post-treatment dosimetry. In holmium-166 (166Ho) RE, scintigraphic images of 166Ho can be used for both treatment planning and post-treatment dosimetry. The aim of this study is to quantitatively evaluate and compare the imaging characteristics of these three isotopes, in order that imaging protocols can be optimized and RE studies with varying isotopes can be compared. Methodology/Principal Findings Phantom experiments were performed in line with NEMA guidelines to assess the spatial resolution, sensitivity, count rate linearity, and contrast recovery of 99mTc, 90Y and 166Ho. In addition, Monte Carlo simulations were performed to obtain detailed information about the history of detected photons. The results showed that the use of a broad energy window and the high-energy collimator gave optimal combination of sensitivity, spatial resolution, and primary photon fraction for 90Y Bremsstrahlung imaging, although differences with the medium-energy collimator were small. For 166Ho, the high-energy collimator also slightly outperformed the medium-energy collimator. In comparison with 99mTc, the image quality of both 90Y and 166Ho is degraded by a lower spatial resolution, a lower sensitivity, and larger scatter and collimator penetration fractions. Conclusions/Significance The quantitative evaluation of the scintillation camera characteristics presented in this study helps to optimize acquisition parameters and supports future analysis of clinical comparisons between RE studies. PMID:22073149

  19. Liver Progenitors Isolated from Adult Healthy Mouse Liver Efficiently Differentiate to Functional Hepatocytes In Vitro and Repopulate Liver Tissue.

    PubMed

    Tanimizu, Naoki; Ichinohe, Norihisa; Ishii, Masayuki; Kino, Junichi; Mizuguchi, Toru; Hirata, Koichi; Mitaka, Toshihiro

    2016-12-01

    It has been proposed that tissue stem cells supply multiple epithelial cells in mature tissues and organs. However, it is unclear whether tissue stem cells generally contribute to cellular turnover in normal healthy organs. Here, we show that liver progenitors distinct from bipotent liver stem/progenitor cells (LPCs) persistently exist in mouse livers and potentially contribute to tissue maintenance. We found that, in addition to LPCs isolated as EpCAM(+) cells, liver progenitors were enriched in CD45(-) TER119(-) CD31(-) EpCAM(-) ICAM-1(+) fraction isolated from late-fetal and postnatal livers. ICAM-1(+) liver progenitors were abundant by 4 weeks (4W) after birth. Although their number decreased with age, ICAM-1(+) liver progenitors existed in livers beyond that stage. We established liver progenitor clones derived from ICAM-1(+) cells between 1 and 20W and found that those clones efficiently differentiated into mature hepatocytes (MHs), which secreted albumin, eliminated ammonium ion, stored glycogen, and showed cytochrome P450 activity. Even after long-term culture, those clones kept potential to differentiate to MHs. When ICAM-1(+) clones were transplanted into nude mice after retrorsine treatment and 70% partial hepatectomy, donor cells were incorporated into liver plates and expressed hepatocyte nuclear factor 4α, CCAAT/enhancer binding protein α, and carbamoylphosphate synthetase I. Moreover, after short-term treatment with oncostatin M, ICAM-1(+) clones could efficiently repopulate the recipient liver tissues. Our results indicate that liver progenitors that can efficiently differentiate to MHs exist in normal adult livers. Those liver progenitors could be an important source of new MHs for tissue maintenance and repair in vivo, and for regenerative medicine ex vivo. Stem Cells 2016;34:2889-2901.

  20. SU-E-J-260: Quantitative Image Feature Analysis of Multiphase Liver CT for Hepatocellular Carcinoma (HCC) in Radiation Therapy

    SciTech Connect

    Choi, W; Wang, J; Lu, W; Kang, M

    2015-06-15

    Purpose: To identify the effective quantitative image features (radiomics features) for prediction of response, survival, recurrence and metastasis of hepatocellular carcinoma (HCC) in radiotherapy. Methods: Multiphase contrast enhanced liver CT images were acquired in 16 patients with HCC on pre and post radiation therapy (RT). In this study, arterial phase CT images were selected to analyze the effectiveness of image features for the prediction of treatment outcome of HCC to RT. Response evaluated by RECIST criteria, survival, local recurrence (LR), distant metastasis (DM) and liver metastasis (LM) were examined. A radiation oncologist manually delineated the tumor and normal liver on pre and post CT scans, respectively. Quantitative image features were extracted to characterize the intensity distribution (n=8), spatial patterns (texture, n=36), and shape (n=16) of the tumor and liver, respectively. Moreover, differences between pre and post image features were calculated (n=120). A total of 360 features were extracted and then analyzed by unpaired student’s t-test to rank the effectiveness of features for the prediction of response. Results: The five most effective features were selected for prediction of each outcome. Significant predictors for tumor response and survival are changes in tumor shape (Second Major Axes Length, p= 0.002; Eccentricity, p=0.0002), for LR, liver texture (Standard Deviation (SD) of High Grey Level Run Emphasis and SD of Entropy, both p=0.005) on pre and post CT images, for DM, tumor texture (SD of Entropy, p=0.01) on pre CT image and for LM, liver (Mean of Cluster Shade, p=0.004) and tumor texture (SD of Entropy, p=0.006) on pre CT image. Intensity distribution features were not significant (p>0.09). Conclusion: Quantitative CT image features were found to be potential predictors of the five endpoints of HCC in RT. This work was supported in part by the National Cancer Institute Grant R01CA172638.

  1. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

    PubMed Central

    Bell, Catherine C.; Hendriks, Delilah F. G.; Moro, Sabrina M. L.; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C. A.; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L.; Jenkins, Rosalind E.; Nordling, Åsa; Mkrtchian, Souren; Park, B. Kevin; Kitteringham, Neil R.; Goldring, Christopher E. P.; Lauschke, Volker M.; Ingelman-Sundberg, Magnus

    2016-01-01

    Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI. PMID:27143246

  2. [Tests of liver function in obese school children].

    PubMed

    Angulo, Nerkis; de Szarvas, Sobeida Barbella; Guevara, Harold; González, Dora; Hernández, Ana

    2015-03-01

    The non alcoholic fatty liver disease (NAFLD) manifests with liver damage and it is associated with obesity. The objective of this work was to detect the risk of obese school students of developing NAFLD, through an analytical, observational study, comparing their liver function with that of a control group, and its relationship with physical activity, dietary, biochemical and anthropometric variables. One hundred and sixty school students (ages 7-11) were evaluated according to their socio-economic status; nutritional status by the body mass index (BMI) and mid-upper arm fat area (MUAC) (Project Venezuela 1994); body fat percentage by anthropometry (% BF), waist circumference (WC); and metabolism by oral glucose tolerance, basal insulin and post-load glucose, total cholesterol (TC), cLDL, cVLDL, cHDL, triglycerides (TG), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), gamma glutamil transpeptidasa (GGTP) and albumin. Their diet was analyzed by the 24-hour recall and their physical activity by a clinical trial. Mean levels of GPT (p < 0.05), greater frequencies of elevated GOT and GPT (p < 0.05) and lower albumin levels (p < 0.05) were observed in 88 obese school students when compared to controls. The GPT correlated significantly with the BMI, MUAC, % BF, WC, basal insulin and post-load glucose, HOMA, cVLDL, cHDL and TG, while the GOT correlated with MUAC and the GGTP with MUAC, basal insulin, HOMA and cLDL. Albumin was negatively correlated with BMI, MUAC, % BF and WC. TGP reflected better the hepatic compromise of obesity. To assess the risk of NAFLD, the TGO/TGP values should be standardized according to age, gender and race.

  3. Breath-hold black blood quantitative T1rho imaging of liver using single shot fast spin echo acquisition

    PubMed Central

    Chan, Queenie; Wáng, Yì-Xiáng J.

    2016-01-01

    Background Liver fibrosis is a key feature in most chronic liver diseases. T1rho magnetic resonance imaging is a potentially important technique for noninvasive diagnosis, severity grading, and therapy monitoring of liver fibrosis. However, it remains challenging to perform robust T1rho quantification of liver on human subjects. One major reason is that the presence of rich blood signal in liver can cause artificially high T1rho measurement and makes T1rho quantification susceptible to motion. Methods A pulse sequence based on single shot fast/turbo spin echo (SSFSE/SSTSE) acquisition, with theoretical analysis and simulation based on the extended phase graph (EPG) algorithm, was presented for breath-hold single slice quantitative T1rho imaging of liver with suppression of blood signal. The pulse sequence was evaluated in human subjects at 3.0 T with 500 Hz spinlock frequency and time-of-spinlock (TSL) 0, 10, 30 and 50 ms. Results Human scan demonstrated that the entire T1rho data sets with four spinlock time can be acquired within a single breath-hold of 10 seconds with black blood effect. T1rho quantification with suppression of blood signal results in significantly reduced T1rho value of liver compared to the results without blood suppression. Conclusions A signal-to-noise ratio (SNR) efficient pulse sequence was reported for T1rho quantification of liver. The black blood effect, together with a short breath-hold, mitigates the risk of quantification errors as would occur in the conventional methods. PMID:27190769

  4. Factors influencing the caffeine test for cytochrome P 448-dependent liver function.

    PubMed

    Joeres, R; Klinker, H; Huesler, H; Epping, J; Hofstetter, G; Drost, D; Reuss, H; Zilly, W; Richter, E

    1987-01-01

    Liver functions in patients with liver disease can be estimated by caffeine clearance. Our data, however, demonstrate the additional influence of factors other than liver disease on the caffeine test. Smoking enhances caffeine clearance in both healthy volunteers and patients with severe hepatic disorders, whereas co-medication with mexiletine strongly inhibits caffeine elimination.

  5. Evaluation of liver function and electroacupuncture efficacy of animals with alcoholic liver injury by the novel imaging methods

    PubMed Central

    Zhang, Dong; Song, Xiao-jing; Li, Shun-yue; Wang, Shu-you; Chen, Bing-jun; Bai, Xiao-Dong; Tang, Li-mei

    2016-01-01

    Imaging methods to evaluate hepatic microcirculation (HM) and liver function (LF) by directly monitoring overall liver tissue remain lacking. This study establish imaging methods for LF that combines Laser speckle perfusion imaging (LSPI) and in vivo optical imaging (IVOI) technologies to investigate changes of hepatic microcirculation and reserve function in the animals gavaged with 50% ethanol (15 ml/kg·bw) for a model of acute alcoholic liver injury (ALI), and for evaluation of electroacupuncture (EA) effect. The liver blood perfusion and indocyanine green (ICG) distribution were observe by LSPI and IVOI separately. After EA, the livers were collected to measure the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), thromboxane A (TXA2), prostacyclin (PGI2) and endothelin (ET). The acquisitions of newly established LSPI of liver and ICG in vivo fluorescence imaging (ICG-IVFI), combining the results of other indexes showed: hepatic microcirculation perfusion (HMP) significantly reduced, ICG metabolism reduced, and ALT/AST increased in animal model with acute ALI. EA can reverse these changes. The use of LSPI of liver and ICG-IVFI, which was novel imaging methods for LF established in this study, could display the LF characteristics of ALI and the EA efficacy. PMID:27443832

  6. Learning Quantitative Sequence-Function Relationships from Massively Parallel Experiments

    NASA Astrophysics Data System (ADS)

    Atwal, Gurinder S.; Kinney, Justin B.

    2016-03-01

    A fundamental aspect of biological information processing is the ubiquity of sequence-function relationships—functions that map the sequence of DNA, RNA, or protein to a biochemically relevant activity. Most sequence-function relationships in biology are quantitative, but only recently have experimental techniques for effectively measuring these relationships been developed. The advent of such "massively parallel" experiments presents an exciting opportunity for the concepts and methods of statistical physics to inform the study of biological systems. After reviewing these recent experimental advances, we focus on the problem of how to infer parametric models of sequence-function relationships from the data produced by these experiments. Specifically, we retrace and extend recent theoretical work showing that inference based on mutual information, not the standard likelihood-based approach, is often necessary for accurately learning the parameters of these models. Closely connected with this result is the emergence of "diffeomorphic modes"—directions in parameter space that are far less constrained by data than likelihood-based inference would suggest. Analogous to Goldstone modes in physics, diffeomorphic modes arise from an arbitrarily broken symmetry of the inference problem. An analytically tractable model of a massively parallel experiment is then described, providing an explicit demonstration of these fundamental aspects of statistical inference. This paper concludes with an outlook on the theoretical and computational challenges currently facing studies of quantitative sequence-function relationships.

  7. Quantitative functional MRI: concepts, issues and future challenges.

    PubMed

    Pike, G Bruce

    2012-08-15

    Since its inception 20 years ago, functional magnetic resonance imaging (fMRI) of the human brain based on the blood oxygenation level dependent (BOLD) contrast phenomenon has proliferated and matured. Today it is the predominant functional brain imaging modality with the majority of applications being in basic cognitive neuroscience where it has primarily been used as a tool to localize brain activity. While the magnitude of the BOLD response is often used in these studies as a surrogate for the level of neuronal activity, the link between the two is, in fact, quite indirect. The BOLD response is dependent upon hemodynamic (blood flow and volume) and metabolic (oxygen consumption) responses as well as acquisition details. Furthermore, the relationship between neuronal activity and the hemodynamic response, termed neurovascular coupling, is itself complex and incompletely understood. Quantitative fMRI techniques have therefore been developed to measure the hemodynamic and metabolic responses to modulations in brain activity. These methods have not only helped clarify the behaviour and origins of the BOLD signal under normal physiological conditions but they have also provided a potentially valuable set of tools for exploring pathophysiological conditions. Such quantitative methods will be critical to realize the potential of fMRI in a clinical context, where simple BOLD measurements cannot be uniquely interpreted, and to enhance the power of fMRI in basic neuroscience research. In this article, recent advances in human quantitative fMRI methods are reviewed, outstanding issues discussed and future challenges and opportunities highlighted.

  8. Functional Linear Models for Association Analysis of Quantitative Traits

    PubMed Central

    Fan, Ruzong; Wang, Yifan; Mills, James L.; Wilson, Alexander F.; Bailey-Wilson, Joan E.; Xiong, Momiao

    2014-01-01

    Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study. PMID:24130119

  9. Functional linear models for association analysis of quantitative traits.

    PubMed

    Fan, Ruzong; Wang, Yifan; Mills, James L; Wilson, Alexander F; Bailey-Wilson, Joan E; Xiong, Momiao

    2013-11-01

    Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study.

  10. Valproate-induced hyperammonemic encephalopathy with normal liver function.

    PubMed

    Rath, Amitav; Naryanan, T Jaishree; Chowdhary, G V S; Murthy, J M K

    2005-06-01

    Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. We retrospectively analyzed the case records of 5 patients of epilepsy on valproate with hyperammonemic encephalopathy. Of the 5 patients, 3 were on monotherapy. The mean valproate dose was 1250 mg/day and the duration of therapy ranged between 4 and 90 days. Alteration in the sensorium was the presenting clinical feature. The risk factors included high initial dose (2), long-term valproate therapy (1), and long-term valproate therapy with concomitant topiramate (1). There was good correlation between the fall in serum ammonia levels and clinical improvement. Hyperammonemic encephalopathy should be suspected in patients on valproate with altered sensorium. Response to treatment is rewarding.

  11. Functional infrared imaging in medicine: a quantitative diagnostic approach.

    PubMed

    Merla, A; Romani, G L

    2006-01-01

    The role and the potentialities of high-resolution infrared thermography, combined to bio-heat modelling, have been largely described in the last years in a wide variety of biomedical applications. Quantitative assessment over time of the cutaneous temperature and/or of other biomedical parameters related to the temperature (e.g., cutaneous blood flow, thermal inertia, sympathetic skin response) allows for a better and more complete understanding and description of functional processes involved and/or altered in presence of ailment and interfering with the regular cutaneous thermoregulation. Such an approach to thermal medical imaging requires both new methodologies and tools, like diagnostic paradigms, appropriate software for data analysis and, even, a completely new way to look at data processing. In this paper, some of the studies recently made in our laboratory are presented and described, with the general intent of introducing the reader to these innovative methods to obtain quantitative diagnostic tools based on thermal imaging.

  12. Quantitative studies on the in vitro metabolic activation of dimethylnitrosamine by rat liver postmitochondrial supernatant

    SciTech Connect

    Doolittle, D.J.; Goodman, J.I.

    1984-08-01

    The metabolic activation of dimethylnitrosamine (DMN) to mutagenic and/or cytotoxic intermediates in vitro has been characterized and the relationship between DMN demethylase and ethoxyresorufin-O-deethylase (EROD) or ethylmorphine-N-demethylase (EMND) has been evaluated. A mammalian assay system which uses the postmitochondrial supernatant (S-15 fraction) prepared from a rat liver homogenate as an enzyme source and V79 Chinese hamster cells as targets for chemically induced damage was used. The enzyme pattern of the S-15 fraction was altered by pretreatment of experimental animals in vivo and/or by the use of enzyme inhibitors in vitro. The results of these studies indicate that the concentration of S-15 fraction in the reaction mixture can markedly influence the degree of DMN-induced cytotoxicity when it is metabolized in vitro and that the degree of DMN-induced cytotoxicity and mutagenicity are linearly related. The degree of cytotoxicity and mutagenicity induced in V79 cells by DMN does not correlate with EROD activity (a measure of 3-methylcholanthrene-inducible mixed-function oxidases) nor with EMND activity (a measure of phenobarbital-inducible mixed function oxidases) in the S-15 fraction. 28 references, 4 figures.

  13. Quantitative evaluation of bioorthogonal chemistries for surface functionalization of nanoparticles.

    PubMed

    Feldborg, Lise N; Jølck, Rasmus I; Andresen, Thomas L

    2012-12-19

    We present here a highly efficient and chemoselective liposome functionalization method based on oxime bond formation between a hydroxylamine and an aldehyde-modified lipid component. We have conducted a systematic and quantitative comparison of this new approach with other state-of-the-art conjugation reactions in the field. Targeted liposomes that recognize overexpressed receptors or antigens on diseased cells have great potential in therapeutic and diagnostic applications. However, chemical modifications of nanoparticle surfaces by postfunctionalization approaches are less effective than in solution and often not high-yielding. In addition, the conjugation efficiency is often challenging to characterize and therefore not addressed in many reports. We present here an investigation of PEGylated liposomes functionalized with a neuroendocrine tumor targeting peptide (TATE), synthesized with a variety of functionalities that have been used for surface conjugation of nanoparticles. The reaction kinetics and overall yield were quantified by HPLC. Reactions were conducted in solution as well as by postfunctionalization of liposomes in order to study the effects of steric hindrance and possible affinity between the peptide and the liposome surface. These studies demonstrate the importance of choosing the correct chemistry in order to obtain a quantitative surface functionalization of liposomes.

  14. Cannabinoid receptor type 2 functional variant influences liver damage in children with non-alcoholic fatty liver disease.

    PubMed

    Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco; Miraglia del Giudice, Emanuele; Nobili, Valerio

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD.CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02).Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.

  15. Cannabinoid Receptor Type 2 Functional Variant Influences Liver Damage in Children with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis. Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD. CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage. We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02). Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage. PMID:22927922

  16. Effects of exercise and ethanol on liver mitochondrial function

    SciTech Connect

    Ardies, C.M.; Morris, G.S.; Erickson, C.K.; Farrar, R.P.

    1987-03-16

    Rates of ADP stimulated respiration for various substrates were determined in mitochondria isolated from the livers of female Sprague-Dawley rats following 8 weeks of treatment with daily swimming, ethanol consumption, or both. All rats were fed an American Institute of Nutrition (AIN) type liquid diet with the ethanol treated rats receiving 35% of the calories as ethanol. Chronic exposure to ethanol depressed both state 3 respiration with glutamate as a substrate and cytochrome oxidase activity. Respiratory control ratios and P:O ratios, however, were unaffected by the ethanol exposure. Exercise alone had no effect on hepatic mitochondrial function. There were also no significant alterations in oxidative function of hepatic mitochondria from rats which were endurance-trained by swimming while receiving the ethanol diet. This lack of alteration in mitochondrial function was in spite of the fact that these rats consumed an identical amount of ethanol as those which incurred mitochondrial dysfunction. These results indicate that regular exercise has the potential to attenuate the ethanol induced decline in hepatic mitochondria. 32 references, 2 figures, 1 table.

  17. Structural and functional changes in acute liver injury.

    PubMed Central

    Smuckler, E A

    1976-01-01

    Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 11. PMID:1001290

  18. Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.

    EPA Science Inventory

    We have previously shown that the conazole fungicides triadimefon and propiconazole, which are tumorigenic in mouse liver, are in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses. The nontumorigenic conazole myclo...

  19. Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.**

    EPA Science Inventory

    We have previously shown that the conazole fungicides triadimefon and propiconazole, which are tumorigenic in mouse liver, are in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses. The nontumorigenic conazole myclo...

  20. LIVER FUNCTION AFTER IRRADIATION BASED UPON CT PORTAL VEIN PERFUSION IMAGING

    PubMed Central

    Cao, Yue; Pan, Charlie; Balter, James M.; Platt, Joel F.; Francis, Isaac R.; Knol, James A.; Normolle, Daniel; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.

    2009-01-01

    Purpose The role of radiation in the treatment of intrahepatic cancer is limited by the development of radiation-induced liver disease (RILD), which occurs weeks after the course of radiation is completed. We hypothesized that, as the pathophysiology of RILD is veno-occlusive disease, we could assess individual and regional liver sensitivity to radiation by measuring liver perfusion during a course of treatment using dynamic contrast enhanced CT (DCE-CT) scanning. Materials and Methods Patients with intrahepatic cancer undergoing conformal radiotherapy underwent DCE-CT (to measure perfusion distribution) and an indocyanine extraction study (to measure liver function) prior to, during, and one month after treatment. We wished to determine if the residual functioning liver (i.e. those regions showing portal vein perfusion) could be used to predict overall liver function after irradiation. Results Radiation doses from 45 to 84 Gy resulted in undectable regional portal vein perfusion one month after treatment. The volume of each liver with undectable portal vein perfusion ranged from 0% to 39% and depended both on the patient’s sensitivity and dose distribution. There was a significant correlation between indocyanine green clearance and the mean of the estimated portal vein perfusion in the functional liver parenchyma (P < .001). Conclusion This study reveals substantial individual variability in the sensitivity of the liver to irradiation. In addition, these findings suggest that hepatic perfusion imaging may be a marker for liver function, and has the potential to be a tool for individualizing therapy. PMID:17855011

  1. A study on the quantitative evaluation of skin barrier function

    NASA Astrophysics Data System (ADS)

    Maruyama, Tomomi; Kabetani, Yasuhiro; Kido, Michiko; Yamada, Kenji; Oikaze, Hirotoshi; Takechi, Yohei; Furuta, Tomotaka; Ishii, Shoichi; Katayama, Haruna; Jeong, Hieyong; Ohno, Yuko

    2015-03-01

    We propose a quantitative evaluation method of skin barrier function using Optical Coherence Microscopy system (OCM system) with coherency of near-infrared light. There are a lot of skin problems such as itching, irritation and so on. It has been recognized skin problems are caused by impairment of skin barrier function, which prevents damage from various external stimuli and loss of water. To evaluate skin barrier function, it is a common strategy that they observe skin surface and ask patients about their skin condition. The methods are subjective judgements and they are influenced by difference of experience of persons. Furthermore, microscopy has been used to observe inner structure of the skin in detail, and in vitro measurements like microscopy requires tissue sampling. On the other hand, it is necessary to assess objectively skin barrier function by quantitative evaluation method. In addition, non-invasive and nondestructive measuring method and examination changes over time are needed. Therefore, in vivo measurements are crucial for evaluating skin barrier function. In this study, we evaluate changes of stratum corneum structure which is important for evaluating skin barrier function by comparing water-penetrated skin with normal skin using a system with coherency of near-infrared light. Proposed method can obtain in vivo 3D images of inner structure of body tissue, which is non-invasive and non-destructive measuring method. We formulate changes of skin ultrastructure after water penetration. Finally, we evaluate the limit of performance of the OCM system in this work in order to discuss how to improve the OCM system.

  2. Caffeine clearance by enzyme multiplied immunoassay technique: a simple, inexpensive, and useful indicator of liver function.

    PubMed Central

    McDonagh, J E; Nathan, V V; Bonavia, I C; Moyle, G R; Tanner, A R

    1991-01-01

    The clinical value and sensitivity of serum caffeine clearance measurement has been evaluated as an indicator of hepatic disease. After a 17 hour caffeine exclusion period, 300 mg of caffeine citrate was administered orally to the study subjects. Serum samples were taken four and 16 hours later. Serum caffeine concentrations were measured using an enzyme multiplied immunoassay technique (EMIT) and a clearance value derived. Conventional liver function tests were measured at the same time. A total of 103 subjects attending the medical unit in a district general hospital were studied. Twenty one had alcoholic liver disease, 11 non-alcoholic cirrhosis, nine non-cirrhotic liver disease, 21 suspected liver disease, six hepatic tumours, and 35 were hospital and normal control subjects. Caffeine clearance values were lowest in subjects with alcoholic liver disease (median 0.19 ml/min/kg, range 0.04-0.61 ml/min/kg) and significantly reduced in all subjects with liver disease (median 0.32 ml/min/kg, range 0.04-2.68 ml/min/kg) compared with control subjects (median 1.27 ml/min/kg, p less than 0.001). In subjects with suspected liver disease subsequently shown to have another explanation for abnormal liver function test results, caffeine clearance values were normal (median 1.31 ml/min/kg, range 0.23-2.64 ml/min/kg) and significantly different, p less than 0.001, from those of subjects with liver disease. Serum albumen values were not different for these latter two groups. Using a cut off value of 0.86 ml/min/kg, caffeine clearance measurement was 100% sensitive for alcoholic liver disease and 89% sensitive for all liver disease. The respective sensitivities for conventional liver function test measurement were 76% and 83%. In the suspected liver disease group, caffeine clearance was abnormal in only 24%, conventional liver function tests were abnormal in 95%. The respective specificities for caffeine clearance and liver function test measurement in control subjects were 93

  3. Quantitative Comparison of PET and Bremsstrahlung SPECT for Imaging the In Vivo Yttrium-90 Microsphere Distribution after Liver Radioembolization

    PubMed Central

    Elschot, Mattijs; Vermolen, Bart J.; Lam, Marnix G. E. H.; de Keizer, Bart; van den Bosch, Maurice A. A. J.; de Jong, Hugo W. A. M.

    2013-01-01

    Background After yttrium-90 (90Y) microsphere radioembolization (RE), evaluation of extrahepatic activity and liver dosimetry is typically performed on 90Y Bremsstrahlung SPECT images. Since these images demonstrate a low quantitative accuracy, 90Y PET has been suggested as an alternative. The aim of this study is to quantitatively compare SPECT and state-of-the-art PET on the ability to detect small accumulations of 90Y and on the accuracy of liver dosimetry. Methodology/Principal Findings SPECT/CT and PET/CT phantom data were acquired using several acquisition and reconstruction protocols, including resolution recovery and Time-Of-Flight (TOF) PET. Image contrast and noise were compared using a torso-shaped phantom containing six hot spheres of various sizes. The ability to detect extra- and intrahepatic accumulations of activity was tested by quantitative evaluation of the visibility and unique detectability of the phantom hot spheres. Image-based dose estimates of the phantom were compared to the true dose. For clinical illustration, the SPECT and PET-based estimated liver dose distributions of five RE patients were compared. At equal noise level, PET showed higher contrast recovery coefficients than SPECT. The highest contrast recovery coefficients were obtained with TOF PET reconstruction including resolution recovery. All six spheres were consistently visible on SPECT and PET images, but PET was able to uniquely detect smaller spheres than SPECT. TOF PET-based estimates of the dose in the phantom spheres were more accurate than SPECT-based dose estimates, with underestimations ranging from 45% (10-mm sphere) to 11% (37-mm sphere) for PET, and 75% to 58% for SPECT, respectively. The differences between TOF PET and SPECT dose-estimates were supported by the patient data. Conclusions/Significance In this study we quantitatively demonstrated that the image quality of state-of-the-art PET is superior over Bremsstrahlung SPECT for the assessment of the 90Y

  4. Quantitation of renal function with technetium-99m MAG3

    SciTech Connect

    Russell, C.D.; Thorstad, B.L.; Yester, M.V.; Stutzman, M.; Dubovsky, E.V.

    1988-12-01

    The technetium-labeled hippuran analog (/sup 99m/Tc)MAG3 was compared with ( T I)hippuran in 50 patients using a quantitative renal function protocol that includes: (a) estimation of effective renal plasma flow by a single-injection, single-sample plasma clearance method, (b) determination of relative function of right and left kidney from the initial count rate over each kidney, and (c) comparison of recovered urine activity with plasma disappearance. This protocol is suitable for routine clinical use, and, in fact, has been used heavily at our clinic for a number of years. By slight modification of the formulas, the results obtained with (/sup 99m/Tc)MAG3 agreed well with those using ( T I)hippuran. We conclude that (/sup 99m/Tc)MAG3 can be substituted for ( T I)hippuran in the quantitative protocol, with the better image quality and lower radiation dose (in abnormals) of a technetium-labeled agent.

  5. Functional Region Annotation of Liver CT Image Based on Vascular Tree

    PubMed Central

    Chen, Yufei; Wang, Gang

    2016-01-01

    Anatomical analysis of liver region is critical in diagnosis and treatment of liver diseases. The reports of liver region annotation are helpful for doctors to precisely evaluate liver system. One of the challenging issues is to annotate the functional regions of liver through analyzing Computed Tomography (CT) images. In this paper, we propose a vessel-tree-based liver annotation method for CT images. The first step of the proposed annotation method is to extract the liver region including vessels and tumors from the CT scans. And then a 3-dimensional thinning algorithm is applied to obtain the spatial skeleton and geometric structure of liver vessels. With the vessel skeleton, the topology of portal veins is further formulated by a directed acyclic graph with geometrical attributes. Finally, based on the topological graph, a hierarchical vascular tree is constructed to divide the liver into eight segments according to Couinaud classification theory and thereby annotate the functional regions. Abundant experimental results demonstrate that the proposed method is effective for precise liver annotation and helpful to support liver disease diagnosis. PMID:27891516

  6. [Glycogen storage of the liver: a determining factor of initial function of the hepatic graft].

    PubMed

    Boudjema, K; Cinqualbre, J; Barguil, Y; Pattou, F; Kerr, J A; Wolf, P; Southard, J H; Jaeck, D

    1991-01-01

    In this study we have investigated the effects of hepatocytes glycogen storage on the quality of livers for transplantation. Rats were fed or fasted for 24 h and hepatocytes isolated and cold stored in UW solution for 24 and 48 hours. Viability of the cells was analyzed by LDH release after 2 hours incubation in L15 with O2. Also, rabbits were fed, fasted (48 h) or glucose fed (48 h) and livers cold stored for 6, 24 and 48 h in UW solution. Functions of the livers were analyzed by isolated perfusion for 2 hours. Hepatocytes from fasted rats released significantly more LDH than hepatocytes from fed rats after 24 and 48 h cold storage. In rabbit livers, fasting depleted glycogen by 85% but had no effect on ATP or glutathione concentration. Livers from fasted rabbits produced similar amount of bile, released similar concentrations of lactate dehydrogenase and aspartate transaminase into the perfusate, maintained similar concentrations of glutathione after 24 hours preservation when compared to fed animals. After 48 h preservation livers from fasted animals were less viable than livers from fed animals and the decrease of liver functions in livers from fasted animals preserved for 48 hours was prevented by feeding glucose. This study shows that liver glycogen storage in hepatocyte is an important metabolite for successful liver preservation. Glycogen may be a source for ATP and antioxydant synthesis during the early period of reperfusion.

  7. TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

    SciTech Connect

    Wu, V; Epelman, M; Feng, M; Cao, Y; Wang, H; Romeijn, E; Matuszak, M

    2014-06-15

    Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUD (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD

  8. Quantitative detection of liver-relevant biomarkers by SERS-immunolabeled gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Payne, William Mark

    Lab-on-a-chip technology has the potential to rapidly change the way experiments are conducted in a variety of fields ranging from medicine to environmental science. Specifically, sensors, detectors, and monitoring devices are increasingly being miniaturized to perform many experiments or measurements on a single chip. In this research, we develop an immunolabeled gold nanoparticle complex capable of detecting liver organoid biomarkers intended for use in a microfluidic device. Human Serum Albumin (HSA) and alpha-Glutathione S-Transferase (alpha-GST) are liver biomarkers that indicate liver health and damage respectively. Herein we demonstrate detection of the liver organoid biomarkers at nanomolar concentrations. Through plasmonic coupling induced by aggregation in the presence of analyte, the SERS signal obtained from the nanoparticles is dramatically increased. Furthermore, detection is demonstrated in a simple fluidic device to show the feasibility of implementing an optimized SERS-immunolabeled nanoparticle for translational application.

  9. Identification of quantitative trait transcripts for growth traits in the large scales of liver and muscle samples.

    PubMed

    Xiong, Xinwei; Yang, Hui; Yang, Bin; Chen, Congying; Huang, Lusheng

    2015-07-01

    Growth-related traits are economically important traits to the pig industry. Identification of causative gene and mutation responsible for growth-related QTL will facilitate the improvement of pig growth through marker-assisted selection. In this study, we applied whole genome gene expression and quantitative trait transcript (QTT) analyses in 497 liver and 586 longissimus dorsi muscle samples to identify candidate genes and dissect the genetic basis of pig growth in a white Duroc × Erhualian F2 resource population. A total of 20,108 transcripts in liver and 23,728 transcripts in muscle with expression values were used for association analysis between gene expression level and phenotypic value. At the significance threshold of P < 0.0005, we identified a total of 169 and 168 QTTs for nine growth-related traits in liver and muscle, respectively. We also found that some QTTs were correlated to more than one trait. The QTTs identified here showed high tissue specificity. We did not identify any QTTs that were associated with one trait in both liver and muscle. Through an integrative genomic approach, we identified SDR16C5 as the important candidate gene in pig growth trait. These findings contribute to further identification of the causative genes for porcine growth traits and facilitate improvement of pig breeding.

  10. Quantitative Analysis of the Effective Functional Structure in Yeast Glycolysis

    PubMed Central

    De la Fuente, Ildefonso M.; Cortes, Jesus M.

    2012-01-01

    The understanding of the effective functionality that governs the enzymatic self-organized processes in cellular conditions is a crucial topic in the post-genomic era. In recent studies, Transfer Entropy has been proposed as a rigorous, robust and self-consistent method for the causal quantification of the functional information flow among nonlinear processes. Here, in order to quantify the functional connectivity for the glycolytic enzymes in dissipative conditions we have analyzed different catalytic patterns using the technique of Transfer Entropy. The data were obtained by means of a yeast glycolytic model formed by three delay differential equations where the enzymatic rate equations of the irreversible stages have been explicitly considered. These enzymatic activity functions were previously modeled and tested experimentally by other different groups. The results show the emergence of a new kind of dynamical functional structure, characterized by changing connectivity flows and a metabolic invariant that constrains the activity of the irreversible enzymes. In addition to the classical topological structure characterized by the specific location of enzymes, substrates, products and feedback-regulatory metabolites, an effective functional structure emerges in the modeled glycolytic system, which is dynamical and characterized by notable variations of the functional interactions. The dynamical structure also exhibits a metabolic invariant which constrains the functional attributes of the enzymes. Finally, in accordance with the classical biochemical studies, our numerical analysis reveals in a quantitative manner that the enzyme phosphofructokinase is the key-core of the metabolic system, behaving for all conditions as the main source of the effective causal flows in yeast glycolysis. PMID:22393350

  11. Functional Regression Models for Epistasis Analysis of Multiple Quantitative Traits.

    PubMed

    Zhang, Futao; Xie, Dan; Liang, Meimei; Xiong, Momiao

    2016-04-01

    To date, most genetic analyses of phenotypes have focused on analyzing single traits or analyzing each phenotype independently. However, joint epistasis analysis of multiple complementary traits will increase statistical power and improve our understanding of the complicated genetic structure of the complex diseases. Despite their importance in uncovering the genetic structure of complex traits, the statistical methods for identifying epistasis in multiple phenotypes remains fundamentally unexplored. To fill this gap, we formulate a test for interaction between two genes in multiple quantitative trait analysis as a multiple functional regression (MFRG) in which the genotype functions (genetic variant profiles) are defined as a function of the genomic position of the genetic variants. We use large-scale simulations to calculate Type I error rates for testing interaction between two genes with multiple phenotypes and to compare the power with multivariate pairwise interaction analysis and single trait interaction analysis by a single variate functional regression model. To further evaluate performance, the MFRG for epistasis analysis is applied to five phenotypes of exome sequence data from the NHLBI's Exome Sequencing Project (ESP) to detect pleiotropic epistasis. A total of 267 pairs of genes that formed a genetic interaction network showed significant evidence of epistasis influencing five traits. The results demonstrate that the joint interaction analysis of multiple phenotypes has a much higher power to detect interaction than the interaction analysis of a single trait and may open a new direction to fully uncovering the genetic structure of multiple phenotypes.

  12. Quantitative elemental analysis on aluminum accumulation by HVTEM-EDX in liver tissues of mice orally administered with aluminum chloride.

    PubMed

    Kametani, Kiyokazu; Nagata, Tetsuji

    2006-06-01

    Quantitative elemental analysis on Al was carried out by high-accelerating voltage transmission electron microscopy (HVTEM) equipped with energy-dispersive X-ray microanalysis (EDX) using an accelerating voltage at 300 kV with high permeability in 1-mum-thick samples obtained from mice administered with aluminum chloride solution for 3, 9, and 17 weeks. By light microscopic observation, no morphological changes were observed in the hepatocytes and macrophages in the liver tissues of mice that were administered with excess Al as compared with the normal control mice. In contrast, by electron microscopic observation, ultrastructural changes were observed in the lysosomes in the hepatocytes as well as the pinocytotic vesicles in the macrophages in the experimental animals. Therefore, the concentrations of Al detected in lysosomes in hepatocytes and pinocytotic vesicles in macrophages of livers of mice administered with Al were measured in relationship to those administration periods. Moreover, transitional changes of hepatocyte lysosome ratios by image analysis and the macrophage counts in the unit area increased in liver tissues of mice administered with Al as compared with normal control mice. From the results, it was demonstrated that hepatocyte lysosome ratio and macrophage count increased in liver tissues of treated mice during those short-term excessive Al administration periods. It was also clarified that the concentrations of Al in both hepatocytes and macrophages increased as observed by HVTEM-EDX. In conclusion, Al accumulated in hepatocytes and macrophages at 3 and 9 weeks administration, while the ultrastructural changes remained in the hepatocytes and macrophages. In contrast, Al concentration did not increase in the liver at 17 weeks administration.

  13. Quantitative Trait Loci Identify Functional Noncoding Variation in Cancer.

    PubMed

    Heyn, Holger

    2016-03-01

    The interpretation of noncoding alterations in cancer genomes presents an unresolved problem in cancer studies. While the impact of somatic variations in protein-coding regions is widely accepted, noncoding aberrations are mostly considered as passenger events. However, with the advance of genome-wide profiling strategies, alterations outside the coding context entered the focus, and multiple examples highlight the role of gene deregulation as cancer-driving events. This review describes the implication of noncoding alterations in oncogenesis and provides a theoretical framework for the identification of causal somatic variants using quantitative trait loci (QTL) analysis. Assuming that functional noncoding alterations affect quantifiable regulatory processes, somatic QTL studies constitute a valuable strategy to pinpoint cancer gene deregulation. Eventually, the comprehensive identification and interpretation of coding and noncoding alterations will guide our future understanding of cancer biology.

  14. Quantitative evaluation of activation state in functional brain imaging.

    PubMed

    Hu, Zhenghui; Ni, Pengyu; Liu, Cong; Zhao, Xiaohu; Liu, Huafeng; Shi, Pengcheng

    2012-10-01

    Neuronal activity can evoke the hemodynamic change that gives rise to the observed functional magnetic resonance imaging (fMRI) signal. These increases are also regulated by the resting blood volume fraction (V (0)) associated with regional vasculature. The activation locus detected by means of the change in the blood-oxygen-level-dependent (BOLD) signal intensity thereby may deviate from the actual active site due to varied vascular density in the cortex. Furthermore, conventional detection techniques evaluate the statistical significance of the hemodynamic observations. In this sense, the significance level relies not only upon the intensity of the BOLD signal change, but also upon the spatially inhomogeneous fMRI noise distribution that complicates the expression of the results. In this paper, we propose a quantitative strategy for the calibration of activation states to address these challenging problems. The quantitative assessment is based on the estimated neuronal efficacy parameter [Formula: see text] of the hemodynamic model in a voxel-by-voxel way. It is partly immune to the inhomogeneous fMRI noise by virtue of the strength of the optimization strategy. Moreover, it is easy to incorporate regional vascular information into the activation detection procedure. By combining MR angiography images, this approach can remove large vessel contamination in fMRI signals, and provide more accurate functional localization than classical statistical techniques for clinical applications. It is also helpful to investigate the nonlinear nature of the coupling between synaptic activity and the evoked BOLD response. The proposed method might be considered as a potentially useful complement to existing statistical approaches.

  15. Functional Nanoparticles Activate a Decellularized Liver Scaffold for Blood Detoxification.

    PubMed

    Xu, Fen; Kang, Tianyi; Deng, Jie; Liu, Junli; Chen, Xiaolei; Wang, Yuan; Ouyang, Liang; Du, Ting; Tang, Hong; Xu, Xiaoping; Chen, Shaochen; Du, Yanan; Shi, Yujun; Qian, Zhiyong; Wei, Yuquan; Deng, Hongxin; Gou, Maling

    2016-04-01

    Extracorporeal devices have great promise for cleansing the body of virulence factors that are caused by venomous injuries, bacterial infections, and biological weaponry. The clinically used extracorporeal devices, such as artificial liver-support systems that are mainly based on dialysis or electrostatic interaction, are limited to remove a target toxin. Here, a liver-mimetic device is shown that consists of decellularized liver scaffold (DLS) populated with polydiacetylene (PDA) nanoparticles. DLS has the gross shape and 3D architecture of a liver, and the PDA nanoparticles selectively capture and neutralize the pore-forming toxins (PFTs). This device can efficiently and target-orientedly remove PFTs in human blood ex vivo without changing blood components or activating complement factors, showing potential application in antidotal therapy. This work provides a proof-of-principle for blood detoxification by a nanoparticle-activated DLS, and can lead to the development of future medical devices for antidotal therapy.

  16. The effects of melatonin on liver functions in arsenic-induced liver damage

    PubMed Central

    Bali, İlhan; Bilir, Bülent; Emir, Seyfi; Turan, Filiz; Yılmaz, Ahsen; Gökkuş, Tuba; Aydın, Murat

    2016-01-01

    Objective Arsenic exposure is increasing in communities due to environmental pollution and industrial development. Arsenic is toxic to organ systems because it causes oxidative stress, enzymatic inhibition, and damage to protein structures. The liver, for example, is an organ that may be damaged by arsenic, and this damage may cause various clinical conditions like hepatic failure or cancer. Melatonin is a hormone that acts like an antioxidant, an anti-inflammatory agent, and a cytoprotective agent. In this study, we aimed to evaluate melatonin’s protective effects on livers damaged by arsenic toxicity. Materials and Methods Twenty-four Sprague-Dawley male rats were classified into three groups: a control group, an arsenic applied group, and an arsenic plus 10 mg/kg melatonin applied group. At the end of the fifteen-day experiment, the rats were sacrificed. Albumin, interleukin-6 (IL-6), total protein, alanine transaminase, aspartate transaminase, macrophage migration inhibitory factor, and monocyte chemotactic protein-1 measurements were obtained. Results In rats with liver damage due to arsenic exposure, melatonin administration significantly decreased the levels of IL-6, macrophage migration inhibitory factor, and monocyte chemotactic protein-1 (p<0.001, p=0.02 and p=0.04, respectively). Conclusion After evaluating liver enzymes and inflammatory markers, this study determined that melatonin exposure improves liver tissue damage caused by arsenic exposure, with the degree of improvement varying based on the levels of arsenic exposure. PMID:28149117

  17. Quantitative assessment of rabbit alveolar macrophage function by chemiluminescence

    SciTech Connect

    Brennan, P.C.; Kirchner, F.R.

    1985-08-01

    Rabbit alveolar macrophages (RAM) were cultured for 24 hr with concentrations ranging from 3 to 12 ..mu..g/ml of vanadium oxide (V/sub 2/O/sub 5/), a known cytotoxic agent, or with high-molecular-weight organic by-products from coal gasification processes. After culture the cells were harvested and tested for functional capacity using three types of indicators: (1) luminol-amplified chemiluminescence (CL), which quantitatively detects photon emission due to respiratory burst activity measured in a newly designed instrument with standardized reagents; (2) the reduction of nitro blue tetrazolium-saturated polyacrylamide beads, a semiquantitative measure of respiratory burst activity; and (3) phagocytic efficiency, defined as percentage of cells incorporating immunoglobulin-coated polyacrylamide beads. Chemiluminescence declined linearly with increasing concentrations of V/sub 2/O/sub 5/ over the dose range tested. Dye reduction and phagocytic efficiency similarly decreased with increasing V/sub 2/O/sub 5/ concentration, but were less sensitive indicators of functional impairment than CL as measured by the amount required to reduce the response to 50% of untreated cells. The effect of coal gasification condensates on RAM function varied, but in general these test also indicated that the CL response was the most sensitive indicator.

  18. [Functional state of the liver at modeling hemodynamic effects of the weightlessness in human organism].

    PubMed

    Afonin, B V; Ermolenko, A E; Inozemtsev, S L

    2012-01-01

    The radioisotope researches (RR) ofcholeresis function of a liver, the ultrasonic researches (USR) of a liver, the contractile gallbladder function (GF) and the gastroduodenoscopy (GDS) were carried out at 8 men after 24 hour duration of stay in antiorthostatic position--12 degrees (AOP), simulating arising in weightlessness of hemodynamics changes in abdominal cavity. The dynamic difficulty of venous blood outflow from a liver at simulated in antiorthostatic position changes of activation choleresis on an empty stomach was produced, by increase of a zone central perfusion of a liver parenchyma, biliary ductules dilation and of a gallbladder reduction, and were accompanied by choleresis in duodenum. The activation choleresis in a liver was accompanied by of reduction of the area of radioactive marker distribution in a liver, the decrease of hepatocytes metabolic activity and concentration function ofbiliary excretion system. Specificity of a functional condition of a liver within AOP reflects reaction caused by plethoric changes induced by body position, which is negative to vector of gravity. The mechanism of the revealed changes includes occurrence dynamic venous plethora in a liver, centralization hepatic blood flow with activation choleresis activity against the background tissual blood flow depletion in peripheral zones, reduction of hepatocytes metabolic activity and concentration function biliary excretion system.

  19. What Is Liver Cancer?

    MedlinePlus

    ... Treatment? Liver Cancer About Liver Cancer What Is Liver Cancer? Cancer starts when cells in the body ... structure and function of the liver. About the liver The liver is the largest internal organ. It ...

  20. The quantitative distinction of hyperplasia from hypertrophy in hepatomegaly induced in the rat liver by phenobarbital.

    PubMed

    Carthew, P; Edwards, R E; Nolan, B M

    1998-07-01

    A histological method utilizing the optical dissector principle has been developed for determining the absolute numbers of rat hepatocytes in the liver after treatment with phenobarbital (PB). The optical dissector is a technique derived from the "new stereology" used to measure the number of features, in this case hepatocyte nuclear profiles, that are present in a reference volume of tissue. The method has been applied to distinguish between the hepatomegaly that commonly occurs in rodents after treatment with chemicals, due to an increase in the number of cells caused by cell division (hyperplasia), rather than the size of cells (hypertrophy). In the case of PB treatment, the hepatomegaly was found to be partly due to hypertrophy and partly to hyperplasia after 2 weeks of treatment. While the increase in the absolute number of hepatocytes was not significant after 2 weeks, after 12 weeks of treatment with PB the number of hepatocytes was significantly increased, compared to the controls at that time point. PCNA labeling index measurements of liver hepatocytes confirmed that there was a significant increase in the growth fraction of hepatocytes during PB treatment. The induction of hyperplasia can be associated with an increased risk of eventual liver tumor formation, and the distinction of hyperplasia from hypertrophy, using a purely histological method, for the determination of increases in absolute hepatocyte cell numbers, will be useful in assessing whether treatment-related sustained hyperplasia is occurring in the liver, although this methodology could be applied to any organ.

  1. Quantitative Proteomic Profiles of Androgen Receptor Signaling in the Liver of Fathead Minnows Pimephalus promelas

    EPA Science Inventory

    Androgenic chemicals are present in the environment at concentrations that impair reproductive processes in fish. The objective of this experiment was to identify proteins altered by an androgen receptor agonist (17â-trenbolone) and antagonist (flutamide) in the liver. Female fa...

  2. The multiple functions of heme oxygenase-1 in the liver.

    PubMed

    Sass, G; Barikbin, R; Tiegs, G

    2012-01-01

    Heme oxygenases (HO) are essential enzymes which degrade heme into carbon monoxide (CO), biliverdin and free iron. Due to its anti-inflammatory, anti-apoptotic and, as recently described, anti-viral properties the inducible HO isoform HO-1 is an important molecule which could find its way into therapy of gastrointestinal diseases. Acute and chronic liver injuries including acute liver failure, alcoholic or viral hepatitis, chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are life threatening diseases and as a consequence might result in the necessity of liver transplantation. HO-1 as well as its reaction products of heme degradation has been linked to cytoprotection. HO-1 induction in rodent models of acute and chronic hepatic inflammation resulted in improvement of liver damage and down-regulation of pro-inflammatory cytokine levels. Furthermore HO-1 induction interfered with fibrosis progression in mice and partially resolved existing fibrosis. Likewise, HO-1 induction interfered with replication of hepatitis viruses B and C, which frequently are the reason for chronic hepatitis and subsequent tumor growth. Liver transplantation is limited by ischemia/reperfusion (I/R) injury, which is characterized by hypoxia and nutrient deficiency resulting in oxidative stress, apoptosis and immune activation. Induction of HO-1 and application predominantly of CO have been shown to interfere with I/R liver injury and to improve recipient and graft survival. On the other hand HO-1 has been shown to be over-expressed in various tumors, including hepatocellular carcinoma (HCC). Due to its anti-apoptotic properties this bears the risk to promote tumor growth. Anti-apoptotic effects are predominantly mediated by CO. This review aims to summarize beneficial as well as detrimental effects of HO-1 and its products within the liver.

  3. Quantitative Assessment of Neuromotor Function in Adolescents with High Functioning Autism and Asperger Syndrome

    ERIC Educational Resources Information Center

    Freitag, Christine M.; Kleser, Christina; Schneider, Marc; von Gontard, Alexander

    2007-01-01

    Background: Motor impairment in children with Asperger Syndrome (AS) or High functioning autism (HFA) has been reported previously. This study presents results of a quantitative assessment of neuromotor skills in 14-22 year old HFA/AS. Methods: 16 HFA/AS and 16 IQ-matched controls were assessed by the Zurich Neuromotor Assessment (ZNA). Results:…

  4. Molecular acidity: A quantitative conceptual density functional theory description.

    PubMed

    Liu, Shubin; Schauer, Cynthia K; Pedersen, Lee G

    2009-10-28

    Accurate predictions of molecular acidity using ab initio and density functional approaches are still a daunting task. Using electronic and reactivity properties, one can quantitatively estimate pKa values of acids. In a recent paper [S. B. Liu and L. G. Pedersen, J. Phys. Chem. A 113, 3648 (2009)], we employed the molecular electrostatic potential (MEP) on the nucleus and the sum of valence natural atomic orbital (NAO) energies for the purpose. In this work, we reformulate these relationships on the basis of conceptual density functional theory and compare the results with those from the thermodynamic cycle method. We show that MEP and NAO properties of the dissociating proton of an acid should satisfy the same relationships with experimental pKa data. We employ 27 main groups and first to third row transition metal-water complexes as illustrative examples to numerically verify the validity of these strong linear correlations. Results also show that the accuracy of our approach and that of the conventional method through the thermodynamic cycle are statistically similar.

  5. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis

    PubMed Central

    Patel, Janki; Bettencourt, Ricki; Cui, Jeffrey; Salotti, Joanie; Hooker, Jonathan; Bhatt, Archana; Hernandez, Carolyn; Nguyen, Phirum; Aryafar, Hamed; Valasek, Mark; Haufe, William; Hooker, Catherine; Richards, Lisa; Sirlin, Claude B.; Loomba, Rohit

    2016-01-01

    Background: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. Methods: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. Results: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of −4.1% ± 4.9 versus −0.6 ± 4.1 (p < 0.04) with a mean relative percent change of −29.3% ± 33.0 versus +2.0% ± 24.0 (p < 0.004), respectively. Conclusions: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint. PMID:27582882

  6. Quantitative proteomics of rat livers shows that unrestricted feeding is stressful for proteostasis with implications on life span

    PubMed Central

    Pinto, Galit; Quadroni, Manfredo; Shtaif, Biana; Goloubinoff, Pierre

    2016-01-01

    Studies in young mammals on the molecular effects of food restriction leading to prolong adult life are scares. Here, we used high-throughput quantitative proteomic analysis of whole rat livers to address the molecular basis for growth arrest and the apparent life-prolonging phenotype of the food restriction regimen. Over 1800 common proteins were significantly quantified in livers of ad libitum, restriction- and re-fed rats, which summed up into 92% of the total protein mass of the cells. Compared to restriction, ad libitum cells contained significantly less mitochondrial catabolic enzymes and more cytosolic and ER HSP90 and HSP70 chaperones, which are hallmarks of heat- and chemically-stressed tissues. Following re-feeding, levels of HSPs nearly reached ad libitum levels. The quantitative and qualitative protein values indicated that the restriction regimen was a least stressful condition that used minimal amounts of HSP-chaperones to maintain optimal protein homeostasis and sustain optimal life span. In contrast, the elevated levels of HSP-chaperones in ad libitum tissues were characteristic of a chronic stress, which in the long term could lead to early aging and shorter life span. PMID:27508340

  7. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice.

    PubMed

    Pumford, N R; Hinson, J A; Potter, D W; Rowland, K L; Benson, R W; Roberts, D W

    1989-01-01

    Using a recently developed enzyme-linked immunosorbent assay specific for 3-(cystein-S-yl)acetaminophen adducts we have quantitated the formation of these specific adducts in liver and serum protein of B6C3F1 male mice dosed with acetaminophen. Administration of acetaminophen at doses of 50, 100, 200, 300, 400 and 500 mg/kg to mice resulted in evidence of hepatotoxicity (increase in serum levels of alanine aminotransferase and aspartate aminotransferase) at 4 hr in the 300, 400 and 500 mg/kg treatment groups only. The formation of 3-(cystein-S-yl)acetaminophen adducts in liver protein was not observed in the groups receiving 50, 100 and 200 mg/kg doses, but was observed in the groups receiving doses above 300 mg/kg of acetaminophen. Greater levels of adduct formation were observed at the higher doses. 3-(Cystein-S-yl)acetaminophen protein adducts were also observed in serum of mice receiving hepatotoxic doses of acetaminophen. After a 400 mg/kg dose of acetaminophen, 3-(cystein-S-yl)acetaminophen adducts in the liver protein reached peak levels 2 hr after dosing. By 12 hr the levels decreased to approximately 10% of the peak level. In contrast, 3-(cystein-S-yl)acetaminophen adducts in serum protein were delayed, reaching a sustained peak 6 to 12 hr after dosing. The dose-response correlation between the appearance of serum aminotransferases and 3-(cystein-S-yl)acetaminophen adducts in serum protein and the temporal correlation between the decrease in 3-(cystein-S-yl)acetaminophen adducts in liver protein and the appearance of adducts in serum protein are consistent with a hepatic origin of the adducts detected in serum protein.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Determining liver stage parasite burden by real time quantitative PCR as a method for evaluating pre-erythrocytic malaria vaccine efficacy.

    PubMed

    Witney, A A; Doolan, D L; Anthony, R M; Weiss, W R; Hoffman, S L; Carucci, D J

    2001-12-01

    The detection and quantitation of blood stage parasitaemia is typically used as a surrogate endpoint for estimating the efficacy of vaccines targeted against the hepatic stage, as well as the erythrocytic stage, of the parasite. However, this does not provide an adequate means of evaluating the efficacy of vaccines, which may be only partially effective at the liver-stage. This is a particular concern for effective evaluation of immune enhancement strategies for candidate pre-erythrocytic stage vaccines. Here, we have developed and validated a method for detecting and quantitating liver stage parasites, using the TaqMan fluorescent real-time quantitative PCR system (PE Applied Biosystems). This method uses TaqMan primers designed to the Plasmodium yoelii 18S rRNA gene and rodent GAPDH to amplify products from infected mouse liver cDNA. The technique is highly reproducible as demonstrated with plasmid controls and capable of efficiently quantitating liver-stage parasite burden following a range of sporozoite challenge doses in strains of mice, which differ in their susceptibility to sporozoite infection. We have further demonstrated the capacity of this technique to evaluate the efficacy of a range of pre-erythrocytic stage vaccines. Our data establish this quantitative real-time PCR assay to be a fast and reproducible way of accurately assessing liver stage parasite burden and vaccine efficacy in rodent malaria models.

  9. Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function

    PubMed Central

    2013-01-01

    Background Interindividual differences in liver functions such as protein synthesis, lipid and carbohydrate metabolism and drug metabolism are influenced by epigenetic factors. The role of the epigenetic machinery in such processes has, however, been barely investigated. 5-hydroxymethylcytosine (5hmC) is a recently re-discovered epigenetic DNA modification that plays an important role in the control of gene expression. Results In this study, we investigate 5hmC occurrence and genomic distribution in 8 fetal and 7 adult human liver samples in relation to ontogeny and function. LC-MS analysis shows that in the adult liver samples 5hmC comprises up to 1% of the total cytosine content, whereas in all fetal livers it is below 0.125%. Immunohistostaining of liver sections with a polyclonal anti-5hmC antibody shows that 5hmC is detected in most of the hepatocytes. Genome-wide mapping of the distribution of 5hmC in human liver samples by next-generation sequencing shows significant differences between fetal and adult livers. In adult livers, 5hmC occupancy is overrepresented in genes involved in active catabolic and metabolic processes, whereas 5hmC elements which are found in genes exclusively in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development. Conclusions Our findings suggest that 5-hydroxymethylcytosine plays an important role in the development and function of the human liver and might be an important determinant for development of liver diseases as well as of the interindividual differences in drug metabolism and toxicity. PMID:23958281

  10. An accurate method of extracting fat droplets in liver images for quantitative evaluation

    NASA Astrophysics Data System (ADS)

    Ishikawa, Masahiro; Kobayashi, Naoki; Komagata, Hideki; Shinoda, Kazuma; Yamaguchi, Masahiro; Abe, Tokiya; Hashiguchi, Akinori; Sakamoto, Michiie

    2015-03-01

    The steatosis in liver pathological tissue images is a promising indicator of nonalcoholic fatty liver disease (NAFLD) and the possible risk of hepatocellular carcinoma (HCC). The resulting values are also important for ensuring the automatic and accurate classification of HCC images, because the existence of many fat droplets is likely to create errors in quantifying the morphological features used in the process. In this study we propose a method that can automatically detect, and exclude regions with many fat droplets by using the feature values of colors, shapes and the arrangement of cell nuclei. We implement the method and confirm that it can accurately detect fat droplets and quantify the fat droplet ratio of actual images. This investigation also clarifies the effective characteristics that contribute to accurate detection.

  11. Simplified [18F]FDG Image-Derived Input Function Using the Left Ventricle, Liver, and One Venous Blood Sample

    PubMed Central

    Tantawy, Mohammed Noor; Peterson, Todd E.

    2014-01-01

    A relatively simple, almost entirely noninvasive imaging-based method is presented for deriving arterial blood input functions for quantitative [18F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomographic (PET) studies in rodents. It requires only one venous blood sample at the end of the scan. MicroPET images and arterial blood time-activity curves (TACs) were downloaded from the Mouse Quantitation Program database at the University of California, Los Angeles. Three-dimensional regions of interest were drawn around the blood-pool region of the left ventricle and within the liver to derive their respective TACs. To construct the “hybrid” image-derived input function (IDIF), the initial part of the left ventricle TAC, containing the peak concentration of [18F]FDG in the arterial blood, was corrected for spillout (ie, partial-volume effect yielding a recovery coefficient < 1) and then joined to the liver TAC (normalized to the 60-minute arterial blood sample) immediately after it peaks. To validate our method, the [18F]FDG influx constant (Ki) was estimated using a two-tissue compartment model and compared to estimates of Ki obtained using measured arterial blood TACs. No significant difference in the Ki estimates was obtained with the arterial blood input function and our hybrid IDIF. We conclude that the normalized hybrid IDIF can be used in practice to obtain reliable Ki estimates. PMID:20236605

  12. Differential proteomics analysis of liver failure in peripheral blood mononuclear cells using isobaric tags for relative and absolute quantitation

    PubMed Central

    Lin, Hua; Tan, Qiu-Pei; Sui, Wei-Guo; Chen, Wen-Biao; Peng, Wu-Jian; Liu, Xing-Chao; Dai, Yong

    2017-01-01

    The aim of the present study was to examine differentially expressed proteome profiles for candidate biomarkers in peripheral blood mononuclear cells (PBMCs) of liver failure (LF) patients. Ten patients were diagnosed as LF and 10 age- and gender-matched subjects were recruited as healthy controls. Isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic technology is efficiently applicable for identification and relative quantitation of the proteomes of PBMCs. Eight-plex iTRAQ coupled with strong cation exchange chromatography, and liquid chromatography coupled with tandem mass spectrometry were used to analyze total proteins in LF patients and healthy control subjects. Molecular variations were detected using the iTRAQ method, and western blotting was used to verify the results. LF is a complex type of medical emergency that evolves following a catastrophic insult to the liver, and its outcome remains the most ominous of all gastroenterologic diseases. Serious complications tend to occur during the course of the disease and further exacerbate the problems. Using the iTRAQ method, differentially expressed proteome profiles of LF patients were determined. In the present study, 627 proteins with different expression levels were identified in LF patients compared with the control subjects; with 409 proteins upregulated and 218 proteins downregulated. Among them, four proteins were significantly differentially expressed; acylaminoacyl-peptide hydrolase and WW domain binding protein 2 were upregulated, and resistin and tubulin β 2A class IIa were downregulated. These proteins demonstrated differences in their expression levels compared with other proteins with normal expression levels and the significant positive correlation with LF. The western blot results were consistent with the results from iTRAQ. Thus, investigation of the molecular mechanism of the proteins involved in LF may facilitate an improved understanding of the

  13. Oral glucose tolerance test for preoperative assessment of liver function in liver resection

    PubMed Central

    Rachapoodivenkata, Raghavendra Rao

    2017-01-01

    Backgrounds/Aims We intended to determine the role of the Oral glucose tolerance test (OGTT), in addition to volumetry, in preoperative assessment of patients undergoing liver resection. Methods This was a prospective study conducted at a tertiary care hospital, between February 2009 and February 2011. OGTT curve (parabolic/linear), linearity index (LI) and Parenchymal Hepatic Resection Rate (PHRR) were correlated with postoperative outcomes in terms of postoperative liver failure (PLF), by 50-50 criteria, morbidity, mortality and hospital stay. Results Of the 33 patients included in the study, 23 (69.7%) patients underwent major liver resections. Hepatocellular carcinoma (30.3%) was the leading indication. The overall postoperative morbidity rate was 72.7%, but major complications occurred in 3 (9.1%) patients only. There was no 90-day mortality. The 50-50 criteria were met by 3 patients undergoing major resection. Significant correlation was noted between the linear OGTT curve and the overall hospital stay (12.1 days vs. 9.6 days in parabolic; p=0.04). Patients with linear OGTT met the 50-50 criteria more often (18%) than those having a parabolic curve (4.5%; p=0.25). Although the OGTT was more often linear with occurrence of morbidity (41.7% vs 11.1%), major morbidity (66.7% vs 30%) and PLF by 50-50 criteria (66.7% vs 30%), it was not statistically significant. The linearity index was marginally lower (0.9 vs 1.2) in the presence of major morbidity and PLF by 50-50 criteria. Conclusions Linear OGTT affects the PLF and major morbidity, therein impacting the hospital stay. OGTT LI and PHRR can help predict postoperative outcome for a given extent of liver resection. PMID:28317039

  14. Quantitative MR Imaging of Hepatic Steatosis: Validation in Ex Vivo Human Livers

    PubMed Central

    Bannas, Peter; Kramer, Harald; Hernando, Diego; Agni, Rashmi; Cunningham, Ashley M.; Mandal, Rakesh; Motosugi, Utaroh; Sharma, Samir D.; del Rio, Alejandro Munoz; Fernandez, Luis; Reeder, Scott B.

    2015-01-01

    Emerging magnetic resonance imaging (MRI) biomarkers of hepatic steatosis have demonstrated tremendous promise for accurate quantification of hepatic triglyceride concentration. These methods quantify the “proton density fat-fraction” (PDFF), which reflects the concentration of triglycerides in tissue. Previous in vivo studies have compared MRI-PDFF with histologic steatosis grading for assessment of hepatic steatosis. However, the correlation of MRI-PDFF with the underlying hepatic triglyceride content remained unknown. The aim of this ex vivo study was to validate the accuracy of MRI-PDFF as an imaging biomarker of hepatic steatosis. Using ex vivo human livers, we compared MRI-PDFF with magnetic resonance spectroscopy-PDFF (MRS-PDFF), biochemical triglyceride extraction and histology as three independent reference standards. A secondary aim was to compare the precision of MRI-PDFF relative to biopsy for the quantification of hepatic steatosis. MRI-PDFF was prospectively performed at 1.5T in 13 explanted human livers. We performed co-localized paired evaluation of liver fat content in all nine Couinaud segments using single-voxel MRS-PDFF (n=117), tissue wedges for biochemical triglyceride extraction (n=117), and five core biopsies performed in each segment for histologic grading (n=585). Accuracy of MRI-PDFF was assessed through linear regression with MRS-PDFF, triglyceride extraction and histology. Intra-observer agreement, inter-observer agreement and repeatability of MRI-PDFF and histologic grading were assessed through Bland-Altman analyses. MRI-PDFF showed an excellent correlation with MRS-PDFF (r=0.984; CI: 0.978–0.989) and strong correlation with histology (r=0.850; CI: 0.791–0.894) and triglyceride extraction (r=0.871; CI: 0.818–0.909). Intra-observer agreement, inter-observer agreement and repeatability showed a significantly smaller variance for MRI-PDFF than for histologic steatosis grading (all p<0.001). Conclusion MRI-PDFF is an accurate

  15. Importance of Endocytic Pathways in Liver Function and Disease

    PubMed Central

    Schroeder, Barbara; McNiven, Mark A.

    2015-01-01

    Hepatocellular endocytosis is a highly dynamic process responsible for the internalization of a variety of different receptor ligand complexes, trophic factors, lipids, and, unfortunately, many different pathogens. The uptake of these external agents has profound effects on seminal cellular processes including signaling cascades, migration, growth, and proliferation. The hepatocyte, like other well-polarized epithelial cells, posses a host of different endocytic mechanisms and entry routes to ensure the selective internalization of cargo molecules. These pathways include receptor-mediated endocytosis, lipid raft associated endocytosis, caveolae, or fluid-phase uptake although there are likely many others. Understanding and defining the regulatory mechanisms underlying these distinct entry routes, sorting and vesicle formation, as well as the postendocytic trafficking pathways is of high importance especially in the liver, as their mis-regulation can contribute to aberrant liver pathology and liver diseases. Further, these processes can be “hijacked” by a variety of different infectious agents and viruses. This review provides an overview of common components of the endocytic and postendocytic trafficking pathways utilized by hepatocytes. It will also discuss in more detail how these general themes apply to liver-specific processes including iron homeostasis, HBV infection, and even hepatic steatosis. PMID:25428849

  16. Quantitative evaluation of statistical inference in resting state functional MRI.

    PubMed

    Yang, Xue; Kang, Hakmook; Newton, Allen; Landman, Bennett A

    2012-01-01

    Modern statistical inference techniques may be able to improve the sensitivity and specificity of resting state functional MRI (rs-fMRI) connectivity analysis through more realistic characterization of distributional assumptions. In simulation, the advantages of such modern methods are readily demonstrable. However quantitative empirical validation remains elusive in vivo as the true connectivity patterns are unknown and noise/artifact distributions are challenging to characterize with high fidelity. Recent innovations in capturing finite sample behavior of asymptotically consistent estimators (i.e., SIMulation and EXtrapolation - SIMEX) have enabled direct estimation of bias given single datasets. Herein, we leverage the theoretical core of SIMEX to study the properties of inference methods in the face of diminishing data (in contrast to increasing noise). The stability of inference methods with respect to synthetic loss of empirical data (defined as resilience) is used to quantify the empirical performance of one inference method relative to another. We illustrate this new approach in a comparison of ordinary and robust inference methods with rs-fMRI.

  17. Cognitive and Adaptive Functioning after Liver Transplantation for Maple Syrup Urine Disease: A Case Series

    PubMed Central

    Shellmer, D. A.; Dabbs, A. DeVito; Dew, M. A.; Noll, R. B.; Feldman, H.; Strauss, K.; Morton, D. H.; Vockley, G.; Mazariegos, G. V.

    2011-01-01

    MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one year and/or three years post-liver transplantation. Findings show either no significant change or improvement in IQ scores pre- to post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced either no significant change or improvement in adaptive scores. In general, findings may indicate that liver transplantation curtails additional central nervous system damage and neurocognitive decline providing an opportunity for stabilization or improvement in functioning. PMID:20946191

  18. Quantitative ionization energies and work functions of aqueous solutions.

    PubMed

    Olivieri, Giorgia; Goel, Alok; Kleibert, Armin; Cvetko, Dean; Brown, Matthew A

    2016-10-26

    Despite the ubiquitous nature of aqueous solutions across the chemical, biological and environmental sciences our experimental understanding of their electronic structure is rudimentary-qualitative at best. One of the most basic and seemingly straightforward properties of aqueous solutions-ionization energies-are (qualitatively) tabulated at the water-air interface for a mere handful of solutes, and the manner in which these results are obtained assume the aqueous solutions behave like a gas in the photoelectron experiment (where the vacuum levels of the aqueous solution and of the photoelectron analyzer are equilibrated). Here we report the experimental measure of a sizeable offset (ca. 0.6 eV) between the vacuum levels of an aqueous solution (0.05 M NaCl) and that of our photoelectron analyzer, indicating a breakdown of the gas-like vacuum level alignment assumption for the aqueous solution. By quantifying the vacuum level offset as a function of solution chemical composition our measurements enable, for the first time, quantitative determination of ionization energies in liquid solutions. These results reveal that the ionization energy of liquid water is not independent of the chemical composition of the solution as is usually inferred in the literature, a finding that has important ramifications as measured ionization energies are frequently used to validate theoretical models that posses the ability to provide microscopic insight not directly available by experiment. Finally, we derive the work function, or the electrochemical potential of the aqueous solution and show that it too varies with the chemical composition of the solution.

  19. Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging

    PubMed Central

    Pepe, Alessia; Meloni, Antonella; Capra, Marcello; Cianciulli, Paolo; Prossomariti, Luciano; Malaventura, Cristina; Putti, Maria Caterina; Lippi, Alma; Romeo, Maria Antonietta; Bisconte, Maria Grazia; Filosa, Aldo; Caruso, Vincenzo; Quarta, Antonella; Pitrolo, Lorella; Missere, Massimiliano; Midiri, Massimo; Rossi, Giuseppe; Positano, Vincenzo; Lombardi, Massimo; Maggio, Aurelio

    2011-01-01

    Background Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. Design and Methods From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique. Results The global heart T2* value was significantly higher in the deferiprone (34±11ms) than in the deferasirox (21±12 ms) and the desferrioxamine groups (27±11 ms) (P=0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P=0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P=0.004). Conclusions The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine. PMID:20884710

  20. Analysis of liver connexin expression using reverse transcription quantitative real-time polymerase chain reaction

    PubMed Central

    Maes, Michaël; Willebrords, Joost; Crespo Yanguas, Sara; Cogliati, Bruno; Vinken, Mathieu

    2016-01-01

    Summary Although connexin production is mainly regulated at the protein level, altered connexin gene expression has been identified as the underlying mechanism of several pathologies. When studying the latter, appropriate methods to quantify connexin mRNA levels are required. The present chapter describes a well-established reverse transcription quantitative real-time polymerase chain reaction procedure optimized for analysis of hepatic connexins. The method includes RNA extraction and subsequent quantification, generation of complementary DNA, quantitative real-time polymerase chain reaction and data analysis. PMID:27207283

  1. Liver Panel

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Liver Panel Share this page: Was this page helpful? Also known as: Liver Profile; Liver Function Tests; LFTs Formal name: Hepatic ...

  2. Effect of Non-speckle Echo Signals on Tissue Characteristics for Liver Fibrosis using Probability Density Function of Ultrasonic B-mode image

    NASA Astrophysics Data System (ADS)

    Mori, Shohei; Hirata, Shinnosuke; Yamaguchi, Tadashi; Hachiya, Hiroyuki

    To develop a quantitative diagnostic method for liver fibrosis using an ultrasound B-mode image, a probability imaging method of tissue characteristics based on a multi-Rayleigh model, which expresses a probability density function of echo signals from liver fibrosis, has been proposed. In this paper, an effect of non-speckle echo signals on tissue characteristics estimated from the multi-Rayleigh model was evaluated. Non-speckle signals were determined and removed using the modeling error of the multi-Rayleigh model. The correct tissue characteristics of fibrotic tissue could be estimated with the removal of non-speckle signals.

  3. Assessment of liver function among nickel-plating workers in Egypt.

    PubMed

    El-Shafei, H M

    2011-06-01

    Currently no reports are available from Egypt regarding occupational exposure to nickel and its effects on the liver. The aim of this study was to assess the liver function of workers occupationally exposed to nickel. Standard liver function tests were applied to blood samples from 25 nickel-plating workers in Damietta, Egypt and 30 administrative workers as a reference group. Levels of urine nickel, measured by inductively coupling plasma-emission spectroscopy, were significantly higher in nickel-exposed workers compared with the reference group. The levels of alanine aminotransferase and aspartate aminotransferase were significantly higher in nickel-exposed workers. The level of serum albumin was significantly negatively correlated and the levels of serum aminotransferases, and serum gamma-glutamyl-transpeptidase were significantly positively correlated with urine nickel levels. Liver function is compromised in nickel-plating workers compared with non-exposed administrative workers.

  4. Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.

    PubMed Central

    Reichen, J; Egger, B; Ohara, N; Zeltner, T B; Zysset, T; Zimmermann, A

    1988-01-01

    We investigated the determinants of hepatic clearance functions in a rat model of liver cirrhosis induced by phenobarbital/CCl4. Aminopyrine N-demethylation (ABT), galactose elimination (GBT), and serum bile acids (SBA) were determined in vivo. The livers were then characterized hemodynamically: intrahepatic shunting (IHS) was determined by microspheres and sinusoidal capillarization by measuring the extravascular albumin space (EVA) by a multiple indicator dilution technique. The intrinsic clearance was determined by assaying the activity of the rate-limiting enzymes in vitro. Hepatocellular volume (HCV) was measured by morphometry. ABT and SBA, but not GBT, differentiated cirrhotic from normal liver. IHS ranged from normal to 10%; all cirrhotic livers showed evidence of sinusoidal capillarization (reduced EVA). The cirrhotic livers showed a bimodal distribution of HCV, HCV being decreased in 50% of the cirrhotic livers. Multivariate analysis showed EVA and portal flow to be the main determinants of microsomal (ABT) and cytosolic (GBT) clearance function; SBA, by contrast, were determined solely by IHS. We conclude that sinusoidal capillarization is the main determinant of hepatic clearance, while serum bile acids reflect intrahepatic shunting. These findings emphasize the importance of alterations of hepatic nutritional flow to explain reduced clearance function in cirrhosis of the liver. PMID:3198765

  5. Lifelong maintenance of composition, function and cellular/subcellular distribution of proteasomes in human liver.

    PubMed

    Bellavista, Elena; Martucci, Morena; Vasuri, Francesco; Santoro, Aurelia; Mishto, Michele; Kloss, Alexander; Capizzi, Elisa; Degiovanni, Alessio; Lanzarini, Catia; Remondini, Daniel; Dazzi, Alessandro; Pellegrini, Sara; Cescon, Matteo; Capri, Miriam; Salvioli, Stefano; D'Errico-Grigioni, Antonia; Dahlmann, Burkhardt; Grazi, Gian Luca; Franceschi, Claudio

    2014-01-01

    Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of β5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation.

  6. Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets.

    PubMed

    Ohashi, Kazuo; Yokoyama, Takashi; Yamato, Masayuki; Kuge, Hiroyuki; Kanehiro, Hiromichi; Tsutsumi, Masahiro; Amanuma, Toshihiro; Iwata, Hiroo; Yang, Joseph; Okano, Teruo; Nakajima, Yoshiyuki

    2007-07-01

    Hepatic tissue engineering using primary hepatocytes has been considered a valuable new therapeutic modality for several classes of liver diseases. Recent progress in the development of clinically feasible liver tissue engineering approaches, however, has been hampered mainly by insufficient cell-to-cell contact of the engrafted hepatocytes. We developed a method to engineer a uniformly continuous sheet of hepatic tissue using isolated primary hepatocytes cultured on temperature-responsive surfaces. Sheets of hepatic tissue transplanted into the subcutaneous space resulted in efficient engraftment to the surrounding cells, with the formation of two-dimensional hepatic tissues that stably persisted for longer than 200 d. The engineered hepatic tissues also showed several characteristics of liver-specific functionality. Additionally, when the hepatic tissue sheets were layered in vivo, three-dimensional miniature liver systems having persistent survivability could be also engineered. This technology for liver tissue engineering is simple, minimally invasive and free of potentially immunogenic biodegradable scaffolds.

  7. Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

    PubMed Central

    Ehler, Johannes; Wagner, Nana-Maria

    2017-01-01

    Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients. PMID:28255555

  8. Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

    PubMed

    Sauer, Martin; Doß, Sandra; Ehler, Johannes; Mencke, Thomas; Wagner, Nana-Maria

    2017-01-01

    Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01-50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.

  9. Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging

    PubMed Central

    Cao, Yue; Wang, Hesheng; Johnson, Timothy D.; Pan, Charlie; Hussain, Hero; Balter, James M.; Normolle, Daniel; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

    2013-01-01

    Purpose To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. Methods and Materials Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. Results There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. Conclusions This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which

  10. Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging

    SciTech Connect

    Cao Yue; Wang Hesheng; Johnson, Timothy D.; Pan, Charlie; Hussain, Hero; Balter, James M.; Normolle, Daniel; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

    2013-01-01

    Purpose: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. Methods and Materials: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. Results: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. Conclusions: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which

  11. In vivo quantitative visualization of hypochlorous acid in the liver using a novel selective two-photon fluorescent probe

    NASA Astrophysics Data System (ADS)

    Wang, Haolu; Jayachandran, Aparna; Gravot, Germain; Liang, Xiaowen; Thorling, Camilla A.; Zhang, Run; Liu, Xin; Roberts, Michael S.

    2016-11-01

    Hypochlorous acid (HOCl) plays a vital role in physiological events and diseases. During hepatic ischemia-reperfusion (I/R) injury, HOCl is generated by neutrophils and diffuses into hepatocytes, causing oxidant stress-mediated injury. Although many probes have been developed to detect HOCl, most were difficult to be distinguished from endogenous fluorophores in intravital imaging and only can be employed under one-photon microscopy. A novel iridium(III) complex-based ferrocene dual-signaling chemosensor (Ir-Fc) was designed and synthesized. Ir-Fc exhibited a strong positive fluorescent response only in the presence of HOCl, whereas negligible fluorescent signals were observed upon the additions of other reactive oxygen/nitrogen species and metal ions. There was a good linear relationship between probe responsive fluorescent intensity and HOCl concentration. Ir-Fc was then intravenously injected into BALB/c mice at the final concentration of 50 μM and the mouse livers were imaged using multiphoton microscopy (MPM). In the I/R liver, reduced autofluorescence was detected by MPM, indicating the hepatocyte necrosis. Remarkable enhancement of red fluorescence was observed in hepatocytes with decreased autofluorescence, indicating the reaction of Ir-Fc with endogenous HOCl molecules. The cellular concentration of HOCl was first calculated based on the intensity of MPM images. No obvious toxic effects were observed in histological examination of major organs after Ir-Fc injection. In summary, Ir-Fc has low cytotoxicity, high specificity to HOCl, and rapid "off-on" fluorescence. It is suitable for dynamic quantitatively monitoring HOCl generation using MPM at the cellular level. This technique can be readily extended to examination of liver diseases and injury.

  12. Mechanical Model Analysis for Quantitative Evaluation of Liver Fibrosis Based on Ultrasound Tissue Elasticity Imaging

    NASA Astrophysics Data System (ADS)

    Shiina, Tsuyoshi; Maki, Tomonori; Yamakawa, Makoto; Mitake, Tsuyoshi; Kudo, Masatoshi; Fujimoto, Kenji

    2012-07-01

    Precise evaluation of the stage of chronic hepatitis C with respect to fibrosis has become an important issue to prevent the occurrence of cirrhosis and to initiate appropriate therapeutic intervention such as viral eradication using interferon. Ultrasound tissue elasticity imaging, i.e., elastography can visualize tissue hardness/softness, and its clinical usefulness has been studied to detect and evaluate tumors. We have recently reported that the texture of elasticity image changes as fibrosis progresses. To evaluate fibrosis progression quantitatively on the basis of ultrasound tissue elasticity imaging, we introduced a mechanical model of fibrosis progression and simulated the process by which hepatic fibrosis affects elasticity images and compared the results with those clinical data analysis. As a result, it was confirmed that even in diffuse diseases like chronic hepatitis, the patterns of elasticity images are related to fibrous structural changes caused by hepatic disease and can be used to derive features for quantitative evaluation of fibrosis stage.

  13. Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

    PubMed

    Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

    2016-07-05

    The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

  14. Modeled Perfluorooctanoic Acid (PFOA) Exposure and Liver Function in a Mid-Ohio Valley Community

    PubMed Central

    Darrow, Lyndsey A.; Groth, Alyx C.; Winquist, Andrea; Shin, Hyeong-Moo; Bartell, Scott M.; Steenland, Kyle

    2016-01-01

    diagnosed liver disease. Citation: Darrow LA, Groth AC, Winquist A, Shin HM, Bartell SM, Steenland K. 2016. Modeled perfluorooctanoic acid (PFOA) exposure and liver function in a Mid-Ohio Valley community. Environ Health Perspect 124:1227–1233; http://dx.doi.org/10.1289/ehp.1510391 PMID:26978841

  15. WE-EF-210-05: Diagnosis and Quantification of Liver Steatosis with Quantitative Ultrasound Backscatter Technique

    SciTech Connect

    Andre, M; Heba, E; Lin, S; Wolfson, T; Ang, B; Gamst, A; Sirlin, C; Loomba, R; Han, A; Erdman, J; O’Brien, W

    2015-06-15

    Purpose: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, affects 30% of adult Americans and may progress to more serious diseases. Liver biopsy is the standard method for diagnosing NAFLD. MRI can accurately diagnose and quantify hepatic steatosis but is expensive. Sonography with qualitative interpretation by radiologists is lower cost, more accessible but less sensitive for detection. The objective of this study, using MRI proton density fat fraction (PDFF) as reference, is to assess the accuracy for diagnosing and quantifying steatosis with two quantitative US parameters-- backscatter coefficient (BSC) and attenuation coefficient (AC)--derived from RF signals using the calibration phantom technique. Methods: We performed a prospective, cross-sectional analysis of a cohort of adults (n=204) with NAFLD (MRI-PDFF≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and BSC and AC US analyses of the liver on the same day. Patients were randomly assigned to training (n=102, mean age 51±17 years, mean body mass index 31±7 kg/m{sup 2}) and validation (n=102, mean age 49±17 years, body mass index 30±6 kg/m{sup 2}) groups; 69% of patients in each group had NAFLD. Results: BSC provided AUC 0.98 (95% CI 0.95–1.00, p<0.0001) for diagnosis of NAFLD; the optimal BSC cut-off provided sensitivity, specificity, positive and negative predictive values (PPV, NPV) of 87%, 91%, 95%, and 76%, respectively. AC provided AUC 0.89 (95% CI 0.81–0.96, p<0.0001) for diagnosis of steatosis; the optimal AC cut-off provided sensitivity, specificity, PPV, NPV of 80%, 84%, 92%, and 66%, respectively. BSC and AC both correlated significantly with MRI-PDFF (P<0.0001). Conclusion: QUS BSC and AC can accurately diagnose and quantify hepatic steatosis, using MRI-PDFF as reference. With further validation, QUS may emerge as an inexpensive, widely available tool for NAFLD assessment. General support: NIH R01 CA111289, K

  16. Role of functional imaging in treatment plan optimization of stereotactic body radiation therapy for liver cancer.

    PubMed

    De Bari, Berardino; Jumeau, Raphael; Deantonio, Letizia; Adib, Salim; Godin, Sarah; Zeverino, Michele; Moeckli, Raphael; Bourhis, Jean; Prior, John O; Ozsahin, Mahmut

    2016-10-13

    We report the first known instance of the clinical use of 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) for the optimization of radiotherapy treatment planning and for the follow-up of acute toxicity in a patient undergoing stereotactic body radiation therapy for hepatocellular carcinoma. In our experience, HBS allowed the identification and the sparing of more functioning liver areas, thus potentially reducing the risk of radiation-induced liver toxicity.

  17. Self-assembling functionalized nanopeptides for immediate hemostasis and accelerative liver tissue regeneration

    NASA Astrophysics Data System (ADS)

    Cheng, Tzu-Yun; Wu, Hsi-Chin; Huang, Ming-Yuan; Chang, Wen-Han; Lee, Chao-Hsiung; Wang, Tzu-Wei

    2013-03-01

    Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine.Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications

  18. Liver function in alpha-1-antitrypsin deficient individuals at 37 to 40 years of age

    PubMed Central

    Mostafavi, Behrouz; Diaz, Sandra; Tanash, Hanan A.; Piitulainen, Eeva

    2017-01-01

    Abstract Severe alpha-1-antitrypsin (AAT) deficiency (PiZZ) is a risk factor for liver disease, but the prevalence of liver cirrhosis and hepatocellular cancer in PiZZ adults is unknown. The risk of liver disease in adults with moderate AAT deficiency (PiSZ) is also unknown. A cohort of 127 PiZZ, 2 PiZnull, 54 PiSZ, and 1 PiSnull individuals were identified by the Swedish national neonatal AAT screening program between 1972 and 1974, when all 200,000 newborn infants in Sweden were screened for AAT deficiency. The cohort has been followed up since birth. Our aim was to study liver function and signs of liver disease in this cohort at 37 to 40 years of age in comparison with a matched, random sample of control subjects identified from the population registry. Eighty seven PiZZ, 32 PiSZ, and 92 control subjects (PiMM) answered a questionnaire on medication and alcohol consumption and provided blood samples. Liver stiffness was assessed by Acoustic Radiation Force Impulse (ARFI) elastography in 32 PiZZ, 15 PiSZ, and 51 PiMM subjects. The median of liver function tests and procollagen-III-peptide were within the normal range in all Pi subgroups. However, the PiZZ men had significantly higher plasma bilirubin than the PiMM men (P = 0.018). Plasma ɣ-glutamyl transferase (GGT) was significantly higher in the PiZZ men (P = 0.009) and the PiSZ men (P = 0.021) compared with the PiMM men. The median of liver stiffness was significantly higher in the PiZZ men (P = 0.037) and the PiSZ men (P = 0.032) compared with the PiMM men. The PiZZ women taking medication influencing liver enzymes had significantly higher GGT than the PiMM women on the corresponding treatment (P = 0.023). These AAT-deficient individuals identified by neonatal screening have normal plasma levels of liver function tests, and no clinical signs indicating liver disease at the age of 37 to 40 years. However, bilirubin, GGT, and liver stiffness are significantly higher in PiZZ men than Pi

  19. In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells

    PubMed Central

    Ramachandran, Sarada Devi; Schirmer, Katharina; Münst, Bernhard; Heinz, Stefan; Ghafoory, Shahrouz; Wölfl, Stefan; Simon-Keller, Katja; Marx, Alexander; Øie, Cristina Ionica; Ebert, Matthias P.; Walles, Heike

    2015-01-01

    In this study we used differentiated adult human upcyte® cells for the in vitro generation of liver organoids. Upcyte® cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte® process). Proliferating upcyte® cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte® cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured in vitro on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions. PMID:26488607

  20. UPF2 Is a Critical Regulator of Liver Development, Function and Regeneration

    PubMed Central

    Waage, Johannes; Jakobsen, Janus S.; Damgaard, Inge; Bergström, Frida C.; Blom, Anna M.; Borup, Rehannah; Bisgaard, Hanne Cathrine; Porse, Bo T.

    2010-01-01

    Background Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues. Methodology/Principal Findings Here we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration. Conclusion/Significance Collectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology. PMID:20657840

  1. Quantitative analysis of aberrant protein glycosylation in liver cancer plasma by AAL-enrichment and MRM mass spectrometry.

    PubMed

    Ahn, Yeong Hee; Shin, Park Min; Kim, Yong-Sam; Oh, Na Ree; Ji, Eun Sun; Kim, Kwang Hoe; Lee, Yeon Jung; Kim, Sung Ho; Yoo, Jong Shin

    2013-11-07

    A lectin-coupled mass spectrometry (MS) approach was employed to quantitatively monitor aberrant protein glycosylation in liver cancer plasma. To do this, we compared the difference in the total protein abundance of a target glycoprotein between hepatocellular carcinoma (HCC) plasmas and hepatitis B virus (HBV) plasmas, as well as the difference in lectin-specific protein glycoform abundance of the target glycoprotein. Capturing the lectin-specific protein glycoforms from a plasma sample was accomplished by using a fucose-specific aleuria aurantia lectin (AAL) immobilized onto magnetic beads via a biotin-streptavidin conjugate. Following tryptic digestion of both the total plasma and its AAL-captured fraction of each HCC and HBV sample, targeted proteomic mass spectrometry was conducted quantitatively by a multiple reaction monitoring (MRM) technique. From the MRM-based analysis of the total plasmas and AAL-captured fractions, differences between HCC and HBV plasma groups in fucosylated glycoform levels of target glycoproteins were confirmed to arise from both the change in the total protein abundance of the target proteins and the change incurred by aberrant fucosylation on target glycoproteins in HCC plasma, even when no significant change occurs in the total protein abundance level. Combining the MRM-based analysis method with the lectin-capturing technique proved to be a successful means of quantitatively investigating aberrant protein glycosylation in cancer plasma samples. Additionally, it was elucidated that the differences between HCC and control groups in fucosylated biomarker candidates A1AT and FETUA mainly originated from an increase in fucosylation levels on these target glycoproteins, rather than an increase in the total protein abundance of the target glycoproteins.

  2. Quantitative alterations in the liver and adrenal gland in pregnant rats induced by Pyralene 3000

    SciTech Connect

    Vreci, M.; Sek, S.; Lorger, J.; Bavdek, S.; Pogacnik, A.

    1995-06-01

    Polychlorinated biphenyls (PCBs) are among the most widespread environmental pollutants known in the world. The half-life of PCBs is very long and, therefore, once released into the environment, they accumulate in food chains and tissues of various mammals, including man. Their presence can cause numerous toxic effects, e.g., hepatotoxicity, immunotoxicity, dermatotoxicity, neurotoxicity, and disorders of the reproductive system, among others. These effects depend on the distribution route in the organism, the rate of metabolism and excretion. Their characteristics are closely associated with the number and position of the chlorine atoms in the molecule. Previous studies of trichlorobiphenyl distributions in various tissues demonstrated that low chlorinated trichlorobiphenyls do no accumulate in endocrine organs, whereas higher chlorinated biphenyls, such as hexa- and octachlorobiphenyl, are deposited and retained in the adrenal gland. A selective distribution of radioabelled tetrachlorobiphenyl to the zona fasciculata, accompanied by morphometric evidence of the hypertrophy of the zona fasciculata, was also noted. The purpose of this study was to examine changes in the tissue structure of the pregnant rat liver and adrenal gland induced experimentally by Pyralene 3000 administration. We chose this commercial low chlorinated PCB because it was in use in Slovenia and, discharged from the electroindustrial plants, caused a serious incidence of environmental pollution in the region of Bela Krajina. Our further aim was to research the transplacental influences of Pyralene 3000 in rats. 17 refs., 1 fig., 3 tabs.

  3. Quantitative Reasoning and the Sine Function: The Case of Zac

    ERIC Educational Resources Information Center

    Moore, Kevin C.

    2014-01-01

    A growing body of literature has identified quantitative and covariational reasoning as critical for secondary and undergraduate student learning, particularly for topics that require students to make sense of relationships between quantities. The present study extends this body of literature by characterizing an undergraduate precalculus…

  4. Real-time elastography in the assessment of liver fibrosis: a review of qualitative and semi-quantitative methods for elastogram analysis.

    PubMed

    Paparo, Francesco; Corradi, Francesco; Cevasco, Luca; Revelli, Matteo; Marziano, Andrea; Molini, Lucio; Cenderello, Giovanni; Cassola, Giovanni; Rollandi, Gian Andrea

    2014-09-01

    Despite its invasiveness, liver biopsy is still considered the gold standard for the assessment of hepatic fibrosis. Non-invasive ultrasound-based techniques are increasingly employed to assess parenchymal stiffness and the progression of chronic diffuse liver diseases. Real-time elastography is a rapidly evolving technique that can reveal the elastic properties of tissues. This review examines qualitative and semi-quantitative methods developed for analysis of real-time liver elastograms, to estimate parenchymal stiffness and, indirectly, the stage of fibrosis. Qualitative analysis is the most immediate approach for elastogram analysis, but this method increases intra- and inter-observer variability, which is seen as a major limitation of real-time elastography. Semi-quantitative methods include analysis of the histogram derived from color-coded maps, as well as calculation of the elastic ratio and fibrosis index.

  5. Association between liver function and metabolic syndrome in Chinese men and women

    PubMed Central

    Wang, Sen; Zhang, Jie; Zhu, Li; Song, Linlin; Meng, Zhaowei; Jia, Qiang; Li, Xue; Liu, Na; Hu, Tianpeng; Zhou, Pingping; Zhang, Qing; Liu, Li; Song, Kun; Jia, Qiyu

    2017-01-01

    Metabolic syndrome (MS) could be associated with liver function. Our study aimed to investigate the association between liver function and MS in a large cohort of Chinese men and women. We enrolled 32,768 ostensibly healthy participants. The associations between liver function and MS of both genders were analyzed separately after dividing total bilirubin (TBIL), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) into quartiles. Young males had significantly higher MS prevalence than females, yet after menopause, females had higher MS prevalence. We used TBIL, GGT and ALT quartiles as categorical variables in binary logistic regression models. Significantly decreased MS risks were demonstrated in TBIL quartiles 2 to 4 for males, and quartiles 3 to 4 for females. As to GGT and ALT, significantly increased MS risks were shown in high quartiles for both genders. Aging also resulted in significantly higher MS risks in both genders except for young females. This study displayed close associations between liver function and MS, which were influenced by gender and age. A high TBIL level had protective effect against MS, while high GGT and ALT levels were risk factors for MS. It is meaningful that liver function is used as clinical risk predictors for MS. PMID:28317840

  6. Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion

    PubMed Central

    Waked, Imam; Berhane, Sarah; Toyoda, Hidenori; Chan, Stephen L; Stern, Nicholas; Palmer, Daniel; Tada, Toshifumi; Yeo, Winnie; Mo, Frankie; Bettinger, Dominik; Kirstein, Martha M; Iñarrairaegui, Mercedes; Gomaa, Asmaa; Vogel, Arndt; Meyer, Tim; Sangro, Bruno; Lai, Paul; Kumada, Takashi; Johnson, Philip J

    2017-01-01

    Background: Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI). Methods: In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival. Results: Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI. Conclusions: The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown. PMID:28125820

  7. Association between liver function and metabolic syndrome in Chinese men and women.

    PubMed

    Wang, Sen; Zhang, Jie; Zhu, Li; Song, Linlin; Meng, Zhaowei; Jia, Qiang; Li, Xue; Liu, Na; Hu, Tianpeng; Zhou, Pingping; Zhang, Qing; Liu, Li; Song, Kun; Jia, Qiyu

    2017-03-20

    Metabolic syndrome (MS) could be associated with liver function. Our study aimed to investigate the association between liver function and MS in a large cohort of Chinese men and women. We enrolled 32,768 ostensibly healthy participants. The associations between liver function and MS of both genders were analyzed separately after dividing total bilirubin (TBIL), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) into quartiles. Young males had significantly higher MS prevalence than females, yet after menopause, females had higher MS prevalence. We used TBIL, GGT and ALT quartiles as categorical variables in binary logistic regression models. Significantly decreased MS risks were demonstrated in TBIL quartiles 2 to 4 for males, and quartiles 3 to 4 for females. As to GGT and ALT, significantly increased MS risks were shown in high quartiles for both genders. Aging also resulted in significantly higher MS risks in both genders except for young females. This study displayed close associations between liver function and MS, which were influenced by gender and age. A high TBIL level had protective effect against MS, while high GGT and ALT levels were risk factors for MS. It is meaningful that liver function is used as clinical risk predictors for MS.

  8. Clinical evaluation of liver structure and function in humans exposed to halogenated hydrocarbons.

    PubMed Central

    Guzelian, P S

    1985-01-01

    An unresolved question is whether humans exposed to comparatively low doses of persistent environmental chemicals such as polyhalogenated biphenyls or organochlorine pesticides are at risk for injury to the liver. Cross-sectional epidemiologic studies suggest that these chemicals may produce statistically significant but clinically mild abnormalities in the commonly employed chemical tests of liver function. The few reports of human liver morphology reveal nonspecific changes reflecting effects of lipophilic chemicals. There is evidence that chemicals of this category in at least some doses cause induction of liver microsomal enzymes involved in biotransformation of foreign substances. This finding has been documented by measurements of the clearance of model drugs or the appearance in the urine of steroid metabolites or glucaric acid. Although a positive statistical correlation between the concentrations of these chemicals in serum and the serum gamma-glutamyltranspeptidase activity has been reported, the non-specificity of the latter enzyme precludes conclusion that this change is indicative of induction of liver microsomal enzymes. Although the effects of this type of environmental chemical are not indicative of progressive liver disease, only prospective clinical trials can resolve the issue of the risk for future development of liver malignancy. PMID:2411535

  9. Irisin levels in relation to metabolic and liver functions in Egyptian patients with metabolic syndrome.

    PubMed

    Rizk, Fatma H; Elshweikh, Samah A; Abd El-Naby, Amira Y

    2016-04-01

    Irisin is a new myokine that is suspected to influence metabolic syndrome (MetS). However, there is a great controversy with respect to its level in cases of MetS and its correlation with different metabolic parameters. The present study assesses irisin levels in MetS patients and studies its relationship to metabolic and liver functions to evaluate the possible role of the liver in regulation of this level. Sixty subjects were included in this experiment, who were divided into 3 groups: group I (normal control), group II (MetS patients with normal liver enzymes), and group III (MetS with elevated liver enzymes and fatty liver disease). Serum irisin levels showed significant increases in groups II and III compared with group I, and significant increases in group III compared with group II. Also, irisin levels were positively correlated with body mass index, serum triglycerides, homeostatic model assessment of insulin resistance index (HOMA-IR), and liver enzymes. We concluded that serum irisin levels increased in patients with MetS, especially those with elevated liver enzymes, and had a positive correlation with parameters of lipid metabolism and glucose homeostasis with the possibility of hepatic clearance to irisin.

  10. Novel strategy to decrease reperfusion injuries and improve function of cold-preserved livers using normothermic ex vivo liver perfusion machine.

    PubMed

    Banan, Babak; Xiao, Zhenyu; Watson, Rao; Xu, Min; Jia, Jianluo; Upadhya, Gundumi A; Mohanakumar, Thalachallour; Lin, Yiing; Chapman, William

    2016-03-01

    Normothermic extracorporeal liver perfusion (NELP) can decrease ischemia/reperfusion injury to the greatest degree when cold ischemia time is minimized. Warm perfusion of cold-stored livers results in hepatocellular damage, sinusoidal endothelial cell (SEC) dysfunction, and Kupffer cell activation. However, the logistics of organ procurement mandates a period of cold preservation before NELP. The aim of this study was to determine the beneficial effects of gradual rewarming of cold-stored livers by placement on NELP. Three female porcine livers were used for each group. In the immediate NELP group, procured livers were immediately placed on NELP for 8 hours. In the cold NELP group, livers were cold-stored for 4 hours followed by NELP for 4 hours. In rewarming groups, livers were cold-stored for 4 hours, then gradually rewarmed in different durations to 38°C and kept on NELP for an additional 4 hours. For comparison purposes, the last 4 hours of NELP runs were considered to be the evaluation phase. Immediate NELP livers had significantly lower concentrations of liver transaminases, hyaluronic acid, and β-galactosidase and had higher bile production compared to the other groups. Rewarming livers had significantly lower concentrations of hyaluronic acid and β-galactosidase compared to the cold NELP livers. In addition, there was a significant decline in international normalized ratio values, improved bile production, reduced biliary epithelial cell damage, and improved cholangiocyte function. Thus, if a NELP machine is not available at the procurement site and livers will need to undergo a period of cold preservation, a gradual rewarming protocol before NELP may greatly reduce damages that are associated with reperfusion. In conclusion, gradual rewarming of cold-preserved livers upon NELP can minimize the hepatocellular damage, Kupffer cell activation, and SEC dysfunction.

  11. Functional renal failure (FRF) in cirrhosis of the liver and liver carcinoma

    PubMed Central

    Vesin, P.; Traverso, H.

    1975-01-01

    The term ‘functional renal failure’ has been used to describe the renal failure developing in advanced cirrhosis in which tubular function and structure remain intact. It may develop spontaneously, in which case prognosis is poor, but may be secondary to gastro-intestinal haemorrhage or excessive use of diuretics, in which case correction of the precipitating factor leads to improvement in renal function. It is suggested that the renal failure is due to a reduction in effective circulating plasma volume. PMID:1234327

  12. Dual function microscope for quantitative DIC and birefringence imaging

    NASA Astrophysics Data System (ADS)

    Li, Chengshuai; Zhu, Yizheng

    2016-03-01

    A spectral multiplexing interferometry (SXI) method is presented for integrated birefringence and phase gradient measurement on label-free biological specimens. With SXI, the retardation and orientation of sample birefringence are simultaneously encoded onto two separate spectral carrier waves, generated by a crystal retarder oriented at a specific angle. Thus sufficient information for birefringence determination can be obtained from a single interference spectrum, eliminating the need for multiple acquisitions with mechanical rotation or electrical modulation. In addition, with the insertion of a Nomarski prism, the setup can then acquire quantitative differential interference contrast images. Red blood cells infected by malaria parasites are imaged for birefringence retardation as well as phase gradient. The results demonstrate that the SXI approach can achieve both quantitative phase imaging and birefringence imaging with a single, high-sensitivity system.

  13. Quantitative assessment of regional right ventricular function with color kinesis.

    PubMed

    Vignon, P; Weinert, L; Mor-Avi, V; Spencer, K T; Bednarz, J; Lang, R M

    1999-06-01

    We used color kinesis, a recent echocardiographic technique that provides regional information on the magnitude and timing of endocardial wall motion, to quantitatively assess regional right ventricular (RV) systolic and diastolic properties in 76 subjects who were divided into five groups, as follows: normal (n = 20), heart failure (n = 15), pressure/volume overload (n = 14), pressure overload (n = 12), and RV hypertrophy (n = 15). Quantitative segmental analysis of color kinesis images was used to obtain regional fractional area change (RFAC), which was displayed in the form of stacked histograms to determine patterns of endocardial wall motion. Time curves of integrated RFAC were used to objectively identify asynchrony of diastolic endocardial motion. When compared with normal subjects, patients with pressure overload or heart failure exhibited significantly decreased endocardial motion along the RV free wall. In the presence of mixed pressure/volume overload, the markedly increased ventricular septal motion compensated for decreased RV free wall motion. Diastolic endocardial wall motion was delayed in 17 of 72 segments (24%) in patients with RV pressure overload, and in 31 of 90 segments (34%) in patients with RV hypertrophy. Asynchrony of diastolic endocardial wall motion was greater in the latter group than in normal subjects (16% versus 10%: p < 0.01). Segmental analysis of color kinesis images allows quantitative assessment of regional RV systolic and diastolic properties.

  14. Purinergic effects of a hydroalcoholic Agaricus brasiliensis (A. blazei) extract on liver functions.

    PubMed

    de Oliveira, Andrea L; Eler, G Jacklin; Bracht, Adelar; Peralta, Rosane M

    2010-06-23

    The effects of a hydroalcoholic extract of Agaricus brasiliensis (A. blazei) on functional parameters in the perfused rat liver were examined with emphasis on its content of nucleotides and nucleosides. Several nucleosides and nucleotides were identified in the A. brasiliensis extract, which was active on several liver functions. A significant part of the effects is the result of the purinergic action of nucleosides and nucleotides: pressure increment, glycogenolysis stimulation, transient inhibition of oxygen consumption, and redox state changes. Other phenomena such as the stimulation of gluconeogenesis, ureogenesis, and oxygen consumption are more likely consequences of the metabolic transformation of substrates contained within the extract, especially amino acids. It seems apparent that consumption of A. brasiliensis represents not only the ingestion of metabolic precursors but also the ingestion of substances that, even at low concentrations, can exert important signaling functions in the liver as well as in the organism as a whole.

  15. Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Dai, Xin; Wang, Bangmao

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease. PMID:25945084

  16. Functional liver tissue engineering by an adult mouse liver-derived neuro-glia antigen 2-expressing stem/progenitor population.

    PubMed

    Zhang, Hongyu; Siegel, Christopher T; Li, Jing; Lai, Jiejuan; Shuai, Ling; Lai, Xiangdong; Zhang, Yujun; Jiang, Yan; Bie, Ping; Bai, Lianhua

    2016-09-17

    Deaths due to end-stage liver diseases (ESLD) are increasingly registered annually in the world. Liver transplantation is the ultimate treatment for ESLD to date, which has been hampered by a critical shortage of organs. The potential of decellularized liver scaffolds (DLS) derived from solid organs as a three dimensional (3D) platform has been evolved as a promising approach in liver tissue engineering for translating functional liver organ replacements, but questions still exist regarding the optimal cell population for seeding in DLS and the preparation of the DLS themselves. The aim of our study was to utilize a sodium dodecyl sulfate (SDS) decellularization procedure in combination with a low concentration of trypsin (0.005%)-EDTA (0.002%) process to manufacture DLS from whole mouse livers and recellularized with hepatic stem/progenitors for use in liver tissue engineering and injured liver treatment. Results showed that the DLS generated with all the necessary microstructure and the extracellular components to support seeded hepatic stem/progenitor cell attachment, functional hepatic cell differentiation. Hepatic differentiation from stem/progenitor cells loaded by DLS was more efficient than that of the stem/progenitor cells in the 2D cell culture model. In summary, the method of DLS loaded by hepatic stem/progenitor cells provided by this study was effective in maintaining DLS extracellular matrix (ECM) to introduce seeded stem/progenitor cell differentiation, hepatic-like tissue formation and functional hepatic protein production in vitro that promoted functional recovery and survival in a mouse model of dimethylnitrosamine (DEN)-induced liver cirrhosis after auxiliary heterotopic liver transplantation.

  17. The function of a colloid in liver cold-storage preservation.

    PubMed

    Ar'Rajab, A; Ahrén, B; Sundberg, R; Bengmark, S

    1991-07-01

    the development of interstitial edema, and, hence, improve the liver function.

  18. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

    PubMed

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-09-14

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

  19. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

    PubMed Central

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-01-01

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully. PMID:27649152

  20. Dietary restriction reduces blood lipids and ameliorates liver function of mice with hyperlipidemia.

    PubMed

    Gao, Hai-Tao; Cheng, Wen-Zhao; Xu, Qian; Shao, Lin-Xiang

    2017-02-01

    Dietary restriction (DR) can delay senescence, prolong lifespan of mammals and improve their learning-memory activity. The purpose of the study was to explore the effects of DR on hypolipidemic action and liver function of mice with hyperlipidemia. To investigate these effects, hyperlipidemia mouse models were established with high-fat diet (HFD) (34% of energy), then randomly divided into HFD group, DR30% group and DR50% group. Mice in DR30% and DR50% group were respectively supplied with HFD as much as about 70% and 50% of the consumption of HFD in the mice of HFD group. Rats in control group were fed routinely. After DR for 5 weeks, the average body weight, liver weight, liver index, serum lipids and glucose levels in both DR groups decreased significantly as compared with the HFD group (P<0.05 or P<0.01), so did alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels and the ratio of LDL-C/HDL-C in the DR50% group (P<0.05 or P<0.01). Histopathology examination of liver tissues further proved ameliorative effect of DR on liver function. Western blotting showed that DR significantly increased the expression of silent mating type information regulation 2 homolog 1 (SIRT1) in liver and adipose, while notably decreased the expression of peroxisome proliferators-activated receptors-gamma (PPARγ) in adipose (P<0.05 or P<0.01). The increase of SIRT1 and decrease of PPARγ may be a mechanism by which DR reduces blood lipids and ameliorates liver function.

  1. Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging.

    PubMed

    Wang, Hongbo; Shu, Shengjie; Li, Jinping; Jiang, Huijie

    2016-02-01

    The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy.

  2. Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.

    PubMed Central

    Cotting, J; Lentze, M J; Reichen, J

    1990-01-01

    The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fibrosis and chronic cholestasis. Bile acid treatment improved inflammatory activity (average decrease in alanine aminotransferase, 60%, p less than 0.005) and cholestasis (alkaline phosphatase, 47%; p less than 0.01) in all patients. Quantitative liver function, measured by 45 minute sulphobromophthalein retention and by the 14C-aminopyrine breath test, improved in all patients while galactose elimination capacity showed a slight decrease. Patients' nutritional state improved as evidenced by a 1.8 kg weight gain and an increase in muscle mass suggested by a 26% increase in 24 hour urinary creatinine excretion. Steatorrhea was not affected by bile acid treatment. Ursodeoxycholic acid may be beneficial in the treatment of chronic cholestasis in cystic fibrosis by improving liver function and also the patient's nutritional state. PMID:2387518

  3. Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.

    PubMed

    Cotting, J; Lentze, M J; Reichen, J

    1990-08-01

    The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fibrosis and chronic cholestasis. Bile acid treatment improved inflammatory activity (average decrease in alanine aminotransferase, 60%, p less than 0.005) and cholestasis (alkaline phosphatase, 47%; p less than 0.01) in all patients. Quantitative liver function, measured by 45 minute sulphobromophthalein retention and by the 14C-aminopyrine breath test, improved in all patients while galactose elimination capacity showed a slight decrease. Patients' nutritional state improved as evidenced by a 1.8 kg weight gain and an increase in muscle mass suggested by a 26% increase in 24 hour urinary creatinine excretion. Steatorrhea was not affected by bile acid treatment. Ursodeoxycholic acid may be beneficial in the treatment of chronic cholestasis in cystic fibrosis by improving liver function and also the patient's nutritional state.

  4. Functional Role of Monocytes and Macrophages for the Inflammatory Response in Acute Liver Injury

    PubMed Central

    Zimmermann, Henning W.; Trautwein, Christian; Tacke, Frank

    2012-01-01

    Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF. PMID:23091461

  5. Two- and Three-Dimensional Quantitative Structure-Activity Relationships Studies on a Series of Liver X Receptor Ligands

    PubMed Central

    Honório, Káthia M; Salum, Lívia B; Garratt, Richard C; Polikarpov, Igor; Andricopulo, Adriano D

    2008-01-01

    Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r2 = 0.98 and q2 = 0.69; HQSAR, r2 = 0.99 and q2 = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency. PMID:19696872

  6. Acoustic radiation force impulse elastography for chronic liver disease: comparison with ultrasound-based scores of experienced radiologists, Child-Pugh scores and liver function tests.

    PubMed

    Kim, Ji Eun; Lee, Jae Young; Kim, Yoon Jun; Yoon, Jung Hwan; Kim, Se Hyung; Lee, Jeong Min; Han, Joon Koo; Choi, Byung Ihn

    2010-10-01

    The purpose of our study was to investigate whether acoustic radiation force impulse (ARFI) elastography provides better diagnostic performance for diagnosis of chronic liver disease and correlates better with Child-Pugh scores and liver function tests, compared with an ultrasound (US) scoring system based on visual assessment of conventional B-mode US images by experienced radiologists. Five hundred and twenty-one patients with clinically proven chronic liver disease (n = 293), fatty liver (n = 95) or normal liver (n = 133) were included in this study. B-mode liver US and ARFI elastography were performed in all patients. ARFI elastography was performed at least five times, with each measurement obtained at a different area of the right hepatic lobe; mean shear wave velocity (SWV) was calculated for each patient. The mean SWV was compared with US-based scores from two radiologists (based on liver surface nodularity, parenchyma echotexture and hepatic vein contour), Child-Pugh scores and liver function tests. The mean SWV of the normal liver group was 1.08 m/s ± 0.15; of the fatty liver group, 1.02 m/s ± 0.16; and of the chronic liver disease group, 1.66 m/s ± 0.60 (p < 0.001). The area under the receiver operating characteristics curve of the mean SWV in ARFI elastography was significantly higher than that of the conventional B-mode US-based scores by two radiologists (0.89 vs. 0.74 and 0.77, p < 0.05), with a sensitivity of 75.4% and a specificity of 89.5% at the cut-off value of 1.22 m/s. The sensitivity of the mean SWV was significantly higher than the US-based scores (p < 0.001), although the specificity was not (p > 0.05). The mean SWV was better correlated with Child-Pugh scores and all liver function tests (except total protein) than the US-based scores from two radiologists. In conclusion, ARFI elastography showed better diagnostic performance than visual assessment of experienced radiologists for diagnosis of chronic liver disease, as well as for

  7. Functional abnormalities of sinusoidal endothelial cells in rats with acute liver rejection.

    PubMed

    Yokoi, Y; Nakamura, S; Muro, H; Baba, S

    1994-01-01

    The purpose of this study was to determine the changes of hepatic sinusoidal endothelial cell (SEC) function in acute liver rejection with respect to receptor-mediated endocytosis. Orthotopic rat liver transplantation was performed in Lewis rats grafted with DA livers and in Lewis rats grafted with Lewis livers as rejectors and controls, respectively. Animals were killed at 1, 3, 5, 7, and 10 days after the operation. Fc receptors (FcRs) were histochemically stained on frozen liver sections by applying peroxidase-antiperoxidase IgG complex as a ligand, and the FcR activity, i.e., capacity of binding the ligands represented by the FcR staining intensity, was semiquantitatively analyzed as an indicator of SEC function. The serum level of hyaluronic acid, which is specifically cleared from the circulation by receptor-mediated SEC endocytosis, was also assayed, along with the total serum bilirubin. Three days after the operation, the SECs of rejectors showed a significantly weaker FcR staining intensity of about half the value of that seen in the controls (P < 0.05), and staining disappeared after 5 days (P < 0.01). The decrease of FcR staining intensity, i.e., FcR activity, showed a correlation with elevation of the serum hyaluronic acid level (r = -0.77; P < 0.001). Histological evidence of endothelialitis and a significant elevation of total serum bilirubin (P < 0.01) were also present at 3 and 5 days, respectively. These results suggest that impairment of the endocytic function of SECs occurs at an earlier phase of acute liver rejection when compared with development of abnormalities of traditional indicators. Determination of receptor-mediated SEC endocytic functions may thus provide useful information for the early diagnosis of acute rejection.

  8. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    PubMed

    Nantasanti, Sathidpak; Toussaint, Mathilda J M; Youssef, Sameh A; Tooten, Peter C J; de Bruin, Alain

    2016-01-01

    The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  9. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    SciTech Connect

    Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.; Mueller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these

  10. Gd-EOB-DTPA-enhanced MRI for evaluation of liver function: Comparison between signal-intensity-based indices and T1 relaxometry

    PubMed Central

    Haimerl, Michael; Verloh, Niklas; Zeman, Florian; Fellner, Claudia; Nickel, Dominik; Lang, Sven A.; Teufel, Andreas; Stroszczynski, Christian; Wiggermann, Philipp

    2017-01-01

    Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a paramagnetic hepatobiliary magnetic resonance (MR) contrast agent. Due to its OATP1B1/B3-dependent hepatocyte-specific uptake and paramagnetic properties increasing evidence has emerged to suggest that Gd-EOB-DTPA-enhanced MRI can be potentially used for evaluation of liver function. In this paper we compare the diagnostic performance of Gd-EOB-DTPA-enhanced relaxometry-based and commonly used signal-intensity (SI)-based indices, including the hepatocellular uptake index (HUI) and SI-based indices corrected by spleen or muscle, for evaluation of liver function, determined using the Indocyanin green clearance (ICG) test. Simple linear regression model showed a significant correlation of the plasma disappearance rate of ICG (ICG-PDR) with all Gd-EOB-DTPA-enhanced MRI-based liver function indices with a significantly better correlation of relaxometry-based indices on ICG-PDR compared to SI-based indices. Among SI-based indices, HUI achieved best correlation on ICG-PDR and no significant difference of respective correlations on ICG-PDR could be shown. Assessment of liver volume and consecutive evaluation of multiple linear regression model revealed a stronger correlation of ICG-PDR with both (SI)-based and T1 relaxometry-based indices. Thus, liver function can be estimated quantitatively from Gd-EOB-DTPA–enhanced MRI-based indices. Here, indices derived from T1 relaxometry are superior to SI-based indices, and all indices benefit from taking into account respective liver volumes. PMID:28266528

  11. Quantitative assessment of protein function prediction from metagenomics shotgun sequences.

    PubMed

    Harrington, E D; Singh, A H; Doerks, T; Letunic, I; von Mering, C; Jensen, L J; Raes, J; Bork, P

    2007-08-28

    To assess the potential of protein function prediction in environmental genomics data, we analyzed shotgun sequences from four diverse and complex habitats. Using homology searches as well as customized gene neighborhood methods that incorporate intergenic and evolutionary distances, we inferred specific functions for 76% of the 1.4 million predicted ORFs in these samples (83% when nonspecific functions are considered). Surprisingly, these fractions are only slightly smaller than the corresponding ones in completely sequenced genomes (83% and 86%, respectively, by using the same methodology) and considerably higher than previously thought. For as many as 75,448 ORFs (5% of the total), only neighborhood methods can assign functions, illustrated here by a previously undescribed gene associated with the well characterized heme biosynthesis operon and a potential transcription factor that might regulate a coupling between fatty acid biosynthesis and degradation. Our results further suggest that, although functions can be inferred for most proteins on earth, many functions remain to be discovered in numerous small, rare protein families.

  12. Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System

    PubMed Central

    Tsamandouras, N.; Kostrzewski, T.; Stokes, C. L.; Griffith, L. G.; Hughes, D. J.

    2017-01-01

    In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro–in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process. PMID:27760784

  13. Comparison of five incubation systems for rat liver slices using functional and viability parameters.

    PubMed

    Olinga, P; Groen, K; Hof, I H; De Kanter, R; Koster, H J; Leeman, W R; Rutten, A A; Van Twillert, K; Groothuis, G M

    1997-10-01

    Precision-cut liver slices are presently used for various research objects, e.g. to study metabolism, transport, and toxicity of xenobiotics. Various incubation systems are presently employed, but a systematic comparison between these incubation systems with respect to preservation of slice function has not been performed yet. Therefore, we started a comparative study to evaluate five of these systems: the shaken flask (an Erlenmeyer in a shaking water bath), the stirred-well (24-well culture plate equipped with grids and magnetic stirrers), rocker platform (6-well culture plate with Netwell insert rocked on a platform), the roller system (dynamic organ culture rolled on an insert in a glass vial), and the 6-well shaker (6-well culture plate in a shaking water bath). The liver slices were incubated in these incubation systems for 0.5, 1.5, and 24.5 h and subsequently subjected to viability and metabolic function tests. The viability of the incubated liver slices was evaluated by: potassium content, MTT assay, energy charge, histomorphology, and LDH leakage. Their metabolic functions were studied by determination of the metabolism of lidocaine, testosterone, and antipyrine. Up to 1.5 h of incubation all five incubation systems gave similar results with respect to viability and metabolic function of the liver slices. However, after 24 h, the shaken flask, the rocker platform, and the 6-well shaker incubation systems appeared to be superior to the stirred well and the roller incubation systems.

  14. Liver condition of Holstein cows affects mitochondrial function and fertilization ability of oocytes

    PubMed Central

    TANAKA, Hiroshi; TAKEO, Shun; ABE, Takahito; KIN, Airi; SHIRASUNA, Koumei; KUWAYAMA, Takehito; IWATA, Hisataka

    2016-01-01

    The aim of the present study was to examine the fertilization ability and mitochondrial function of oocytes derived from cows with or without liver damage. Oocytes were collected from the ovaries of cows with damaged livers (DL) and those of cows with healthy livers (HL), subjected to in vitro maturation, and fertilized in vitro. A significantly high abnormal fertilization rate was observed for oocytes from DL cows compared to oocytes from HL cows. The time to dissolve the zona pellucida by protease before fertilization was similar between the two liver conditions, whereas after fertilization treatment this time was shorter for DL cows than for HL cows. The percentage of oocytes with equivalent cortical granule distributions underneath the membrane was greater for in vitro matured oocytes from HL cows, whereas an immature distribution pattern was observed for oocytes from DL cows. In addition, a greater percentage of oocytes derived from HL cows released cortical granules following fertilization compared with oocytes from DL cows. Mitochondrial function determined by ATP content and membrane potential were similar at the germinal vesicle stage, but post-in vitro maturation, the oocytes derived from HL cows showed higher values than DL cows. The mitochondrial DNA copy number in oocytes was similar between the two liver conditions for both the germinal vesicle and post-in vitro maturation oocytes. In conclusion, liver damage induces low fertilization, likely because of incomplete cortical granule distribution and release, and the maturation of oocytes from DL cows contain low-functioning mitochondria compared to their HL counterparts. PMID:26832309

  15. Quantitative Evaluation of the Reticuloendothelial System Function with Dynamic MRI

    PubMed Central

    Liu, Ting; Choi, Hoon; Zhou, Rong; Chen, I-Wei

    2014-01-01

    Purpose To evaluate the reticuloendothelial system (RES) function by real-time imaging blood clearance as well as hepatic uptake of superparamagnetic iron oxide nanoparticle (SPIO) using dynamic magnetic resonance imaging (MRI) with two-compartment pharmacokinetic modeling. Materials and Methods Kinetics of blood clearance and hepatic accumulation were recorded in young adult male 01b74 athymic nude mice by dynamic T2* weighted MRI after the injection of different doses of SPIO nanoparticles (0.5, 3 or 10 mg Fe/kg). Association parameter, Kin, dissociation parameter, Kout, and elimination constant, Ke, derived from dynamic data with two-compartment model, were used to describe active binding to Kupffer cells and extrahepatic clearance. The clodrosome and liposome were utilized to deplete macrophages and block the RES function to evaluate the capability of the kinetic parameters for investigation of macrophage function and density. Results The two-compartment model provided a good description for all data and showed a low sum squared residual for all mice (0.27±0.03). A lower Kin, a lower Kout and a lower Ke were found after clodrosome treatment, whereas a lower Kin, a higher Kout and a lower Ke were observed after liposome treatment in comparison to saline treatment (P<0.005). Conclusion Dynamic SPIO-enhanced MR imaging with two-compartment modeling can provide information on RES function on both a cell number and receptor function level. PMID:25090653

  16. Direct, quantitative clinical assessment of hand function: usefulness and reproducibility.

    PubMed

    Goodson, Alexander; McGregor, Alison H; Douglas, Jane; Taylor, Peter

    2007-05-01

    Methods of assessing functional impairment in arthritic hands include pain assessments and disability scoring scales which are subjective, variable over time and fail to take account of the patients' need to adapt to deformities. The aim of this study was to evaluate measures of functional strength and joint motion in the assessment of the rheumatoid (RA) and osteoarthritic (OA) hand. Ten control subjects, ten RA and ten OA patients were recruited for the study. All underwent pain and disability scoring and functional assessment of the hand using measures of pinch/grip strength and range of joint motion (ROM). Functional assessments including ROM analyses at interphalangeal (IP), metacarpophalangeal (MCP) and wrist joints along with pinch/grip strength clearly discriminated between patient groups (RA vs. OA MCP ROM P<0.0001), pain and disability scales were unable to. In the RA there were demonstrable relationships between ROM measurements and disability (R2=0.31) as well as disease duration (R2=0.37). Intra-patient measures of strength were robust whereas inter-patient comparisons showed variability. In conclusion, pinch/grip strength and ROM are clinically reproducible assessments that may more accurately reflect functional impairment associated with arthritis.

  17. Reformation of functional liver polyribosomes from ribosome monomers in the absence of RNA synthesis.

    PubMed

    Stewart, G A; Farber, E

    1967-07-07

    The administration to rats of the ethyl analog of methionine, ethionine, results in the rapid decrease in the hepatic concentration of adenosine triphosphate followed by an extensive disaggregation of polysomes to ribosome monomers and a concomitant inhibition of protein synthesis. These effects are readily reversed by the injection of methionine or precursors of adenine nucleotides such as adenine. The reformation of liver polyribosomes in such animals following the administration of adenine plus methionine was found to occur under conditions in which new RNA synthesis was markedly inhibited. Free messenger RNA without attached ribosomes must be capable of remaining functionally active in the liver cytoplasm for many hours.

  18. Three Perspectives in Research on Functions: Multi-Representational, Quantitative, and Phenomenological.

    ERIC Educational Resources Information Center

    Lobato, Joanne; Bowers, Janet

    Much research on student understanding of functions has been characterized by a "multi-representational" perspective that investigates students' efforts to make connections among conventionally accepted mathematical representations such as graphs, tables, and equations. In contrast, a "quantitative" perspective explores…

  19. Synthesis of functionalized magnetite nanoparticles to use as liver targeting MRI contrast agent

    NASA Astrophysics Data System (ADS)

    Yazdani, Farshad; Fattahi, Bahare; Azizi, Najmodin

    2016-05-01

    The aim of this research was the preparation of functionalized magnetite nanoparticles to use as a liver targeting contrast agent in magnetic resonance imaging (MRI). For this purpose, Fe3O4 nanoparticles were synthesized via the co-precipitation method. The synthesized nanoparticles were coated with silica via the Stober method and finally the coated nanoparticles were functionalized with mebrofenin. Formation of crystalline magnetite particles was confirmed by X-ray diffraction (XRD) analysis. The Fourier transform infrared spectroscopy (FTIR) and energy dispersive X-ray analyzer (EDX) of the final product showed that silica had been effectively bonded onto the surface of the magnetite nanoparticles and the coated nanoparticles functionalized with mebrofenin. The magnetic resonance imaging of the functional nanoparticles showed that the Fe3O4-SiO2-mebrofenin composite is an effective MRI contrast agent for liver targeting.

  20. A quantitative overview of biophysical forces impinging on neural function

    NASA Astrophysics Data System (ADS)

    Mueller, Jerel K.; Tyler, William J.

    2014-10-01

    The fundamentals of neuronal membrane excitability are globally described using the Hodgkin-Huxley (HH) model. The HH model, however, does not account for a number of biophysical phenomena associated with action potentials or propagating nerve impulses. Physical mechanisms underlying these processes, such as reversible heat transfer and axonal swelling, have been compartmentalized and separately investigated to reveal neuronal activity is not solely influenced by electrical or biochemical factors. Instead, mechanical forces and thermodynamics also govern neuronal excitability and signaling. To advance our understanding of neuronal function and dysfunction, compartmentalized analyses of electrical, chemical, and mechanical processes need to be revaluated and integrated into more comprehensive theories. The present perspective is intended to provide a broad overview of biophysical forces that can influence neural function, but which have been traditionally underappreciated in neuroscience. Further, several examples where mechanical forces have been shown to exert their actions on nervous system development, signaling, and plasticity are highlighted to underscore their importance in sculpting neural function. By considering the collective actions of biophysical forces influencing neuronal activity, our working models can be expanded and new paradigms can be applied to the investigation and characterization of brain function and dysfunction.

  1. A quantitative overview of biophysical forces impinging on neural function.

    PubMed

    Mueller, Jerel K; Tyler, William J

    2014-08-26

    The fundamentals of neuronal membrane excitability are globally described using the Hodgkin-Huxley (HH) model. The HH model, however, does not account for a number of biophysical phenomena associated with action potentials or propagating nerve impulses. Physical mechanisms underlying these processes, such as reversible heat transfer and axonal swelling, have been compartmentalized and separately investigated to reveal neuronal activity is not solely influenced by electrical or biochemical factors. Instead, mechanical forces and thermodynamics also govern neuronal excitability and signaling. To advance our understanding of neuronal function and dysfunction, compartmentalized analyses of electrical, chemical, and mechanical processes need to be revaluated and integrated into more comprehensive theories. The present perspective is intended to provide a broad overview of biophysical forces that can influence neural function, but which have been traditionally underappreciated in neuroscience. Further, several examples where mechanical forces have been shown to exert their actions on nervous system development, signaling, and plasticity are highlighted to underscore their importance in sculpting neural function. By considering the collective actions of biophysical forces influencing neuronal activity, our working models can be expanded and new paradigms can be applied to the investigation and characterization of brain function and dysfunction.

  2. An in vivo and in vitro comparison of CYP induction in rat liver and intestine using slices and quantitative RT-PCR.

    PubMed

    Martignoni, Marcella; de Kanter, Ruben; Grossi, Pietro; Mahnke, Axel; Saturno, Grazia; Monshouwer, Mario

    2004-12-30

    Xenobiotics, including drugs, can influence cytochrome P450 (CYP) activity by upregulating the transcription of CYP genes. To minimize potential drug interactions, it is important to ascertain whether a compound will be an inducer of CYP enzymes early in the development of new therapeutic agents. In vivo and in vitro studies are reported that demonstrate the use of liver and intestinal slices as an in vitro model to predict potential CYP induction in vivo. Rat liver slices and intestinal slices were incubated, for 24 h and 6 h, respectively, with beta-naphthoflavone (betaNF), phenobarbital (PB) or dexamethasone (DEX). In an in vivo study, rats were treated with the same compounds for 3 days. In vivo and in vitro CYP mRNA levels were measured by using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, CYP enzyme activities were determined in rat liver slices after 48 h incubation. In both rat liver and intestinal slices, betaNF significantly induced CYP1A1, CYP1A2 and CYP2B1 mRNA levels. PB significantly induced CYP2B1. In liver slices a minor induction of CYP1A1 and CYP3A1 by PB was observed, whereas DEX significantly induced CYP3A1, CYP2B1 and CYP1A2 mRNA levels. The induction profiles (qualitative and quantitative) observed in vivo and in vitro are quite similar. All together, these data demonstrate that liver and intestinal slices are a useful and predictive tool to study CYP induction.

  3. Establishment of steady-state metabolism of ethanol in perfused rat liver: the quantitative analysis using kinetic mechanism-based rate equations of alcohol dehydrogenase.

    PubMed

    Yao, Chung-Tay; Lai, Ching-Long; Hsieh, Hsiu-Shan; Chi, Chin-Wen; Yin, Shih-Jiun

    2010-09-01

    Alcohol dehydrogenase (ADH) catalyzes oxidation of ingested ethanol to acetaldehyde, the first step in hepatic metabolism. The purpose of this study was to establish an ex vivo rat liver perfusion system under defined and verified steady states with respect to the metabolites and the metabolic rates, and to quantitatively correlate the observed rates with simulations based on the kinetic mechanism-based rate equations of rat liver ADH. Class I ADH1 was isolated from male Sprague-Dawley rats and characterized by steady-state kinetics in the Krebs-Ringer perfusion buffer with supplements. Nonrecirculating liver perfusion with constant input of ethanol at near physiological hepatic blood flow rate was performed in situ. Ethanol and the related metabolites acetaldehyde, acetate, lactate, and pyruvate in perfusates were determined. Results of the initial velocity, product, and dead-end inhibition studies showed that rat ADH1 conformed to the Theorell-Chance Ordered Bi Bi mechanism. Steady-state metabolism of ethanol in the perfused liver maintained up to 3h as evidenced by the steady-state levels of ethanol and metabolites in the effluent, and the steady-state ethanol disappearance rates and acetate production rates. The changes of the metabolic rates were qualitatively and in general quantitatively correlated to the results from simulations with the kinetic rate equations of ADH1 under a wide range of ethanol, in the presence of competitive inhibitor 4-methylpyrazole and of uncompetitive inhibitor isobutyramide. Preliminary flux control analysis estimated that apparent C(ADH)(J) in the perfused liver may approximate 0.7 at constant infusion with 1-2 mM ethanol, suggesting that ADH plays a major but not the exclusive role in governing hepatic ethanol metabolism. The reported steady-state rat liver perfusion system may potentially be applicable to other drug or drug-ethanol interaction studies.

  4. Quantitative analysis of cytochrome P450 isoforms in human liver microsomes by the combination of proteomics and chemical probe-based assay.

    PubMed

    Liu, Xidong; Hu, Lianghai; Ge, Guangbo; Yang, Bo; Ning, Jing; Sun, Shixin; Yang, Ling; Pors, Klaus; Gu, Jingkai

    2014-08-01

    Cytochrome P450 (CYP) is one of the most important drug-metabolizing enzyme families, which participates in the biotransformation of many endogenous and exogenous compounds. Quantitative analysis of CYP expression levels is important when studying the efficacy of new drug molecules and assessing drug-drug interactions in drug development. At present, chemical probe-based assay is the most widely used approach for the evaluation of CYP activity although there are cross-reactions between the isoforms with high sequence homologies. Therefore, quantification of each isozyme is highly desired in regard to meeting the ever-increasing requirements for carrying out pharmacokinetics and personalized medicine in the academic, pharmaceutical, and clinical setting. Herein, an absolute quantification method was employed for the analysis of the seven isoforms CYP1A2, 2B6, 3A4, 3A5, 2C9, 2C19, and 2E1 using a proteome-derived approach in combination with stable isotope dilution assay. The average absolute amount measured from twelve human liver microsomes samples were 39.3, 4.3, 54.0, 4.6, 10.3, 3.0, and 9.3 (pmol/mg protein) for 1A2, 2B6, 3A4, 3A5, 2C9, 2C19, and 2E1, respectively. Importantly, the expression level of CYP3A4 showed high correlation (r = 0.943, p < 0.0001) with the functional activity, which was measured using bufalin-a highly selective chemical probe we have developed. The combination of MRM identification and analysis of the functional activity, as in the case of CYP3A4, provides a protocol which can be extended to other functional enzyme studies with wide application in pharmaceutical research.

  5. Quantitative Study of Elasticity of Rabbit VX2 Liver Tumor with Alternated Cooling and Heating Treatment based on ARFI Ultrasound Imaging Technique

    PubMed Central

    Sun, Di; Wei, Cong; Shen, E.; Ying, Tao; Hu, Bing

    2016-01-01

    Acoustic radiation force impulse (ARFI) ultrasound imaging technique is used to quantitatively evaluate the elasticity of rabbit VX2 liver tumor with alternated cooling and heating treatment (ACHT). ACHT was performed on fifteen VX2 liver tumor models established in fifteen male New Zealand white rabbits with open tumor plant. ARFI was performed on day 0, 1, 7 and 14 after ACHT and shear wave velocity (SWV) in ARFI was recorded to evaluate the elasticity of the treated area. The SWV value of the lesion on day 0, 1, 7 and 14 was 2.33 ± 0.19 m/s, 3.09 ± 0.40 m/s, 2.64 ± 0.37 m/s and 2.26 ± 0.24 m/s, respectively, indicating the treated areas get stiffer on day 1 and then get softer gradually by day. All the difference between adjacent time points was statistically significant. The SWV value of different parts on day 7 approved that the hardness of the treated area is heterogenous: the treated area in the center >the peripheral strip-shaped area >normal liver tissues, consistent with pathological changes. Meanwhile, ARFI combined with conventional US imaging can qualitatively and quantitatively exam the healing process of rabbit VX2 liver tumor after ACHT, and corresponds well to the pathological results. PMID:27381362

  6. Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s.

    PubMed

    Tang, Ling; Peng, Hui; Zhou, Jing; Chen, Yongyan; Wei, Haiming; Sun, Rui; Yokoyama, Wayne M; Tian, Zhigang

    2016-02-01

    Group 1 innate lymphoid cells (ILCs) consist of conventional natural killer (cNK) cells, tissue-resident NK cells and mucosal ILC1s. Recently identified liver-resident NK cells, which can mount contact hypersensitivity responses, and mucosal ILC1s that are involved in pathogenesis of colitis are distinct from cNK cells in several aspects, but the issue of how they are related to each other has not been clearly clarified. Here, we show that liver-resident NK cells and mucosal ILC1s have different phenotypes, as evidenced by distinct expression patterns of homing-associated molecules. Moreover, mucosal ILC1s exhibit tissue residency akin to liver-resident NK cells. Importantly, liver-resident NK cells express relative high levels of cytotoxic effector molecules, which are poorly expressed by mucosal ILC1s, and exhibit stronger cytotoxic activity compared with mucosal ILC1s. These results demonstrate differential phenotypic and functional characteristics of liver-resident NK cells and mucosal ILC1s, shedding new light on the diversity of ILC family.

  7. Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease

    PubMed Central

    Calvopina, Diego A.; Coleman, Miranda A.; Lewindon, Peter J.; Ramm, Grant A.

    2016-01-01

    MicroRNAs (miRNAs) are short non-coding RNAs involved in biological and pathological processes of every cell type, including liver cells. Transcribed from specific genes, miRNA precursors are processed in the cytoplasm into mature miRNAs and as part of the RNA-induced silencing complex (RISC) complex binds to messenger RNA (mRNA) by imperfect complementarity. This leads to the regulation of gene expression at a post-transcriptional level. The function of a number of different miRNAs in fibrogenesis associated with the progression of chronic liver disease has recently been elucidated. Furthermore, miRNAs have been shown to be both disease-and tissue-specific and are stable in the circulation, which has led to increasing investigation on their utility as biomarkers for the diagnosis of chronic liver diseases, including those in children. Here, we review the current knowledge on the biogenesis of microRNA, the mechanisms of translational repression and the use of miRNA as circulatory biomarkers in chronic paediatric liver diseases including cystic fibrosis associated liver disease, biliary atresia and viral hepatitis B. PMID:27801781

  8. Quantitative Amyloid Imaging Using Image-Derived Arterial Input Function

    PubMed Central

    Su, Yi; Blazey, Tyler M.; Snyder, Abraham Z.; Raichle, Marcus E.; Hornbeck, Russ C.; Aldea, Patricia; Morris, John C.; Benzinger, Tammie L. S.

    2015-01-01

    Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer’s disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization

  9. Quantitative amyloid imaging using image-derived arterial input function.

    PubMed

    Su, Yi; Blazey, Tyler M; Snyder, Abraham Z; Raichle, Marcus E; Hornbeck, Russ C; Aldea, Patricia; Morris, John C; Benzinger, Tammie L S

    2015-01-01

    Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer's disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may

  10. Improvement of graft function and animal survival by fat emulsion in liver transplant rats.

    PubMed

    Ma, Zheng-Wei; Liu, Li-Dong; Li, Kun; Zhang, Yu-Jun; Dong, Jia-Hong

    2007-01-15

    Nutritional supports are required for liver transplant patients. However, no systematical assessment has been made of the optimal composition of energy yielding substrates in these patients. This study is to evaluate whether mixed energy system consisting of carbohydrate and lipid emulsions is more advantageous over single energy source of glucose for nutritional support in liver transplant recipients and whether structured lipid emulsion (STG) is superior to medium-chain triglyceride/long-chain triglycerides (MCT/LCT) and long-chain triglycerides (LCT) using a total parenteral nutrition model. Liver transplant rats were randomly divided to four groups according to the energy source, i.e. glucose (GLU), MCT/LCT, STG and LCT groups. Sham operated rats served as control. Hepatic function and lipid profile were determined to investigate the roles of lipid emulsion in hepatic function and lipid metabolism. Morphological changes of liver were observed, and nitrogen balance was determined. The results showed that infusion of lipid emulsion was well tolerated. The 1-week survival rate in the lipid emulsion groups was significantly higher than in the GLU group (100% versus 50%, P<0.05); compared with the GLU group, hepatic function recovered quickly and returned to normal level, and morphological alterations were less severer in the lipid emulsion groups, especially in the STG group; the lipid emulsions groups had normal serum TG and TC levels, especially STG and MCT/LCT groups; the lipid emulsions groups achieved a positive nitrogen balance on day 7 compared with the GLU group, and the STG group had the highest nitrogen balance. In conclusion, lipid emulsion is beneficial in improving hepatic function and the recipients' survival and does not influence the lipid metabolism. Mixed energy system consisting of carbohydrate and lipid is more advantageous over single energy source of glucose after liver transplantation, and STG is superior to MCT/LCT and LCT.

  11. Quantitative Measurements of Enhancement on Preprocedure Triphasic CT Can Predict Response of Colorectal Liver Metastases to Radioembolization

    PubMed Central

    Boas, F. Edward; Brody, Lynn A.; Erinjeri, Joseph P.; Yarmohammadi, Hooman; Shady, Waleed; Kishore, Sirish; Sofocleous, Constantinos T.

    2016-01-01

    Objective Colorectal liver metastases (CLM) have a variable response to radioembolization. This may be due at least partly to differences in tumor arterial perfusion. The present study examines whether quantitative measurements of enhancement on preprocedure triphasic CT can be used to predict the response of CLM to radioembolization. Materials and Methods We retrospectively reviewed patients with CLM treated with radioembolization who underwent pretreatment PET/CT and triphasic CT examinations and posttreatment PET/CT examinations. A total of 31 consecutive patients with 60 target tumors were included in the present study. For each tumor, we calculated the hepatic artery coefficient (HAC), portal vein coefficient (PVC), and arterial enhancement fraction (AEF) based on enhancement measurements on pretreatment triphasic CT. HAC and PVC are estimates of the hepatic artery and portal vein blood supply. AEF, which is the arterial phase enhancement divided by the portal phase enhancement, provides an estimate of the hepatic artery blood supply as a fraction of the total blood supply. For each tumor, the metabolic response to radioembolization was based on findings from the initial follow-up PET/CT scan obtained at 4–8 weeks after treatment. Results A total of 55% of CLM had a complete or partial metabolic response. Arterial phase enhancement, the HAC, and the PVC did not predict which tumors responded to radioembolization. However, the AEF was statistically significantly greater in tumors with a complete or partial metabolic response than in tumors with no metabolic response (i.e., those with stable disease or disease progression) (p = 0.038). An AEF of less than 0.4 was associated with a 40% response rate, whereas an AEF greater than 0.75 was associated with a 78% response rate. Conclusion Response to radioembolization can be predicted using the AEF calculated from the preprocedure triphasic CT. PMID:27248430

  12. Quantitative imaging of basic functions in renal (patho)physiology.

    PubMed

    Kang, Jung Julie; Toma, Ildiko; Sipos, Arnold; McCulloch, Fiona; Peti-Peterdi, Janos

    2006-08-01

    Multiphoton fluorescence microscopy offers the advantages of deep optical sectioning of living tissue with minimal phototoxicity and high optical resolution. More importantly, dynamic processes and multiple functions of an intact organ can be visualized in real time using noninvasive methods, and quantified. These studies aimed to extend existing methods of multiphoton fluorescence imaging to directly observe and quantify basic physiological parameters of the kidney including glomerular filtration rate (GFR) and permeability, blood flow, urinary concentration/dilution, renin content and release, as well as more integrated and complex functions like the tubuloglomerular feedback (TGF)-mediated oscillations in glomerular filtration and tubular flow. Streptozotocin-induced diabetes significantly increased single-nephron GFR (SNGFR) from 32.4 +/- 0.4 to 59.5 +/- 2.5 nl/min and glomerular permeability to a 70-kDa fluorophore approximately eightfold. The loop diuretic furosemide 2-fold diluted and increased approximately 10-fold the volume of distal tubular fluid, while also causing the release of 20% of juxtaglomerular renin content. Significantly higher speeds of individual red blood cells were measured in intraglomerular capillaries (16.7 +/- 0.4 mm/s) compared with peritubular vessels (4.7 +/- 0.2 mm/s). Regular periods of glomerular contraction-relaxation were observed, resulting in oscillations of filtration and tubular flow rate. Oscillations in proximal and distal tubular flow showed similar cycle times ( approximately 45 s) to glomerular filtration, with a delay of approximately 5-10 and 25-30 s, respectively. These innovative technologies provide the most complex, immediate, and dynamic portrayal of renal function, clearly depicting the components and mechanisms involved in normal physiology and pathophysiology.

  13. Transplantation of mouse fetal liver cells for analyzing the function of hematopoietic stem and progenitor cells.

    PubMed

    Gudmundsson, Kristbjorn Orri; Stull, Steven W; Keller, Jonathan R

    2012-01-01

    Hematopoietic stem cells are defined by their ability to self-renew and differentiate through progenitor cell stages into all types of mature blood cells. Gene-targeting studies in mice have demonstrated that many genes are essential for the generation and function of hematopoietic stem and progenitor cells. For definitively analyzing the function of these cells, transplantation studies have to be performed. In this chapter, we describe methods to isolate and transplant fetal liver cells as well as how to analyze donor cell reconstitution. This protocol is tailored toward mouse models where embryonic lethality precludes analysis of adult hematopoiesis or where it is suspected that the function of fetal liver hematopoietic stem and progenitor cells is compromised.

  14. Functional life-long maintenance of engineered liver tissue in mice following transplantation under the kidney capsule.

    PubMed

    Ohashi, Kazuo; Koyama, Fumikazu; Tatsumi, Kohei; Shima, Midori; Park, Frank; Nakajima, Yoshiyuki; Okano, Teruo

    2010-02-01

    The ability to engineer biologically active cells and tissue matrices with long-term functional maintenance has been a principal focus for investigators in the field of hepatocyte transplantation and liver tissue engineering. The present study was designed to determine the efficacy and temporal persistence of functional engineered liver tissue following transplantation under the kidney capsule of a normal mouse. Hepatocytes were isolated from human alpha-1 antitrypsin (hA1AT) transgenic mouse livers. Hepatocytes were subsequently transplanted under the kidney capsule space in combination with extracellular matrix components (Matrigel) for engineering liver tissues. The primary outcome of interest was to assess the level of engineering liver tissue function over the experimental period, which was 450 days. Long-term survival by the engineered liver tissue was confirmed by measuring the serum level of hA1AT in the recipient mice throughout the experimental period. In addition, administration of chemical compounds at day 450 resulted in the ability of the engineered liver tissue to metabolize exogenously circulating compounds and induce drug-metabolizing enzyme production. Moreover, we were able to document that the engineered tissues could retain their native regenerative potential similar to that of naïve livers. Overall, these results demonstrated that liver tissues could be engineered at a heterologous site while stably maintaining its functionality for nearly the life span of a normal mouse.

  15. HepatoProteomics: Applying Proteomic Technologies to the Study of Liver Function and Disease

    SciTech Connect

    Diamond, Deborah L.; Proll, Sean; Jacobs, Jon M.; Chan, Eric Y.; Camp, David G.; Smith, Richard D.; Katze, Michael G.

    2006-08-01

    The wealth of human genome sequence information now available, coupled with technological advances in robotics, nanotechnology, mass spectrometry, and information systems, has given rise to a method of scientific inquiry known as functional genomics. By using these technologies to survey gene expression and protein production on a near global scale, the goal of functional genomics is to assign biological function to genes with currently unknown roles in physiology. This approach carries particular appeal in disease research, where it can uncover the function of previously unknown genes and molecular pathways that are directly involved in disease progression. With this knowledge may come improved diagnostic techniques, prognostic capabilities, and novel therapeutic approaches. In this regard, the continuing evolution of proteomic technologies has resulted in an increasingly greater impact of proteome studies in many areas of research and hepatology is no exception. Our laboratory has been extremely active in this area, applying both genomic and proteomic technologies to the analysis of virus-host interactions in several systems, including the study of hepatitis C virus (HCV) infection and HCV-associated liver disease. Since proteomic technologies are foreign to many hepatologists (and to almost everyone else), this article will provide an overview of proteomic methods and technologies and describe how they're being used to study liver function and disease. We use our studies of HCV infection and HCV-associated liver disease to present an operational framework for performing high throughput proteome analysis and extracting biologically meaningful information.

  16. Peripheral blood monocytes from patients with HBV related decompensated liver cirrhosis can differentiate into functional hepatocytes.

    PubMed

    Yan, Li; Han, Ying; Wang, Jingbo; Liu, Jingmei; Hong, Liu; Fan, Daiming

    2007-11-01

    Peripheral blood monocytes (PBMCs) have the potential to differentiate into various progenitor cells. Here we have investigated the differentiation potential of PBMCs derived from patients with HBV related decompensated liver cirrhosis into hepatocyte-like cells. In our clinical trial, the PBMCs from 2 patients were mobilized by the recombinant human granulocyte colony stimulating factor, followed by leukapheresis and transplantation of PBMCs. PBMCs, induced by recombinant human hepatocyte growth factors, were identified by the expression of hepatocyte markers and specific biological functions with biochemical assays in vitro. Patients showed a lasting clinical amelioration for more than one year after transplantation, and hepatocyte-like cells were identified by expressing liver specific genes, synthesizing albumin, urea, aspirate transaminase, and glycogen, which were all similar to the human normal hepatic cell line QZG. Our results clearly demonstrated that mobilized PBMCs from patients with HBV related decompensated liver cirrhosis could differentiate into functional hepatocyte-like cells, indicating the possibility of autologous cell transplantation for treating patients with HBV related decompensated liver cirrhosis.

  17. Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

    SciTech Connect

    Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki; Fukuda, Kuniaki; Oshiro, Yoshiko; Fukumitsu, Nobuyoshi; Abei, Masato; Kawaguchi, Atsushi; Hayashi, Yasutaka; Ohkawa, Ayako; Hashii, Haruko; Kanemoto, Ayae; Moritake, Takashi; Tohno, Eriko; Tsuboi, Koji; Sakae, Takeji; Sakurai, Hideyuki

    2012-03-01

    Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

  18. Chenodeoxycholic Acid Derivative HS-1200 Inhibits Hepatocarcinogenesis and Improves Liver Function in Diethylnitrosamine-Exposed Rats by Downregulating MTH1

    PubMed Central

    Zhao, Qi; Liu, Hui; Qi, Jianni

    2017-01-01

    Aim. To investigate the effects of HS-1200 on liver tumorigenesis and liver function in a diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC) rat model. Methods. Rats were randomly assigned into five groups: control, HS-1200, HCC, HCC + low dose HS-1200, and HCC + high dose HS-1200 groups. Rat HCC model was established by intraperitoneal injection of DEN. And rats were given HS-1200 by daily oral gavage. After 20 weeks, we examined animal body weight, liver weight, liver pathological changes, serum levels of AST, ALT, and AFP, and mutT homologue gene 1 (MTH1) in liver tissue. Results. Oral gavage of HS-1200 significantly increased animal body weight and decreased liver weight as well as liver coefficient in HCC rats (P < 0.05 versus HCC group). Moreover, oral administration of HS-1200 suppressed tumorigenesis, attenuated pathological changes in liver tissues, and decreased serum levels of AST, ALT, and AFP in HCC rats (P < 0.05 versus HCC group). In addition, the mRNA level of MTH1 was upregulated in the liver tissues of HCC rats (P < 0.05 versus control group), which was reversed by HS-1200 treatment in a dose-dependent manner (P < 0.05 versus HCC group). Conclusions. HS-1200 inhibits hepatocarcinogenesis and improves liver function maybe by inducing downregulation of MTH1. PMID:28261604

  19. Chronic kidney disease-epidemiology formula and model for end-stage liver disease score in the assessment of renal function in candidates for liver transplantation.

    PubMed

    Tinti, F; Lai, S; Umbro, I; Mordenti, M; Barile, M; Ginanni Corradini, S; Rossi, M; Poli, L; Nofroni, I; Berloco, P B; Mitterhofer, A P

    2010-05-01

    Assessment of renal function in patients with end-stage liver disease (ESLD) awaiting liver transplantation (OLT) is critical. Various conditions may cause renal damage in ESLD. Renal and liver functions are intertwined due to splanchnic hemodynamic relationships; renal failure rarely occurs in patients without advanced decompensated cirrhosis. The recent literature suggests that evaluation of renal function should include an assessment of liver function. The aim of this study was to evaluate different methods to estimate glomerular filtration rate (GFR) in patient among ESLD candidates for OLT over 1 year. We also correlated renal and hepatic functions. Fifty-two cirrhotic patients Model for End-Stage Liver Disease [MELD] > 10) were enrolled in the study. All patients were evaluated at baseline and every 4 months (T1-T4) thereafter for 1 year. The GFR was calculated by creatinine clearance, and estimated by Cockroft and Gault, Modified Diet Renal Disease (MDRD) 4 and 6 variable and Chronic Kidney Disease-Epidemiology (CKD-EPI) formulae. Hepatic functions were evaluated by MELD score, albumin, bilirubin, and International Normalized Ratio (INR). We observed not statistically significant increase mean value of MELD score, bilirubin, serum creatinine, and blood urea nitrogen and a reduced serum sodium. There were no significant differences among various methods to evaluate GFR at each time over 1 year. We did not observe any association between renal and hepatic function, except at T4 for MELD and GFR estimated with MDRD 4 (P = .009) and 6 (P = .008) parameters or CKD-EPI (P = .036), and MELD and sodium (P = .001). Our results showed that evaluation of renal function in cirrhosis should include an evaluation of hepatic function. In our case, MDRD and CKD-EPI seemed to be the more accurate formulae to evaluate renal function in relation to hepatic function.

  20. A quantitative confidence signal detection model: 1. Fitting psychometric functions

    PubMed Central

    Yi, Yongwoo

    2016-01-01

    Perceptual thresholds are commonly assayed in the laboratory and clinic. When precision and accuracy are required, thresholds are quantified by fitting a psychometric function to forced-choice data. The primary shortcoming of this approach is that it typically requires 100 trials or more to yield accurate (i.e., small bias) and precise (i.e., small variance) psychometric parameter estimates. We show that confidence probability judgments combined with a model of confidence can yield psychometric parameter estimates that are markedly more precise and/or markedly more efficient than conventional methods. Specifically, both human data and simulations show that including confidence probability judgments for just 20 trials can yield psychometric parameter estimates that match the precision of those obtained from 100 trials using conventional analyses. Such an efficiency advantage would be especially beneficial for tasks (e.g., taste, smell, and vestibular assays) that require more than a few seconds for each trial, but this potential benefit could accrue for many other tasks. PMID:26763777

  1. Quantitative simulation of intracellular signaling cascades in a Virtual Liver: estimating dose dependent changes in hepatocellular proliferation and apoptosis

    EPA Science Inventory

    The US EPA Virtual Liver (v-Liver™) is developing an approach to predict dose-dependent hepatotoxicity as an in vivo tissue level response using in vitro data. The v-Liver accomplishes this using an in silico agent-based systems model that dynamically integrates environmental exp...

  2. The Groningen hypothermic liver perfusion pump: functional evaluation of a new machine perfusion system.

    PubMed

    van der Plaats, A; Maathuis, M H J; 'T Hart, N A; Bellekom, A A; Hofker, H S; van der Houwen, E B; Verkerke, G J; Leuvenink, H G D; Verdonck, P; Ploeg, R J; Rakhorst, G

    2006-12-01

    To improve preservation of donor livers, we have developed a portable hypothermic machine perfusion (HMP) system as an alternative for static cold storage. A prototype of the system was built and evaluated on functionality. Evaluation criteria included 24 h of adequate pressure controlled perfusion, sufficient oxygenation, a maintained 0-4 degrees C temperature and sterile conditions. Porcine livers were perfused with pump pressures that were set at 4 mmHg (continuous, portal vein) and 30/20 mmHg, at 60 BPM (pulsatile, hepatic artery). Control livers were preserved using the clinical golden standard: static cold storage. In the HMP group, pressure, flow and temperature were continuously monitored for 24 h. At time-points t = 0, 2, 4, 8, 12, and 24 h samples of University of Wisconsin machine preservation solution were taken for measurement of partial oxygen pressure (pO(2)) and lacto-dehydrogenase. Biopsies in every lobe were taken for histology and electron microscopy; samples of ice, preservation solution, liver surface, and bile were taken and cultured to determine sterility. Results showed that temperature was maintained at 0-4 degrees C; perfusion pressure was maintained at 4 mmHg and 30/20 mmHg for portal vein and hepatic artery, respectively. Flow was approximately 350 and 80 ml/min, respectively, but decreased in the portal vein, probably due to edema formation. Arterial pO(2) was kept at 100 kPa. Histology showed complete perfusion of the liver with no major damage to hepatocytes, bile ducts, and non-parenchymal cells compared to control livers. The machine perfusion system complied to the design criteria and will have to demonstrate the superiority of machine perfusion over cold storage in transplant experiments.

  3. [The clinical practice of improvement the "Volume and Quality" of functional liver in autologous liver transplantation for the patients with alveolar echinococcosis].

    PubMed

    Tuerganaili, Aji; Shao, Y M; Zhao, J M; Li, T; Ran, B; Jiang, T M; Zhang, R Q; Tuerhongjiang, Tuxun; Wu, L; Guo, M; Wen, H

    2017-01-24

    Objective: To investigate the clinical significance of accurate assessment of "volume and quality" of functional liver in Autologous liver transplantation (ALT) in the treatment of the advanced hepatic alveolar echinococcosis (HAE). Methods: The clinical data of 12 patients with advanced HAE who underwent ALT at the First Affiliated Hospital of Xinjiang Medical University from May 2015 to July 2016 were retrospectively analyzed. Results: The preoperative hepatic functions of 12 patients were 8 Child-Pugh Grade A, 1 Grade B, and 3 Grade C. Three of the patients had moderate or severe jaundice. Three of the patients calculated functional liver graft volume (GV) and standard liver volume (SLV) ratio (GV/SLV) were <30%. After the protection of liver function, anti-infection, percutaneous transhepatic cholangiography drainage (PTCD), selective portal vein embolization (PVE), and staging liver resection, liver function Child-Pugh grade of 11 patients was raised to A grade, and the other patient was B grade, meanwhile the bilirubin was reduced to 2 times the normal value. The GV/SLV ratios of 3 patients with low GV/SLV ratio had reached 44.4%, 47.2% and 56.2% respectively. In this study, the GV/SLV ratios of the 12 patients were between 73.2% and 40.8% with an average of 55.6%. Operation time was 11.5-20.5 h, with an average of 12.3 h. Anhepatic phase time was 193-375 min with median 253.5 min. The red blood cell suspension was 0-6 U during the operation. The average hospitalization was 10-42 d, with the average 22.7 d. Total hospital costs were 121 600-434 800 Yuan, with the median cost of 174 400 Yuan. One patient died of septic shock a week after surgery. Conclusion: (1)ALT may provide feasibility for the advanced HAE. (2)Accurate assessment of functional liver "volume and quality" appeared as the key points to the ALT. (3)Precise surgery and individualized treatment could improve and protect the functional liver "volume and quality" .

  4. Quantitative Assessment of Liver Fat in an Obese Patient Population Using Non-contrast CT Fat Percent Index

    PubMed Central

    Jon, Ali F.; Cheema, Ahmad R.; Khan, Atif N.; Raptopoulos, V.; Hauser, T.; Nasser, I.; Welty, F.K.; Karellas, A.; Clouse, Melvin E.

    2014-01-01

    Objective To develop a simplified method to quantify liver fat using CT fat % index (CTFPI) compared to liver spleen method (CTL/S, CTL-S) Methods Non-contrast CT of the liver was performed in 89 patients (overweight, obese, severely obese) to quantify fat, using: CTFPI= [(65-patient HU)/65] ×100, normal liver =65 HU. Results There was strong linear correlation between CTFPI and the standard method of assessing liver fat using CTL/S (r = −0.901), CTL-S (r = −0.911). Hepatic HU and CTFPI were significantly different in the severely obese group compared to other two groups(p<0.05). Conclusion Significant correlation indicates equal diagnostic accuracy of the two methods in appropriately calibrated scanners. PMID:24559751

  5. Estimating Functional Liver Reserve Following Hepatic Irradiation: Adaptive Normal Tissue Response Models

    PubMed Central

    Stenmark, Matthew H.; Cao, Yue; Wang, Hesheng; Jackson, Andrew; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

    2014-01-01

    Purpose To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. Materials and Methods From 2005–2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1−(ICG-R15pre-RT/ICG-R15post-RT)] where no toxicity was observed using a beta distribution function. Results Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of ≥78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p<0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. Conclusion The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient’s tolerance to hepatic irradiation. PMID:24813090

  6. Restoration of Liver Function and Portosystemic Pressure Gradient after TIPSS and Late TIPSS Occlusion

    SciTech Connect

    Maedler, U.; Hansmann, J.; Duex, M.; Noeldge, G.; Sauer, P.; Richter, G.M.

    2002-03-15

    TIPSS (transjugular intrahepatic portosystemic shunt) may be indicated to control bleeding from esophageal and gastric varicose veins, to reduce ascites, and to treat patients with Budd-Chiari syndrome and veno-occlusive disease. Numerous measures to improve the safety and methodology of the procedure have helped to increase the technical and clinical success. Follow-up of TIPSS patients has revealed shunt stenosis to occur more often in patients with preserved liver function (Child A, Child B). In addition, the extent of liver cirrhosis is the main factor that determines prognosis in the long term. Little is known about the effects of TIPSS with respect to portosystemic hemodynamics. This report deals with a cirrhotic patient who stopped drinking 7 months prior to admission. He received TIPSS to control ascites and recurrent esophageal bleeding. Two years later remarkable hypertrophy of the left liver lobe and shunt occlusion was observed. The portosystemic pressure gradient dropped from 24 mmHg before TIPSS to 11 mmHg and remained stable after shunt occlusion. The Child's B cirrhosis prior to TIPSS turned into Child's A cirrhosis and remained stable during the follow-up period of 32 months. This indicates that liver function of TIPSS patients may recover due to hypertrophy of the remaining non-cirrhotic liver tissue. In addition the hepatic hemodynamics may return to normal. In conclusion, TIPSS cannot cure cirrhosis but its progress may be halted if the cause can be removed. This may result in a normal portosystemic gradient, leading consequently to shunt occlusion.

  7. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

    PubMed Central

    Manon-Jensen, Tina; Genovese, Federica; Kristensen, Jacob H.; Nielsen, Mette J.; Sand, Jannie Marie B.; Hansen, Niels-Ulrik B.; Bay-Jensen, Anne-Christine; Bager, Cecilie L.; Krag, Aleksander; Blanchard, Andy; Krarup, Henrik; Leeming, Diana J.; Schuppan, Detlef

    2015-01-01

    Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases. PMID:25767261

  8. The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver.

    PubMed

    Reinehr, Roland; Sommerfeld, Annika; Häussinger, Dieter

    2013-04-01

    The Src family kinases Yes, Fyn, and c-Src play a pivotal role in regulating diverse liver functions such as bile flow, proteolysis, apoptosis, and proliferation and are regulated by anisoosmotic cell volume changes, death receptor ligands, and bile acids. For example, cell swelling leads to an integrin-sensed and focal adhesion kinase-mediated activation of c-Src-triggering choleresis, proteolysis inhibition, regulatory volume decrease via p38MAPK and proliferation via the activation of the epidermal growth factor receptor and extracellular regulated kinases 1 and 2. In contrast, hepatocyte shrinkage generates an almost instantaneous oxidative stress response that triggers the activation of c-Jun N-terminal kinase and the Src family kinases Fyn and Yes. Whereas Fyn activation mediates cholestasis, Yes triggers CD95 activation and apoptosis. This review will discuss the role of Src family kinases in the regulation of liver function with emphasis on their role in osmo-signaling and bile acid signaling.

  9. Vicarious liver visualization in solitary functioning kidney with technetium-99m ethylenedicysteine renal scintigraphy

    PubMed Central

    Jain, Tarun Kumar; Phulsunga, Rohit Kumar; Gupta, Nitin; Sood, Ashwani; Bhattacharya, Anish; Mittal, Bhagwant Rai

    2015-01-01

    We present a case of 3-year-old boy who was incidentally diagnosed to have single left kidney on ultrasonography. Dynamic technetium-99m ethylenedicysteine renal scintigraphy was acquired for assessing the existing kidney function showed the tracer localization in bilateral renal fossae during the entire study. The single-photon emission computerized tomography/computerized tomography study revealed activity in the right renal fossa to be in the enlarged right lobe of the liver, which was mimicking as impaired functioning right kidney in planar images. The hybrid imaging helped in accurate delineation of tracer uptake by confirming it to be the false appearance of the right kidney in planar imaging. This case report also highlights the possible mechanism of renal tracer uptake in the liver parenchyma. PMID:26170576

  10. Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain

    PubMed Central

    Quinkert, Amy Wells; Vimal, Vivek; Weil, Zachary M.; Reeke, George N.; Schiff, Nicholas D.; Banavar, Jayanth R.; Pfaff, Donald W.

    2011-01-01

    We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA. PMID:21555568

  11. Long Term Liver Engraftment of Functional Hepatocytes Obtained from Germline Cell-Derived Pluripotent Stem Cells

    PubMed Central

    Fagoonee, Sharmila; Famulari, Elvira Smeralda; Silengo, Lorenzo; Tolosano, Emanuela; Altruda, Fiorella

    2015-01-01

    One of the major hurdles in liver gene and cell therapy is availability of ex vivo-expanded hepatocytes. Pluripotent stem cells are an attractive alternative. Here, we show that hepatocyte precursors can be isolated from male germline cell-derived pluripotent stem cells (GPSCs) using the hepatoblast marker, Liv2, and induced to differentiate into hepatocytes in vitro. These cells expressed hepatic-specific genes and were functional as demonstrated by their ability to secrete albumin and produce urea. When transplanted in the liver parenchyma of partially hepatectomised mice, Liv2-sorted cells showed regional and heterogeneous engraftment in the injected lobe. Moreover, approximately 50% of Y chromosome-positive, GPSC-derived cells were found in the female livers, in the region of engraftment, even one month after cell injection. This is the first study showing that Liv2-sorted GPSCs-derived hepatocytes can undergo long lasting engraftment in the mouse liver. Thus, GPSCs might offer promise for regenerative medicine. PMID:26323094

  12. Proteomic analysis of physiological function response to hot summer in liver from lactating dairy cows.

    PubMed

    Wang, Qiangjun; Zhao, Xiaowei; Zhang, Zijun; Zhao, Huiling; Huang, Dongwei; Cheng, Guanglong; Yang, Yongxin

    2017-04-01

    Lactation performance of dairy cattle is susceptible to heat stress. The liver is one of the most crucial organs affected by high temperature in dairy cows. However, the physiological adaption by the liver to hot summer conditions has not been well elucidated in lactating dairy cows. In the present study, proteomic analysis of the liver in dairy cows in spring and hot summer was performed using a label-free method. In total, 127 differentially expressed proteins were identified; most of the upregulated proteins were involved in protein metabolic processes and responses to stimuli, whereas most of the downregulated proteins were related to oxidation-reduction. Pathway analysis indicated that 3 upregulated heat stress proteins (HSP90α, HSP90β, and endoplasmin) were enriched in the NOD-like receptor signaling pathway, whereas several downregulated NADH dehydrogenase proteins were involved in the oxidative phosphorylation pathway. The protein-protein interaction network indicated that several upregulated HSPs (HSP90α, HSP90β, and GRP78) were involved in more interactions than other proteins and were thus considered as central hub nodes. Our findings provide novel insights into the physiological adaption of liver function in lactating dairy cows to natural high temperature.

  13. Linking multidimensional functional diversity to quantitative methods: a graphical hypothesis--evaluation framework.

    PubMed

    Boersma, Kate S; Dee, Laura E; Miller, Steve J; Bogan, Michael T; Lytle, David A; Gitelman, Alix I

    2016-03-01

    Functional trait analysis is an appealing approach to study differences among biological communities because traits determine species' responses to the environment and their impacts on ecosystem functioning. Despite a rapidly expanding quantitative literature, it remains challenging to conceptualize concurrent changes in multiple trait dimensions ("trait space") and select quantitative functional diversity methods to test hypotheses prior to analysis. To address this need, we present a widely applicable framework for visualizing ecological phenomena in trait space to guide the selection, application, and interpretation of quantitative functional diversity methods. We describe five hypotheses that represent general patterns of responses to disturbance in functional community ecology and then apply a formal decision process to determine appropriate quantitative methods to test ecological hypotheses. As a part of this process, we devise a new statistical approach to test for functional turnover among communities. Our combination of hypotheses and metrics can be applied broadly to address ecological questions across a range of systems and study designs. We illustrate the framework with a case study of disturbance in freshwater communities. This hypothesis-driven approach will increase the rigor and transparency of applied functional trait studies.

  14. RIFLE criteria and hepatic function in the assessment of acute renal failure in liver transplantation.

    PubMed

    Tinti, F; Umbro, I; Meçule, A; Rossi, M; Merli, M; Nofroni, I; Corradini, S Ginanni; Poli, L; Pugliese, F; Ruberto, F; Berloco, P B; Mitterhofer, A P

    2010-05-01

    Renal dysfunction in cirrhotic patients is primary related to disturbances of circulatory function, triggered by portal hypertension with chronic intrarenal vasoconstriction and hypoperfusion. Pretransplant renal function is an important factor implicated in the development of acute renal failure (ARF) after liver transplantation (OLT), but other factors mostly related to liver function seem to influence the development of ARF. The Acute Dialysis Quality Initiative workgroup developed the RIFLE classification to define ARF. We sought to evaluate the incidence of ARF among patients undergoing OLT, to evaluate the association of ARF with pre-OLT renal and hepatic functions, and to evaluate the influence of ARF on chronic kidney disease (CKD) at 1 month post-OLT. Clinical, renal, hepatic function, and donor risk index data of 24 patients who underwent deceased donor OLT were collected before transplantation, in the perioperative period and in the first month post-OLT. ARF occurred in 37.5% of patients with 56% developing the R grade and 44% the I grade; no patient showed the F grade. An association was observed between ARF and a higher Model for End-Stage Liver Disease (MELD) score and between ARF and a reduced pre-OLT serum albumin. No association was noted between ARF and other pre-OLT parameters. In cirrhotic patients serum creatinine is a bias for renal function assessment and the Modification of Diet in Renal Disease formula overestimates GFR. Post-OLT CKD was present in 6.7% of patients without ARF and in 44.4% of patients with ARF. The R grade developed more frequently among patients with viral cirrhosis. The association of ARF with MELD and hypoalbuminemia may be the result of a close relationship between renal and hepatic functions among cirrhotic patients. Post-OLT CKD may be the result of unrecognized, preexisting CKD and/or the effects of not fully resolved acute damage to an injured kidney.

  15. Quantitative theory of a relaxation function in a glass-forming system.

    PubMed

    Lerner, Edan; Procaccia, Itamar

    2008-08-01

    We present a quantitative theory for a relaxation function in a simple glass-forming model (binary mixture of particles with different interaction parameters). It is shown that the slowing down is caused by the competition between locally favored regions (clusters) that are long-lived but each of which relaxes as a simple function of time. Without the clusters, the relaxation of the background is simply determined by one typical length, which we deduce from an elementary statistical mechanical argument. The total relaxation function (which depends on time in a nontrivial manner) is quantitatively determined as a weighted sum over the clusters and the background. The "fragility" in this system can be understood quantitatively since it is determined by the temperature dependence of the number fractions of the locally favored regions.

  16. Anatrophic nephrolithotomy: preservation of renal function demonstrated by differential quantitative radionuclide renal scans.

    PubMed

    Belis, J A; Morabito, R A; Kandzari, S J; Lai, J C; Gabriele, O F

    1981-06-01

    Differential quantitative radionuclide renal scans have been used to confirm that early removal of staghorn calculi by anatrophic nephrolithotomy preserves renal parenchyma without significant renal damage by the surgical procedure. The 99mtechnetium diethylenetriaminepentaacetic acid scan was useful in predicting recovery of function in the involved kidney, while the 131iodine orthoiodohippurate scan provided a quantitative evaluation of the effect of the surgical procedure on individual kidney function. All of 13 consecutive patients evaluated by 131iodine orthoiodohippurate renal scans had stable or improved effective renal plasma flow to the involved kidney and an unchanged or improved total excretory index 6 months after nephrolithotomy.

  17. Anatrophic nephrolithotomy: preservation of renal function demonstrated by differential quantitative radionuclide renal scans

    SciTech Connect

    Belis, J.A.; Morabito, R.A.; Kandzari, S.J.; Lai, J.C.; Gabriele, O.F.

    1981-06-01

    Differential quantitative radionuclide renal scans have been used to confirm that early removal of staghorn calculi by anatrophic nephrolithotomy preserves renal parenchyma without significant renal damage by the surgical procedure. The /sup 99m/technetium diethylenetriaminepentaacetic acid scan was useful in predicting recovery of function in the involved kidney, while the /sup 131/iodine orthoiodohippurate scan provided a quantitative evaluation of the effect of the surgical procedure on individual kidney function. All of 13 consecutive patients evaluated by /sup 131/iodine orthoiodohippurate renal scans had stable or improved effective renal plasma flow to the involved kidney and an unchanged or improved total excretory index 6 months after nephrolithotomy.

  18. Role of exercise in optimizing the functional status of patients with nonalcoholic fatty liver disease.

    PubMed

    Gerber, Lynn H; Weinstein, Ali; Pawloski, Lisa

    2014-02-01

    Nonalcoholic fatty liver disease (NAFLD) is frequently concomitant with obesity. This article discusses factors that influence health and functional outcomes of people who develop NAFLD, including increased burden of illness, whole body function, performance, and perception of self-efficacy. Changes in macronutrients, amount of calories consumed, and decreased physical activity all negatively influence patient outcome. The benefits of exercise in this population are also discussed. To be effective, exercise must be performed, regularly and in conjunction with dietary and other behavioral change. Therefore, a lifelong commitment to exercise, activity, and diet are needed if NAFLD is to be successfully treated.

  19. Impact of splenic artery ligation after major hepatectomy on liver function, regeneration and viability

    PubMed Central

    Carrapita, Jorge; Abrantes, Ana Margarida; Campelos, Sofia; Gonçalves, Ana Cristina; Cardoso, Dulce; Sarmento-Ribeiro, Ana Bela; Rocha, Clara; Santos, Jorge Nunes; Botelho, Maria Filomena; Tralhão, José Guilherme; Farges, Olivier; Barbosa, Jorge Maciel

    2016-01-01

    It was reported that prevention of acute portal overpressure in small-for-size livers by inflow modulation results in a better postoperative outcome. The aim is to investigate the impact of portal blood flow reduction by splenic artery ligation after major hepatectomy in a murine model. Forty-eight rats were subjected to an 85% hepatectomy or 85% hepatectomy and splenic artery ligation. Both groups were evaluated at 24, 48, 72 and 120 post-operative hours: liver function, regeneration and viability. All methods and experiments were carried out in accordance with Coimbra University guidelines. Splenic artery ligation produces viability increase after 24 h, induces a relative decrease in oxidative stress during the first 48 hours, allows antioxidant capacity increment after 24 h, which is reflected in a decrease of half-time normalized liver curve at 48 h and at 72 h and in an increase of mitotic index between 48 h and 72 h. Splenic artery ligation combined with 85% hepatectomy in a murine model, allows portal inflow modulation, promoting an increase in hepatocellular viability and regeneration, without impairing the function, probably by inducing a less marked elevation of oxidative stress at first 48 hours. PMID:27725728

  20. Green light for liver function monitoring using indocyanine green? An overview of current clinical applications.

    PubMed

    Vos, J J; Wietasch, J K G; Absalom, A R; Hendriks, H G D; Scheeren, T W L

    2014-12-01

    The dye indocyanine green is familiar to anaesthetists, and has been studied for more than half a century for cardiovascular and hepatic function monitoring. It is still, however, not yet in routine clinical use in anaesthesia and critical care, at least in Europe. This review is intended to provide a critical analysis of the available evidence concerning the indications for clinical measurement of indocyanine green elimination as a diagnostic and prognostic tool in two areas: its role in peri-operative liver function monitoring during major hepatic resection and liver transplantation; and its role in critically ill patients on the intensive care unit, where it is used for prediction of mortality, and for assessment of the severity of acute liver failure or that of intra-abdominal hypertension. Although numerous studies have demonstrated that indocyanine green elimination measurements in these patient populations can provide diagnostic or prognostic information to the clinician, 'hard' evidence - i.e. high-quality prospective randomised controlled trials - is lacking, and therefore it is not yet time to give a green light for use of indocyanine green in routine clinical practice.

  1. Function of the liver and bile ducts in humans exposed to lead.

    PubMed

    Kasperczyk, A; Dziwisz, M; Ostałowska, A; Swietochowska, E; Birkner, E

    2013-08-01

    Lead is very common in the environment, and it is therefore important to characterize its possible adverse health effects. The aim of this study was to evaluate the impact of lead exposure on selected functions of the liver and bile ducts in people who are chronically exposed to the metal because of their occupations. To provide this information, the activity of specific enzymes and the bilirubin concentration were determined in blood serum, and morphological parameters of the liver and bile ducts were evaluated using the ultrasonic imaging method. Healthy male employees of a lead-zinc processing facility (n = 145) who were occupationally exposed to lead were divided into two subgroups as a function of the lead concentrations in blood (PbB): low lead exposure (PbB = 20-35 μg/dl; n = 57) and high lead exposure (PbB = 35-60 μg/dl; n = 88). Human exposure to lead compounds was found to cause liver enlargement and to activate inflammatory reactions with the characteristics of moderate cholestasis within the bile ducts, while no characteristics of necrotic damage of hepatic cells were noted. It seems that lipid peroxidation can be one of the toxic mechanisms of lead which induce moderate cholestasis. The effects depend on the extent of the lead exposure and were greater in subjects with higher exposure levels, particularly subjects with PbB values greater than 35 μg/dl.

  2. Impact of splenic artery ligation after major hepatectomy on liver function, regeneration and viability.

    PubMed

    Carrapita, Jorge; Abrantes, Ana Margarida; Campelos, Sofia; Gonçalves, Ana Cristina; Cardoso, Dulce; Sarmento-Ribeiro, Ana Bela; Rocha, Clara; Santos, Jorge Nunes; Botelho, Maria Filomena; Tralhão, José Guilherme; Farges, Olivier; Barbosa, Jorge Maciel

    2016-10-11

    It was reported that prevention of acute portal overpressure in small-for-size livers by inflow modulation results in a better postoperative outcome. The aim is to investigate the impact of portal blood flow reduction by splenic artery ligation after major hepatectomy in a murine model. Forty-eight rats were subjected to an 85% hepatectomy or 85% hepatectomy and splenic artery ligation. Both groups were evaluated at 24, 48, 72 and 120 post-operative hours: liver function, regeneration and viability. All methods and experiments were carried out in accordance with Coimbra University guidelines. Splenic artery ligation produces viability increase after 24 h, induces a relative decrease in oxidative stress during the first 48 hours, allows antioxidant capacity increment after 24 h, which is reflected in a decrease of half-time normalized liver curve at 48 h and at 72 h and in an increase of mitotic index between 48 h and 72 h. Splenic artery ligation combined with 85% hepatectomy in a murine model, allows portal inflow modulation, promoting an increase in hepatocellular viability and regeneration, without impairing the function, probably by inducing a less marked elevation of oxidative stress at first 48 hours.

  3. Comparison of conventional PCR, quantitative PCR, bacteriological culture and the Warthin Starry technique to detect Leptospira spp. in kidney and liver samples from naturally infected sheep from Brazil.

    PubMed

    Fornazari, Felipe; da Silva, Rodrigo Costa; Richini-Pereira, Virginia Bodelão; Beserra, Hugo Enrique Orsini; Luvizotto, Maria Cecília Rui; Langoni, Helio

    2012-09-01

    Leptospirosis is an infectious disease of worldwide importance. The development of diagnostic techniques allows sick animals to be identified, reservoirs to be eliminated and the disease prevented and controlled. The present study aimed to compare different techniques for diagnosing leptospirosis in sheep. Samples of kidney, liver and blood were collected from 465 animals that originated from a slaughterhouse. The sera were analyzed by the Microscopic Agglutination Test (MAT), and kidney and liver samples of seropositive animals were analyzed using four techniques: bacteriological culture, the Warthin Starry (WS) technique, conventional PCR (cPCR), and quantitative PCR (qPCR). With the MAT, 21 animals were positive (4.5%) to serovars Hardjo (n=12), Hebdomadis (n=5), Sentot (n=2), Wolfii (n=1) and Shermani (n=1). Titers were 100 (n=10), 200 (n=2), 400 (n=6) and 1600 (n=3). No animal was positive by bacteriological culture; four animals were positive by the WS technique in kidney samples; six animals were positive by cPCR in kidney samples; and 11 animals were positive by qPCR, eight of which in kidney samples and three in liver. The bacterial quantification revealed a median of 4.3 bacteria/μL in liver samples and 36.6 bacteria/μL in kidney samples. qPCR presented the highest sensitivity among the techniques, followed by cPCR, the WS technique and bacteriological culture. These results indicate that sheep can carry leptospires of the Sejroe serogroup, and demonstrate the efficiency of quantitative PCR to detect Leptospira spp. in tissue samples.

  4. Lipid Profiling and Transcriptomic Analysis Reveals a Functional Interplay between Estradiol and Growth Hormone in Liver

    PubMed Central

    Fernández-Pérez, Leandro; Santana-Farré, Ruymán; de Mirecki-Garrido, Mercedes; García, Irma; Guerra, Borja; Mateo-Díaz, Carlos; Iglesias-Gato, Diego; Díaz-Chico, Juan Carlos; Flores-Morales, Amilcar; Díaz, Mario

    2014-01-01

    17β-estradiol (E2) may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARα. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a marked influence on

  5. Liver disease alters high-density lipoprotein composition, metabolism and function.

    PubMed

    Trieb, Markus; Horvath, Angela; Birner-Gruenberger, Ruth; Spindelboeck, Walter; Stadlbauer, Vanessa; Taschler, Ulrike; Curcic, Sanja; Stauber, Rudolf E; Holzer, Michael; Pasterk, Lisa; Heinemann, Akos; Marsche, Gunther

    2016-07-01

    High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.

  6. A case of Hodgkin’s lymphoma with severely impaired liver function treated successfully with gemcitabine followed by ABVD

    PubMed Central

    Chakraborty, Rajshekhar; Mukkamalla, Shiva Kumar Reddy; Gutzmore, Garfield; Chan, Hon Cheung

    2015-01-01

    Hodgkin’s lymphoma (HL) originates from clonal B cells and is the most common malignancy in the second decade of life. Liver involvement is uncommon at presentation in patients with HL and there is a paucity of data for treatment of patients with severely impaired liver function. We present an unusual case of HL with severe hepatic impairment, splenomegaly and multiple chromosomal abnormalities that was treated initially with gemcitabine and steroids. Once liver function tests improved, six cycles of Adriamycin, bleomycin, vinblastine, and dacarbazine were administered. The patient remains in remission at 3.5 years of follow-up. PMID:25848330

  7. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.

    PubMed

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.

  8. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro

    PubMed Central

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotransformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID:27959388

  9. Risk factors for damaged liver function after chemotherapy in hepatitis B virus carriers with non-Hodgkin lymphoma.

    PubMed

    Li, X; Fan, X W; Liu, W; Guo, L; Li, Y; Hu, X; Liang, X; Ma, X P; Yang, S E

    2015-03-30

    The goal of this study was to investigate damaged liver function after chemotherapy in hepatitis B virus (HBV) carriers with non-Hodgkin lymphoma (NHL) and to evaluate risk factors associated with a high risk of damaged liver function. Clinical histories of 134 HBV carriers with NHL who were treated with chemotherapy were obtained and analyzed for the occurrence of damaged liver function and other related high-risk factors. Analysis showed that 76 patients (56.7%) had damaged liver function after chemotherapy: 6 patients (7.9%) had I degree, 17 patients (22.4%) had II degree, 20 patients (26.3%) had III degree, and 33 patients (43.4%) had IV degree damage. After treatment, 18 patients (23.7%) continued to receive chemotherapy according to their original schedule, 39 patients (51.3%) delayed chemotherapy, 16 patients (21.1%) stopped chemotherapy, and 3 patients (3.9%) died. Analysis of a binary multivariate logistic regression model showed that administration of steroids was a high-risk factor for damaged liver function after chemotherapy in NHL patients. The incidence of damaged liver function after chemotherapy is high among HBV carriers with NHL; therefore, administration of steroid chemotherapy is a high-risk factor.

  10. Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment.

    PubMed

    Schmid, A I; Chmelík, M; Szendroedi, J; Krssák, M; Brehm, A; Moser, E; Roden, M

    2008-06-01

    The liver plays a central role in intermediate metabolism. Accumulation of liver fat (steatosis) predisposes to various liver diseases. Steatosis and abnormal muscle energy metabolism are found in insulin-resistant and type-2 diabetic states. To examine hepatic energy metabolism, we measured hepatocellular lipid content, using proton MRS, and rates of hepatic ATP synthesis in vivo, using the 31P magnetization transfer experiment. A suitable localization scheme was developed and applied to the measurements of longitudinal relaxation times (T1) in six healthy volunteers and the ATP-synthesis experiment in nine healthy volunteers. Liver 31P spectra were modelled and quantified successfully using a time domain fit and the AMARES (advanced method for accurate, robust and efficient spectral fitting of MRS data with use of prior knowledge) algorithm describing the essential components of the dataset. The measured T1 relaxation times are comparable to values reported previously at lower field strengths. All nine subjects in whom saturation transfer was measured had low hepatocellular lipid content (1.5 +/- 0.2% MR signal; mean +/- SEM). The exchange rate constant (k) obtained was 0.30 +/- 0.02 s(-1), and the rate of ATP synthesis was 29.5 +/- 1.8 mM/min. The measured rate of ATP synthesis is about three times higher than in human skeletal muscle and human visual cortex, but only about half of that measured in perfused rat liver. In conclusion, 31P MRS at 3 T provides sufficient sensitivity to detect magnetization transfer effects and can therefore be used to assess ATP synthesis in human liver.

  11. Quantitating Cell-Cell Interaction Functions, with Applications to Glioblastoma Multiforme Cancer Cells

    PubMed Central

    Wang, Jun; Tham, Douglas; Wei, Wei; Shin, Young Shik; Ma, Chao; Ahmad, Habib; Shi, Qihui; Yu, Jenkan; Levine, Raphael D.; Heath, James R.

    2013-01-01

    We report on a method for quantitating the distance dependence of cell-cell interactions. We employ a microchip design that permits a multiplex, quantitative protein assay from statistical numbers of cell pairs, as a function of cell separation, with a 0.15 nanoliter volume microchamber. We interrogate interactions between pairs of model brain cancer cells by assaying for 6 functional proteins associated with PI3k signaling. At short incubation times, cells do not appear to influence each other, regardless of cell separation. For 6 hour incubation times, the cells exert an inhibiting influence on each other at short separations, and a predominately activating influence at large separation. Protein-specific cell-cell interaction functions are extracted, and by assuming pairwise additivity of those interactions, the functions are shown to correctly predict the results from 3-cell experiments carried out under the identical conditions. PMID:23130660

  12. Quantitation of TCE-Induced Radicals in Liver of B6C3Fl Mice In Vivo: An EPR Study

    DTIC Science & Technology

    1996-02-01

    PAGE 1 First derivative EPR spectrum of B6C3F1 mouse liver (a) after and (b) before lyophilization 8 2 GC/MS of PBN extract (a) Total ion current...of TCE-induced cancer in a number of animal species remains to be elucidated. The biological effects of TCE are of special interest to us because TCE...injection the mouse was killed and the liver was harvested. Figure 2A shows the total ion current gas chromatogram of the GC/MS analysis of.a non polar

  13. Effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver.

    PubMed

    Gao, Feng; Liu, Yingchun; Li, Lingyao; Li, Ming; Zhang, Chongzhi; Ao, Changjin; Hou, Xianzhi

    2014-06-30

    This study investigated the effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver. Eighteen ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.175MJMEkgBW(-0.75)d(-1), n=6), Restricted Group 2 (RG2, 0.33MJMEkgBW(-0.75)d(-1), n=6) and a Control Group (CG, ad libitum, 0.67MJMEkgBW(-0.75)d(-1), n=6). Fetuses were recovered at slaughter on d 140. Fetuses in the RG1 group exhibited decreased (P<0.05) liver weight, total antioxidant capacity (T-AOC), superoxide dismutase activity (SOD), cholinesterase (CHE), total protein (TP), globulin (GLB), and alanine transaminase (ALT). In addition, intermediate changes were found in the RG2 fetuses, including decreased liver weight, T-AOC and CHE (P<0.05). In contrast, increases in fetal hepatic collagen fibers and reticular fibers, glutathione peroxidase (GSH-Px), malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOs), monoamine oxidase (MAO), albumin (ALB)/GLB, aspartate transaminase (AST), and AST/ALT were found in the RG1 fetuses (P<0.05). The RG2 fetuses had increased fetal hepatic collagen fibers, NOs and MAO (P<0.05) relative to the control fetuses. These results indicate that impaired fetal hepatic growth, fibrosis, antioxidant imbalance and dysfunction were associated with maternal undernutrition.

  14. Functional genomics bridges the gap between quantitative genetics and molecular biology.

    PubMed

    Lappalainen, Tuuli

    2015-10-01

    Deep characterization of molecular function of genetic variants in the human genome is becoming increasingly important for understanding genetic associations to disease and for learning to read the regulatory code of the genome. In this paper, I discuss how recent advances in both quantitative genetics and molecular biology have contributed to understanding functional effects of genetic variants, lessons learned from eQTL studies, and future challenges in this field.

  15. Evaluation of Pistacia lentiscus fatty oil effects on glycemic index, liver functions and kidney functions of New Zealand rabbits.

    PubMed

    Djerrou, Zouhir; Hamdi-Pacha, Y; Belkhiri, A M; Djaalab, H; Riachi, F; Serakta, M; Boukeloua, A; Maameri, Z

    2011-01-01

    Pistacia lentiscus fatty oil (PLFO) is a well known natural remedy in eastern Algeria folk medicine. It is widely used in the treatment of respiratory disorders and dermal burns. The present study has been carried out to investigate effects of this oil on fasting glucose and some functional parameters of the liver and kidney in white male New Zealand rabbits (Initial mean weight 1.95 Kg). PLFO was applied to tested rabbits (PLFO group) via rectal route, once daily 5-day per week, for six consecutive weeks at the dose of 1 ml/Kg body weight. The same number of animals (n=6) was not treated and served as control (CRL group). The results showed that PLFO was tolerated by rectal route. No significant differences were observed in body weights of the two groups. Biochemical analysis showed that aspartate transaminase (AST) and alanine transaminase (ALT) were significantly decreased in blood plasma at (P< 0.05) and (P< 0.01) respectively in PLFO group (Mann-Whitney test). On the other hand, the fasting glucose level (GLU) was significantly increased (Mann-Whitney test, P< 0.05), while the rest of the tested parameters (Albumin, total proteins, creatinine, urea) was not significantly affected. However, these variations have not biologic signification toxicity. The study concludes that PLFO is tolerable via rectal route; it is safe with no adverse effect on liver functions and renal functions with possible anti-glycogenesis activity.

  16. Liver functions in silica-exposed workers in Egypt: possible role of matrix remodeling and immunological factors

    PubMed Central

    Zawilla, Nermin; Taha, Fatma; Ibrahim, Yasser

    2014-01-01

    Background: Brick manufacturing constitutes an important industrial sector in Egypt with considerable exposure to silica. Objectives: We aimed for evaluating hepatic functions in silica-exposed workers in the clay brick industry, and the possible role of matrix remodeling and immunological factors. Methods: A case–control study, 87 workers as exposed and 45 as control subjects. Questionnaire, clinical examination, and laboratory investigations: liver functions, matrix metalloproteinase-9, immunoglobulins G and E, and anti-liver kidney microsomal antibody. Results: In the exposed workers, mean levels of liver functions, matrix metalloproteinase-9 (MMP-9), and IgG and IgE were significantly higher. In the silicotic subgroup the mean level of GGT was almost twice the level in the non-silicotic subjects. Logistic regression showed that abnormal GGT and ALT were associated with production workers. Conclusion: Workers in the clay brick industry showed evidence of liver disease that could be related to matrix remodeling. PMID:24999850

  17. Protective effect of salvianolic acid B on NASH rat liver through restoring intestinal mucosal barrier function

    PubMed Central

    Wang, Ying-Chun; Jin, Qing-Mei; Kong, Wei-Zong; Chen, Juan

    2015-01-01

    Aim: To investigate the effect of Salvianolic acid B (Sal B) on the disease progress of NASH and change of intestinal barrier function. Methods: Sixty Sprague-Dawley (SD) rats were randomly divided into control group, model group and treated group, with the former given normal diet and the latter 2 groups rats fed high-fat diet. In treated group, rats were infused through the stomach with 1 mg/ml Sal B every day at a dose of 20 mL/kg body weight. All animals were killed at the 24th week and plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), endotoxin (ET) and diamine oxdase (DAO) were analyzed using the blood samples. The histopathology of liver was observed by H&E staining. The expression changes of tight junction protein occludin and ZO-1 were analyzed by immunocytochemistry. Ultrastructural morphology of small intestinal tissues was investigated by transmission electron microscopy. Results: Plasma levels of ALT, AST, TG, TC, ET and DAO were significantly higher in model group than those in both control group and group treated with Sal B. In model group, vacuolated swelling of the cytoplasm with aggregates of chronic inflammatory cells was observed in the liver tissue but not in Sal B-treated group. NAFLD Activity Score in the treated group was significantly lower than that in model group. Immunohistochemical staining showed that Sal B administration recovered the expression of occludin and ZO-1, which was downregulated in the model group. Transmission electron microscopy analysis demonstrated that cell surface microvilli and major intercellular junctional complex including tight junction, gap junction and adherens junction were restored in Sal B-treated group. Conclusion: Sal B exerted protective function against high-fat diet-induced liver damage by restoring healthy barrier function of intestine in NASH rat model. PMID:26191218

  18. Impact of therapeutic and high doses of florfenicol on kidney and liver functional indicators in goat

    PubMed Central

    Shah, Jan Muhammad; Qureshi, Toufique Ahmed; Shah, Tahmina; Shah, Qurban Ali; Arain, Muhammad Asif; Bhutto, Zohaib Ahmed; Saeed, Muhammad; Siyal, Farman Ali

    2016-01-01

    Aim: The aim of this study was to evaluate the impact of therapeutic and high doses of florfenicol on kidney and liver functional indicators in goat species. Materials and Methods: Six mature, healthy goats (combine breed and sex) with average weight 25 kg were selected for this study. The therapeutic (20 mg/kg b.w.) and high doses (40 and 60 mg) of florfenicol were administered for 3 days with 24 h interval. Blood samples were collected at 0, 24, 48, 72, 96, and 120 h following the each administered dose. Results: The results showed that the therapeutic dose of florfenicol produced nonsignificant effect on serum urea, creatinine, total protein (TP), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and bilirubin on all timings, and increased (p<0.05) the serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate-pyruvate transaminase (SGPT) levels for 48 h. Whereas the high doses of florfenicol (40 and 60 mg) significantly altered the kidney and liver functional indicators in the blood. In contrast with control, the serum urea level was (p<0.01) increased at all timing points. Creatinine values were altered (p<0.01, <0.05) in increasing manner from 24 to 96 h. The high dose of 40 mg decreased the TP (p<0.05) for 72 h and 60 mg persisted same effect (p<0.01) up to 120 h. The indices of ALP, GGT, SGOT, and SGPT were raised (p<0.01, <0.05) at all timings. The bilirubin indexes also (p<0.05) elevated from 48 to 72. Conclusion: It was concluded that the high doses of florfenicol produced reversible dose-dependent effects on functional indicators of kidney and liver such as urea, creatinine, TP, ALP, SGOT, SGPT, GGT, and bilirubin. PMID:27847425

  19. Liver Immunology

    PubMed Central

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  20. Quantitative protein localization signatures reveal an association between spatial and functional divergences of proteins.

    PubMed

    Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

    2014-03-01

    Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein

  1. Deranged liver function tests following laparoscopic cholecystectomy: What would Occam have to say?

    PubMed Central

    Appleton, S

    2016-01-01

    Postoperative complications can pose a significant obstacle in the ongoing management of surgical patients. However, it is pertinent to remember that postoperative events are not always complications of the preceding operation. We present the case of a patient with calculous cholecystitis and gallbladder empyema who underwent laparoscopic cholecystectomy. Postoperatively, he continued to have right upper quadrant pain associated with abnormal liver function tests. Ultimately, the cause of his postoperative symptoms was rather prosaic and ran counter to Occam’s razor, the relevance of which is discussed below. PMID:27310811

  2. An in vivo and in vitro comparison of CYP gene induction in mice using liver slices and quantitative RT-PCR.

    PubMed

    Martignoni, Marcella; de Kanter, Ruben; Grossi, Pietro; Saturno, Grazia; Barbaria, Elena; Monshouwer, Mario

    2006-02-01

    The scope of this study was to compare in vitro and in vivo cytochrome P450 (CYP) gene induction in mice, using liver slices as an in vitro model. We have chosen to study mice to be able to better interpret CYP induction during long-term safety studies in this species. Mouse liver slices were incubated with beta-naphthoflavone (betaNF), phenobarbital (PB) or dexamethasone (DEX) for 24 h. In addition, in an in vivo study, mice were treated with the same compounds for three days. The mRNA expression of cyp1a1, cyp1a2, cyp2b10 and cyp3a11, which are important for drug metabolism and inducible by xenobiotics, were investigated in vivo and in vitro by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Both in mouse liver slices and in vivo, betaNF was found to be a potent inducer of cyp1a1 and to a lesser extent of cyp1a2. All three compounds induced cyp2b10 mRNA levels, while the cyp3a11 mRNA level was induced only by DEX. Overall, these data demonstrated a good predictive in vitro-in vivo correlation of CYP induction.

  3. Comparison of yttrium-90 quantitative imaging by TOF and non-TOF PET in a phantom of liver selective internal radiotherapy

    NASA Astrophysics Data System (ADS)

    van Elmbt, Larry; Vandenberghe, Stefaan; Walrand, Stephan; Pauwels, Stanislas; Jamar, François

    2011-11-01

    The aim of this study is to determine the feasibility of achieving quantitative measurement in 90Y-microspheres liver selective internal radiotherapy (SIRT) by imaging 90Y with a conventional non-time of flight (TOF) PET device. Instead of the bremsstrahlung x-rays of the β-decay, the low branch of e-- e+ pair production in the 90Y-decay was used. The activity distribution in a phantom-simulated liver SIRT was obtained by direct 90Y-PET imaging. We tested a LYSO TOF PET and two GSO and BGO non-TOF PET scanners using a 3.6-l cylindrical phantom filled with the 90Y solution containing two sets of hot and cold spheres. The best hot contrast was obtained with the LYSO TOF. It was close to the expected value and remained constant, even for short acquisition times. The LYSO non-TOF was about 10% lower. The GSO performed similarly but degraded for shorter times whilst the BGO was the worst with 40% loss. For the cold spheres, the LYSO TOF and the GSO provided the best results, while the LYSO non-TOF and the BGO were the worst. 90Y PET imaging in liver SIRT is achievable with LYSO TOF. Conventional LYSO and GSO show a loss of contrast and require longer acquisition times. BGO imaging is not feasible for dosimetry calculation.

  4. Quantitative study of liver magnetic resonance spectroscopy quality at 3T using body and phased array coils with physical analysis and clinical evaluation.

    PubMed

    Xu, Li; Gu, Shiyong; Feng, Qianjin; Liang, Changhong; Xin, Sherman Xuegang

    2015-01-01

    This study aims to investigate the quality difference of short echo time (TE) breathhold 1H magnetic resonance spectroscopy (MRS) of the liver at 3.0T using the body and phased array coils, respectively. In total, 20 pairs of single-voxel proton spectra of the liver were acquired at 3.0T using the phased array and body coils as receivers. Consecutive stacks of breathhold spectra were acquired using the point resolved spectroscopy (PRESS) technique at a short TE of 30 ms and a repetition time (TR) of 1500 ms. The first spectroscopy sequence was "copied" for the second acquisition to ensure identical voxel positioning. The MRS prescan adjustments of shimming and water suppression, signal-to noise ratio (SNR), and major liver quantitative information were compared between paired spectra. Theoretical calculation of the SNR and homogeneity of the region of interest (ROI, 2 cm×2 cm×2 cm) using different coils loaded with 3D liver electromagnetic model of real human body was implemented in the theoretical analysis. The theoretical analysis showed that, inside the ROI, the SNR of the phase array coil was 2.8387 times larger than that of body coil and the homogeneity of the phase array coil and body coil was 80.10% and 93.86%, respectively. The experimental results showed excellent correlations between the paired data (all r > 0.86). Compared with the body coil group, the phased array group had slightly worse shimming effect and better SNR (all P values < .01). The discrepancy of the line width because of the different coils was approximately 0.8 Hz (0.00625 ppm). No significant differences of the major liver quantitative information of Cho/Lip2 height, Cho/Lip2 area, and lipid content were observed (all P values >0.05). The theoretical analysis and clinical experiment showed that the phased array coil was superior to the body coil with respect to 3.0T breathhold hepatic proton MRS.

  5. Three-dimensional personalized dosimetry for 188Re liver selective internal radiation therapy based on quantitative post-treatment SPECT studies

    NASA Astrophysics Data System (ADS)

    Shcherbinin, S.; Grimes, J.; Bator, A.; Cwikla, J. B.; Celler, A.

    2014-01-01

    We demonstrate that accurate patient-specific distributions of microspheres labeled with 188Re and resulting absorbed doses can be obtained from single-photon emission computed tomography (SPECT) studies performed after 188Re selective internal radiation therapy when accurate correction methods are employed in image reconstruction. Our quantitative image reconstruction algorithm includes corrections for attenuation, resolution degradations and scatter as well as a window-based compensation for contamination. The procedure has been validated using four phantom experiments containing an 18 ml cylindrical source (82-93 MBq of 188Re activity) simulating a liver tumor. In addition, we applied our approach to post-therapy SPECT studies of ten patients with progressive primary or metastatic liver carcinomas. Our quantitative algorithm accurately (within 9%) recovered 188Re activity from four phantom experiments. In addition, for two patients that received three scans, deviations remained consistent between the measured and the reconstructed activities that were determined from studies with differing severity of the dead-time effect. The analysis of absorbed doses for patient studies allowed us to hypothesize that D90 (the minimum dose received by 90% of the tumor volume) may be a reliable metric relating therapy outcomes to the calculated doses. Among several considered metrics, only D90 showed statistically significant correlation with the overall survival.

  6. Enterocyte Fatty Acid Binding Proteins (FABPs): Different Functions of Liver- and Intestinal- FABPs in the Intestine

    PubMed Central

    Gajda, Angela M.; Storch, Judith

    2014-01-01

    SUMMARY Fatty acid binding proteins (FABP) are highly abundant cytosolic proteins that are expressed in most mammalian tissues. In the intestinal enterocyte, both Liver- (LFABP; FABP1) and Intestinal-fatty acid binding proteins (IFABP; FABP2) are expressed. These proteins display high affinity binding for long chain fatty acids (FA) and other hydrophobic ligands, thus they are believed to be involved with uptake and trafficking of lipids in the intestine. In vitro studies have identified differences in ligand binding stoichiometry and specificity, and in mechanisms of FA transfer to membranes, and it has been hypothesized that LFABP and IFABP have difference functions in the enterocyte. Studies directly comparing LFABP- and IFABP-null mice have revealed markedly different phenotypes, indicating that these proteins indeed have different functions in intestinal lipid metabolism and whole body energy homeostasis. In this review, we discuss the evolving knowledge of the functions of LFABP and IFABP in the intestinal enterocyte. PMID:25458898

  7. Pre- and postoperative evaluation of renal function in patients with staghorn calculi utilizing quantitative renal scanning.

    PubMed

    Stage, K H; Lewis, S

    1981-01-01

    Differential quantitative renal scans using 99-technetium diethylene triaminepentaacetic acid (DTPA) or 131I Hippuran were obtained properatively on 12 patients with unilateral or bilateral staghorn calculi. Of the 14 renal units studied, 12 kidneys underwent anatrophic nephrolithotomy, pyelolithotomy, or a combination of both techniques; 2 patients underwent nephrectomy based on poor function of the affected side preoperatively. Postoperative follow-up scans were obtained on the 12 kidneys undergoing stone cleanout. Seven of 12 kidneys (58 per cent) studied pre- and postoperatively showed moderate to significant improvement in per cent contribution to total renal function. Seven of 10 kidneys (70 per cent) studied pre- and postoperatively showed improvement in glomerular filtration rate or effective renal plasma flow. The scans revelaed no dramatic difference in postoperative functional loss between pyelolithotomy and anatrophic nephrolithotomy. The computerizewd quantitative renal scan helps in selection of surgical technique and objective postoperative assessment of surgical results.

  8. Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation.

    PubMed

    Basile, J; Busuttil, A; Sheiner, P A; Emre, S; Guy, S; Schwartz, M E; Boros, P; Miller, C M

    1999-02-01

    Cold preservation/reperfusion leads to sinusoidal endothelial cell (SEC) activation and damage in nearly every liver transplantation; the extent of these changes influences early graft function. Upon reperfusion, activated SEC show increased expression of adhesion molecules, including von Willebrand factor (vWF) which is released into the circulation. This study was designed to evaluate the levels of vWF measured in the caval effluent and correlate these findings with known markers of SEC damage and early graft function. Data were obtained from 35 patients undergoing orthotopic liver transplantation (LTx). Two samples were taken from each patient for measurement of vWF: a) from the portal vein immediately prior to reperfusion; and b) from the first 50 ml of the caval effluent. Commercial assays were used to measure vWF, as well as hyaluronic acid (HA), thrombomodulin (TM), IL-1 beta, IL-6, IL-8 and TNF-alpha. Patients were divided into two groups based on early graft function. Poor early graft function (PEGF) was defined as a peak aspartate transaminase (AST) or alanine transaminase (ALT) level > 2500 U/L during the first three postoperative days (POD) and a prothrombin time (PT) > 16 s on POD 2 (n = 8). The remaining 27 patients had good early graft function (GEGF). In patients with GEGF, vWF levels dropped significantly between the two time points. This change was not observed in those with PEGF. A positive linear correlation was observed in the PEGF group between vWF and HA and IL-6. The different pattern of change in vWF between the two groups, as well as the positive correlation between HA, IL-6 and vWF in PEGF, suggest that vWF may be a useful marker of early graft function.

  9. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis: possible association with hepatic function impairment.

    PubMed

    Jaroszewicz, Jerzy; Januszkiewicz, Marcin; Flisiak, Robert; Rogalska, Magdalena; Kalinowska, Alicja; Wierzbicka, Iwona

    2008-10-01

    Recent studies provided in vivo evidences of an increased angiogenesis in animal model of portal hypertension and cirrhosis which was linked to increased expression of vascular endothelial growth factor. The aim of study was to evaluate the plasma concentration of VEGF and its receptors in liver cirrhosis and the possible association with the degree of liver insufficiency. Methods. Vascular endothelial growth factor (VEGF) and its soluble receptors: sVEGF-R1, sVEGF-R2 were measured in plasma of 78 patients with liver cirrhosis by ELISA. Results. The significant increase of plasma VEGF and sVEGF-R1 was observed in liver cirrhosis compared to healthy individuals (153.1+/-51.9 vs. 46.8+/-4.1pg/mL, P<0.05; 279.8+/-34.3 vs. 105.1+/-5.9pg/mL, P<0.001, respectively). Plasma VEGF and foremost sVEGF R1 showed significant associations with biochemical indices of liver function. Among clinical parameters, only ascites revealed significant association with plasma VEGR and sVEGF-R1. VEGF and sVEGF-R1 were increased respectively to the degree of liver insufficiency. It was demonstrated through a significant positive correlation with Child-Pugh score and MELD classification. In conclusion, our study suggests that serum VEGF and VEGF-R1 may reflect the hepatic function impairment in liver cirrhosis and seems to be associated with portal hypertension symptoms.

  10. Suppression of intralysosomal proteolysis aggravates structural damage and functional impairment of liver lysosomes in rats with toxic hepatitis

    SciTech Connect

    Korolenko, T.A.; Gavrilova, N.I.; Kurysheva, N.G.; Malygin, A.E.; Pupyshev, A.B.

    1986-01-01

    This paper estimates the effect of lowering protein catabolism in the lysosomes on structural and functional properties of the latter during liver damage. For comparison, polyvinylpyrrolidone (PVP), which is inert relative to intralysosomal proteolysis, and which also accumulates largely in lysosomes of the kupffer cells of the liver, was used. The uptake of labeled bovine serum albuman (C 14-BSA) by the liver is shown and the rate of intralysosomal proteolysis is given 24 hours after administration of suramin an CCl/sub 4/ to rats. It is suggested that it is risky to use drugs which inhibit intralysosomal proteolysis in the treatment of patients with acute hepatitis.

  11. β-cell function prior to liver transplantation contributes to post-operative diabetes

    PubMed Central

    Ichikawa, Tatsuki; Taura, Naota; Miyaaki, Hisamitsu; Miuma, Satoshi; Shibata, Hidetaka; Honda, Takuya; Hidaka, Masaaki; Soyama, Akihiko; Takatsuki, Mitsuhisa; Eguchi, Susumu; Nakao, Kazuhiko

    2016-01-01

    Liver cirrhosis and diabetes mellitus (DM) are closely associated. The present study aimed to determine whether liver transplantation (LT) may prevent/cure DM in patients with cirrhosis and whether the degree of glucose tolerance prior to transplantation is associated with the onset of DM after transplantation. Seventy-three patients who received a living donor LT at Nagasaki University Hospital (Nagasaki, Japan) between November 2005 and December 2012 were recruited. Among them, patients were considered diabetic if they had been prescribed diabetes medications or had impaired glucose tolerance, as evidenced by an oral glucose tolerance test (OGTT). Patients were followed up until December 31, 2013 to evaluate glucose tolerance. Patients who had developed DM 2 years after transplantation were found to be older and the incidence of diabetes prior to transplantation (n=73) was higher than in those who did not. Multivariate analysis revealed that DM requiring treatment prior to transplantation was the only independent factor for DM developed at 2 years after transplantation. OGTT results showed that in patients with poor insulin sensitivity indices prior to transplantation (n=45), improvements were seen at 2 years after transplantation, while β-cell function and insulinogenic index had decreased, which may have been the cause of DM after transplantation. In conclusion, the pre-operative β-cell function determined by an OGTT may be a useful predictive tool for the recurrence of DM after LT. PMID:28101345

  12. The Correlation between NK Cell and Liver Function in Patients with Primary Hepatocellular Carcinoma

    PubMed Central

    Zeng, Xiao-Hui; Min, Lu

    2014-01-01

    Background/Aims This study aimed to detect the expression of natural killer (NK) cell receptor natural killer group 2D (NKG2D) in the peripheral blood of patients with primary hepatocellular carcinoma and to discuss the correlation between NK cell cytotoxicity and liver function. Methods The number of NK cells and the expression of NK cell receptor NKG2D in peripheral blood were determined by flow cytometry in patients with primary hepatocellular carcinoma, hepatitis B cirrhosis, chronic hepatitis B, and healthy controls. Results When compared with patients in the healthy and the chronic hepatitis B groups, the primary hepatocellular carcinoma group showed significant decreases in all parameters, including the cytotoxicity of NK cells on K562 cells, expression rate of NKG2D in NK cells, number of NKG2D+ NK cells, expression level of NKG2D, and number of NK cells (p<0.05). The activity of NK cells showed a positive correlation, whereas the Child-Pugh scores in the primary hepatocellular carcinoma and the hepatitis B cirrhosis groups showed a negative correlation with all parameters detected above. Conclusions The decrease of NK cell activity in patients with primary hepatocellular carcinoma is closely related to their lower expression of NKG2D. Liver function affects the expression of NKG2D and the activity of NK cells. PMID:24827627

  13. Effects of steroid anaesthesia on some liver function tests in goats.

    PubMed

    Amer, H A; Ahmed, A S; Gohar, H M; Abdel Mamid, M A

    1989-03-01

    The effect of Saffan, a steroid anaesthetic, on the liver function of goats has been studied. Forty healthy animals were divided into 4 equal groups. The first 2 groups were given 2 and 4 mg Saffan/kg b. wt respectively. A mixture of Saffan (1 mg) and Xylazine (0.1 mg)/kg b. wt was given to the third group and Xylazine alone to the fourth group (0.1 mg/kg b. wt). Serum samples from all groups were analysed for glucose, total protein, total and direct bilirubin and the level of activity of transaminases. Administration of Saffan evoked more hyperglycemia than a mixture with Xylazine, or Xylazine alone. The hyperglycemic effect of both doses of Saffan (2 and 4 mg) was equivocal beyond 2 h. The effect then differed and glucose was increased 4-fold by 2 mg and 3-fold by 4 mg Saffan. Serum total protein, conjugated and total bilirubin, and GPT and GOT were not changed in the four experimental groups. This was good evidence of a normally functioning liver during the course of steroid anaesthesia administration in goats.

  14. Optical nanoscopy to reveal structural and functional properties of liver cells (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    McCourt, Peter; Huser, Thomas R.; Sørensen, Karen K.; Øie, Cristina I.; Mönkemöller, Viola; Ahluwalia, Balpreet S.

    2015-08-01

    The advent of optical nanoscopy has provided an opportunity to study fundamental properties of nanoscale biological functions, such as liver sinusoidal endothelial cells (LSEC) and their fenestrations. The fenestrations are nano-pores (50-200 nm) on the LSEC plasma membrane that allow free passage of molecules through cells. The fenestrated LSEC also hase a voracious appetite for waste molecules, viruses and nanoparticles. LSEC daily remove huge amounts of waste, nanoparticles and virus from the blood. Pharmaceuticals also need to pass through these fenestrations to be activated (e.g. cholesterol reducing statins) or detoxified by hepatocytes. And, when we age, our LSEC fenestrations become smaller and fewer. Today, we study these cells and structures using either conventional light microscopy on living cells, or high-resolution (but static) methods such as transmission and scanning electron microscopy on fixed (i.e. dead) tissue. Such methods, while very powerful, yield no real time information about the uptake of virus or nanoparticles, nor any information about fenestration dynamics. Therefore, to study LS-SEC, we are now using optical nanoscopy methods, and developing our own, to map their functions in 4 dimensions. Attaining this goal will shed new light on the cell biology of the liver and how it keeps us alive. This paper describes the challenges of studying LS-SEC with light microscopy, as well as current and potential solutions to this challenge using optical nanoscopy.

  15. A quantitative analysis of the thermal properties of porcine liver with glycerol at subzero and cryogenic temperatures.

    PubMed

    Choi, Jeung Hwan; Bischof, John C

    2008-10-01

    There is a lack of information on the effect of cryoprotective agents (CPAs) on the thermal properties of biomaterials at cryobiologically relevant temperatures (i.e. <233.15K, -40 degrees C). Thermal properties that are of most interest include: thermal conductivity, density, specific heat, and latent heat resulting from phase change in tissue systems. Availability of such information would be beneficial for accurate mathematical modeling of cryobiological applications. Recently, we reported these thermal properties in phosphate buffered saline (PBS) with varying concentrations of glycerol, a widely used cryoprotective agent. In this study we extend these results by assessing the effects of glycerol on the thermal properties of porcine liver at subzero temperatures. Differential scanning calorimeter (DSC) was used to measure the specific heat and the latent heat release of porcine liver immersed in PBS and varying concentrations of glycerol. The specific heat data obtained from the DSC experiments were also used to predict the bulk thermal conductivity. This was done using a transient heat transfer model with a thermistor probe technique. Results show that the introduction of glycerol significantly alters thermal properties from known values for H2O and non-treated liver. Therefore, inaccuracies in thermal predictions can be expected due to the application of measured vs. predicted thermal properties such as from weight averaging. This supports the need for these and other measurements of biomaterial thermal properties, with and without CPA addition, in the cryogenic regime.

  16. The effects of low carbohydrate diets on liver function tests in nonalcoholic fatty liver disease: A systematic review and meta-analysis of clinical trials

    PubMed Central

    Haghighatdoost, Fahimeh; Salehi-Abargouei, Amin; Surkan, Pamela J.; Azadbakht, Leila

    2016-01-01

    Background: Although several observational and experimental studies have examined the effects of low carbohydrate diets (LCDs) on nonalcoholic fatty liver disease (NAFLD), there are considerable inconsistencies among studies. We summarized the effect of LCDs on liver function tests, including intrahepatic lipid content (IHLC), alanine transaminase (ALT), aspartate aminotransferases (AST), and gamma-glutamyl transferase (GGT) in patients with NAFLD. Materials and Methods: PubMed, ISI Web of Science, Scopus, and Google Scholar databases were searched for relevant publications until July 2014, resulting in ten relevant papers that were included in meta-analysis. Related articles were found by searching Medical Subject Heading terms of “NAFLD” in combination with “low carbohydrate”. For this meta-analysis, we used mean differences and standard errors of liver function biomarkers. Summary effect and corresponding confidence interval (CI) were estimated using random effect models. Heterogeneity between studies was assessed using Cochran's Q- and I-squared tests. Results: Our search led to ten eligible papers that evaluated serum ALT levels (n = 238), nine reported serum AST levels (n = 216), five reported serum GGT concentrations (n = 91), and four assessed IHLC (n = 50). LCD decreased IHLC by −11.53% (95% CI: −18.10, −4.96; I2 = 83.2%). However, the effect of LCD on liver enzymes was not significant. Mean differences for the effects of LCDs on ALT, AST, and GGT were −4.35 IU/L (95% CI: −12.91, 4.20; I2 = 87.9%), −1.44 IU/L (95% CI: −4.98, 2.10; I2 = 61.4%), and −7.85 IU/L (95% CI: −29.65, 13.96; I2 = 99.4%), respectively. Conclusion: LCD consumption in subjects with NAFLD led to a significant reduction in IHLC, but did not significantly affect the concentration of liver enzymes. PMID:27904598

  17. The Relationship of Liver Function Tests to Mixed Exposure to Lead and Organic Solvents

    PubMed Central

    2013-01-01

    Objective This study aims to compare liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]) among males who work with lead, organic solvents, or both lead and organic solvents, under the permissible exposure limit (PEL). Methods A total of 593 (out of 2,218) male workers who agreed to share their personal health information for medical research were selected for this study. Those excluded were hepatitis B carriers, individuals exposed to occupational risk factors other than lead and organic solvents, and individuals without liver function results. The 593 were divided into five groups: a lead-exposed group, an organic solvent-exposed group exposed to trichloroethylene (TCE co-exposed solvent group), an organic solvent-exposed group not exposed to trichloroethylene (TCE non-exposed solvent group), a lead and organic solvent-exposed group (mixed exposure group), and a non-exposed group (control group). We performed a one way-analysis of variance (one way-ANOVA) test to compare the geometric means of liver function indices among the groups, using a general linear model (GLM) to adjust for age, work duration, body mass index (BMI), smoking, and alcohol intake. In addition, we performed a binary logistic regression analysis to compare the odds ratios among groups with an abnormal liver function index, according to a cut-off value. Results The ALT and AST of the mixed exposure group were higher than those of the other groups. The GGT of the mixed exposure group was higher than the TCE co-exposed solvent group, but there was no difference among the control group, TCE non-exposed solvent group, lead-exposed group, and mixed exposure group. The same result was evident after adjusting by GLM for age, work duration, BMI, smoking, and alcohol intake, except that ALT from the mixed exposure group showed no difference from the TCE co-exposed solvent group. When the cut-off values of the AST, ALT, and GGT

  18. Natural Schistosoma mansoni Infection in the Wild Reservoir Nectomys squamipes Leads to Excessive Lipid Droplet Accumulation in Hepatocytes in the Absence of Liver Functional Impairment

    PubMed Central

    Amaral, Kátia B.; Silva, Thiago P.; Malta, Kássia K.; Carmo, Lívia A. S.; Dias, Felipe F.; Almeida, Mariana R.; Andrade, Gustavo F. S.; Martins, Jefferson S.; Pinho, Roberto R.; Costa-Neto, Sócrates F.; Gentile, Rosana

    2016-01-01

    Schistosomiasis is a neglected tropical disease of a significant public health impact. The water rat Nectomys squamipes is one of the most important non-human hosts in the schistosomiasis mansoni transmission in Brazil, being considered a wild reservoir. Cellular mechanisms that contribute to the physiological adaptation of this rodent to the Schistosoma mansoni parasite are poorly understood. Here we identified, for the first time, that a hepatic steatosis, a condition characterized by excessive lipid accumulation with formation of lipid droplets (LDs) within hepatocytes, occurs in response to the natural S. mansoni infection of N. squamipes, captured in an endemic region. Significant increases of LD area in the hepatic tissue and LD numbers/hepatocyte, detected by quantitative histopathological and ultrastructural analyses, were paralleled by increased serum profile (total cholesterol and triglycerides) in infected compared to uninfected animals. Raman spectroscopy showed high content of polyunsaturated fatty acids (PUFAs) in the liver of both groups. MALDI-TOFF mass spectroscopy revealed an amplified pool of omega-6 PUFA arachidonic acid in the liver of infected animals. Assessment of liver functional activity by the levels of hepatic transaminases (ALT and AST) did not detect any alteration during the natural infection. In summary, this work demonstrates that the natural infection of the wild reservoir N. squamipes with S. mansoni elicits hepatic steatosis in the absence of liver functional harm and that accumulation of lipids, markedly PUFAs, coexists with low occurrence of inflammatory granulomatous processes, suggesting that lipid stores may be acting as a protective mechanism for dealing with the infection. PMID:27880808

  19. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

    2011-01-01

    BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

  20. Beneficial effects of ventromedial hypothalamus (VMH) lesioning on function and morphology of the liver after hepatectomy in rats.

    PubMed

    Lee, Eun Young; Inoue, Shuji; Senoo, Akira; Shimizu, Hiroyuki; Suzuki, Yoko; Ishizuka, Noriko; Imazeki, Nobuo; Sasaki, Kahoru; Kako, Masako; Osaka, Toshimasa; Miki, Takashi

    2011-11-03

    Liver has a high regenerative capacity and restores its mass and function shortly after partial hepatectomy through increased proliferation and metabolic modification of hepatocytes. The proliferation of hepatocytes can be triggered by its mass reduction after hepatectomy or by the neural factors including lesioning of the ventromedial hypothalamus (VMH). In the present study, we examined the effect of VMH lesioning on liver regeneration in hepatectomized rats by evaluating liver function and morphology. We found that functional deficits caused by partial hepatectomy [prolonged prothrombin time (PT), increased indocyanine green (ICG) retention, and decrease in PAS (periodic Acid-Schiff staining)-positive hepatocytes] were restored by VMH lesioning at 1 week after the surgery, whereas these alterations disappeared at 4 weeks. Morphologically, lipid microdroplets, which are considered to be important for maintaining contiguous liver function via supplying fuel for cell proliferation, were found to accumulate in hepatocytes of the hepatectomized rats at early period (1 day) after partial hepatectomy. Interestingly, such lipid microdroplets were also detected in the VMH lesioned rats and the more abundantly in the VMH lesioned, hepatectomized rats up to 1 week after the surgery. In conclusion, our results suggest that VMH lesioning in rats promotes recovery of liver anatomically and functionally after partial hepatectomy by promoting cell proliferation process.

  1. Subclinical change of liver function could also provide a clue on prognosis for patients with spontaneous intracerebral hemorrhage.

    PubMed

    Tan, Ge; Hao, Zilong; Lei, Chunyan; Chen, Yanchao; Yuan, Ruozhen; Xu, Mangmang; Liu, Ming

    2016-10-01

    Whether subclinical change of liver function is associated with outcome of spontaneous intracerebral hemorrhage remains to be an open question. A total of 639 patients of spontaneous intracerebral hemorrhage within 7 days from stroke onset were finally enrolled. Liver function indicators, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (BIL), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), albumin (ALB), and international normalized ratio (INR), were collected and collapsed into quartiles. The main outcomes were 30-day death, 90-day death, and 90-day poor outcome (modified Rankin Scale score of 3-6). Two adjusted model, Model 1 and Model 2 (Model 1 plus GCS score), were established to identify independent association between liver function indicators and ICH outcomes. The mortality rate was 19.9 % (127/639) at 30 days and 21.3 % (136/639) at 90 days. Rate of 90-day poor outcome was 51.5 % (329/639). Among liver function indicators, AST and ALP were associated with all the three outcomes, which did not alter significantly when adjusted by Model 1. After adjusted by Model 2, ALP was still associated with outcomes. Association between AST and outcomes was, however, weakened significantly by GCS score. In conclusions, among liver function indicators, AST and ALP were associated with outcomes after spontaneous intracerebral hemorrhage.

  2. Differences in cognitive function between patients with viral and alcoholic compensated liver cirrhosis.

    PubMed

    Lee, Yunhyeong; Kim, Chulho; Suk, Ki Tae; Choi, Hui Chul; Bang, Chang Seok; Yoon, Jai Hoon; Baik, Gwang Ho; Kim, Dong Joon; Jang, Min Uk; Sohn, Jong Hee

    2016-04-01

    As alcohol induces change in frontal cortex primarily involved in cognition, cognitive function may be different between viral and alcoholic liver cirrhosis (LC). This study aimed to determine the differences of cognitive function between viral and alcoholic compensated LC. From October 2011 to March 2013, 80 patients (viral: 37; alcohol: 43) with compensated LC were prospectively enrolled. Neuropsychological functions including attention, language, visuospatial, verbal memory, visual memory, and frontal/executive function were evaluated between two groups and compared with age-matched normal group (n = 1000). Cumulative incidence rate of overt hepatic encephalopathy (HE) was calculated. In the comparison with normal group, both two groups showed decreased memory function, frontal/executive function, and Korea-Mini Mental Status Examination. In the analysis of two groups, memory function by Verbal Learning Test (recognition: 20.1 ± 3.6 and 17.8 ± 4.8, p = 0.022), visuospatial function by Ray-Complex Figure Copy Test (recognition: 19.0 ± 2.6 and 17.3 ± 4.0, p = 0.043), frontal/executive function by Controlled Oral Ward Association (semantic: 17.1 ± 6.9 and 12.7 ± 6.9, p = 0.004), and the Korea-Mini Mental Status Examination (27.5 ± 1.9 and 26.2 ± 3.1, p = 0.03) showed low scores in alcoholic compensated LC patients. The 1-, 2-, and 3-year cumulative incidence rates of overt HE were 23%, 26%, and 26% and 33%, 43%, and 49% in the viral and alcoholic compensated LC group, respectively (p = 0.033). Impaired memory and frontal lobe executive functions and early development of overt HE were more common in patients with alcoholic LC. For patients with alcoholic LC, more integrated tests for early detection of minimal HE and intensive treatment should be considered to prevent overt HE.

  3. Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia.

    PubMed

    Jamshidzadeh, Akram; Heidari, Reza; Abasvali, Mozhgan; Zarei, Mehdi; Ommati, Mohammad Mehdi; Abdoli, Narges; Khodaei, Forouzan; Yeganeh, Yasaman; Jafari, Faezeh; Zarei, Azita; Latifpour, Zahra; Mardani, Elnaz; Azarpira, Negar; Asadi, Behnam; Najibi, Asma

    2017-02-01

    Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis.

  4. Effect of scheduled monitoring of liver function during anti-Tuberculosis treatment in a retrospective cohort in China

    PubMed Central

    2012-01-01

    Background Data on effect of regular liver function monitoring during anti-TB treatment is limited in China. This study aimed to evaluate the effects of scheduled liver function monitoring on identification of asymptomatic liver damage and anti-TB treatment outcomes during anti-TB treatment. Methods A retrospective analysis was performed based on a national-level cohort study. A total of 273 patients developing liver dysfunction were divided into two groups, 111 patients who were diagnosed through scheduled liver function test within two months after initiation of anti-TB treatment formed scheduled monitoring group, others who were diagnosed due to developing symptoms formed passive detection group (n = 162). The two groups were compared through clinical features, prognosis of liver dysfunction and impact on anti-TB treatment using propensity score weighting analysis. Results 33.3% of 273 patients did not have any clinical symptoms, including 8 with severe hepatotoxicity. 1.8% in scheduled monitoring group and 11.1% in passive detection group required hospitalization (P = 0.004). Regarding the prognosis of liver dysfunction, most patients recovered, no death happened in scheduled monitoring group while 3 died in passive detection group. In terms of impact on anti-TB treatment, 35.1% in scheduled monitoring group and 56.8% in passive detection group changed their anti-TB treatment (P = 0.001). Conclusions Scheduled monitoring is effective in identifying asymptomatic liver damage, reducing hospitalization rate and improving compliance of anti-TB treatment. PMID:22712786

  5. Liver Function Parameters in Hip Fracture Patients: Relations to Age, Adipokines, Comorbidities and Outcomes

    PubMed Central

    Fisher, Leon; Srikusalanukul, Wichat; Fisher, Alexander; Smith, Paul

    2015-01-01

    Aim: To asses liver markers in older patients with hip fracture (HF) in relation to age, comorbidities, metabolic characteristics and short-term outcomes. Methods: In 294 patients with HF (mean age 82.0±7.9 years, 72.1% women) serum alanine aminotransferase (ALT), gammaglutamyltransferase (GGT), alkaline phosphatase (ALP), albumin, bilirubin, 25(OH)vitaminD, PTH, calcium, phosphate, magnesium, adiponectin, leptin, resistin, thyroid function and cardiac troponin I were measured. Results: Elevated ALT, GGT, ALP or bilirubin levels on admission were observed in 1.7% - 9.9% of patients. With age GGT, ALT and leptin decrease, while PTH and adiponectin concentrations increase. Higher GGT (>30U/L, median level) was associated with coronary artery disease (CAD), diabetes mellitus (DM), and alcohol overuse; lower ALT (≤20U/L, median level) with dementia; total bilirubin >20μmol/L with CAD and alcohol overuse; and albumin >33g/L with CAD. Multivariate adjusted regression analyses revealed ALT, ALP, adiponectin, alcohol overuse and DM as independent and significant determinants of GGT (as continuous or categorical variable); GGT for each other liver marker; and PTH for adiponectin. The risk of prolonged hospital stay (>20 days) was about two times higher in patients with GGT>30U/L or adiponectin >17.14 ng/L (median level) and 4.7 times higher if both conditions coexisted. The risk of in-hospital death was 3 times higher if albumin was <33g/L. Conclusions: In older HF patients liver markers even within the normal range are associated with age-related disorders and outcomes. Adiponectin (but not 25(OH)vitaminD, PTH, leptin or resistin) is an independent contributor to higher GGT. Serum GGT and albumin predict prolonged hospital stay and in-hospital death, respectively. A unifying hypothesis of the findings presented. PMID:25589886

  6. Artificial stone dust-induced functional and inflammatory abnormalities in exposed workers monitored quantitatively by biometrics.

    PubMed

    Ophir, Noa; Shai, Amir Bar; Alkalay, Yifat; Israeli, Shani; Korenstein, Rafi; Kramer, Mordechai R; Fireman, Elizabeth

    2016-01-01

    The manufacture of kitchen and bath countertops in Israel is based mainly on artificial stone that contains 93% silica as natural quartz, and ∼3500 workers are involved in cutting and processing it. Artificial stone produces high concentrations of silica dust. Exposure to crystalline silica may cause silicosis, an irreversible lung disease. Our aim was to screen exposed workers by quantitative biometric monitoring of functional and inflammatory parameters. 68 exposed artificial stone workers were compared to 48 nonexposed individuals (controls). Exposed workers filled in questionnaires, and all participants underwent pulmonary function tests and induced sputum analyses. Silica was quantitated by a Niton XL3 X-ray fluorescence spectrometer. Pulmonary function test results of exposed workers were significantly lower and induced sputa showed significantly higher neutrophilic inflammation compared to controls; both processes were slowed down by the use of protective measures in the workplace. Particle size distribution in induced sputum samples of exposed workers was similar to that of artificial stone dust, which contained aluminium, zirconium and titanium in addition to silica. In conclusion, the quantitation of biometric parameters is useful for monitoring workers exposed to artificial stone in order to avoid deterioration over time.

  7. Artificial stone dust-induced functional and inflammatory abnormalities in exposed workers monitored quantitatively by biometrics

    PubMed Central

    Ophir, Noa; Shai, Amir Bar; Alkalay, Yifat; Israeli, Shani; Korenstein, Rafi; Kramer, Mordechai R.

    2016-01-01

    The manufacture of kitchen and bath countertops in Israel is based mainly on artificial stone that contains 93% silica as natural quartz, and ∼3500 workers are involved in cutting and processing it. Artificial stone produces high concentrations of silica dust. Exposure to crystalline silica may cause silicosis, an irreversible lung disease. Our aim was to screen exposed workers by quantitative biometric monitoring of functional and inflammatory parameters. 68 exposed artificial stone workers were compared to 48 nonexposed individuals (controls). Exposed workers filled in questionnaires, and all participants underwent pulmonary function tests and induced sputum analyses. Silica was quantitated by a Niton XL3 X-ray fluorescence spectrometer. Pulmonary function test results of exposed workers were significantly lower and induced sputa showed significantly higher neutrophilic inflammation compared to controls; both processes were slowed down by the use of protective measures in the workplace. Particle size distribution in induced sputum samples of exposed workers was similar to that of artificial stone dust, which contained aluminium, zirconium and titanium in addition to silica. In conclusion, the quantitation of biometric parameters is useful for monitoring workers exposed to artificial stone in order to avoid deterioration over time. PMID:27730180

  8. Quantitative analysis of receptor tyrosine kinase-effector coupling at functionally relevant stimulus levels.

    PubMed

    Li, Simin; Bhave, Devayani; Chow, Jennifer M; Riera, Thomas V; Schlee, Sandra; Rauch, Simone; Atanasova, Mariya; Cate, Richard L; Whitty, Adrian

    2015-04-17

    A major goal of current signaling research is to develop a quantitative understanding of how receptor activation is coupled to downstream signaling events and to functional cellular responses. Here, we measure how activation of the RET receptor tyrosine kinase on mouse neuroblastoma cells by the neurotrophin artemin (ART) is quantitatively coupled to key downstream effectors. We show that the efficiency of RET coupling to ERK and Akt depends strongly on ART concentration, and it is highest at the low (∼100 pM) ART levels required for neurite outgrowth. Quantitative discrimination between ERK and Akt pathway signaling similarly is highest at this low ART concentration. Stimulation of the cells with 100 pM ART activated RET at the rate of ∼10 molecules/cell/min, leading at 5-10 min to a transient peak of ∼150 phospho-ERK (pERK) molecules and ∼50 pAkt molecules per pRET, after which time the levels of these two signaling effectors fell by 25-50% while the pRET levels continued to slowly rise. Kinetic experiments showed that signaling effectors in different pathways respond to RET activation with different lag times, such that the balance of signal flux among the different pathways evolves over time. Our results illustrate that measurements using high, super-physiological growth factor levels can be misleading about quantitative features of receptor signaling. We propose a quantitative model describing how receptor-effector coupling efficiency links signal amplification to signal sensitization between receptor and effector, thereby providing insight into design principles underlying how receptors and their associated signaling machinery decode an extracellular signal to trigger a functional cellular outcome.

  9. Quantitative Analysis of Receptor Tyrosine Kinase-Effector Coupling at Functionally Relevant Stimulus Levels*♦

    PubMed Central

    Li, Simin; Bhave, Devayani; Chow, Jennifer M.; Riera, Thomas V.; Schlee, Sandra; Rauch, Simone; Atanasova, Mariya; Cate, Richard L.; Whitty, Adrian

    2015-01-01

    A major goal of current signaling research is to develop a quantitative understanding of how receptor activation is coupled to downstream signaling events and to functional cellular responses. Here, we measure how activation of the RET receptor tyrosine kinase on mouse neuroblastoma cells by the neurotrophin artemin (ART) is quantitatively coupled to key downstream effectors. We show that the efficiency of RET coupling to ERK and Akt depends strongly on ART concentration, and it is highest at the low (∼100 pm) ART levels required for neurite outgrowth. Quantitative discrimination between ERK and Akt pathway signaling similarly is highest at this low ART concentration. Stimulation of the cells with 100 pm ART activated RET at the rate of ∼10 molecules/cell/min, leading at 5–10 min to a transient peak of ∼150 phospho-ERK (pERK) molecules and ∼50 pAkt molecules per pRET, after which time the levels of these two signaling effectors fell by 25–50% while the pRET levels continued to slowly rise. Kinetic experiments showed that signaling effectors in different pathways respond to RET activation with different lag times, such that the balance of signal flux among the different pathways evolves over time. Our results illustrate that measurements using high, super-physiological growth factor levels can be misleading about quantitative features of receptor signaling. We propose a quantitative model describing how receptor-effector coupling efficiency links signal amplification to signal sensitization between receptor and effector, thereby providing insight into design principles underlying how receptors and their associated signaling machinery decode an extracellular signal to trigger a functional cellular outcome. PMID:25635057

  10. Quantitative evaluation of interaction force between functional groups in protein and polymer brush surfaces.

    PubMed

    Sakata, Sho; Inoue, Yuuki; Ishihara, Kazuhiko

    2014-03-18

    To understand interactions between polymer surfaces and different functional groups in proteins, interaction forces were quantitatively evaluated by force-versus-distance curve measurements using atomic force microscopy with a functional-group-functionalized cantilever. Various polymer brush surfaces were systematically prepared by surface-initiated atom transfer radical polymerization as well-defined model surfaces to understand protein adsorption behavior. The polymer brush layers consisted of phosphorylcholine groups (zwitterionic/hydrophilic), trimethylammonium groups (cationic/hydrophilic), sulfonate groups (anionic/hydrophilic), hydroxyl groups (nonionic/hydrophilic), and n-butyl groups (nonionic/hydrophobic) in their side chains. The interaction forces between these polymer brush surfaces and different functional groups (carboxyl groups, amino groups, and methyl groups, which are typical functional groups existing in proteins) were quantitatively evaluated by force-versus-distance curve measurements using atomic force microscopy with a functional-group-functionalized cantilever. Furthermore, the amount of adsorbed protein on the polymer brush surfaces was quantified by surface plasmon resonance using albumin with a negative net charge and lysozyme with a positive net charge under physiological conditions. The amount of proteins adsorbed on the polymer brush surfaces corresponded to the interaction forces generated between the functional groups on the cantilever and the polymer brush surfaces. The weakest interaction force and least amount of protein adsorbed were observed in the case of the polymer brush surface with phosphorylcholine groups in the side chain. On the other hand, positive and negative surfaces generated strong forces against the oppositely charged functional groups. In addition, they showed significant adsorption with albumin and lysozyme, respectively. These results indicated that the interaction force at the functional group level might be

  11. Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies

    PubMed Central

    Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

    2016-01-01

    Background: It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. Patients and Methods: So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. Results: There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Conclusion: Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function. PMID:27326244

  12. Quantitative values of blood flow through the human forearm, hand, and finger as functions of temperature

    NASA Technical Reports Server (NTRS)

    Montgomery, L. D.

    1974-01-01

    A literature search was made to obtain values of human forearm, hand and finger blood flow as functions of environmental temperature. The sources used include both government and laboratory reports and the research presented in the open literature. An attempt was made to review many of the more quantitative noninvasive determinations and to collate the results in such a way as to yield blood flow values for each body segment as continuous functions of temperature. A brief review of the various ways used to measure blood flow is included along with an abstract of each work from which data was taken.

  13. Comparing Early Liver Graft Function From Heart Beating and Living-Donors: A Pilot Study Aiming to Identify New Biomarkers of Liver Injury.

    PubMed

    Yang, Qi Joy; Kluger, Michael; Goryński, Krzysztof; Pawliszyn, Janusz; Bojko, Barbara; Yu, Ai-Ming; Noh, Keumhan; Selzner, Markus; Jerath, Angela; McCluskey, Stuart; Sandy Pang, K; Wąsowicz, Marcin

    2017-01-19

    Liver and kidney functions among recipients of liver transplantation (LT) surgery with heart beating (HBD, n = 13) or living donors (LD, n = 9) with different cold ischemic times were examined during the neohepatic phase for clearing rocuronium bromide (ROC, cleared by liver and kidney) and tranexamic acid (TXA, cleared by kidney). Solid phase micro-extraction and LC-MS/MS was applied to determine the plasma concentrations of ROC and TXA, and creatinine was determined by standard laboratory methods. Metabolomics and the relative expressions of miRNA122, miRNA148a, and γ-glutamyltranspeptidase (GGT), liver injury biomarkers, were also measured. ROC clearance for HBD was significantly lower than that for LD (0.147 ± 0.052 vs. 0.265 ± 0.148 mL · min(-1)  · g(-1) liver) after intravenous injection (0.6 mg · kg(-1) ). Clearance of TXA, a compound cleared by glomerular filtration, given as a 1 g bolus followed by infusion (10 mg · kg(-1)  · h(-1) ), was similar between HBD and LD (~1 mL · min(-1)  · kg(-1) ). Metabolomics data revealed higher bile acids, phospholipids, and lipid ω-oxidation metabolite clusters for HBD. miR122 and miR148a expressions were similar for HBD and LD whereas GGT expression was significantly increased for HBD. TXA clearance in both groups was lower than GFR, showing a small extent of hepatorenal coupling.

  14. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases.

    PubMed

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng; Zhou, Zhiwei

    2014-08-01

    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 ((125)I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life.

  15. Improvement of liver function in humans using a mixture of schisandra fruit extract and sesamin.

    PubMed

    Chiu, Hui-Fang; Chen, Tzy-Yen; Tzeng, Yu-Te; Wang, Chin-Kun

    2013-03-01

    This was a randomized, parallel, and placebo-controlled study. Forty subjects were divided into a test group and a placebo group. The study was focused on the potential effects of a mixture of Schisandra fruit extract and sesamin (hereinafter called 'SCH') in the subjects with borderline high levels (40-60 U/L) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Twenty subjects taking SCH (four tablets per day) and 20 subjects taking a placebo (four tablets per day) were studied. The effects of SCH on ALT, AST, total bilirubin, direct bilirubin, free radical levels, total antioxidant status, glutathione peroxidase, glutathione reductase, and the lag time for low-density lipoprotein oxidation were determined. The total test period was 5 months. Intervention of SCH clearly reduced the levels of ALT and AST, but it made no change in the total bilirubin and direct bilirubin. Intake of SCH also greatly increased the antioxidant capacity and decreased the values of thiobarbituric acid reactive substances, total free radicals, and superoxide anion radicals in the plasma. The activities of glutathione peroxidase and reductase in the erythrocytes were significantly increased. In addition, the lag time for low-density lipoprotein oxidation, an inflammatory marker, was evidently increased. Fatty liver was found to have been significantly improved in this study. SCH proved to have the effects of antioxidation and improving liver function.

  16. Recent insights into the biological functions of liver fatty acid binding protein 1

    PubMed Central

    Wang, GuQi; Bonkovsky, Herbert L.; de Lemos, Andrew; Burczynski, Frank J.

    2015-01-01

    Over four decades have passed since liver fatty acid binding protein (FABP)1 was first isolated. There are few protein families for which most of the complete tertiary structures, binding properties, and tissue occurrences are described in such detail and yet new functions are being uncovered for this protein. FABP1 is known to be critical for fatty acid uptake and intracellular transport and also has an important role in regulating lipid metabolism and cellular signaling pathways. FABP1 is an important endogenous cytoprotectant, minimizing hepatocyte oxidative damage and interfering with ischemia-reperfusion and other hepatic injuries. The protein may be targeted for metabolic activation through the cross-talk among many transcriptional factors and their activating ligands. Deficiency or malfunction of FABP1 has been reported in several diseases. FABP1 also influences cell proliferation during liver regeneration and may be considered as a prognostic factor for hepatic surgery. FABP1 binds and modulates the action of many molecules such as fatty acids, heme, and other metalloporphyrins. The ability to bind heme is another cytoprotective property and one that deserves closer investigation. The role of FABP1 in substrate availability and in protection from oxidative stress suggests that FABP1 plays a pivotal role during intracellular bacterial/viral infections by reducing inflammation and the adverse effects of starvation (energy deficiency). PMID:26443794

  17. Toxicological studies of "Chondrokola Rosh", an Ayurvedic preparation on liver function tests of rats.

    PubMed

    Nasrin, S; Bachar, S C; Choudhuri, M S K

    2011-01-01

    Chondrokola Rosh (CKR) is a traditional metallic Ayurvedic preparation widely used by the rural and ethnic people of Bangladesh in dysuria. It is a preparation of various roasted metals (Hg and Cu), non-metal (sulphur and Mica) and medicinal herbs. Considering the controversy over the risk of toxic heavy metals in Ayurvedic herbo-mineral preparations, toxicological parameters on liver functions were investigated. A single dose of 100mg/kg body weight of the preparation was administered orally to the rats of both sexes for ninety days. In this evaluation a statistically significant (p<0.001) increase of serum albumin levels in male (17%) and female (15%) rat groups were observed. On the other hand, the plasma bilirubin level was decreased 50% and 28% respectively in both rats groups. But no remarkable differences were observed in plasma protein, sGPT, sGOT and ALP activities from their corresponding control values. This study showed that CKR had no remarkable toxic effect on liver of the animals despite the presence of traces of transformed heavy metals.

  18. Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

    PubMed Central

    Unzu, Carmen; Morales-Kastresana, Aizea; Sampedro, Ana; Serrano-Mendioroz, Irantzu; Azpilikueta, Arantza; Ochoa, María Carmen; Dubrot, Juan; Martínez-Ansó, Eduardo

    2014-01-01

    The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naïve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naïve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors. PMID:24465560

  19. High functional hollow fiber membrane modified with phospholipid polymers for a liver assist bioreactor.

    PubMed

    Ho Ye, Sang; Watanabe, Junji; Takai, Madoka; Iwasaki, Yasuhiko; Ishihara, Kazuhiko

    2006-03-01

    For practical application of a liver assist system with a tissue-conjugated hollow fiber membrane (HFM) bioreactor used in an extracorporeal therapy, it would require a highly sophisticated HFM which has both hemocompatibility on one side and cytocompatibility on the other side. In this study, we present a cellulose acetate (CA) HFM modified with 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers (PMB30 (MPC-co-n-butyl methacrylate) and PMA30 (MPC-co-methacrylic acid) for preparing a novel liver assist HFM bioreactor. A CA/PMB-PMA30 HFM modified asymmetrically on the inner and outer surface with the PMB30 and PMA30 was prepared successfully. Analysis with an X-ray photoelectron spectroscope showed that the intensity of the phosphorus atom attributed to the MPC units on the outer surface of the modified HFM was stronger than that of the inner surface. The PMA30 was immobilized on the outer surface of the CA/PMB30 blend HFM by a chemical condensation reaction. The CA/PMB-PMA30 HFM showed good water and solute permeability in comparison with the CA HFM. The morphologies of the adherent hepatocytes were round in shape in comparison with the cells that adhered on CA HFM. Furthermore, hepatocytes cultured on the inner surface of the CA/PMB-PMA30 HFM showed higher functional expression in terms of urea synthesis and albumin synthesis than that of the CA HFM.

  20. Innate functions of immunoglobulin M lessen liver gene transfer with helper-dependent adenovirus.

    PubMed

    Unzu, Carmen; Melero, Ignacio; Morales-Kastresana, Aizea; Sampedro, Ana; Serrano-Mendioroz, Irantzu; Azpilikueta, Arantza; Ochoa, María Carmen; Dubrot, Juan; Martínez-Ansó, Eduardo; Fontanellas, Antonio

    2014-01-01

    The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naïve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naïve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors.

  1. Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice.

    PubMed

    Li, Songpei; Zeng, Xiao-Yi; Zhou, Xiu; Wang, Hao; Jo, Eunjung; Robinson, Stephen R; Xu, Aimin; Ye, Ji-Ming

    2016-01-01

    The present study investigated the role of dietary cholesterol and fat in the development of nonalcoholic fatty liver disease, a common liver disease in metabolic disorders. Mice were fed a diet of regular chow (CH), chow supplemented with 0.2% w/w cholesterol (CHC), high fat (HF, 45kcal%) or HF with cholesterol (HFC) for 17weeks. While both HF and HFC groups displayed hepatic steatosis and metabolic syndrome, only HFC group developed the phenotype of liver injury, as indicated by an increase in plasma level of alanine transaminase (ALT, by 50-80%). There were ~2-fold increases in mRNA expression of tumor necrosis factor α, interleukin 1β and monocyte chemotactic protein 1 in the liver of HFC-fed mice (vs. HF) but no endoplasmic reticulum stress or oxidative stress was observed. Furthermore, cholesterol suppressed HF-induced increase of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial transcription factor A expression and blunted fatty acid oxidation. Interestingly, after switching HFC to HF diet for 5weeks, the increases in plasma ALT and liver inflammatory markers were abolished but the blunted of mitochondrial function remained. These findings suggest that cholesterol plays a critical role in the conversion of a simple fatty liver toward nonalcoholic steatohepatitis possibly by activation of inflammatory pathways together with retarded mitochondrial function.

  2. Quantitative assessment of p-glycoprotein expression and function using confocal image analysis.

    PubMed

    Hamrang, Zahra; Arthanari, Yamini; Clarke, David; Pluen, Alain

    2014-10-01

    P-glycoprotein is implicated in clinical drug resistance; thus, rapid quantitative analysis of its expression and activity is of paramout importance to the design and success of novel therapeutics. The scope for the application of quantitative imaging and image analysis tools in this field is reported here at "proof of concept" level. P-glycoprotein expression was utilized as a model for quantitative immunofluorescence and subsequent spatial intensity distribution analysis (SpIDA). Following expression studies, p-glycoprotein inhibition as a function of verapamil concentration was assessed in two cell lines using live cell imaging of intracellular Calcein retention and a routine monolayer fluorescence assay. Intercellular and sub-cellular distributions in the expression of the p-glycoprotein transporter between parent and MDR1-transfected Madin-Derby Canine Kidney cell lines were examined. We have demonstrated that quantitative imaging can provide dose-response parameters while permitting direct microscopic analysis of intracellular fluorophore distributions in live and fixed samples. Analysis with SpIDA offers the ability to detect heterogeniety in the distribution of labeled species, and in conjunction with live cell imaging and immunofluorescence staining may be applied to the determination of pharmacological parameters or analysis of biopsies providing a rapid prognostic tool.

  3. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    NASA Astrophysics Data System (ADS)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  4. Intentional Movement Performance Ability (IMPA): a method for robot-aided quantitative assessment of motor function.

    PubMed

    Shin, Sung Yul; Kim, Jung Yoon; Lee, Sanghyeop; Lee, Junwon; Kim, Seung-Jong; Kim, ChangHwan

    2013-06-01

    The purpose of this paper is to propose a new assessment method for evaluating motor function of the patients who are suffering from physical weakness after stroke, incomplete spinal cord injury (iSCI) or other diseases. In this work, we use a robotic device to obtain the information of interaction occur between patient and robot, and use it as a measure for assessing the patients. The Intentional Movement Performance Ability (IMPA) is defined by the root mean square of the interactive torque, while the subject performs given periodic movement with the robot. IMPA is proposed to quantitatively determine the level of subject's impaired motor function. The method is indirectly tested by asking the healthy subjects to lift a barbell to disturb their motor function. The experimental result shows that the IMPA has a potential for providing a proper information of the subject's motor function level.

  5. Expression of bax and bcl2 Genes in MDMA-induced Hepatotoxicity on Rat Liver Using Quantitative Real-Time PCR Method through Triggering Programmed Cell Death

    PubMed Central

    Behroozaghdam, Mitra; Hashemi, Mehrdad; Javadi, Gholamreza; Mahdian, Reza; Soleimani, Mansoureh

    2015-01-01

    Background: 3-4methylenedioxymethamphetamine (MDMA) is a synthetic and psychoactive drug, which is known popularly as Ecstasy and has toxic effects on human organs. Objectives: Considering the potential toxic interaction, this study was performed to quantify the expression of bax and bcl2 genes in MDMA-induced hepatotoxicity on rat liver. Subsequently, we evaluated pentoxifylline as a possible protective drug on hepatotoxicity. Materials and Methods: Adult male Wistar rats weighting 250 - 300 grams were used in the study. The rats were equally distributed into four experimental groups (5 rat/group). MDMA was dissolved in PBS and injected intraperitoneally (IP) including untreated control, MDMA (MDMA dissolved in PBS), treated-1 (MDMA followed by PTX) and treated-2 (PTX followed by MDMA). All animals given MDMA received 3 doses of 7.5mg/kg with two hours gap between doses. Liver tissue was removed after anaesthetizing. Subsequently, RNA isolation, cDNA synthesis and Real-Time PCR were performed. Finally, data analyzed statistically to determine significantly differences between the groups (P value < 0.05). Results: Using Real-Time quantitative PCR results, the gene expression ratio of bcl2 were calculated 93.80±20.64, 340.45 ± 36.60 and 47.13 ± 5.84 fold in MDMA, treated-1 and treated-2 groups, respectively. Furthermore, this ratio for bax gene obtained 2.13±0.33 fold in MDMA, 1.55 ± 0.26 fold in treated-1 and 10.44 ± 1.56 fold in treated-2 groups. Conclusions: The present study focused on molecular mechanism of MDMA in programmed cell death using gene expression quantification of a pro-apoptotic and anti-apoptoic gene in MDMA-induced hepatotoxocity. The results showed that MDMA prompted apoptosis in liver and pentoxifylline protected against hepatotoxicity before and after taking MDMA. PMID:26732379

  6. The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics.

    PubMed

    Michaels, Scott; Wang, Michael Zhuo

    2014-08-01

    The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds (arachidonic acid and leukotriene B4), nutrients (vitamins K1 and E), and xenobiotics (pafuramidine and fingolimod). CYP4F2 and CYP4F3B are reported to be expressed in the human liver. However, absolute concentrations of these enzymes in human liver microsomes (HLMs) and their interindividual variability have yet to be determined because of the lack of specific antibodies. Here, an liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of CYP4F2 and CYP4F3B compared with CYP3A in two panels of HLMs (n = 31). As a result, the human hepatic cytochrome P450 (P450) "pie" has been revised to include the contribution of CYP4F enzymes, which amounts to 15% of the total hepatic cytochrome P450 enzymes. CYP4F3B displayed low interindividual variability (3.3-fold) in the HLM panels whereas CYP4F2 displayed large variability (21-fold). However, CYP4F2 variability decreased to 3.4-fold if the two donors with the lowest expression were excluded. In contrast, CYP3A exhibited 29-fold interindividual variability in the same HLM panels. The proposed marker reaction for CYP4F enzymes pafuramidine/DB289 M1 formation did not correlate with CYP4F protein content, suggesting alternate metabolic pathways for DB289 M1 formation in HLMs. In conclusion, CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation.

  7. Liver extracellular matrix providing dual functions of two-dimensional substrate coating and three-dimensional injectable hydrogel platform for liver tissue engineering.

    PubMed

    Lee, Jung Seung; Shin, Jisoo; Park, Hae-Min; Kim, Yun-Gon; Kim, Byung-Gee; Oh, Jong-Won; Cho, Seung-Woo

    2014-01-13

    Decellularization of tissues or organs can provide an efficient strategy for preparing functional scaffolds for tissue engineering. Microstructures of native extracellular matrices and their biochemical compositions can be retained in the decellularized matrices, providing tissue-specific microenvironments for efficient tissue regeneration. Here, we report the versatility of liver extracellular matrix (LEM) that can be used for two-dimensional (2D) coating and three-dimensional (3D) hydrogel platforms for culture and transplantation of primary hepatocytes. Collagen type I (Col I) has typically been used for hepatocyte culture and transplantation. In this study, LEM was compared with Col I in terms of biophysical and mechanical characteristics and biological performance for enhancing cell viability, differentiation, and hepatic functions. Surface properties of LEM coating and mechanical properties and gelation kinetics of LEM hydrogel could be manipulated by adjusting the LEM concentration. In addition, LEM hydrogel exhibited improved elastic properties, rapid gelation, and volume maintenance compared to Col I hydrogel. LEM coating significantly improved hepatocyte functions such as albumin secretion and urea synthesis. More interestingly, LEM coating upregulated hepatic gene expression of human adipose-derived stem cells, indicating enhanced hepatic differentiation of these stem cells. The viability and hepatic functions of primary hepatocytes were also significantly improved in LEM hydrogel compared to Col I hydrogel both in vitro and in vivo. Albumin and hepatocyte transcription factor expression was upregulated in hepatocytes transplanted in LEM hydrogels. In conclusion, LEM can provide functional biomaterial platforms for diverse applications in liver tissue engineering by promoting survival and maturation of hepatocytes and hepatic commitment of stem cells. This study demonstrates the feasibility of decellularized matrix for both 2D coating and 3D hydrogel in

  8. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver.

    PubMed

    Nakajima, Mayuka; Arimatsu, Kei; Kato, Tamotsu; Matsuda, Yumi; Minagawa, Takayoshi; Takahashi, Naoki; Ohno, Hiroshi; Yamazaki, Kazuhisa

    2015-01-01

    Although periodontitis has been implicated as a risk factor for various systemic diseases, the precise mechanisms by which periodontitis induces systemic disease remain to be elucidated. We have previously revealed that repeated oral administration of Porphyromonas gingivalis elicits endotoxemia via changes in the gut microbiota of the ileum, and thereby induces systemic inflammation and insulin resistance. However, it is not clear to what extent a single administration of P. gingivalis could affect gut microbiota composition, gut barrier function, and subsequent influx of gut microbiota into the liver. Therefore, in the present study, C57BL/6 mice were orally administered P. gingivalis (strain W83) once and compared to sham-inoculated mice. The phylogenetic structure and diversity of microbial communities in the gut and liver were analyzed by pyrosequencing the 16S ribosomal RNA genes. Serum endotoxin activity was determined by a Limulus amebocyte lysate test. Gene expression in the intestine and expression of 16S rRNA genes in the blood and liver were examined by quantitative polymerase chain reaction. Administration of P. gingivalis significantly altered gut microbiota, with an increased proportion of phylum Bacteroidetes, a decreased proportion of phylum Firmicutes, and increased serum endotoxin levels. In the intestinal tissues, gene expression of tjp-1 and occludin, which are involved in intestinal permeability, were downregulated. Higher amounts of bacterial DNA were detected in the liver of infected mice. Importantly, changes in gut microbiota preceded systemic inflammatory changes. These results further support the idea that disturbance of the gut microbiota composition by orally derived periodontopathic bacteria may be a causal mechanism linking periodontitis and systemic disease.

  9. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver

    PubMed Central

    Nakajima, Mayuka; Arimatsu, Kei; Kato, Tamotsu; Matsuda, Yumi; Minagawa, Takayoshi; Takahashi, Naoki; Ohno, Hiroshi; Yamazaki, Kazuhisa

    2015-01-01

    Although periodontitis has been implicated as a risk factor for various systemic diseases, the precise mechanisms by which periodontitis induces systemic disease remain to be elucidated. We have previously revealed that repeated oral administration of Porphyromonas gingivalis elicits endotoxemia via changes in the gut microbiota of the ileum, and thereby induces systemic inflammation and insulin resistance. However, it is not clear to what extent a single administration of P. gingivalis could affect gut microbiota composition, gut barrier function, and subsequent influx of gut microbiota into the liver. Therefore, in the present study, C57BL/6 mice were orally administered P. gingivalis (strain W83) once and compared to sham-inoculated mice. The phylogenetic structure and diversity of microbial communities in the gut and liver were analyzed by pyrosequencing the 16S ribosomal RNA genes. Serum endotoxin activity was determined by a Limulus amebocyte lysate test. Gene expression in the intestine and expression of 16S rRNA genes in the blood and liver were examined by quantitative polymerase chain reaction. Administration of P. gingivalis significantly altered gut microbiota, with an increased proportion of phylum Bacteroidetes, a decreased proportion of phylum Firmicutes, and increased serum endotoxin levels. In the intestinal tissues, gene expression of tjp-1 and occludin, which are involved in intestinal permeability, were downregulated. Higher amounts of bacterial DNA were detected in the liver of infected mice. Importantly, changes in gut microbiota preceded systemic inflammatory changes. These results further support the idea that disturbance of the gut microbiota composition by orally derived periodontopathic bacteria may be a causal mechanism linking periodontitis and systemic disease. PMID:26218067

  10. Exposure to mixtures of solvents among paint workers and biochemical alterations of liver function.

    PubMed Central

    Chen, J D; Wang, J D; Jang, J P; Chen, Y Y

    1991-01-01

    The objective of this study was to determine biochemical alterations of liver function among paint manufacturers and sprayers associated with exposure to organic solvents. Two paint manufacturing factories and 22 various kinds of spray painting factories (16 car painting, two aircraft painting, three video terminal painting; and one trailer painting) were included. Air concentrations of organic solvents were collected by personal samplers and analysed by gas chromatography. A total of 180 workers were given a comprehensive physical examination, a questionnaire, a liver function test, and a test for hepatitis B surface antigen. The questionnaire contained questions regarding detailed personal medical history, intake of alcohol, and use of medicine. Mixtures of solvents were used throughout the factories, and xylene and toluene were the major components found in almost all air samples with average contents of 46% and 29% on a weight basis of 67 air samples. No strong hepatotoxic solvents were detected. Workers were classified according to the different exposure patterns and different air concentrations of breathing zones as: high (eight hour time weighted average (8 h TWA) hygienic effects of solvents 0.25-9.83, median 1.66), short term high (8 h TWA hygienic effects of solvents 0-3.38, median 0.12), and low (8 h TWA hygienic effects of solvents all below 0.38). After applying a multivariate model to control the non-occupational factors (alcohol, medication, age, and hepatitis B viral infection), increase in gamma-glutamyl transferase (GGT) activity was found to be associated with severity of exposure to the mixture of solvents. Because the possible effects on GGT activity of non-occupational factors were controlled for, it is concluded that increased GGT activity among exposed workers may be due to a higher exposure to the mixture of solvents. PMID:1931729

  11. Liver kinase B1 regulates hepatocellular tight junction distribution and function in vivo

    PubMed Central

    Tietgens, Amber J.; Van Itallie, Christina M.; Vitale‐Cross, Lynn; Jarnik, Michal; Harding, Olivia J.; Anderson, James M.; Gutkind, J. Silvio; Weigert, Roberto; Arias, Irwin M.

    2016-01-01

    Liver kinase B1 (LKB1) and its downstream effector AMP‐activated protein kinase (AMPK) play critical roles in polarity establishment by regulating membrane trafficking and energy metabolism. In collagen sandwich‐cultured hepatocytes, loss of LKB1 or AMPK impaired apical ABCB11 (Bsep) trafficking and bile canalicular formation. In the present study, we used liver‐specific (albumin‐Cre) LKB1 knockout mice (LKB1−/−) to investigate the role of LKB1 in the maintenance of functional tight junction (TJ) in vivo. Transmission electron microscopy examination revealed that hepatocyte apical membrane with microvilli substantially extended into the basolateral domain of LKB1−/− livers. Immunofluorescence studies revealed that loss of LKB1 led to longer and wider canalicular structures correlating with mislocalization of the junctional protein, cingulin. To test junctional function, we used intravital microscopy to quantify the transport kinetics of 6‐carboxyfluorescein diacetate (6‐CFDA), which is processed in hepatocytes into its fluorescent derivative 6‐carboxyfluorescein (6‐CF) and secreted into the canaliculi. In LKB1−/− mice, 6‐CF remained largely in hepatocytes, canalicular secretion was delayed, and 6‐CF appeared in the blood. To test whether 6‐CF was transported through permeable TJ, we intravenously injected low molecular weight (3 kDa) dextran in combination with 6‐CFDA. In wild‐type mice, 3 kDa dextran remained in the vasculature, whereas it rapidly appeared in the abnormal bile canaliculi in LKB1−/− mice, confirming that junctional disruption resulted in paracellular exchange between the blood stream and the bile canaliculus. Conclusion: LKB1 plays a critical role in regulating the maintenance of TJ and paracellular permeability, which may explain how various drugs, chemicals, and metabolic states that inhibit the LKB1/AMPK pathway result in cholestasis. (Hepatology 2016;64:1317‐1329) PMID:27396550

  12. Prospective Randomized Trial Comparing Hepatic Venous Outflow and Renal Function after Conventional versus Piggyback Liver Transplantation

    PubMed Central

    Brescia, Marília D’Elboux Guimarães; Massarollo, Paulo Celso Bosco; Imakuma, Ernesto Sasaki; Mies, Sérgio

    2015-01-01

    Background This randomized prospective clinical trial compared the hepatic venous outflow drainage and renal function after conventional with venovenous bypass (n = 15) or piggyback (n = 17) liver transplantation. Methods Free hepatic vein pressure (FHVP) and central venous pressure (CVP) measurements were performed after graft reperfusion. Postoperative serum creatinine (Cr) was measured daily on the first week and on the 14th, 21st and 28th postoperative days (PO). The prevalence of acute renal failure (ARF) up to the 28th PO was analyzed by RIFLE-AKIN criteria. A Generalized Estimating Equation (GEE) approach was used for comparison of longitudinal measurements of renal function. Results FHVP-CVP gradient > 3 mm Hg was observed in 26.7% (4/15) of the patients in the conventional group and in 17.6% (3/17) in the piggyback group (p = 0.68). Median FHVP-CVP gradient was 2 mm Hg (0–8 mmHg) vs. 3 mm Hg (0–7 mm Hg) in conventional and piggyback groups, respectively (p = 0.73). There is no statistically significant difference between the conventional (1/15) and the piggyback (2/17) groups regarding massive ascites development (p = 1.00). GEE estimated marginal mean for Cr was significantly higher in conventional than in piggyback group (2.14 ± 0.26 vs. 1.47 ± 0.15 mg/dL; p = 0.02). The conventional method presented a higher prevalence of severe ARF during the first 28 PO days (OR = 3.207; 95% CI, 1.010 to 10.179; p = 0.048). Conclusion Patients submitted to liver transplantation using conventional or piggyback methods present similar results regarding venous outflow drainage of the graft. Conventional with venovenous bypass technique significantly increases the harm of postoperative renal dysfunction. Trial Registration ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01707810 PMID:26115520

  13. Parametric modeling for quantitative analysis of pulmonary structure to function relationships

    NASA Astrophysics Data System (ADS)

    Haider, Clifton R.; Bartholmai, Brian J.; Holmes, David R., III; Camp, Jon J.; Robb, Richard A.

    2005-04-01

    While lung anatomy is well understood, pulmonary structure-to-function relationships such as the complex elastic deformation of the lung during respiration are less well documented. Current methods for studying lung anatomy include conventional chest radiography, high-resolution computed tomography (CT scan) and magnetic resonance imaging with polarized gases (MRI scan). Pulmonary physiology can be studied using spirometry or V/Q nuclear medicine tests (V/Q scan). V/Q scanning and MRI scans may demonstrate global and regional function. However, each of these individual imaging methods lacks the ability to provide high-resolution anatomic detail, associated pulmonary mechanics and functional variability of the entire respiratory cycle. Specifically, spirometry provides only a one-dimensional gross estimate of pulmonary function, and V/Q scans have poor spatial resolution, reducing its potential for regional assessment of structure-to-function relationships. We have developed a method which utilizes standard clinical CT scanning to provide data for computation of dynamic anatomic parametric models of the lung during respiration which correlates high-resolution anatomy to underlying physiology. The lungs are segmented from both inspiration and expiration three-dimensional (3D) data sets and transformed into a geometric description of the surface of the lung. Parametric mapping of lung surface deformation then provides a visual and quantitative description of the mechanical properties of the lung. Any alteration in lung mechanics is manifest by alterations in normal deformation of the lung wall. The method produces a high-resolution anatomic and functional composite picture from sparse temporal-spatial methods which quantitatively illustrates detailed anatomic structure to pulmonary function relationships impossible for translational methods to provide.

  14. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial.

    PubMed

    Hallsworth, Kate; Thoma, Christian; Hollingsworth, Kieren G; Cassidy, Sophie; Anstee, Quentin M; Day, Christopher P; Trenell, Michael I

    2015-12-01

    Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.

  15. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  16. A simple regression-based method to map quantitative trait loci underlying function-valued phenotypes.

    PubMed

    Kwak, Il-Youp; Moore, Candace R; Spalding, Edgar P; Broman, Karl W

    2014-08-01

    Most statistical methods for quantitative trait loci (QTL) mapping focus on a single phenotype. However, multiple phenotypes are commonly measured, and recent technological advances have greatly simplified the automated acquisition of numerous phenotypes, including function-valued phenotypes, such as growth measured over time. While methods exist for QTL mapping with function-valued phenotypes, they are generally computationally intensive and focus on single-QTL models. We propose two simple, fast methods that maintain high power and precision and are amenable to extensions with multiple-QTL models using a penalized likelihood approach. After identifying multiple QTL by these approaches, we can view the function-valued QTL effects to provide a deeper understanding of the underlying processes. Our methods have been implemented as a package for R, funqtl.

  17. Functional Ultrasound Imaging for Assessment of Extracellular Matrix Scaffolds Used for Liver Organoid Formation

    PubMed Central

    Gessner, Ryan C.; Hanson, Ariel D.; Feingold, Steven; Cashion, Avery T.; Corcimaru, Ana; Wu, Bryant T.; Mullins, Christopher R.; Aylward, Stephen R.; Reid, Lola M.; Dayton, Paul A.

    2015-01-01

    A method of 3D functional ultrasound imaging has been developed to enable non-destructive assessment of extracellular matrix scaffolds that have been prepared by decellularization protocols and are intended for recellularization to create organoids. A major challenge in organ decellularization is retaining patent micro-vascular structures crucial for nutrient access and functionality of organoids. The imaging method described here provides statistical distributions of flow rates throughout the tissue volumes, 3D vessel network architecture visualization, characterization of microvessel volumes and sizes, and delineation of matrix from vascular circuits. The imaging protocol was tested on matrix scaffolds that are tissue-specific, but not species-specific, matrix extracts, prepared by a process that preserved >98% of the collagens, collagen-associated matrix components, and matrix-bound growth factors and cytokines. Image-derived data are discussed with respect to assessment of scaffolds followed by proof-of-concept studies in organoid establishment using Hep3B, human hepatoblast-like cells. Histology showed that the cells attached to scaffolds with patent vasculature within minutes, achieved engraftment at near 100%, expressed liver-specific functions within 24h, and yielded evidence of proliferation and increasing differentiation of cells throughout the two weeks of culture studies. This imaging method should prove valuable in analyses of such matrix scaffolds. PMID:24011714

  18. Toward a quantitative theory of intrinsically disordered proteins and their function.

    PubMed

    Liu, Jintao; Faeder, James R; Camacho, Carlos J

    2009-11-24

    A large number of proteins are sufficiently unstable that their full 3D structure cannot be resolved. The origins of this intrinsic disorder are not well understood, but its ubiquitous presence undercuts the principle that a protein's structure determines its function. Here we present a quantitative theory that makes predictions regarding the role of intrinsic disorder in protein structure and function. In particular, we discuss the implications of analytical solutions of a series of fundamental thermodynamic models of protein interactions in which disordered proteins are characterized by positive folding free energies. We validate our predictions by assigning protein function by using the gene ontology classification--in which "protein binding", "catalytic activity", and "transcription regulator activity" are the three largest functional categories--and by performing genome-wide surveys of both the amount of disorder in these functional classes and binding affinities for both prokaryotic and eukaryotic genomes. Specifically, without assuming any a priori structure-function relationship, the theory predicts that both catalytic and low-affinity binding (K(d) greater, >or= 0(-7) M) proteins prefer ordered structures, whereas only high-affinity binding proteins (found mostly in eukaryotes) can tolerate disorder. Relevant to both transcription and signal transduction, the theory also explains how increasing disorder can tune the binding affinity to maximize the specificity of promiscuous interactions. Collectively, these studies provide insight into how natural selection acts on folding stability to optimize protein function.

  19. Altered resting-state functional activity in posttraumatic stress disorder: A quantitative meta-analysis

    PubMed Central

    Wang, Ting; Liu, Jia; Zhang, Junran; Zhan, Wang; Li, Lei; Wu, Min; Huang, Hua; Zhu, Hongyan; Kemp, Graham J.; Gong, Qiyong

    2016-01-01

    Many functional neuroimaging studies have reported differential patterns of spontaneous brain activity in posttraumatic stress disorder (PTSD), but the findings are inconsistent and have not so far been quantitatively reviewed. The present study set out to determine consistent, specific regional brain activity alterations in PTSD, using the Effect Size Signed Differential Mapping technique to conduct a quantitative meta-analysis of resting-state functional neuroimaging studies of PTSD that used either a non-trauma (NTC) or a trauma-exposed (TEC) comparison control group. Fifteen functional neuroimaging studies were included, comparing 286 PTSDs, 203 TECs and 155 NTCs. Compared with NTC, PTSD patients showed hyperactivity in the right anterior insula and bilateral cerebellum, and hypoactivity in the dorsal medial prefrontal cortex (mPFC); compared with TEC, PTSD showed hyperactivity in the ventral mPFC. The pooled meta-analysis showed hypoactivity in the posterior insula, superior temporal, and Heschl’s gyrus in PTSD. Additionally, subgroup meta-analysis (non-medicated subjects vs. NTC) identified abnormal activation in the prefrontal-limbic system. In meta-regression analyses, mean illness duration was positively associated with activity in the right cerebellum (PTSD vs. NTC), and illness severity was negatively associated with activity in the right lingual gyrus (PTSD vs. TEC). PMID:27251865

  20. Importance of renal depth correction for quantitation of differential renal function

    SciTech Connect

    Choi, H.; Kirchner, P.T.

    1985-05-01

    To assess the frequency and magnitude of errors caused by asymmetries in renal depth, when estimates of differential function are based only posterior projections (as in DTPA studies). The authors compared ratios of right-to-left (R/L) DMSA localization derived from posterior camera images with R/L ratios based on geometric mean of posterior and anterior counts of each kidney. The factor (X) required to convert the ratio of R/L posterior counts to the more accurate R/L geometric counts (Rp/Lp.X = Rg/Lg) was determined in 55 randomly selected patients referred for DMSA studies. Frequency distributions for X and l/X reveal that the use of posterior counts alone is likely to produce differential flow/function estimates with errors greater than 30% in 5% of patients, greater than 20% in 16 of patients. Lack of depth correction also widens the normal range derived from normal controls, thus reducing sensitivity and specificity of quantitative renal studies by two different mechanisms. The authors recommend routine application of depth correction by conjugate counting or ultrasound techniques for all quantitations of renal function.

  1. Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve

    PubMed Central

    Wang, Po-Ming; Chung, Na-Na; Hsu, Wei-Chung; Chang, Feng-Ling; Jang, Chin-Jyh; Scorsetti, Marta

    2015-01-01

    Aim To discuss current dosage for stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) patients and suggest alternative treatment strategies according to liver segmentation as defined by the Couinaud classification. Background SBRT is a safe and effective alternative treatment for HCC patients who are unable to undergo liver ablation/resection. However, the SBRT fractionation schemes and treatment planning strategies are not well established. Materials and methods In this article, the latest developments and key findings from research studies exploring the efficacy of SBRT fractionation schemes for treatment of HCC are reviewed. Patients’ characteristics, fractionation schemes, treatment outcomes and toxicities were compiled. Special attention was focused on SBRT fractionation approaches that take into consideration liver segmentation according to the Couinaud classification and functional hepatic reserve based on Child–Pugh (CP) liver cirrhosis classification. Results The most common SBRT fractionation schemes for HCC were 3 × 10–20 Gy, 4–6 × 8–10 Gy, and 10 × 5–5.5 Gy. Based on previous SBRT studies, and in consideration of tumor size and CP classification, we proposed 3 × 15–25 Gy for patients with tumor size <3 cm and adequate liver reserve (CP-A score 5), 5 × 10–12 Gy for patients with tumor sizes between 3 and 5 cm or inadequate liver reserve (CP-A score 6), and 10 × 5–5.5 Gy for patients with tumor size >5 cm or CP-B score. Conclusions Treatment schemes in SBRT for HCC vary according to liver segmentation and functional hepatic reserve. Further prospective studies may be necessary to identify the optimal dose of SBRT for HCC. PMID:26696781

  2. Serum glutathione S-transferase B1 activity as an index of liver function in cystic fibrosis.

    PubMed Central

    Rattenbury, J M; Taylor, C J; Heath, P K; Howie, A F; Beckett, G J

    1995-01-01

    AIMS--To evaluate serum glutathione S-transferase B1 (GST B1), a highly sensitive test of hepatocellular function, as a means of identifying liver disease in patients with cystic fibrosis (CF). METHODS--The presence of liver disease was sought over a three year period in 60 children with CF, using a combination of clinical assessment, ultrasound examination, conventional biochemical tests of liver function (LFTs), and measurement of GST B1. RESULTS--Reference ranges for serum GST B1 were established in a paediatric control population. The 95% value (4.55 micrograms/l) was similar to the upper limit of normal previously derived in adults. Mean (SE) serum GST B1 activities were higher in the CF population (9.0 (1.14) micrograms/l) than in age matched controls (2.4 (0.15) micrograms/l). Ten patients with CF showed clinical signs of liver dysfunction. All but one had a serum GST B1 > 4.55 micrograms/l. Twelve other patients had elevated LFTs without clinically evident liver dysfunction, six had abnormal ultrasound scans and two showed both of these anomalies. Thirty patients with CF had neither biochemical, ultrasonographic nor clinical signs of liver disease. On review three years later, clinically important liver disease was reaffirmed in eight of the 10 index cases and had become apparent in a further eight, all of whom had elevated GST B1 activities. Five (36%) of the patients with elevated LFTs and two (33%) with isolated ultrasound changes continued to show these abnormalities. CONCLUSIONS--The limitations of conventional LFTs and ultrasound scans were evident from this study. The results suggest that elevated GST B1 activities may be a better predictor of hepatic dysfunction in CF than conventional LFTs. PMID:7560208

  3. [Liver function of workers occupationally exposed to mixed organic solvents in a petrochemical industry].

    PubMed

    Fernández-D'Pool, J; Oroño-Osorio, A

    2001-06-01

    A descriptive and cross sectional study was conducted to determine whether hepatic function changes in workers occupationally exposed to a mixture of organic solvents, were due to the exposure or confusing factors. A non random sample of 77 workers, operators and supervisors of the Olefin Plant I and II of a petrochemical industry in Maracaibo, Venezuela, was used. Their mean age was 29 +/- 7 years, and had at least one year of exposure to the solvents. This sample was compared with a group of employees of the administrative offices or control panel workers, with a mean age of 36 +/- 8 year and with similar anthropometric characteristics. Workers with a known history of liver disease, blood transfusions and diabetes mellitus were excluded of the study. In addition to a complete occupational disease medical history and a physical examination, serum samples were obtained to determine the activity of the aspartato aminotransferase (AST), alanin aminotransferase (ALT), gamma glutamiltransferase (GGT), alkaline phosphatase (AF), the concentration of the total bile acids (BAS), the surface antigen of hepatitis B(HbsAg) and the hepatitis A virus antibodies: AntiHAV-IgG and the AntiHAV-IgM. An urine sample was taken and analyzed by standard methodology to determine urinary phenols. The air concentrations of benzene, ethylbenzene, toluene and xylene were analyzed by gas chromathography. The serum activities of the liver enzymes, the concentration of bile acids and urinary phenols were not influenced by the exposure to the solvents. The increase of the activity of GGT was associated with obesity and alcohol consumption. The antibodies of the surface antigen of hepatitis A-IgM were normal in both groups and the antibodies for the antigen of hepatitis A-IgG presented a prevalence of 6% in the exposed group and 9% in the non exposed not being associated with liver abnormalities. The individual air concentrations of the solvents were below the environmentally permissible

  4. Quantitative Nanostructure Characterization Using Atomic Pair Distribution Functions Obtained From Laboratory Electron Microscopes

    SciTech Connect

    Abeykoon M.; Billinge S.; Malliakas, C.D.; Juhas, P.; Bozin, E.S.; Kanatzidis, M.G.

    2012-05-01

    Quantitatively reliable atomic pair distribution functions (PDFs) have been obtained from nanomaterials in a straightforward way from a standard laboratory transmission electron microscope (TEM). The approach looks very promising for making electron derived PDFs (ePDFs) a routine step in the characterization of nanomaterials because of the ubiquity of such TEMs in chemistry and materials laboratories. No special attachments such as energy filters were required on the microscope. The methodology for obtaining the ePDFs is described as well as some opportunities and limitations of the method.

  5. Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering.

    PubMed

    Jiang, Wei-Cheng; Cheng, Yu-Hao; Yen, Meng-Hua; Chang, Yin; Yang, Vincent W; Lee, Oscar K

    2014-04-01

    Liver transplantation is the ultimate treatment for severe hepatic failure to date. However, the limited supply of donor organs has severely hampered this treatment. So far, great potentials of using mesenchymal stem cells (MSCs) to replenish the hepatic cell population have been shown; nevertheless, there still is a lack of an optimal three-dimensional scaffold for generation of well-transplantable hepatic tissues. In this study, we utilized a cryo-chemical decellularization method which combines physical and chemical approach to generate acellular liver scaffolds (ALS) from the whole liver. The produced ALS provides a biomimetic three-dimensional environment to support hepatic differentiation of MSCs, evidenced by expression of hepatic-associated genes and marker protein, glycogen storage, albumin secretion, and urea production. It is also found that hepatic differentiation of MSCs within the ALS is much more efficient than two-dimensional culture in vitro. Importantly, the hepatic-like tissues (HLT) generated by repopulating ALS with MSCs are able to act as functional grafts and rescue lethal hepatic failure after transplantation in vivo. In summary, the cryo-chemical method used in this study is suitable for decellularization of liver and create acellular scaffolds that can support hepatic differentiation of MSCs and be used to fabricate functional tissue-engineered liver constructs.

  6. The utility of pulmonary function testing in predicting outcomes following liver transplantation.

    PubMed

    Kia, Leila; Cuttica, Michael J; Yang, Amy; Donnan, Erica N; Whitsett, Maureen; Singhvi, Ajay; Lemmer, Alexander; Levitsky, Josh

    2016-06-01

    Although pulmonary function tests (PFTs) are routinely performed in patients during the evaluation period before liver transplantation (LT), their utility in predicting post-LT mortality and morbidity outcomes is not known. The aim of this study was to determine the impact of obstructive and/or restrictive lung disease on post-LT outcomes. We conducted a retrospective analysis of patients who had pre-LT PFTs and underwent a subsequent LT (2007-2013). We used statistical analyses to determine independent associations between PFT parameters and outcomes (graft/patient survival, time on ventilator, and hospital/intensive care unit [ICU] length of stay [LOS]). A total of 415 LT recipients with available PFT data were included: 65% of patients had normal PFTs; 8% had obstructive lung disease; and 27% had restrictive lung disease. There was no difference in patient and graft survival between patients with normal, obstructive, and restrictive lung disease. However, restrictive lung disease was associated with longer post-LT time on ventilator and both ICU and hospital LOS (P < 0.05). More specific PFT parameters (diffusing capacity of the lungs for carbon monoxide, total lung capacity, and residual volume) were all significant predictors of ventilator time and both ICU and hospital LOS (P < 0.05). Although pre-LT PFT parameters may not predict post-LT mortality, restrictive abnormalities correlate with prolonged post-LT ventilation and LOS. Efforts to identify and minimize the impact of restrictive abnormalities on PFTs might improve such outcomes. Liver Transplantation 22 805-811 2016 AASLD.

  7. Effects of repeat exposure to inhalation anesthetics on liver and renal function

    PubMed Central

    Nishiyama, Tomoki

    2013-01-01

    Background: Cross hypersensitivity to inhalation anesthetics has not been studied. The aim of this study was to investigate it by comparing liver and renal function after repeated anesthesia with sevoflurane and isoflurane retrospectively. Materials and Methods: The adult patients who received general anesthesia twice within the interval of 14 days to 1 year were retrospectively analyzed. Those who received sevoflurane anesthesia twice (SS group, 53 cases), isoflurane anesthesia twice (II group, 31 cases), sevoflurane followed by isoflurane anesthesia (SI group, 29 cases), isoflurane followed by sevoflurane anesthesia (IS group, 35 cases), and propofol–fentanyl anesthesia twice (PP group, 58 cases) were enrolled. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (Bil), gamma-glutamyl transpeptidase (γ-GTP), blood urea nitrogen (BUN), and creatinine (Cr) measured 1-3, 5-8, and 12-16 days after surgery were investigated. Results: In the IS group, the number of the patients with abnormal values of ALT and γ-GTP 5–8 days after surgery were significantly smaller at second anesthesia compared to the first anesthesia. The number of the patients with abnormal values of AST, ALT, and γ-GTP were significantly larger in the II group than the SS and PP groups. The number of patients who had higher values in each parameter at second anesthesia compared to the first anesthesia was not different among the groups. Conclusions: Sevoflurane and isoflurane might have no cross hypersensitivity. Both anesthetics might not have any additional risks to increase liver and renal damage by second anesthesia. PMID:23493664

  8. Thyroid Function in Obese Children with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Bilgin, Hüseyin; Pirgon, Özgür

    2014-01-01

    Ob­jec­ti­ve: To investigate the relationships between thyroid function and metabolic risk factors in obese adolescents with non-alcoholic fatty liver disease (NAFLD). Methods: One hundred sixty obese adolescents and 40 control subjects were enrolled in the study. The obese subjects were divided into two groups based on presence or absence of liver steatosis (NAFLD group and non-NAFLD group). Serum samples were assayed for glucose, insulin, cholesterol, alanine aminotransferase, aspartate aminotransferase, free thyroxine (fT4), free triiodothyronine (fT3) and thyroid-stimulating hormone (TSH). The ratio of fT3 to fT4 was evaluated as an indirect index of deiodinase activity. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. Results: NAFLD and non-NAFLD groups had slightly higher fasting blood glucose values than the control group. Fasting insulin levels in the NAFLD group were significantly higher than those in the non-NAFLD and control groups. The NAFLD group had significantly greater HOMA-IR values compared with the non-NAFLD group and also with the control group. The NAFLD group had significantly higher fT3/fT4 ratio values compared to both non-NAFLD and control groups. fT3/fT4 was positively correlated with serum insulin levels in the NAFLD group. Conclusion: This study showed that obese adolescents with hepatosteatosis had elevated values for fT3/fT4 ratio. This finding suggested a high conversion of T4 to T3 due to increased deiodinase activity as a compensatory mechanism for fat accumulation. PMID:25241608

  9. Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus

    PubMed Central

    Pakharukova, Mariya Y.; Vavilin, Valentin A.; Sripa, Banchob; Laha, Thewarach; Brindley, Paul J.; Mordvinov, Viatcheslav A.

    2015-01-01

    The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium) are considered by the International Agency for Research on Cancer (IARC) as definite causes of cancer. We focused our research on the human liver fluke Opisthorchis felineus, an emerging source of biliary tract disease including bile duct cancer in Russia and central Europe. The aims of this study were (i) to determine the significance of the CYP activity for the morphology and survival of the liver fluke, (ii) to assess CYP ability to metabolize xenobiotics, and (iii) to localize the CYP activity in O. felineus tissues. We observed high constitutive expression of CYP mRNA (Real-time PCR) in O. felineus. This enzyme metabolized xenobiotics selective for mammalian CYP2E1, CYP2B, CYP3A, but not CYP1A, as determined by liquid chromatography and imaging analyses. Tissue localization studies revealed the CYP activity in excretory channels, while suppression of CYP mRNA by RNA interference was accompanied by morphological changes of the excretory system and increased mortality rates of the worms. These results suggest that the CYP function is linked to worm metabolism and detoxification. The findings also suggest that the CYP enzyme is involved in vitally important processes in the organism of parasites and is a potential drug target. PMID:26625139

  10. Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus.

    PubMed

    Pakharukova, Mariya Y; Vavilin, Valentin A; Sripa, Banchob; Laha, Thewarach; Brindley, Paul J; Mordvinov, Viatcheslav A

    2015-12-01

    The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium) are considered by the International Agency for Research on Cancer (IARC) as definite causes of cancer. We focused our research on the human liver fluke Opisthorchis felineus, an emerging source of biliary tract disease including bile duct cancer in Russia and central Europe. The aims of this study were (i) to determine the significance of the CYP activity for the morphology and survival of the liver fluke, (ii) to assess CYP ability to metabolize xenobiotics, and (iii) to localize the CYP activity in O. felineus tissues. We observed high constitutive expression of CYP mRNA (Real-time PCR) in O. felineus. This enzyme metabolized xenobiotics selective for mammalian CYP2E1, CYP2B, CYP3A, but not CYP1A, as determined by liquid chromatography and imaging analyses. Tissue localization studies revealed the CYP activity in excretory channels, while suppression of CYP mRNA by RNA interference was accompanied by morphological changes of the excretory system and increased mortality rates of the worms. These results suggest that the CYP function is linked to worm metabolism and detoxification. The findings also suggest that the CYP enzyme is involved in vitally important processes in the organism of parasites and is a potential drug target.

  11. The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity

    PubMed Central

    Pacifico, Lucia; Bonci, Enea; Andreoli, Gian Marco; Di Martino, Michele; Gallozzi, Alessia; De Luca, Ester; Chiesa, Claudio

    2016-01-01

    The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ≥5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m2. Abnormal albuminuria was defined as urinary excretion of ≥30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m2 was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16–5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. PMID:27472326

  12. Quantitative analysis of PEG-functionalized colloidal gold nanoparticles using charged aerosol detection.

    PubMed

    Smith, Mackensie C; Crist, Rachael M; Clogston, Jeffrey D; McNeil, Scott E

    2015-05-01

    Surface characteristics of a nanoparticle, such as functionalization with polyethylene glycol (PEG), are critical to understand and achieve optimal biocompatibility. Routine physicochemical characterization such as UV-vis spectroscopy (for gold nanoparticles), dynamic light scattering, and zeta potential are commonly used to assess the presence of PEG. However, these techniques are merely qualitative and are not sensitive enough to distinguish differences in PEG quantity, density, or presentation. As an alternative, two methods are described here which allow for quantitative measurement of PEG on PEGylated gold nanoparticles. The first, a displacement method, utilizes dithiothreitol to displace PEG from the gold surface. The dithiothreitol-coated gold nanoparticles are separated from the mixture via centrifugation, and the excess dithiothreitol and dissociated PEG are separated through reversed-phase high-performance liquid chromatography (RP-HPLC). The second, a dissolution method, utilizes potassium cyanide to dissolve the gold nanoparticles and liberate PEG. Excess CN(-), Au(CN)2 (-), and free PEG are separated using RP-HPLC. In both techniques, the free PEG can be quantified against a standard curve using charged aerosol detection. The displacement and dissolution methods are validated here using 2-, 5-, 10-, and 20-kDa PEGylated 30-nm colloidal gold nanoparticles. Further value in these techniques is demonstrated not only by quantitating the total PEG fraction but also by being able to be adapted to quantitate the free unbound PEG and the bound PEG fractions. This is an important distinction, as differences in the bound and unbound PEG fractions can affect biocompatibility, which would not be detected in techniques that only quantitate the total PEG fraction.

  13. Supplementation with selenium can influence nausea, fatigue, physical, renal, and liver function of children and adolescents with cancer.

    PubMed

    Vieira, Maria Luiza Dos Santos; Fonseca, Fernando Luiz Affonso; Costa, Larissa Grossi; Beltrame, Registila Libania; Chaves, Carolina Machado de Sousa; Cartum, Jairo; Alves, Sarah Isabel P M do N; Azzalis, Ligia Ajaime; Junqueira, Virginia Berlanga Campos; Pereria, Edimar Cristiano; Rocha, Katya Cristina

    2015-01-01

    The drugs used in chemotherapy treatments have little specificity, attack tumor cells, and also injure proliferative tissues. Knowledge of the functions of micronutrients has greatly increased, especially of Selenium (Se) that presents immunomodulatory and antitumor functions. The present study evaluated the health-related quality of life of patients undergoing chemotherapy for the treatment of leukemias and lymphomas (LL) and solid tumors (ST) while receiving Selenium (Se) supplementation. This is a randomized, double-blind, crossover study that evaluated the quality of life (EORTC-QLQ-C30 questionnaire), renal and liver functions of patients supplemented with Se. There was no statistically significant alteration in LL patients. However, the fatigue and nausea scores after 30 days did decrease in this group as well as in the ST group. After 1 year supplementation with Selenium, a more noticeable decrease in the scores concerning fatigue and nausea could be observed in the ST group, when compared with the beginning of the study. The LL patients also presented a decrease in the fatigue scores and physical functions. The kidney function as well as liver function has improved after Selenium supplementation when compared with the placebo intake in LL and ST patients, more remarkably in the LL group. Supplementation with Selenium promotes the reduction of chemotherapy side effects in cancer patients, especially by improving the conditions of patients with fatigue, nausea, and impaired physical function. Renal and liver functions have also improved.

  14. Linking Functional Connectivity and Structural Connectivity Quantitatively: A Comparison of Methods.

    PubMed

    Huang, Haiqing; Ding, Mingzhou

    2016-03-01

    Structural connectivity in the brain is the basis of functional connectivity. Quantitatively linking the two, however, remains a challenge. For a pair of regions of interest (ROIs), anatomical connections derived from diffusion-weighted imaging are often quantified by fractional anisotropy (FA) or edge weight, whereas functional connections, derived from resting-state functional magnetic resonance imaging, can be characterized by non-time-series measures such as zero-lag cross correlation and partial correlation, as well as by time-series measures such as coherence and Granger causality. In this study, we addressed the question of linking structural connectivity and functional connectivity quantitatively by considering two pairs of ROIs, one from the default mode network (DMN) and the other from the central executive network (CEN), using two different data sets. Selecting (1) posterior cingulate cortex and medial prefrontal cortex of the DMN as the first pair of ROIs and (2) left dorsal lateral prefrontal cortex and left inferior parietal lobule of the CEN as the second pair of ROIs, we show that (1) zero-lag cross correlation, partial correlation, and pairwise Granger causality were not significantly correlated with either mean FA or edge weight and (2) conditional Granger causality (CGC) was significantly correlated with edge weight but not with mean FA. These results suggest that (1) edge weight may be a more appropriate measure to quantify the strength of the anatomical connection between ROIs and (2) CGC, which statistically removes common input and the indirect influences between a given ROI pair, may be a more appropriate measure to quantify the strength of the functional interaction enabled by the fibers linking the two ROIs.

  15. Functional mapping of quantitative trait loci underlying the character process: a theoretical framework.

    PubMed

    Ma, Chang-Xing; Casella, George; Wu, Rongling

    2002-08-01

    Unlike a character measured at a finite set of landmark points, function-valued traits are those that change as a function of some independent and continuous variable. These traits, also called infinite-dimensional characters, can be described as the character process and include a number of biologically, economically, or biomedically important features, such as growth trajectories, allometric scalings, and norms of reaction. Here we present a new statistical infrastructure for mapping quantitative trait loci (QTL) underlying the character process. This strategy, termed functional mapping, integrates mathematical relationships of different traits or variables within the genetic mapping framework. Logistic mapping proposed in this article can be viewed as an example of functional mapping. Logistic mapping is based on a universal biological law that for each and every living organism growth over time follows an exponential growth curve (e.g., logistic or S-shaped). A maximum-likelihood approach based on a logistic-mixture model, implemented with the EM algorithm, is developed to provide the estimates of QTL positions, QTL effects, and other model parameters responsible for growth trajectories. Logistic mapping displays a tremendous potential to increase the power of QTL detection, the precision of parameter estimation, and the resolution of QTL localization due to the small number of parameters to be estimated, the pleiotropic effect of a QTL on growth, and/or residual correlations of growth at different ages. More importantly, logistic mapping allows for testing numerous biologically important hypotheses concerning the genetic basis of quantitative variation, thus gaining an insight into the critical role of development in shaping plant and animal evolution and domestication. The power of logistic mapping is demonstrated by an example of a forest tree, in which one QTL affecting stem growth processes is detected on a linkage group using our method, whereas it cannot

  16. Functional mapping of quantitative trait loci underlying the character process: a theoretical framework.

    PubMed Central

    Ma, Chang-Xing; Casella, George; Wu, Rongling

    2002-01-01

    Unlike a character measured at a finite set of landmark points, function-valued traits are those that change as a function of some independent and continuous variable. These traits, also called infinite-dimensional characters, can be described as the character process and include a number of biologically, economically, or biomedically important features, such as growth trajectories, allometric scalings, and norms of reaction. Here we present a new statistical infrastructure for mapping quantitative trait loci (QTL) underlying the character process. This strategy, termed functional mapping, integrates mathematical relationships of different traits or variables within the genetic mapping framework. Logistic mapping proposed in this article can be viewed as an example of functional mapping. Logistic mapping is based on a universal biological law that for each and every living organism growth over time follows an exponential growth curve (e.g., logistic or S-shaped). A maximum-likelihood approach based on a logistic-mixture model, implemented with the EM algorithm, is developed to provide the estimates of QTL positions, QTL effects, and other model parameters responsible for growth trajectories. Logistic mapping displays a tremendous potential to increase the power of QTL detection, the precision of parameter estimation, and the resolution of QTL localization due to the small number of parameters to be estimated, the pleiotropic effect of a QTL on growth, and/or residual correlations of growth at different ages. More importantly, logistic mapping allows for testing numerous biologically important hypotheses concerning the genetic basis of quantitative variation, thus gaining an insight into the critical role of development in shaping plant and animal evolution and domestication. The power of logistic mapping is demonstrated by an example of a forest tree, in which one QTL affecting stem growth processes is detected on a linkage group using our method, whereas it cannot

  17. Validation of density functionals for transition metals and intermetallics using data from quantitative electron diffraction.

    PubMed

    Sang, Xiahan; Kulovits, Andreas; Wang, Guofeng; Wiezorek, Jörg

    2013-02-28

    Accurate low-order structure factors (Fg) measured by quantitative convergent beam electron diffraction (QCBED) were used for validation of different density functional theory (DFT) approximations. Twenty-three low-order Fg were measured for the transition metals Cr, Fe, Co, Ni, and Cu, and the transition metal based intermetallic phases γ-TiAl, β-NiAl, and γ1-FePd using a multi-beam off-zone axis QCBED method and then compared with Fg calculated by ab initio DFT using the local density approximation (LDA) and LDA + U, and different generalized gradient approximations (GGA) functionals. Different functionals perform very differently for different materials and crystal structures regarding prediction of low-order Fg. All the GGA functionals tested in the paper except for EV93 achieve good overall agreement with the experimentally determined low-order Fg for BCC Cr and Fe, while EV93 performs the best for FCC Ni and Cu. The LDA and GGA functional fail to predict accurately the low-order Fg for β-NiAl and γ1-FePd. The LDA + U approach, through tuning of U, can achieve excellent matches with the experimentally measured Fg for all the metallic systems investigated in this paper. The use of experimentally accessible low order Fg as an additional set of metrics in approaches of validation of DFT calculations is discussed and has potential to assist in and to stimulate development of improved functionals.

  18. Validation of density functionals for transition metals and intermetallics using data from quantitative electron diffraction

    NASA Astrophysics Data System (ADS)

    Sang, Xiahan; Kulovits, Andreas; Wang, Guofeng; Wiezorek, Jörg

    2013-02-01

    Accurate low-order structure factors (Fg) measured by quantitative convergent beam electron diffraction (QCBED) were used for validation of different density functional theory (DFT) approximations. Twenty-three low-order Fg were measured for the transition metals Cr, Fe, Co, Ni, and Cu, and the transition metal based intermetallic phases γ-TiAl, β-NiAl, and γ1-FePd using a multi-beam off-zone axis QCBED method and then compared with Fg calculated by ab initio DFT using the local density approximation (LDA) and LDA + U, and different generalized gradient approximations (GGA) functionals. Different functionals perform very differently for different materials and crystal structures regarding prediction of low-order Fg. All the GGA functionals tested in the paper except for EV93 achieve good overall agreement with the experimentally determined low-order Fg for BCC Cr and Fe, while EV93 performs the best for FCC Ni and Cu. The LDA and GGA functional fail to predict accurately the low-order Fg for β-NiAl and γ1-FePd. The LDA + U approach, through tuning of U, can achieve excellent matches with the experimentally measured Fg for all the metallic systems investigated in this paper. The use of experimentally accessible low order Fg as an additional set of metrics in approaches of validation of DFT calculations is discussed and has potential to assist in and to stimulate development of improved functionals.

  19. Effect of in utero exposure of Toddy (coconut palm wine) on liver function and lipid metabolism in rat fetuses.

    PubMed

    Lal, J J; Sreeranjit Kumar, C V; Suresh, M V; Indira, M; Vijayammal, P L

    1998-01-01

    The objective of this study was to determine the effects of a country liquor Toddy (Coconut palm wine) and an equivalent quantity of ethanol on liver function and lipid metabolism in utero. Female albino rats with an average weight of 125 +/- 5 g were exposed to Toddy from coconut palm (24.5 ml/kg body weight/day) and ethanol (0.52 ml/kg body weight/day) for 15 days before conception and during pregnancy. On day 13 and day 19 of gestation, altered liver function and hyperlipidemia were seen in the fetuses of both the treated groups. Altered liver function was evidenced by the increased activity of alcohol dehydrogenase, aldehyde dehydrogenase, glutamic oxaloacetic transaminase (aspartate amino transferase (GOT)), glutamic pyruvic transaminase (alanine amino transferase (GPT)). Hyperlipidemia was caused by increased biosynthesis since the incorporation of 14C acetate into lipids and activities of HMG CoA reductase and lipogenic enzymes were elevated. Toddy treated fetuses were more severely affected than those exposed to an equivalent quantity of ethanol. Toddy seemed to potentiate the toxicity induced by alcohol suggesting the role of non alcoholic components. Hepatic functions of the day 13 fetuses were effected to a lesser degree than those in the day 19 hepatic liver.

  20. An MRM-based workflow for absolute quantitation of lysine-acetylated metabolic enzymes in mouse liver.

    PubMed

    Xu, Leilei; Wang, Fang; Xu, Ying; Wang, Yi; Zhang, Cuiping; Qin, Xue; Yu, Hongxiu; Yang, Pengyuan

    2015-12-07

    As a key post-translational modification mechanism, protein acetylation plays critical roles in regulating and/or coordinating cell metabolism. Acetylation is a prevalent modification process in enzymes. Protein acetylation modification occurs in sub-stoichiometric amounts; therefore extracting biologically meaningful information from these acetylation sites requires an adaptable, sensitive, specific, and robust method for their quantification. In this work, we combine immunoassays and multiple reaction monitoring-mass spectrometry (MRM-MS) technology to develop an absolute quantification for acetylation modification. With this hybrid method, we quantified the acetylation level of metabolic enzymes, which could demonstrate the regulatory mechanisms of the studied enzymes. The development of this quantitative workflow is a pivotal step for advancing our knowledge and understanding of the regulatory effects of protein acetylation in physiology and pathophysiology.

  1. Disc Degeneration Assessed by Quantitative T2* (T2 star) Correlated with Functional Lumbar Mechanics

    PubMed Central

    Ellingson, Arin M.; Mehta, Hitesh; Polly, David W.; Ellermann, Jutta; Nuckley, David J.

    2013-01-01

    Study Design Experimental correlation study design to quantify features of disc health, including signal intensity and distinction between the annulus fibrosus (AF) and nucleus pulposus (NP), with T2* magnetic resonance imaging (MRI) and correlate with the functional mechanics in corresponding motion segments. Objective Establish the relationship between disc health assessed by quantitative T2* MRI and functional lumbar mechanics. Summary of Background Data Degeneration leads to altered biochemistry in the disc, affecting the mechanical competence. Clinical routine MRI sequences are not adequate in detecting early changes in degeneration and fails to correlate with pain or improve patient stratification. Quantitative T2* relaxation time mapping probes biochemical features and may offer more sensitivity in assessing disc degeneration. Methods Cadaveric lumbar spines were imaged using quantitative T2* mapping, as well as conventional T2-weighted MRI sequences. Discs were graded by the Pfirrmann scale and features of disc health, including signal intensity (T2* Intensity Area) and distinction between the AF and NP (Transition Zone Slope), were quantified by T2*. Each motion segment was subjected to pure moment bending to determine range of motion (ROM), neutral zone (NZ), and bending stiffness. Results T2* Intensity Area and Transition Zone Slope were significantly correlated with flexion ROM (p=0.015; p=0.002), ratio of NZ/ROM (p=0.010; p=0.028), and stiffness (p=0.044; p=0.026), as well as lateral bending NZ/ROM (p=0.005; p=0.010) and stiffness (p=0.022; p=0.029). T2* Intensity Area was also correlated with LB ROM (p=0.023). Pfirrmann grade was only correlated with lateral bending NZ/ROM (p=0.001) and stiffness (p=0.007). Conclusions T2* mapping is a sensitive quantitative method capable of detecting changes associated with disc degeneration. Features of disc health quantified with T2* predicted altered functional mechanics of the lumbar spine better than

  2. Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

    SciTech Connect

    Moreira, Paula I.; Custodio, Jose B.A.; Nunes, Elsa; Moreno, Antonio; Seica, Raquel; Oliveira, Catarina R.; Santos, Maria S. . E-mail: mssantos@ci.uc.pt

    2007-05-15

    Given the tremendous importance of mitochondria to basic cellular functions as well as the critical role of mitochondrial impairment in a vast number of disorders, a compelling question is whether 17{beta}-estradiol (E2) modulates mitochondrial function. To answer this question we exposed isolated liver mitochondria to E2. Three groups of rat females were used: control, ovariectomized and ovariectomized treated with tamoxifen. Tamoxifen has antiestrogenic effects in the breast tissue and is the standard endocrine treatment for women with breast cancer. However, under certain circumstances and in certain tissues, tamoxifen can also exert estrogenic agonist properties. We observed that at basal conditions, ovariectomy and tamoxifen treatment do not induce any statistical alteration in oxidative phosphorylation system and respiratory chain parameters. Furthermore, tamoxifen treatment increases the capacity of mitochondria to accumulate Ca{sup 2+} delaying the opening of the permeability transition pore. The presence of 25 {mu}M E2 impairs respiration and oxidative phosphorylation system these effects being similar in all groups of animals studied. Curiously, E2 protects against lipid peroxidation and increases the production of H{sub 2}O{sub 2} in energized mitochondria of control females. Our results indicate that E2 has in general deleterious effects that lead to mitochondrial impairment. Since mitochondrial dysfunction is a triggering event of cell degeneration and death, the use of exogenous E2 must be carefully considered.

  3. Effect of sulodexide on vascular responses and liver mitochondrial function in diabetic rats.

    PubMed

    Dobiaš, L; Petrová, M; Vojtko, R; Uličná, O; Vančová, O; Kristová, V

    2015-01-01

    This study investigates the effects of long-term treatment with sulodexide (SLX) on norepinephrine (NE)-induced contractions, acetylcholine(Ach)-induced relaxations, acute cyclooxygenase blockade by diclofenac (DIC) in isolated femoral arteries (FA) and the parameters of oxidative phosporylation in liver mitochondria. 15-weeks old Wistar rats were divided into four groups: control (C; injected with saline solution), treated control (C+SLX), diabetic (DM) and treated diabetic (DM+SLX). Diabetes was induced with a single i.v. dose of streptozotocin (STZ) 45 mg.kg(-1). SLX was administered i.p., at dose 100 IU.kg(-1) daily for 5 weeks. Vascular responses of isolated femoral arteries were measured using Mulvany-Halpern myograph. Respiratory function of the mitochondria was determined using voltamperometric method on oxygraph Gilson. In diabetic rats the amplitude of maximal response to NE was elevated. DIC pretreatment decreased the amplitudes of NE-induced contractions in all groups of rats. SLX treatment decreased sensitivity of FA to NE and caused higher relaxatory responses to Ach in C and DM. Oxygen consumption and phosphorylation rates ([QO(2)(S(3))], [QO(2)(S(4))] and (OPR)) and respiratory control ratio (RCR) were decreased in the mitochondria of DM rats. Mitochondria of C rats were not affected with SLX treatment. Administration of SLX in DM rats was associated with increase of RCR, other parameters were not affected. Our findings suggest that SLX treatment might be associated with vasculoprotective effects during diabetes and improvement of mitochondrial function.

  4. Gene Level Meta-Analysis of Quantitative Traits by Functional Linear Models

    PubMed Central

    Fan, Ruzong; Wang, Yifan; Boehnke, Michael; Chen, Wei; Li, Yun; Ren, Haobo; Lobach, Iryna; Xiong, Momiao

    2015-01-01

    Meta-analysis of genetic data must account for differences among studies including study designs, markers genotyped, and covariates. The effects of genetic variants may differ from population to population, i.e., heterogeneity. Thus, meta-analysis of combining data of multiple studies is difficult. Novel statistical methods for meta-analysis are needed. In this article, functional linear models are developed for meta-analyses that connect genetic data to quantitative traits, adjusting for covariates. The models can be used to analyze rare variants, common variants, or a combination of the two. Both likelihood-ratio test (LRT) and F-distributed statistics are introduced to test association between quantitative traits and multiple variants in one genetic region. Extensive simulations are performed to evaluate empirical type I error rates and power performance of the proposed tests. The proposed LRT and F-distributed statistics control the type I error very well and have higher power than the existing methods of the meta-analysis sequence kernel association test (MetaSKAT). We analyze four blood lipid levels in data from a meta-analysis of eight European studies. The proposed methods detect more significant associations than MetaSKAT and the P-values of the proposed LRT and F-distributed statistics are usually much smaller than those of MetaSKAT. The functional linear models and related test statistics can be useful in whole-genome and whole-exome association studies. PMID:26058849

  5. Gene Level Meta-Analysis of Quantitative Traits by Functional Linear Models.

    PubMed

    Fan, Ruzong; Wang, Yifan; Boehnke, Michael; Chen, Wei; Li, Yun; Ren, Haobo; Lobach, Iryna; Xiong, Momiao

    2015-08-01

    Meta-analysis of genetic data must account for differences among studies including study designs, markers genotyped, and covariates. The effects of genetic variants may differ from population to population, i.e., heterogeneity. Thus, meta-analysis of combining data of multiple studies is difficult. Novel statistical methods for meta-analysis are needed. In this article, functional linear models are developed for meta-analyses that connect genetic data to quantitative traits, adjusting for covariates. The models can be used to analyze rare variants, common variants, or a combination of the two. Both likelihood-ratio test (LRT) and F-distributed statistics are introduced to test association between quantitative traits and multiple variants in one genetic region. Extensive simulations are performed to evaluate empirical type I error rates and power performance of the proposed tests. The proposed LRT and F-distributed statistics control the type I error very well and have higher power than the existing methods of the meta-analysis sequence kernel association test (MetaSKAT). We analyze four blood lipid levels in data from a meta-analysis of eight European studies. The proposed methods detect more significant associations than MetaSKAT and the P-values of the proposed LRT and F-distributed statistics are usually much smaller than those of MetaSKAT. The functional linear models and related test statistics can be useful in whole-genome and whole-exome association studies.

  6. The renal quantitative scintillation camera study for determination of renal function

    SciTech Connect

    Thompson, I.M. Jr.; Boineau, F.G.; Evans, B.B.; Schlegel, J.U.

    1983-03-01

    The renal quantitative scintillation camera study assesses glomerular filtration rate and effective renal plasma flow based upon renal uptake of 99mtechnetium-iron ascorbate and 131iodine-hippuran, respectively. The method was compared to inulin, para-aminohippuric acid and creatinine clearance studies in 7 normal subjects and 9 patients with various degrees of reduced renal function. The reproducibility of the technique was determined in 15 randomly selected pediatric patients. The values of glomerular filtration rate and effective renal plasma flow were not significantly different from those of inulin and para-aminohippuric acid studies. The reproducibility of the technique was comparable to that of inulin and para-aminohippuric acid studies. Patient acceptance of the technique is excellent and the cost is minimal. Renal morphology and excretory dynamics also are demonstrated. The technique is advocated as a clinical measure of renal function.

  7. Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases.

    PubMed

    Jeffery, H C; Jeffery, L E; Lutz, P; Corrigan, M; Webb, G J; Hirschfield, G M; Adams, D H; Oo, Y H

    2017-02-08

    CD4(+) CD25(high) CD127(low) forkhead box protein 3 (FoxP3(+) ) regulatory T cells (Treg ) are essential for the maintenance of peripheral tolerance. Impaired Treg function and an imbalance between effector and Tregs contribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)-2, a cytokine essential for Treg survival and function. Consequently, few liver-infiltrating Treg demonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation. To establish the potential of IL-2 to enhance Treg therapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT-5 and the subsequent survival and function of Treg and T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, at less than 5 IU/ml, resulted in selective phosphorylation of STAT-5 in Treg but not effector T cells or natural killer cells and associated with increased expression of cytotoxic T lymphocyte antigen-4 (CTLA-4), FoxP3 and CD25 and the anti-apoptotic protein Bcl-2 in Treg with the greatest enhancement of regulatory phenotype in the effector memory Treg population. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Treg function in a CTLA-4-dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination with clinical grade Treg in autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic Treg .

  8. Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

    PubMed

    Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

    2017-03-14

    Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS.

  9. Levels and interactions of plasma xanthine oxidase, catalase and liver function parameters in Nigerian children with Plasmodium falciparum infection.

    PubMed

    Iwalokun, B A; Bamiro, S B; Ogunledun, A

    2006-12-01

    Elevated plasma levels of xanthine oxidase and liver function parameters have been associated with inflammatory events in several human diseases. While xanthine oxidase provides in vitro protection against malaria, its pathophysiological functions in vivo and interactions with liver function parameters remain unclear. This study examined the interactions and plasma levels of xanthine oxidase (XO) and uric acid (UA), catalase (CAT) and liver function parameters GOT, GPT and bilirubin in asymptomatic (n=20), uncomplicated (n=32), and severe (n=18) falciparum malaria children aged 3-13 years. Compared to age-matched control (n=16), significant (p<0.05) elevation in xanthine oxidase by 100-550%, uric acid by 15.4-153.8%, GOT and GPT by 22.1-102.2%, and total bilirubin by 2.3-86% according to parasitaemia (geometric mean parasite density (GMPD)=850-87100 parasites/microL) was observed in the malarial children. Further comparison with control revealed higher CAT level (16.2+/-0.5 vs 14.6+/-0.4 U/L; p<0.05) lacking significant (p>0.05) correlation with XO, but lower CAT level (13.4-5.4 U/L) with improved correlations (r=-0.53 to -0.91; p<0.05) with XO among the asymptomatic and symptomatic malaria children studied. 75% of control, 45% of asymptomatic, 21.9% of uncomplicated, and none of severe malaria children had Hb level>11.0 g/dL. Multivariate analyses further revealed significant (p<0.05) correlations between liver function parameters and xanthine oxidase (r=0.57-0.64) only in the severe malaria group. We conclude that elevated levels of XO and liver enzymes are biochemical features of Plasmodium falciparum parasitaemia in Nigerian children, with both parameters interacting differently to modulate the catalase response in asymptomatic and symptomatic falciparum malaria.

  10. Liver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings

    PubMed Central

    Verstuyft, Céline; Corruble, Emmanuelle; Perlemuter, Gabriel; Colle, Romain

    2016-01-01

    Background Concerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment. Aim To evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug. Methods We studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease. Results An LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations. Conclusion These results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment. PMID:27171561

  11. Characterization of Functional Reprogramming during Osteoclast Development Using Quantitative Proteomics and mRNA Profiling*

    PubMed Central

    An, Eunkyung; Narayanan, Manikandan; Manes, Nathan P.; Nita-Lazar, Aleksandra

    2014-01-01

    In addition to forming macrophages and dendritic cells, monocytes in adult peripheral blood retain the ability to develop into osteoclasts, mature bone-resorbing cells. The extensive morphological and functional transformations that occur during osteoclast differentiation require substantial reprogramming of gene and protein expression. Here we employ -omic-scale technologies to examine in detail the molecular changes at discrete developmental stages in this process (precursor cells, intermediate osteoclasts, and multinuclear osteoclasts), quantitatively comparing their transcriptomes and proteomes. The data have been deposited to the ProteomeXchange with identifier PXD000471. Our analysis identified mitochondrial changes, along with several alterations in signaling pathways, as central to the development of mature osteoclasts, while also confirming changes in pathways previously implicated in osteoclast biology. In particular, changes in the expression of proteins involved in metabolism and redirection of energy flow from basic cellular function toward bone resorption appeared to play a key role in the switch from monocytic immune system function to specialized bone-turnover function. These findings provide new insight into the differentiation program involved in the generation of functional osteoclasts. PMID:25044017

  12. Distinct Quantitative Computed Tomography Emphysema Patterns Are Associated with Physiology and Function in Smokers

    PubMed Central

    San José Estépar, Raúl; Mendoza, Carlos S.; Hersh, Craig P.; Laird, Nan; Crapo, James D.; Lynch, David A.; Silverman, Edwin K.; Washko, George R.

    2013-01-01

    Rationale: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. Objectives: To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. Methods: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. Measurements and Main Results: Compared with percentage of low-attenuation area less than −950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). Conclusions: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures. PMID:23980521

  13. Robust reference intervals for Liver function test (LFT) analytes in newborns and infants

    PubMed Central

    2012-01-01

    Background Reference intervals (RIs) are ranges of upper and lower limits of a given analyte which are used for a laboratory test to determine whether a disease is present or absent or to know if the patient is at risk for future disease states. In Ethiopia, a country with highly diversified population groups and geographical sites, there are no established RIs to metabolic analytes including the liver function test (LFT) analytes for the pediatric population though it has been known that liver function assessment in this population is vital as a result of varied vulnerability to both endogenous and xenobiotic substances. Methods A cross sectional study was conducted in Tikur Anbessa Specialized Hospital (TASH) and Teklehaymanot Health Center (THC) from November 2010 to April 2011. 117 cord blood (from newborns) and venous blood samples (from infants) were collected and analyzed using HumaStar 300. All pre-analytical, analytical and post-analytical aspects were thoroughly controlled. A robust, CLSI/ IFCC recommended, method was used for the determination of upper and lower end points covering 95% of the reference values of each analyte with respective 90% CIs using MedCalc® software. Results Combined RIs for newborns and infants were established for albumin, AST, ALP, direct bilirubin and total bilirubin to be 3.88-5.82 g/dl, 16.1-55.4U/l, 130-831U/l, <0.41 mg/dl and <1.37 mg/dl respectively. But, separated RIs were indicated for ALT and GGT as 1.2-23.1U/l and 6.94-24.8U/l ALT; and 30.6-160.7U/L and 10–28.2U/l GGT for newborns and infants respectively. Some maternal and infantile factors were identified to affect the values of analytes. Conclusion Almost all analytes were different from previously reported values for other target population of similar age group, kit insert values and adult values. So, interpretation of values of these analytes in newborns and infants of Ethiopian population sounds better to be performed by using such RIs taking the effect of

  14. What is the best strategy for investigating abnormal liver function tests in primary care? Implications from a prospective study

    PubMed Central

    Lilford, Richard J; Bentham, Louise M; Armstrong, Matthew J; Neuberger, James; Girling, Alan J

    2013-01-01

    Objective Evaluation of predictive value of liver function tests (LFTs) for the detection of liver-related disease in primary care. Design A prospective observational study. Setting 11 UK primary care practices. Participants Patients (n=1290) with an abnormal eight-panel LFT (but no previously diagnosed liver disease). Main outcome measures Patients were investigated by recording clinical features, and repeating LFTs, specific tests for individual liver diseases, and abdominal ultrasound scan. Patients were characterised as having: hepatocellular disease; biliary disease; tumours of the hepato-biliary system and none of the above. The relationship between LFT results and disease categories was evaluated by stepwise regression and logistic discrimination, with adjustment for demographic and clinical factors. True and False Positives generated by all possible LFT combinations were compared with a view towards optimising the choice of analytes in the routine LFT panel. Results Regression methods showed that alanine aminotransferase (ALT) was associated with hepatocellular disease (32 patients), while alkaline phosphatase (ALP) was associated with biliary disease (12 patients) and tumours of the hepatobiliary system (9 patients). A restricted panel of ALT and ALP was an efficient choice of analytes, comparing favourably with the complete panel of eight analytes, provided that 48 False Positives can be tolerated to obtain one additional True Positive. Repeating a complete panel in response to an abnormal reading is not the optimal strategy. Conclusions The LFT panel can be restricted to ALT and ALP when the purpose of testing is to exclude liver disease in primary care. PMID:23794594

  15. Synthesis, characterization and liver targeting evaluation of self-assembled hyaluronic acid nanoparticles functionalized with glycyrrhetinic acid.

    PubMed

    Wang, Xiaodan; Gu, Xiangqin; Wang, Huimin; Sun, Yujiao; Wu, Haiyang; Mao, Shirui

    2017-01-01

    Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6-260.7nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting.

  16. Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase.

    PubMed

    Ghafourian, T; Rashidi, M R

    2001-09-01

    Aldehyde oxidase is a molybdenum-containing enzyme distributed throughout the animal kingdom. Although this enzyme is capable of metabolizing a wide range of aldehydes and N-heterocyclic compounds, there is no reported detailed study of physicochemical requirements of the enzyme-substrate interactions. The aim of this study, therefore, was to investigate quantitatively the relationships between the kinetic constants of aldehyde oxidase-catalyzed oxidation of some phthalazine and quinazoline derivatives (as substrates) and their structural parameters. Multiple regression and stepwise regression analyses showed that polarity of phthalazines (expressed as dipole moment mu, cohesive energy density deltaT and an indicator variable for hydrogen-bond acceptor ability of R1 substituent, HBA) had a negative effect on the enzyme activity (leading to the reduction of Vmax and increase of Km). Electron withdrawing substituents in the quinazoline series are favorable for interaction with the enzyme. This finding and also the relationships of 1/Km of phthalazines with the energy of the lowest unoccupied molecular orbital and log Vmax/log Km of phthalazines with degree of bonding of the two nitrogen atoms in the molecules are consistent with the mechanism of action. The reaction involves a nucleophilic attack on an electron-deficient sp2-hybridized carbon atom and formation of an epoxide intermediate following the disruption of the aromatic structure.

  17. Liver transplant

    MedlinePlus

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  18. SU-E-J-225: Quantitative Evaluation of Rigid and Non-Rigid Motion of Liver Tumors Using Stereo Imaging During SBRT

    SciTech Connect

    Xu, Q; Hanna, G; Kubicek, G; Asbell, S; Chen, Y; LaCouture, T; Grimm, J; Pahlajani, N; Fan, J

    2014-06-01

    Purpose: To quantitatively evaluate rigid and nonrigid motion of liver tumors based on fiducial tracking in 3D by stereo imaging during CyberKnife SBRT. Methods: Twenty-five liver patients previously treated with three-fractions of SBRT were retrospectively recruited in this study. During treatment, the 3D locations of fiducials were reported by the CyberKnife system after two orthogonal kV X-ray images were taken and further validated by geometry derivations. A total of 5004 pairs of X-ray images acquired during the course of treatment for all the patients, were analyzed. For rigid motion, the rotational angles and translational shifts by aligning 3D fiducial groups in different image pairs after least-square fitting were reported. For nonrigid motion, the relative interfractional tumor shape variations were reported and correlated to the sum of inter-fiducial distances. The individual fiducial displacements were also reported after rigid corrections and without angle corrections. Results: The relative tumor volume variation indicated by the inter-fiducial distances demonstrated an increasing trend in the second (101.6±3.4%) and third fraction (101.2±5.6%) among most patients. The cause could be possibly due to radiation-induced edema. For all the patients, the translational shift was 8.1±5.7 mm, with shifts in LR, AP and SI were 2.1±2.4 mm, 2.8±2.9 mm and 6.7±5.1 mm, respectively. The greatest translation shift occurred in SI, mainly due the breathing motion of diaphragm The rotational angles were 1.1±1.7°, 1.9±2.6° and 1.6±2.2°, in roll, pitch, and yaw, respectively. The 3D fiducial displacement with rigid corrections were 0.2±0.2 mm and increased to 0.6±0.3 mm without rotational corrections. Conclusion: The fiducial locations in 3D can be precisely reconstructed from CyberKnife stereo imaging system during treatment. The fiducials provide close estimation of both rigid and nonrigid motion of .liver tumors. The reported data could be further

  19. Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver.

    PubMed

    Duarte, Filipe V; Amorim, João A; Varela, Ana T; Teodoro, João S; Gomes, Ana P; Cunha, Rodrigo A; Palmeira, Carlos M; Rolo, Anabela P

    2016-11-15

    Although adenosine A1 receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC- or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/R-induced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser(9) GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Akt-mediated Ser(9)-GSK-3β phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.

  20. Input functions for 6-[fluorine-18]Fluorodopa quantitation in parkinsonism: Comparative studies and clinical correlations

    SciTech Connect

    Takikawa, S.; Dhawan, V.; Chaly, T.; Robeson, W.; Dahl, R.; Zanzi, I.; Mandel, F.; Spetsieris, P.; Eidelberg, D.

    1994-06-01

    PET has been used to quantify striatal 6-[{sup 18}F]fluro-L-dopa (FDOPA) uptake as a measure of presynaptic dopaminergic function. Striatal FDOPA uptake rate constants (K{sub 1}) can be calculated using dynamic PET imaging with measurements of the plasma FDOPA input function determined either directly or by several estimation procedures. The authors assessed the comparative clinical utility of these methods by calculating the striato-occipital ratio (SOR) and striatal K{sub 1} values in 12 patients with mild to moderate PD and 12 age-matched normal volunteers. The plasma FDOPA time-activity curve (K{sub 1}{sup FD}); the plasma {sup 18}F time-activity curve (K{sub i}{sup P}); the occipital time-activity curve (K{sub i}{sup OCC}); and a simplified population-derived FDOPA input function (K{sub i}{sup EFD}) were used to calculate striatal K{sub i}. Mean values for all striatal K{sub i} estimates and SOR were significantly lower in the PD group. Although all measured parameters discriminated PD patients with normals, K{sub i}{sup FD} and K{sub i}{sup EFD} provided the best between-group separation. K{sub i}{sup FD}, K{sub i}{sup EFD}, and K{sub i}{sup OCC} measures correlated significantly with quantitative disease severity ratings, although K{sub i}{sup FD} predicted quantitative clinical disability most accurately. These results suggest that K{sub i}{sup FD} may be an optimal marker of the parkinsonian disease process. K{sub i}{sup EFD} may be a useful alternative to K{sub i}{sup FD} for most clinical research applications. 40 refs., 4 figs., 7 tabs.

  1. Visual-Functional Mismatch Between Coronary Angiography, Fractional Flow Reserve, and Quantitative Coronary Angiography.

    PubMed

    Safi, Morteza; Eslami, Vahid; Namazi, Mohammad Hasan; Vakili, Hossain; Saadat, Habib; Alipourparsa, Saeid; Adibi, Ali; Movahed, Mohammad Reza

    2016-12-01

    Anatomical and functional mismatches are not uncommon in the assessment of coronary lesions. The aim of this study was to identify clinical and lesion-specific factors affecting angiographic, anatomical, and functional mismatch in intermediate coronary lesions. In patients who underwent coronary angiography for clinical reasons, fractional flow reserve (FFR), and quantitative coronary angiography (QCA) analyses for intermediate stenotic lesions were performed simultaneously. Mismatches between the measured values were analyzed. A total of 95 intermediate lesions were assessed simultaneously by visual angiography, FFR, and QCA. The visual-FFR mismatch was found in 40% of the lesions while reverse visual-FFR mismatch was determined in nearly 14% of the lesions. Mismatch and reverse mismatch between FFR and QCA parameters were observed in 10 and 23% of the lesions. FFR value was significant in 32% of the lesions while visually significant stenosis was shown in 61% of the lesions. Among the visual-FFR reverse mismatch group, the prevalence of culprit lesions within the left anterior descending (LAD) was significantly higher than other vessels (p value < 0.02). There were high frequencies of angiographic, QCA, and functional mismatches in analyses of intermediate coronary lesions. LAD lesions showed the highest mismatch. Angiographic or QCA estimation of lesion severity has consistently resulted in inappropriate stenting of functionally nonsignificant lesions or undertreatment of significant lesions based on FFR.

  2. Quantitative evaluation of simulated functional brain networks in graph theoretical analysis.

    PubMed

    Lee, Won Hee; Bullmore, Ed; Frangou, Sophia

    2017-02-01

    There is increasing interest in the potential of whole-brain computational models to provide mechanistic insights into resting-state brain networks. It is therefore important to determine the degree to which computational models reproduce the topological features of empirical functional brain networks. We used empirical connectivity data derived from diffusion spectrum and resting-state functional magnetic resonance imaging data from healthy individuals. Empirical and simulated functional networks, constrained by structural connectivity, were defined based on 66 brain anatomical regions (nodes). Simulated functional data were generated using the Kuramoto model in which each anatomical region acts as a phase oscillator. Network topology was studied using graph theory in the empirical and simulated data. The difference (relative error) between graph theory measures derived from empirical and simulated data was then estimated. We found that simulated data can be used with confidence to model graph measures of global network organization at different dynamic states and highlight the sensitive dependence of the solutions obtained in simulated data on the specified connection densities. This study provides a method for the quantitative evaluation and external validation of graph theory metrics derived from simulated data that can be used to inform future study designs.

  3. Multi-functionality of computer-aided quantitative vertebral fracture morphometry analyses

    PubMed Central

    Oei, Ling; Ly, Felisia; El Saddy, Salih; Makurthou, Ater A.; Hofman, Albert; van Rooij, Frank J. A.; Uitterlinden, André G.; Zillikens, M. Carola; Rivadeneira, Fernando

    2013-01-01

    Osteoporotic vertebral fractures are an increasingly active area of research. Oftentimes assessments are performed by software-assisted quantitative morphometry. Here, we will discuss multi-functionality of these data for research purposes. A team of trained research assistants processed lateral spine radiographs from the population-based Rotterdam Study with SpineAnalyzer® software (Optasia Medical Ltd, Cheadle, UK). Next, the raw coordinate data of the two upper corners of Th5 and the two lower corners of Th12 were extracted to calculate the Cobb’s kyphosis angle. In addition, two readers performed independent manual measurements of the Cobb’s kyphosis angle between Th5 and Th12 for a sample (n=99). The mean kyphosis angle and its standard deviation were 53° and 10° for the SpineAnalyzer® software measurements and 54° and 12° by manual measurements, respectively. The Pearson’s correlation coefficient was 0.65 [95% confidence interval (CI): 0.53-0.75; P=2×10–13]. There was a substantial intraclass correlation with a coefficient of 0.64 (95% CI: 0.51-0.74). The mean difference between methods was 1° (95% CI: –2°-4°), with 95% limits of agreement of –20°-17° and there were no systematic biases. In conclusion, vertebral fracture morphometry data can be used to derive the Cobb’s kyphosis angle. Even more quantitative measures could be derived from the raw data, such as vertebral wedging, intervertebral disc space, spondylolisthesis and the lordosis angle. These measures may be of interest for research into musculoskeletal disorders such as osteoporosis, degenerative disease or Scheuermann’s disease. Large-scale studies may benefit from efficient capture of multiple quantitative measures in the spine. PMID:24273742

  4. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions.

    PubMed

    Kanagasegar, Sivalingam; Cimaz, Rolando; Kurien, Biji T; Brucato, Antonio; Scofield, R Hal

    2002-01-01

    Neonatal lupus is characterized by typical clinical features and the presence of maternal autoantibodies. Mothers can have systemic lupus erythematosus (SLE) or Sjögren's syndrome, but are commonly not affected with any clinical disease. The major clinical manifestations in the infants are cardiac, dermatological and hepatic with rare instances of hemolytic anemia, thrombocytopenia or neutropenia. We describe an infant born to a mother with anti-Ro and anti-La, who had neutropenia and mildly abnormal liver functions without other major clinical features of neonatal lupus such as cardiac or dermatological manifestations. Neutropenia improved as maternal antibody was metabolized. Antibodies from both the infant and mother bound intact neutrophils, and this binding was inhibited by 60 kDa Ro. These data imply neutropenia may be an isolated manifestation of neonatal lupus. We studied the anti-Ro antibodies of 2 other mothers who gave birth to infants with complete congenital heart block and neutropenia. Their sera also bound neutrophils. Because healthy infants do not commonly undergo complete blood counts, the incidence of neutropenia among infants of anti-Ro-positive mothers may be much higher than previously recognized. Furthermore, although other factors may contribute, these data suggest that anti-60 kDa Ro is directly involved in the pathogenesis of neutropenia.

  5. Identification of proteins suppressing the functions of oncogenic phosphatase of regenerating liver 1 and 3

    PubMed Central

    Lee, Ju-Dong; Jung, Haiyoung; Min, Sang-Hyun

    2016-01-01

    The phosphatase of regenerating liver (PRL) family, including PRL-1, PRL-2, and PRL-3, comprises protein tyrosine phosphatases whose deregulation is associated with the tumorigenesis and metastasis of many types of cancer. However, the underlying mechanism is poorly understood. In this study, aiming to increase understanding of the molecular mechanisms underlying the functions of PRL-1 and PRL-3, a yeast two-hybrid system was employed to screen for their interacting proteins. Alignment with the NCBI BLAST database revealed 12 interactive proteins: Synaptic nuclear envelope protein 2, emerin, mannose 6-phosphate receptor-binding protein 1, low-density lipoprotein receptor-related protein 10, Rab acceptor 1, tumor protein D52-like 2, selectin P ligand (SELPLG), guanylate binding protein 1, transmembrane and ubiquitin-like domain-containing 2, NADH:ubiquinone oxidoreductase subunit B8, syndecan 4 and FK506-binding protein 8 (FKBP8). These proteins are associated with cell proliferation, apoptosis, immune response, cell fate specification and metabolic process in biological process categories, and involved in various signaling pathways, including Alzheimer's disease, Parkinson's disease, Huntington's disease, hypertrophic cardiomyopathy and cell adhesion molecules. Interactions of PRL-1 with the prey proteins SELPLG and FKBP8 were confirmed by immunoprecipitation or immunostaining. Furthermore, SELPLG and FKBP8 suppressed PRL-1− or PRL-3-mediated p53 activity. Identification of the proteins interacting with PRL family proteins may provide valuable information to better understand the mechanism of PRL-mediated signal transduction in cancer and other diverse diseases. PMID:27882103

  6. Effect of green tea extracts on liver functions in Wistar rats.

    PubMed

    Bun, S S; Bun, H; Guédon, D; Rosier, C; Ollivier, E

    2006-07-01

    An herbal medicinal product (Exolise) containing as active ingredient an hydro-alcoholic extract of green tea named AR25 (standardized to 25% catechins) has been implicated in hepatic failures, leading to the withdrawal of the marketing authorization. The active ingredient of Exolise being manufactured with 80% ethanol, the question to know whether the extraction solvent could introduce some toxic components was hypothesized. Two investigations were conducted in Wistar rats to determine if repeated oral administration of different green tea extracts could corroborate the reported hepatotoxicity in humans. In a preliminary 6 week-study, experimental groups (n=9/group) received either the vehicle or a methylene chloride extract (2500 mg/kg body weight) where potential non-polar hepatotoxin(s) could be concentrated. In a second experiment (12 week-study), rats were divided in three groups (n=10/group) and treated with either the vehicle, or an aqueous extract (1400 mg/kg) or AR25 green tea extract (2000 mg/kg). Rat liver functions were assessed by serum biochemistry of hepatotoxicity markers. No sign of evidence of characteristic hepatotoxicity was found in rats treated with very high amount of different green tea extracts in these two experiments (respectively a daily dosage, which was about 900 and 80 times higher to the therapeutic daily dosage of Exolise.

  7. MINKOWSKI FUNCTIONALS FOR QUANTITATIVE ASSESSMENTS OF SHOCK-INDUCED MIXING FLOWS

    SciTech Connect

    STRELITZ, RICHARD A.; KAMM, JAMES R.

    2007-01-22

    We describe the morphological descriptors known as Minkowski Functionals (MFs) on a shock-induced mixing problem. MFs allow accurate and compact characterization of complex images. MFs characterize connectivity, size, and shape of disordered structures. They possess several desirable properties, such as additivity, smoothness, and a direct relationship to certain physical properties. The scalar MFs that we describe can be extended to a moment-based tensor form that allows more thorough image descriptions. We apply MFs to experimental data for shock-induced mixing experiments conducted at the LANL shock tube facility. Those experiments, using low Mach number shock waves in air to induce the Richtmyer-Meshkov instability on air-SF{sub 6} interfaces, provide high-resolution, quantitative planar laser-induced fluorescence (PLIF) images. We describe MFs and use them to quantify experimental PLIF images of shock-induced mixing. This method can be used as a tool fo r validation, i.e., the quantitative comparison of simulation results against experimental data.

  8. Quantitative analysis of structure and function of the cardiovascular system by roentgen-video-computer techniques.

    PubMed

    Heintzen, P H; Brennecke, R; Bürsch, J H; Hahne, H J; Lange, P E; Moldenhauer, K; Onnasch, D; Radtke, W

    1982-07-01

    A survey of the evolution of roentgen-video-computer techniques is given which was initiated by the development of videodensitometry by Wood and his associates. Following fundamental studies of the usefulness and limitations of x-ray equipment for quantitative measurements and the applicability of the Lambert-Beers law to x-ray absorption, videodensitometry has been used experimentally and clinically for various circulatory studies and has proved to be particularly valuable for the quantitation of aortic, pulmonic, and mitral valvular regurgitation. The second offspring of these techniques, so-called videometry, uses dimensional measurements from single and biplane angiocardiograms for the assessment of size, shape, and contraction pattern of the heart chambers. Volumes of the right and left ventricles can be determined clinically with a standard error of estimate below 10%. On the basis of these studies, normal values have been derived for all age groups, and they depict geometric changes of the growing heart. Cardiac index and ejection fractions proved to be age-independent biologic constants. Finally, methods for complete digital processing of video-image sequences in an off-line and real-time mode are described which allow digital image storage and documentation, dynamic background subtraction for contrast enhancement, and intravenous angiocardiography, in addition to functional imaging by parameter extraction from a matrix of pixel densitograms. Wall thickness and motion determinations, regional flow distribution measurements, and various image-composition techniques are also feasible.

  9. Quantitative investigations of axonal and dendritic arbors: development, structure, function, and pathology.

    PubMed

    Parekh, Ruchi; Ascoli, Giorgio A

    2015-06-01

    The branching structures of neurons are a long-standing focus of neuroscience. Axonal and dendritic morphology affect synaptic signaling, integration, and connectivity, and their diversity reflects the computational specialization of neural circuits. Altered neuronal morphology accompanies functional changes during development, experience, aging, and disease. Technological improvements continuously accelerate high-throughput tissue processing, image acquisition, and morphological reconstruction. Digital reconstructions of neuronal morphologies allow for complex quantitative analyses that are unattainable from raw images or two-dimensional tracings. Furthermore, digitized morphologies enable computational modeling of biophysically realistic neuronal dynamics. Additionally, reconstructions generated to address specific scientific questions have the potential for continued investigations beyond the original reason for their acquisition. Facilitating multiple reuse are repositories like NeuroMorpho.Org, which ease the sharing of reconstructions. Here, we review selected scientific literature reporting the reconstruction of axonal or dendritic morphology with diverse goals including establishment of neuronal identity, examination of physiological properties, and quantification of developmental or pathological changes. These reconstructions, deposited in NeuroMorpho.Org, have since been used by other investigators in additional research, of which we highlight representative examples. This cycle of data generation, analysis, sharing, and reuse reveals the vast potential of digital reconstructions in quantitative investigations of neuronal morphology.

  10. Quantitative mapping of functional MAO-A in the brain with radioiodinated clorgyline derivative

    SciTech Connect

    Magata, Y.; Konishi, J.; Hirata, M.

    1994-05-01

    The alteration of monoamine oxidase (MAO) activity in the brain may be associated with a number of neurological and psychiatric disorders. C-11 labeled clorgyline and deprenyl have been reported as imaging agents for MAO in the human brain. In order to expand this imaging technique to SPECT, the authors have reported the synthesis and biological evaluation of a number of iodinated clorgyline derivatives. On this basis, 2,4-dichloro-6-iodo-clorgyline analog (SIC) was selected as the most potential agent for mapping MAO-A with SPECT. In this paper, quantitative mapping of functional MAO-A in the brain with this compound was estimated. Pretreatment study with clorgyline showed the selective binding to MAO-A in the brain at 24 hr post injection of I-125-SIC. Good linear correlation between the enzyme activity and the brain up-take of I-125-SIC was observed in the pretreated study with several dose of clorgyline. Furthermore, local MAO-A activity was estimated by the autoradiographic method. High MAO-A activities were observed in midbrain and pons. This result was well agreed with another reported value obtained in vitro assay. In conclusion, this compound is indicated to be variable for quantitative analysis of MAO-A in the brain with SPECT.

  11. Induced pluripotent stem cell–derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice

    PubMed Central

    Espejel, Silvia; Roll, Garrett R.; McLaughlin, K. John; Lee, Andrew Y.; Zhang, Jenny Y.; Laird, Diana J.; Okita, Keisuke; Yamanaka, Shinya; Willenbring, Holger

    2010-01-01

    The ability to generate induced pluripotent stem (iPS) cells from a patient’s somatic cells has provided a foundation for organ regeneration without the need for immune suppression. However, it has not been established that the differentiated progeny of iPS cells can effectively reverse failure of a vital organ. Here, we examined whether iPS cell–derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice with fumarylacetoacetate hydrolase deficiency. To avoid biases resulting from random genomic integration, we used iPS cells generated without viruses. To exclude compensation by hepatocytes not derived from iPS cells, we generated chimeric mice in which all hepatocytes were iPS cell derived. In vivo analyses showed that iPS cells were intrinsically able to differentiate into fully mature hepatocytes that provided full liver function. The iPS cell–derived hepatocytes also replicated the unique proliferative capabilities of normal hepatocytes and were able to regenerate the liver after transplantation and two-thirds partial hepatectomy. Thus, our results establish the feasibility of using iPS cells generated in a clinically acceptable fashion for rapid and stable liver regeneration. PMID:20739754

  12. Subnormothermic Perfusion in the Isolated Rat Liver Preserves the Antioxidant Glutathione and Enhances the Function of the Ubiquitin Proteasome System

    PubMed Central

    Alva, Norma; Sanchez-Nuño, Sergio; Dewey, Shannamar; Gomes, Aldrin V.

    2016-01-01

    The reduction of oxidative stress is suggested to be one of the main mechanisms to explain the benefits of subnormothermic perfusion against ischemic liver damage. In this study we investigated the early cellular mechanisms induced in isolated rat livers after 15 min perfusion at temperatures ranging from normothermia (37°C) to subnormothermia (26°C and 22°C). Subnormothermic perfusion was found to maintain hepatic viability. Perfusion at 22°C raised reduced glutathione levels and the activity of glutathione reductase; however, lipid and protein oxidation still occurred as determined by malondialdehyde, 4-hydroxynonenal-protein adducts, and advanced oxidation protein products. In livers perfused at 22°C the lysosomal and ubiquitin proteasome system (UPS) were both activated. The 26S chymotrypsin-like (β5) proteasome activity was significantly increased in the 26°C (46%) and 22°C (42%) groups. The increased proteasome activity may be due to increased Rpt6 Ser120 phosphorylation, which is known to enhance 26S proteasome activity. Together, our results indicate that the early events produced by subnormothermic perfusion in the liver can induce oxidative stress concomitantly with antioxidant glutathione preservation and enhanced function of the lysosomal and UPS systems. Thus, a brief hypothermia could trigger antioxidant mechanisms and may be functioning as a preconditioning stimulus. PMID:27800122

  13. The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis.

    PubMed

    Cheng, Yahui; Tian, Yuanyao; Xia, Jialu; Wu, Xiaoqin; Yang, Yang; Li, Xiaofeng; Huang, Cheng; Meng, Xiaoming; Ma, Taotao; Li, Jun

    2017-02-15

    Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis.

  14. The Analysis of Polymorphism of Alcohol Dehydrogenase 3 (ADH3) Gene and Influence of Liver Function Status in Indonesia.

    PubMed

    Suhartini; Mustofa; Nurhantari, Yudha; Rianto, Bambang Udji Djoko

    2017-01-31

    Indonesian culture actually has no historical record of behaviors in consuming alcohol, but there are many recent reports of alcohol abuse among Asian people involving their traditional drink. In genotype studies, the damage of the liver caused by consuming alcohol is influenced by the presence of the polymorphism enzyme gene. The lack of study regarding such topic is a signal to further investigate ADH3 gene distribution and its effect on liver function status. The total of 197 research subjects of Javanese descent received alcohol dehydrogenase 3 (ADH3) genetic polymorphism and liver status tests in the city of Yogyakarta, Indonesian. An analytical study with a cross-sectional design was then conducted on the subjects, with the resulting isolated DNAs amplified through polymerase chain reaction (PCR). The genotype of ADH3 was determined by means of restriction fragment length polymorphism (RFLP) using Ssp1 restricting enzyme. Liver function status was assessed by measuring serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and gamma glutamyl transferase (GGT) using a photometric system. Gene types of ADH3*1 (2.1%), ADH3*2 (82.7%) and ADH3*1/3*2 (15.2%) on the subjects were concluded, finding that there is no difference between the gender. In conclusion most of the ADH3 gene polymorphism of the subjects were ADH3*2 (82.7%). The influence of genetic polymorphisms on the status of liver function in the subjects showed significant difference according to GGT measurement, but the same cannot be said on the other two values measuring SGOT and SGPT.

  15. Ethanol oxidation and the inhibition by drugs in human liver, stomach and small intestine: Quantitative assessment with numerical organ modeling of alcohol dehydrogenase isozymes.

    PubMed

    Chi, Yu-Chou; Lee, Shou-Lun; Lai, Ching-Long; Lee, Yung-Pin; Lee, Shiao-Pieng; Chiang, Chien-Ping; Yin, Shih-Jiun

    2016-10-25

    Alcohol dehydrogenase (ADH) is the principal enzyme responsible for metabolism of ethanol. Human ADH constitutes a complex isozyme family with striking variations in kinetic function and tissue distribution. Liver and gastrointestinal tract are the major sites for first-pass metabolism (FPM). Their relative contributions to alcohol FPM and degrees of the inhibitions by aspirin and its metabolite salicylate, acetaminophen and cimetidine remain controversial. To address this issue, mathematical organ modeling of ethanol-oxidizing activities in target tissues and that of the ethanol-drug interactions were constructed by linear combination of the corresponding numerical rate equations of tissue constituent ADH isozymes with the documented isozyme protein contents, kinetic parameters for ethanol oxidation and the drug inhibitions of ADH isozymes/allozymes that were determined in 0.1 M sodium phosphate at pH 7.5 and 25 °C containing 0.5 mM NAD(+). The organ simulations reveal that the ADH activities in mucosae of the stomach, duodenum and jejunum with ADH1C*1/*1 genotype are less than 1%, respectively, that of the ADH1B*1/*1-ADH1C*1/*1 liver at 1-200 mM ethanol, indicating that liver is major site of the FPM. The apparent hepatic KM and Vmax for ethanol oxidation are simulated to be 0.093 ± 0.019 mM and 4.0 ± 0.1 mmol/min, respectively. At 95% clearance in liver, the logarithmic average sinusoidal ethanol concentration is determined to be 0.80 mM in accordance with the flow-limited gradient perfusion model. The organ simulations indicate that higher therapeutic acetaminophen (0.5 mM) inhibits 16% of ADH1B*1/*1 hepatic ADH activity at 2-20 mM ethanol and that therapeutic salicylate (1.5 mM) inhibits 30-31% of the ADH1B*2/*2 activity, suggesting potential significant inhibitions of ethanol FPM in these allelotypes. The result provides systematic evaluations and predictions by computer simulation on potential ethanol FPM in target tissues and hepatic

  16. Targeted Enlargement of Aptamer Functionalized Gold Nanoparticles for Quantitative Protein Analysis

    PubMed Central

    Li, Feng; Li, Jingjing; Tang, Yanan; Wang, Chuan; Li, Xing-Fang; Le, X. Chris

    2016-01-01

    The ability to selectively amplify the detection signals for targets over interferences is crucial when analyzing proteins in a complicated sample matrix. Here, we describe a targeted enlargement strategy that can amplify the light-scattering signal from aptamer-functionalized gold nanoparticles (Apt-AuNP) with high specificity for quantitative protein analysis. This strategy is achieved by labeling target proteins with competitively protected Apt-AuNP probes and enlarging the probes with gold enhancement. This competitive protection strategy could effectively eliminate nonspecific protein adsorptions from a sample matrix, leading to a highly specific labeling of the target protein. As a result, the subsequent amplification of the light-scattering signal by gold enhancement only occurs in the presence of the target protein. This strategy was successfully demonstrated by analyzing human α-thrombin in human serum samples in a Western blot format. PMID:28248252

  17. Quantitative assessment of electrostatic embedding in Density Functional Theory calculations of biomolecular systems

    SciTech Connect

    Fattebert, J; Law, R J; Bennion, B; Lau, E Y; Schwegler, E; Lightstone, F C

    2009-04-24

    We evaluate the accuracy of density functional theory quantum calculations of biomolecular subsystems using a simple electrostatic embedding scheme. Our scheme is based on dividing the system of interest into a primary and secondary subsystem. A finite difference discretization of the Kohn-Sham equations is used for the primary subsystem, while its electrostatic environment is modeled with a simple one-electron potential. Force-field atomic partial charges are used to generate smeared Gaussian charge densities and to model the secondary subsystem. We illustrate the utility of this approach with calculations of truncated dipeptide chains. We analyze quantitatively the accuracy of this approach by calculating atomic forces and comparing results with fullQMcalculations. The impact of the choice made in terminating dangling bonds at the frontier of the QM region is also investigated.

  18. SUePDF: a program to obtain quantitative pair distribution functions from electron diffraction data

    PubMed Central

    Tran, Dung Trung; Svensson, Gunnar; Tai, Cheuk-Wai

    2017-01-01

    SUePDF is a graphical user interface program written in MATLAB to achieve quantitative pair distribution functions (PDFs) from electron diffraction data. The program facilitates structural studies of amorphous materials and small nanoparticles using electron diffraction data from transmission electron microscopes. It is based on the physics of electron scattering as well as the total scattering methodology. A method of background modeling is introduced to treat the intensity tail of the direct beam, inelastic scattering and incoherent multiple scattering. Kinematical electron scattering intensity is scaled using the electron scattering factors. The PDFs obtained after Fourier transforms are normalized with respect to number density, nanoparticle form factor and the non-negativity of probability density. SUePDF is distributed as free software for academic users. PMID:28190994

  19. Comparison of quantitative real-time polymerase chain reaction with NanoString® methodology using adipose and liver tissues from rats fed seaweed.

    PubMed

    Bentley-Hewitt, Kerry L; Hedderley, Duncan I; Monro, John; Martell, Sheridan; Smith, Hannah; Mishra, Suman

    2016-05-25

    Experimental methods are constantly being improved by new technology. Recently a new technology, NanoString®, has been introduced to the market for the analysis of gene expression. Our experiments used adipose and liver samples collected from a rat feeding trial to explore gene expression changes resulting from a diet of 7.5% seaweed. Both quantitative real-time polymerase chain reaction (qPCR) and NanoString methods were employed to look at expression of genes related to fat and glucose metabolism and this paper compares results from both methods. We conclude that NanoString offers a valuable alternative to qPCR and our data suggest that results are more accurate because of the reduced sample handling and direct quantification of gene copy number without the need for enzymatic amplification. However, we have highlighted a potential challenge for both methods, which needs to be addressed when designing primers or probes. We suggest a literature search for known splice variants of a particular gene to be completed so that primers or probes can be designed that do not span exons which may be affected by alternative gene sequences.

  20. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues.

    PubMed

    Bruderer, Roland; Bernhardt, Oliver M; Gandhi, Tejas; Miladinović, Saša M; Cheng, Lin-Yang; Messner, Simon; Ehrenberger, Tobias; Zanotelli, Vito; Butscheid, Yulia; Escher, Claudia; Vitek, Olga; Rinner, Oliver; Reiter, Lukas

    2015-05-01

    The data-independent acquisition (DIA) approach has recently been introduced as a novel mass spectrometric method that promises to combine the high content aspect of shotgun proteomics with the reproducibility and precision of selected reaction monitoring. Here, we evaluate, whether SWATH-MS type DIA effectively translates into a better protein profiling as compared with the established shotgun proteomics. We implemented a novel DIA method on the widely used Orbitrap platform and used retention-time-normalized (iRT) spectral libraries for targeted data extraction using Spectronaut. We call this combination hyper reaction monitoring (HRM). Using a controlled sample set, we show that HRM outperformed shotgun proteomics both in the number of consistently identified peptides across multiple measurements and quantification of differentially abundant proteins. The reproducibility of HRM in peptide detection was above 98%, resulting in quasi complete data sets compared with 49% of shotgun proteomics. Utilizing HRM, we profiled acetaminophen (APAP)(1)-treated three-dimensional human liver microtissues. An early onset of relevant proteome changes was revealed at subtoxic doses of APAP. Further, we detected and quantified for the first time human NAPQI-protein adducts that might be relevant for the toxicity of APAP. The adducts were identified on four mitochondrial oxidative stress related proteins (GATM, PARK7, PRDX6, and VDAC2) and two other proteins (ANXA2 and FTCD). Our findings imply that DIA should be the preferred method for quantitative protein profiling.

  1. Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues*

    PubMed Central

    Bruderer, Roland; Bernhardt, Oliver M.; Gandhi, Tejas; Miladinović, Saša M.; Cheng, Lin-Yang; Messner, Simon; Ehrenberger, Tobias; Zanotelli, Vito; Butscheid, Yulia; Escher, Claudia; Vitek, Olga; Rinner, Oliver; Reiter, Lukas

    2015-01-01

    The data-independent acquisition (DIA) approach has recently been introduced as a novel mass spectrometric method that promises to combine the high content aspect of shotgun proteomics with the reproducibility and precision of selected reaction monitoring. Here, we evaluate, whether SWATH-MS type DIA effectively translates into a better protein profiling as compared with the established shotgun proteomics. We implemented a novel DIA method on the widely used Orbitrap platform and used retention-time-normalized (iRT) spectral libraries for targeted data extraction using Spectronaut. We call this combination hyper reaction monitoring (HRM). Using a controlled sample set, we show that HRM outperformed shotgun proteomics both in the number of consistently identified peptides across multiple measurements and quantification of differentially abundant proteins. The reproducibility of HRM in peptide detection was above 98%, resulting in quasi complete data sets compared with 49% of shotgun proteomics. Utilizing HRM, we profiled acetaminophen (APAP)1-treated three-dimensional human liver microtissues. An early onset of relevant proteome changes was revealed at subtoxic doses of APAP. Further, we detected and quantified for the first time human NAPQI-protein adducts that might be relevant for the toxicity of APAP. The adducts were identified on four mitochondrial oxidative stress related proteins (GATM, PARK7, PRDX6, and VDAC2) and two other proteins (ANXA2 and FTCD). Our findings imply that DIA should be the preferred method for quantitative protein profiling. PMID:25724911

  2. Patterns and Predictors of Sexual Function After Liver Donation: the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

    PubMed Central

    DiMartini, AF.; Dew, MA.; Butt, Z.; Simpson, MA.; Ladner, DP.; Smith, AR.; Hill-Callahan, P.; Gillespie, BW.

    2015-01-01

    Although sexual functioning is an important facet of living donor quality of life, it has not received extensive evaluation in this population. Using data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we examined donor sexual functioning across the donation process from the predonation evaluation to 3 months and 1 year postdonation. Donors (n=208) and a comparison group of non-donors (n=155) completed self-reported surveys with specific questions on sexual desire, satisfaction, orgasm, and (for men) erectile function. Across the three time points, donor sexual functioning was lower at the evaluation phase and 3 months postdonation than at one year postdonation. In the early recovery period, abdominal pain was associated with difficulty reaching orgasm (OR = 3.98, 95% CI 1.30–12.16), concerns over appearance with lower sexual desire (OR = 4.14, 95% CI 1.02–16.79), and not feeling back to normal was associated with dissatisfaction with sexual life (OR 3.58, 95% CI 1.43–8.99). Efforts to educate donors before the surgery and prepare them for the early recovery phase may improve recovery and reduce distress regarding sexual functioning. PMID:25779554

  3. Pleiotropy Analysis of Quantitative Traits at Gene Level by Multivariate Functional Linear Models

    PubMed Central

    Wang, Yifan; Liu, Aiyi; Mills, James L.; Boehnke, Michael; Wilson, Alexander F.; Bailey-Wilson, Joan E.; Xiong, Momiao; Wu, Colin O.; Fan, Ruzong

    2015-01-01

    In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F-distribution tests based on Pillai–Bartlett trace, Hotelling–Lawley trace, and Wilks’s Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and optimal sequence kernel association test (SKAT-O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F-distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and SKAT-O for the three biochemical traits. The approximate F-distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT-O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT-O in the univariate case. PMID:25809955

  4. Quantitative muscle strength assessment in duchenne muscular dystrophy: longitudinal study and correlation with functional measures

    PubMed Central

    2012-01-01

    Background The aim of this study was to perform a longitudinal assessment using Quantitative Muscle Testing (QMT) in a cohort of ambulant boys affected by Duchenne muscular dystrophy (DMD) and to correlate the results of QMT with functional measures. This study is to date the most thorough long-term evaluation of QMT in a cohort of DMD patients correlated with other measures, such as the North Star Ambulatory Assessment (NSAA) or thee 6-min walk test (6MWT). Methods This is a single centre, prospective, non-randomised, study assessing QMT using the Kin Com® 125 machine in a study cohort of 28 ambulant DMD boys, aged 5 to 12 years. This cohort was assessed longitudinally over a 12 months period of time with 3 monthly assessments for QMT and with assessment of functional abilities, using the NSAA and the 6MWT at baseline and at 12 months only. QMT was also used in a control group of 13 healthy age-matched boys examined at baseline and at 12 months. Results There was an increase in QMT over 12 months in boys below the age of 7.5 years while in boys above the age of 7.5 years, QMT showed a significant decrease. All the average one-year changes were significantly different than those experienced by healthy controls. We also found a good correlation between quantitative tests and the other measures that was more obvious in the stronger children. Conclusion Our longitudinal data using QMT in a cohort of DMD patients suggest that this could be used as an additional tool to monitor changes, providing additional information on segmental strength. PMID:22974002

  5. Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models.

    PubMed

    Wang, Yifan; Liu, Aiyi; Mills, James L; Boehnke, Michael; Wilson, Alexander F; Bailey-Wilson, Joan E; Xiong, Momiao; Wu, Colin O; Fan, Ruzong

    2015-05-01

    In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F-distribution tests based on Pillai-Bartlett trace, Hotelling-Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and optimal sequence kernel association test (SKAT-O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F-distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and SKAT-O for the three biochemical traits. The approximate F-distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT-O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT-O in the univariate case.

  6. Concentrations of Gd-BOPTA in cholestatic fatty rat livers: role of transport functions through membrane proteins.

    PubMed

    Pastor, Catherine M; Wissmeyer, Michael; Millet, Philippe

    2013-01-01

    Gd-BOPTA (gadobenate dimeglumine) is a magnetic resonance (MR) contrast agent that, after i.v. administration, distributes within the extracellular space, enters rat hepatocytes through the sinusoidal transporters organic anion transporting peptides (Oatps) and is excreted unchanged into bile through the multidrug resistance-associated protein 2 (Mrp2). It is unclear how the hepatobiliary contrast agent would accumulate in cholestatic fatty livers from obese rats with bile flow impairment. Indeed, the expression of both Oatps and Mrp2 transporters is decreased in cholestatic hepatocytes. To assess this question, we measured on-line the hepatic concentrations of ¹⁵³Gd-BOPTA with a gamma probe placed over perfused rat livers. During the perfusion of ¹⁵³Gd-BOPTA, we obtained a similar maximal hepatic concentration in normal and fatty livers despite the decreased expression and function of membrane transporters in fatty livers. By pharmacokinetic modeling and mathematical simulations, we show how changes of transport into and out of hepatocytes modify the concentrations of ¹⁵³Gd-BOPTA within hepatocytes. Mathematical simulations help to understand how each parameter (entry into hepatocytes, bile excretion, or efflux back to sinusoids) interferes with the hepatic concentrations. The hepatic concentrations of ¹⁵³Gd-BOPTA within hepatocytes rely on the entry into hepatocytes through the sinusoidal membrane and on two paths of exit, the efflux back to sinusoids and the elimination into bile. Understanding how ¹⁵³Gd-BOPTA accumulates in hepatocytes is then complex. However, such understanding is important to analyze liver imaging with hepatobiliary contrast agents in cholestatic fatty livers.

  7. A miniaturized technique for assessing protein thermodynamics and function using fast determination of quantitative cysteine reactivity.

    PubMed

    Isom, Daniel G; Marguet, Philippe R; Oas, Terrence G; Hellinga, Homme W

    2011-04-01

    Protein thermodynamic stability is a fundamental physical characteristic that determines biological function. Furthermore, alteration of thermodynamic stability by macromolecular interactions or biochemical modifications is a powerful tool for assessing the relationship between protein structure, stability, and biological function. High-throughput approaches for quantifying protein stability are beginning to emerge that enable thermodynamic measurements on small amounts of material, in short periods of time, and using readily accessible instrumentation. Here we present such a method, fast quantitative cysteine reactivity, which exploits the linkage between protein stability, sidechain protection by protein structure, and structural dynamics to characterize the thermodynamic and kinetic properties of proteins. In this approach, the reaction of a protected cysteine and thiol-reactive fluorogenic indicator is monitored over a gradient of temperatures after a short incubation time. These labeling data can be used to determine the midpoint of thermal unfolding, measure the temperature dependence of protein stability, quantify ligand-binding affinity, and, under certain conditions, estimate folding rate constants. Here, we demonstrate the fQCR method by characterizing these thermodynamic and kinetic properties for variants of Staphylococcal nuclease and E. coli ribose-binding protein engineered to contain single, protected cysteines. These straightforward, information-rich experiments are likely to find applications in protein engineering and functional genomics.

  8. Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers

    PubMed Central

    Arumughan, Anup; Roske, Yvette; Barth, Carolin; Forero, Laura Lleras; Bravo-Rodriguez, Kenny; Redel, Alexandra; Kostova, Simona; McShane, Erik; Opitz, Robert; Faelber, Katja; Rau, Kirstin; Mielke, Thorsten; Daumke, Oliver; Selbach, Matthias; Sanchez-Garcia, Elsa; Rocks, Oliver; Panáková, Daniela; Heinemann, Udo; Wanker, Erich E.

    2016-01-01

    Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity. PMID:27762274

  9. [A scale for the quantitative evaluation of male copulative function (the MCF scale)].

    PubMed

    Loran, O B; Segal, A S

    1998-01-01

    A scale of total quantitation of male copulative function (MCF) is offered to facilitate the diagnosis and monitoring of MCF abnormalities, control of MCF correction. The scale is based on normal values provided by statistical data on sexual activity of males and its age-related changes. The patient is asked to answer 13 questions of the questionnaire listed under the numbers I-XIII. Each question has 6 variants of answer having the score 0 to 5. The patient is to choose one variant and write down his choice. Such MCF scale is able to identify both sexual disorder and defects in components of the copulative cycle. The scale was applied 89 times to study sexual function of 68 males aged 24-77 years. The scale findings and those of a comprehensive clinical examination coincided. The scale was found useful in evaluation of male copulative function as a whole and by components, for analysis of the detected disorders, differentiation between psychogenic factor and primarily organic one, for ascertaining attitude of the patient to his sexual dysfunction.

  10. Modelling passive diastolic mechanics with quantitative MRI of cardiac structure and function.

    PubMed

    Wang, Vicky Y; Lam, H I; Ennis, Daniel B; Cowan, Brett R; Young, Alistair A; Nash, Martyn P

    2009-10-01

    The majority of patients with clinically diagnosed heart failure have normal systolic pump function and are commonly categorized as suffering from diastolic heart failure. The left ventricle (LV) remodels its structure and function to adapt to pathophysiological changes in geometry and loading conditions, which in turn can alter the passive ventricular mechanics. In order to better understand passive ventricular mechanics, a LV finite element (FE) model was customized to geometric data segmented from in vivo tagged magnetic resonance images (MRI) data and myofibre orientation derived from ex vivo diffusion tensor MRI (DTMRI) of a canine heart using nonlinear finite element fitting techniques. MRI tissue tagging enables quantitative evaluation of cardiac mechanical function with high spatial and temporal resolution, whilst the direction of maximum water diffusion in each voxel of a DTMRI directly corresponds to the local myocardial fibre orientation. Due to differences in myocardial geometry between in vivo and ex vivo imaging, myofibre orientations were mapped into the geometric FE model using host mesh fitting (a free form deformation technique). Pressure recordings, temporally synchronized to the tagging data, were used as the loading constraints to simulate the LV deformation during diastole. Simulation of diastolic LV mechanics allowed us to estimate the stiffness of the passive LV myocardium based on kinematic data obtained from tagged MRI. Integrated physiological modelling of this kind will allow more insight into mechanics of the LV on an individualized basis, thereby improving our understanding of the underlying structural basis of mechanical dysfunction under pathological conditions.

  11. Functional analysis and quantitative determination of the expression profile of human parvovirus B19.

    PubMed

    Bonvicini, Francesca; Filippone, Claudia; Manaresi, Elisabetta; Zerbini, Marialuisa; Musiani, Monica; Gallinella, Giorgio

    2008-11-25

    Comprehension of the pathogenetic potential of human parvovirus B19 requires the definition of the complete spectrum of cellular tropism and a functional analysis of the viral genome in infected cells. In this study, we carried out a systematic functional analysis of B19 virus genome in the course of infection of susceptible bone marrow mononuclear cells and myeloblastoid UT7/EpoS1 cells, in terms of dynamics of nucleic acid synthesis. A PCR array was designed and a comprehensive analysis was performed by quantitative PCR and RT-PCR, yielding extended information on the presence and abundance of the diverse classes of viral nucleic acids, on the temporal regulation of genome expression and on its relationship with the cell cycle. The analysis performed indicate that the synthesis of viral nucleic acids is correlated to the progression through the S phase of the cell cycle, that an extended pattern of transcriptional activity occurs throughout the course of infection, with a maximal rate of transcription preceding the onset of S-phase dependent replication of the viral genome, and that utilization of transcript processing signals is relatively constant throughout the course of infection. The information obtained led to the definition of a unified model of functional and expression profiling of parvovirus B19 genome.

  12. Quantitative genetics of shape in cricket wings: developmental integration in a functional structure.

    PubMed

    Klingenberg, Christian Peter; Debat, Vincent; Roff, Derek A

    2010-10-01

    The role of developmental and genetic integration for evolution is contentious. One hypothesis states that integration acts as a constraint on evolution, whereas an alternative is that developmental and genetic systems evolve to match the functional modularity of organisms. This study examined a morphological structure, the cricket wing, where developmental and functional modules are discordant, making it possible to distinguish the two alternatives. Wing shape was characterized with geometric morphometrics, quantitative genetic information was extracted using a full-sibling breeding design, and patterns of developmental integration were inferred from fluctuating asymmetry of wing shape. The patterns of genetic, phenotypic, and developmental integration were clearly similar, but not identical. Heritabilities for different shape variables varied widely, but no shape variables were devoid of genetic variation. Simulated selection for specific shape changes produced predicted responses with marked deflections due to the genetic covariance structure. Three hypotheses of modularity according to the wing structures involved in sound production were inconsistent with the genetic, phenotypic, or developmental covariance structure. Instead, there appears to be strong integration throughout the wing. The hypothesis that genetic and developmental integration evolve to match functional modularity can therefore be rejected for this example.

  13. Alcohol and aldehyde dehydrogenases: structures of the human liver enzymes, functional properties and evolutionary aspects.

    PubMed

    Jörnvall, H; Hempel, J; von Bahr-Lindström, H; Höög, J O; Vallee, B L

    1987-01-01

    polyol dehydrogenases are encountered. The two isozymes of human aldehyde dehydrogenase also exhibit considerable differences, with only 68% structural identity. The results show an early divergence into isozymes before the man/horse species radiation. Cys-302 is a functionally important residue and is located in one of the regions with conserved hydrophobic properties. Other regions with large differences in hydropathic properties may explain the absence of cross-hybridizing isozyme forms of human liver aldehyde dehydrogenase.

  14. Quantitative Functional Imaging Using Dynamic Positron Computed Tomography and Rapid Parameter Estimation Techniques

    NASA Astrophysics Data System (ADS)

    Koeppe, Robert Allen

    Positron computed tomography (PCT) is a diagnostic imaging technique that provides both three dimensional imaging capability and quantitative measurements of local tissue radioactivity concentrations in vivo. This allows the development of non-invasive methods that employ the principles of tracer kinetics for determining physiological properties such as mass specific blood flow, tissue pH, and rates of substrate transport or utilization. A physiologically based, two-compartment tracer kinetic model was derived to mathematically describe the exchange of a radioindicator between blood and tissue. The model was adapted for use with dynamic sequences of data acquired with a positron tomograph. Rapid estimation techniques were implemented to produce functional images of the model parameters by analyzing each individual pixel sequence of the image data. A detailed analysis of the performance characteristics of three different parameter estimation schemes was performed. The analysis included examination of errors caused by statistical uncertainties in the measured data, errors in the timing of the data, and errors caused by violation of various assumptions of the tracer kinetic model. Two specific radioindicators were investigated. ('18)F -fluoromethane, an inert freely diffusible gas, was used for local quantitative determinations of both cerebral blood flow and tissue:blood partition coefficient. A method was developed that did not require direct sampling of arterial blood for the absolute scaling of flow values. The arterial input concentration time course was obtained by assuming that the alveolar or end-tidal expired breath radioactivity concentration is proportional to the arterial blood concentration. The scale of the input function was obtained from a series of venous blood concentration measurements. The method of absolute scaling using venous samples was validated in four studies, performed on normal volunteers, in which directly measured arterial concentrations

  15. MicroRNA function in the profibrogenic interplay upon chronic liver disease.

    PubMed

    Huang, Jia; Yu, Xiaojie; Fries, Jochen W U; Zhang, Li'ang; Odenthal, Margarete

    2014-05-27

    In chronic liver disease leading to fibrosis, hepatic stellate cells (HSC) differentiate into myofibroblasts. Myofibroblastic HSC have taken center stage during liver fibrogenesis, due to their remarkable synthesis of extracellular matrix proteins, their secretion of profibrogenic mediators and their contribution to hypertension, due to elevated contractility. MicroRNAs (miRNAs) are small, noncoding RNA molecules of 19-24 nucleotides in length. By either RNA interference or inhibition of translational initiation and elongation, each miRNA is able to inhibit the gene expression of a wide panel of targeted transcripts. Recently, it was shown that altered miRNA patterns after chronic liver disease highly affect the progression of fibrosis by their potential to target the expression of extracellular matrix proteins and the synthesis of mediators of profibrogenic pathways. Here, we underline the role of miRNAs in the interplay of the profibrogenic cell communication pathways upon myofibroblastic differentiation of hepatic stellate cells in the chronically injured liver.

  16. Antifibrotic activity of galangin, a novel function evaluated in animal liver fibrosis model.

    PubMed

    Wang, Xinhui; Gong, Guoqing; Yang, Wenhui; Li, Yunzhan; Jiang, Meiling; Li, Linlin

    2013-09-01

    This study aimed to investigate the effects of galangin on liver fibrosis in rats induced by subcutaneous injection of carbon tetrachloride (CCl4). The administration of CCl4 to rats for 12 weeks caused significant increase of hyaluronic acid, laminin, alanine transaminase, aspartate transaminase and decrease of total protein, albumin in serum, while the influences could be reversed by galangin. Galangin markedly reduced hepatic malondialdehyde, hydroxyproline concentration, increased activities of liver superoxide dismutase, glutathione peroxidase compared with CCl4-treated rats. Histological results indicated that galangin alleviated liver damage. In addition, treatment with galangin significantly down-regulated expressions of α-smooth muscle actin and transforming growth factor β1. These results suggest galangin can inhibit liver fibrosis induced by CCl4 in rats, which was probably associated with its effect on removing oxygen free radicals, decreasing lipid peroxidation, as well as inhibiting hepatic stellate cells activation and proliferation.

  17. [Change in histone proteins in rat liver chromatin during exposure of the animal to functional stress].

    PubMed

    Panin, L E; Svechnikova, I G; Maianskaia, N N

    1996-01-01

    Pattern of rat liver histones at intensive physical exercises with preliminary injection of lysosomotropic drugs was studied by method of electrophoresis in PAAG. Elevation of the acetylated forms of histone H4 was revealed. The increased proteolysis of lysine-rich histones (H1, H2A, H2B) was shown in swimming rats previously stimulated by prodigiosan. The possible role of lysosomal proteinases of liver cells in mechanism of chromatine activation is discussed.

  18. New perspectives in biomonitoring liver function by means of serum bile acids: experimental and hypothetical biochemical basis.

    PubMed Central

    Franco, G

    1991-01-01

    The functional activity of the liver and the variety of its responses to injury makes the choice of appropriate tests of function a difficult task. Because of the highly efficient uptake of bile acids by the normal hepatocyte, the determination of serum bile acid (SBA) concentration has been proposed as a test to detect early changes of liver function not associated with cytotoxicity. Several biomonitoring studies have been carried out on subjects occupationally exposed to hepatotoxic substances, by evaluating SBAs as indicators of early liver dysfunction. Even though these studies are not exactly comparable because of the different protocols adopted, most of them show a significant increase in SBA concentrations among the exposed subjects compared with unexposed controls. Furthermore, higher prevalences of subjects with abnormal SBA concentrations occur in those exposed to mixtures of organic solvents. Increased SBA concentrations among the subjects exposed to various xenobiotics have been explained by assuming a change in function of hepatocytes. As regards the nature of the mechanisms involved in the increase in SBA concentrations, recent experimental observations pointed out that some chlorinated aliphatics were able to inhibit cell membrane ATPases and alter cytosolic calcium homeostasis. The lack of any relation, however, between exposure and SBA concentrations remains an important point to clarify and at present prevents the use of measurement of SBA concentrations as an index of effect. PMID:1878313

  19. Modification of the association of bisphenol A with abnormal liver function by polymorphisms of oxidative stress-related genes.

    PubMed

    Kim, Jin Hee; Lee, Mee-Ri; Hong, Yun-Chul

    2016-05-01

    Some studies suggested oxidative stress as a possible mechanism for the relation between exposure to bisphenol A (BPA) and liver damage. Therefore, we evaluated modification of genetic polymorphisms of cyclooxygenase 2 (COX2 or PTGS2), epoxide hydrolase 1 (EPHX1), catalase (CAT), and superoxide dismutase 2 (SOD2 or MnSOD), which are oxidative stress-related genes, on the relation between exposure to BPA and liver function in the elderly. We assessed the association of visit-to-visit variations in BPA exposure with abnormal liver function by each genotype or haplotype after controlling for age, sex, BMI, alcohol consumption, exercise, urinary cotinine levels, and low density lipoprotein cholesterol using a GLIMMIX model. A significant association of BPA with abnormal liver function was observed only in participants with COX2 GG genotype at rs5277 (odds ratio (OR)=3.04 and p=0.0231), CAT genotype at rs769218 (OR=4.16 and p=0.0356), CAT CT genotype at rs769217 (OR=4.19 and p=0.0348), SOD2 TT genotype at rs4880 (OR=2.59 and p=0.0438), or SOD2 GG genotype at rs2758331 (OR=2.57 and p=0.0457). Moreover, we also found higher OR values in participants with a pair of G-G haplotypes for COX2 (OR=2.81 and p=0.0384), G-C-A haplotype for EPHX1 (OR=4.63 and p=0.0654), A-T haplotype for CAT (OR=4.48 and p=0.0245), or T-G-A haplotype for SOD2 (OR=2.91 and p=0.0491) compared with those with the other pair of haplotypes for each gene. Furthermore, the risk score composed of 4 risky pair of haplotypes showed interactive effect with BPA on abnormal liver function (p=0.0057). Our study results suggest that genetic polymorphisms of COX2, EPHX1, CAT, and SOD2 modify the association of BPA with liver function.

  20. Structural and functional quantitative susceptibility mapping from standard fMRI studies.

    PubMed

    Sun, H; Seres, P; Wilman, A H

    2017-04-01

    Standard functional MRI (fMRI), which includes resting-state or paradigm-driven designs, is widely used in studies of brain function, aging, and disease. These fMRI studies typically use two-dimensional gradient echo-planar imaging, which inherently contains phase data that enables quantitative susceptibility mapping (QSM). This work focuses on the dual value of QSM within fMRI studies, by providing both a localized analysis of functional changes in activated tissue, and iron-sensitive structural maps in deep grey matter (DGM). Using a visual paradigm fMRI study on healthy volunteers at clinical (1.5 T) and high field strength (4.7 T), we perform functional analysis of magnitude and QSM time series, and at the same time harness structural QSM of iron-rich DGM, including globus pallidus, putamen, caudate head, substantia nigra, and red nucleus. The effects of fMRI spatial resolution and time series variation on structural DGM QSM are investigated. Our results indicate that structural DGM QSM is feasible within existing fMRI studies, provided that the voxel dimensions are equal to or less than 3 mm, with higher resolutions preferred. The mean DGM QSM values were about 40 to 220 ppb, while the interquartile ranges of the DGM QSM time series varied from about 3 to 9 ppb, depending on structure and resolution. In contrast, the peak voxel functional QSM (fQSM) changes in activated visual cortex ranged from about -10 to -30 ppb, and functional clusters were consistently smaller on QSM than magnitude fMRI. Mean-level DGM QSM of the time series was successfully extracted in all cases, while fQSM results were more prone to residual background fields and showed less functional change compared with standard magnitude fMRI. Under the conditions prescribed, standard fMRI studies may be used for robust mean-level DGM QSM, enabling study of DGM iron accumulation, in addition to functional analysis. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Renal function after low central venous pressure-assisted liver resection: assessment of 2116 cases

    PubMed Central

    Correa-Gallego, Camilo; Berman, Alexandra; Denis, Stephanie C; Langdon-Embry, Liana; O'Connor, David; Arslan-Carlon, Vittoria; Kingham, T Peter; D'Angelica, Michael I; Allen, Peter J; Fong, Yuman; DeMatteo, Ronald P; Jarnagin, William R; Melendez, Jose; Fischer, Mary

    2015-01-01

    Objectives Low central venous pressure (LCVP)-assisted hepatectomy is associated with decreased blood loss and lower transfusion rates. Concerns about its impact on renal function have prevented widespread application. This study was conducted to review the dynamics of renal function after LCVP-assisted hepatectomy. Methods A retrospective analysis of a prospective surgical database was carried out. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation. The RIFLE (risk–injury–failure–loss–end-stage) criteria were used to define postoperative biochemical acute kidney injury (bAKI). Occurrences of clinically relevant AKI (cAKI) were identified in the study center postoperative database. Results During the period 2003–2012, 2116 LCVP-assisted hepatectomies were performed. The median patient age was 61 years [interquartile range (IQR): 51–70 years] and 51% of patients were male. The median number of resected segments was two; resections involved from one to four segments. Median estimated blood loss was 300 ml (IQR: 200–600 ml). Rates of morbidity and 90-day mortality were 21% and 2%, respectively. Low baseline eGFR (<90 ml/min) was seen in 84% of patients; 29% of patients had eGFR of <30 ml/min. Postoperative bAKI was seen in 17% (n = 350) of patients. Biochemical AKI with low eGFR was seen in 336 patients, representing 16% of the whole cohort; 13% of patients had been at risk, 2% experienced injury and 1% experienced failure. Kidney function had normalized at discharge in 159 of these patients. Nine patients (<1%) developed postoperative cAKI. Conclusions The majority of patients in the study cohort had low baseline eGFR. Biochemical alterations in eGFR are transient in the vast majority of patients after LCVP-assisted hepatectomy and their clinical impact is limited. The present data suggest that clinically relevant renal dysfunction is a very uncommon event in patients

  2. Effects of acute exercise on liver function and blood redox status in heavy drinkers

    PubMed Central

    GEORGAKOULI, KALLIOPI; MANTHOU, EIRINI; FATOUROS, IOANNIS G.; DELI, CHARIKLIA K.; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.; KOURETAS, DEMETRIOS; KOUTEDAKIS, YIANNIS; THEODORAKIS, YANNIS; JAMURTAS, ATHANASIOS Z.

    2015-01-01

    Excessive alcohol consumption can induce oxidative stress, resulting in the development of several diseases. Exercise has been reported to prevent and/or improve a number of health issues through several mechanisms, including an improvement in redox status. It has also been previously suggested that exercise can help individuals with alcohol use disorders reduce their alcohol intake; however, research in this field is limited. The aim of the present study was to investigage the effects of acute exercise of moderate intensity on the liver function and blood redox status in heavy drinkers. For this purpose, a total of 17 heavy drinkers [age, 31.6±3.2 years; body mass index (BMI), 27.4±0.8 kg/m2; experimental group (EG)] and 17 controls [age, 33.5±1.3 years; BMI, 26.1±1.4 kg/m2; control group (CG), who did not exceed moderate alcohol consumption], underwent one trial of acute exercise of moderate intensity (50–60% of the heart rate reserve) for 30 min on a cycle ergometer, following an overnight fast, and abstaining from smoking and alcohol consumption. Blood samples were obtained before and immediately after exercise for later determination of the indices of liver function and blood redox status. The subjects in the EG had significantly higher (p<0.05) baseline γ-glutamyl transferase (γ-GT) levels compared to the subjects in the CG. Exercise thus resulted in significantly higher γ-GT levels (p<0.005) only in the EG. No significant differences in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) baseline levels were observed between the 2 groups. Following exercise, the AST levels increased significantly (p<0.001) in both groups, whereas the ALT levels increased significantly (p<0.01) only in the EG. The baseline glutathione (GSH) levels were significantly lower (p<0.05) and remained low following exercise in the EG. In addition, we observed a trend for higher (p=0.07) baseline levels of thiobarbituric acid-reactive substances (TBARS), which

  3. Changes in portal blood flow and liver functions in cirrhotics during Ramadan fasting in the summer; a pilot study

    PubMed Central

    Mohamed, Salem Y; Emara, Mohamed H; Hussien, Hala IM; Elsadek, Hany M

    2016-01-01

    Aim: Assessment of short term changes in portal blood flow and long term changes in liver functions in cirrhotic patients who chose to fast during the month of Ramadan in summer. Background: During Ramadan, healthy Muslims obligated to fast from predawn to sunset. Patients and methods: Forty cirrhotic patients intended to fast during the month of Ramadan in the year 2014, were examined by Congestion index (CI) as a non-invasive indicator of short term changes in the portal blood flow, while liver function tests were determined as an indicator of long term changes in liver functions. Results: A total of 38 patients completed the whole month fasting and two patients discontinued fasting due to variceal bleeding. The complicated patients were 7. CI showed a statistically significant increase from fasting to postprandial status (P<0.001), with statistically significant increases from fasting to postprandial status in Child class A (P<0.001), and B (P<0.001). We did not find a statistical significance between patients with complications and those without complications (P=0.6). There was a statistically significant rise in the serum bilirubin after Ramadan. Deterioration noticed as advanced Child classes, development of lower limb edema, increasing ascites, increasing jaundice and overt encephalopathy. Conclusion: Cirrhotic patients showed significant short-term changes in the portal blood flow. However, these changes are not linked to complications or deterioration of liver functions and accommodated especially in patients with Child class A and B. Child class C patients should not fast. PMID:27458510

  4. A galactose-functionalized dendritic siRNA-nanovector to potentiate hepatitis C inhibition in liver cells.

    PubMed

    Lakshminarayanan, Abirami; Reddy, B Uma; Raghav, Nallani; Ravi, Vijay Kumar; Kumar, Anuj; Maiti, Prabal K; Sood, A K; Jayaraman, N; Das, Saumitra

    2015-10-28

    A RNAi based antiviral strategy holds the promise to impede hepatitis C viral (HCV) infection overcoming the problem of emergence of drug resistant variants, usually encountered in the interferon free direct-acting antiviral therapy. Targeted delivery of siRNA helps minimize adverse 'off-target' effects and maximize the efficacy of therapeutic response. Herein, we report the delivery of siRNA against the conserved 5'-untranslated region (UTR) of HCV RNA using a liver-targeted dendritic nano-vector functionalized with a galactopyranoside ligand (DG). Physico-chemical characterization revealed finer details of complexation of DG with siRNA, whereas molecular dynamic simulations demonstrated sugar moieties projecting "out" in the complex. Preferential delivery of siRNA to the liver was achieved through a highly specific ligand-receptor interaction between dendritic galactose and the asialoglycoprotein receptor. The siRNA-DG complex exhibited perinuclear localization in liver cells and co-localization with viral proteins. The histopathological studies showed the systemic tolerance and biocompatibility of DG. Further, whole body imaging and immunohistochemistry studies confirmed the preferential delivery of the nucleic acid to mice liver. Significant decrease in HCV RNA levels (up to 75%) was achieved in HCV subgenomic replicon and full length HCV-JFH1 infectious cell culture systems. The multidisciplinary approach provides the 'proof of concept' for restricted delivery of therapeutic siRNAs using a target oriented dendritic nano-vector.

  5. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.

    PubMed

    Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark; Deak, Maria; Wan, Min; Kaestner, Klaus H; Göransson, Olga; Viollet, Benoit; Gray, Nathanael S; Birnbaum, Morris J; Sutherland, Calum; Sakamoto, Kei

    2014-08-04

    LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.

  6. Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function

    PubMed Central

    Hagemann, S; Wohlschlaeger, J; Bertram, S; Levkau, B; Musacchio, A; Conway, E M; Moellmann, D; Kneiseler, G; Pless-Petig, G; Lorenz, K; Sitek, B; Baba, H A

    2013-01-01

    The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis. PMID:23519077

  7. Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster

    PubMed Central

    Iyer, Janani; Wang, Qingyu; Le, Thanh; Pizzo, Lucilla; Grönke, Sebastian; Ambegaokar, Surendra S.; Imai, Yuzuru; Srivastava, Ashutosh; Troisí, Beatriz Llamusí; Mardon, Graeme; Artero, Ruben; Jackson, George R.; Isaacs, Adrian M.; Partridge, Linda; Lu, Bingwei; Kumar, Justin P.; Girirajan, Santhosh

    2016-01-01

    About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (http://flynotyper.sourceforge.net), to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes. Flynotyper utilizes a series of image processing operations to automatically detect the fly eye and the individual ommatidium, and calculates a phenotypic score as a measure of the disorderliness of ommatidial arrangement in the fly eye. As a proof of principle, we tested our method by analyzing the defects due to eye-specific knockdown of Drosophila orthologs of 12 neurodevelopmental genes to accurately document differenti