bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contractile activity of bile canaliculi: Contraction or collapse?
Authors: Boyer James L. 
Published: March 2007

The discovery that bile canaliculi are capable of spontaneous contractile activity has led to their use in the investigation of the physiology of the liver cell. The contraction of a bile canaliculus is dependent on the network of actin, which is found in the pericanalicular region of the hepatocyte, and agents that inhibit actin filaments interfere with canalicular contraction. Injection of calcium directly into the cytoplasm of one hepatocyte of a cell pair results in contraction of the canaliculus. To determine whether the contractile activity of adjacent bile canaliculi was coordinated, calcium was injected into one cell of a group of three hepatocytes that formed two neighboring bile canaliculi. Calcium microinjection resulted in contraction of the bile canaliculus contiguous with the microinjected cell and was followed by a contraction of the second, adjacent canaliculus. These secondary contractions occurred after an interval of approximately 45 seconds. The finding that bile canalicular contractions are coordinated with contractions occurring in a sequential fashion supports the hypothesis that within the liver lobule, transport of bile within the canalicular network results from the coordinated contractions of the canaliculi.
Rat hepatocytes, when isolated and maintained in primary culture, are capable of producing forceful contractions of their bile canaliculi, with contractions occurring on a regular basis once every 5.5 minutes. To determine whether the contraction of one bile canaliculus affected the contraction of a neighboring canaliculus, cinephotomicrographic studies of pairs of contiguous canaliculi were undertaken. The activity of 10 pairs of contiguous canaliculi, and 10 pairs of noncontiguous canaliculi which served as a control group, was recorded for a period of 12.5 hours at the rate of 1 frame every 15 seconds. Using frame-by-frame analysis of this period of observation, we determined the time of contraction of each of the canaliculi in the pairs. Cross-correlations were obtained for the contraction times of each of the 10 pairs of contiguous canaliculi and 10 control pairs. A peak in activity was found, with that peak occurring five frames 75 seconds from the midline, whereas the noncontiguous controls showed no correlation in contractile activity. This finding indicates that, when one bile canaliculus contracts, a neighboring canaliculus is likely to contract after an interval of 1.25 minutes. That there is coordination of contractile activity of bile canaliculi suggests that, within the intact liver lobule, ordered motility function of the bile canaliculi may facilitate bile flow.
Different susceptibilities to the formation of cholesterol gallstones in mice
Authors: Alexander Manfred , Portman Oscar W. 
Published: March 2007

In the search for an animal model of genetic determinants of cholesterol cholelithiasis, we found strain, gender and individual differences in mice. Male black (C57BL6J) mice had a 50% incidence of cholesterol gallstones after they consumed lithogenic food similar to that used by Tepperman et al. for 2 weeks, whereas similarly treated male agouti (CBA/J) mice and females of both strains were free of gallstones. The male and female mice of both strains were fertile at 8 weeks of age, and the male black mice were first susceptible to induction of gallstones at 24 weeks of age. Male agouti mice of the same age did not form gallstones until they had consumed the lithogenic food for 8 weeks. The gallbladder biles of both strains were supersaturated with cholesterol during the lithogenic regimen. The male agouti mice had much higher fractional turnover rates of [24-14C]cholic acid than did the male black mice. In spite of their small total cholate pools, the agouti mice had higher rates of new cholate synthesis than did the black mice. The rate of disappearance of [1,2-3H]cholesterol from the blood was higher in the male agouti than in the black mice. The gallbladders of the agouti mice contained less bile and weighed less empty than gallbladders of the black mice. They also did not increase in volume in response to the lithogenic diet as much as gallbladders of the black mice.
The difference in gallstone induction times between male and female black mice was as great as the difference between the two strains. In spite of their resistance to gallstone formation, the black females had gallbladder bile that was usually supersaturated with cholesterol; however, in one experiment their increase in biliary cholesterol concentration was delayed compared to that of males. The concentrations of esterified cholesterol in the liver were higher in the females than in the males, and the plasma cholesterol concentrations were lower. The pattern of metabolism of labeled cholate and cholesterol in the black females was intermediate between that of black male and agouti male mice. The empty gallbladders of the black females were heavier and increased more in volume during the lithogenic regimen than those of the black males.
The black males that formed gallstones had bile which was more supersaturated with cholesterol after 2 weeks on the lithogenic regimen than the black males which were free of stones. They also had lower rates of new cholate synthesis and lower concentrations of esterified cholesterol in the liver than the animals which were free of stones. After 4 and 8 weeks of the experiment, the concentrations of esterified cholesterol in the livers of agouti mice with gallstones were also less than in the livers of those without stones. Thus, resistance to cholesterol gallstone formation in mice may be related to increased activities of the liver in converting cholesterol to bile acids and to esterified cholesterol.
Hepatic metabolism during acute ethanol administration: A phosphorus-31 nuclear magnetic resonance study on the perfused rat liver under normoxic or hypoxic conditions
Authors: Desmoulin Franck , Canioni Paul , Crotte Christian , Gérolami André , Cozzone Patrick J. 
Published: March 2007

The effect of ethanol metabolism on the energetic parameters and intracellular pH of the isolated perfused rat liver from fed rats was studied by phosphorus-31 nuclear magnetic resonance spectroscopy. This technique allowed us to analyze nondestructively and in real time the role of low oxygen tension on the possible injurious effect of ethanol on the liver cells.
A quantitative analysis of nuclear magnetic resonance data recorded on a perfused rat liver within a 30 mm diameter probe has been performed at 80.9 MHz. Under normoxic and normothermic conditions, the levels of phosphorylated metabolites detected by nuclear magnetic resonance were 2.8, 0.3 and 2 μmoles per gm liver wet weight for ATP, ADP and inorganic orthophosphate, respectively. The cytosolic pH was 7.25 ± 0.05. During a period of 4 min of hypoxia induced by reducing the perfusion flow rate to 25% of its initial value (i.e., from 12 ml to 3 ml per min per 100 gm body weight), the level of ATP dropped to 2.2 μmoles per gm liver wet weight. Concomitantly, ADP and inorganic orthophosphate increased to 0.6 and 3.3 μmolès per gm liver wet weight. Cytosolic pH fell to 7.02 ± 0.05.
Perfusion of the liver with a Krebs medium containing 70 mM (0.4%) ethanol induced a sharp decrease in intracellular inorganic orthophosphate to reach 1.3 μmole per gm liver wet weight and after a lag time of 4 to 6 min, a decrease in ATP level (2.15 μmoles per gm liver wet weight). A large increase in phosphomonoesters (mainly sn-glycerol 3-phosphate) up to 6 μmoles per gm liver wet weight was also observed. No significant cytosolic pH variation was noted after 20 min of ethanol perfusion (pH 7.20 ± 0.05). In the presence of 70 mM ethanol, a 4-min period of hypoxia caused pronounced changes; in particular, the level of ATP dropped to 1.15 μmole per gm liver wet weight, and a large intracellular acidosis occurred (pH 6.80 ± 0.05). Ethanol oxidation during hypoxia is also correlated to a dramatic increase in the cytosolic content of sn-glycerol 3-phosphate, as compared to the level found under normoxic ethanol perfusion.
Data presented here indicate that ethanol hepatotoxicity might be enhanced under hypoxia due to accumulation of protons in the cytosol. This severe metabolic acidosis is likely to contribute to metabolic disturbances occurring during ethanol exidation. Ethanol metabolism in fed rats gives rise to a synthesis of sn-glycerol 3-phosphate correlated with a decrease in cytosolic inorganic orthophosphate which in turn becomes limiting for ATP production. Finally, the observed increase in sn-glycerol 3-phosphate under hypoxia indicates that the sn-glycerol 3-phosphate/dihydroxyacetone phosphate shuttle could play a very important role as a compensatory mechanism in hypoxic regions of the liver in order to compensate for the decreased activity of the malate/aspartate shuttle.
The role of propranolol in congestive gastropathy of portal hypertension
Authors: Hosking Shorland W. , Kennedy Hugh J. , Seddon Ian , Triger David R. 
Published: March 2007

Heavy diffuse bleeding from congested gastric mucosa (congestive gastropathy) was treated by propranolol (dose = 24 to 480 mg per day) in 14 consecutive patients with portal hypertension. Thirteen patients (93%) stopped bleeding within 3 days. Gastric mucosal cherry red spots (a sign of severe gastropathy) were unchanged in 5 patients, became less obvious in 4 and appearances returned to normal in 5. Propranolol was discontinued electively in seven patients after 2 to 6 months; four of these patients rebled from the same lesion and stopped bleeding when propranolol was recommenced. No patient has rebled from congestive gastropathy while receiving propranolol during follow-up of 12 to 42 (median = 23) months.
A further 24 patients with nonbleeding congestive gastropathy received 160 mg long-acting propranolol per day in a double-blind placebo controlled cross-over trial. Twenty-two patients completed the study; in nine patients, endoscopic grading of congestive gastropathy improved after propranolol compared to three after placebo (p < 0.05). Although the mechanism of action is not understood, propranolol appears to have a clinically significant role in the management of nonvariceal gastric bleeding in portal hypertension.
Plasma gaba, gaba-like activity and the brain gaba-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy
Authors: Maddison Jill E. , Dodd Peter R. , Morrison Murray , Johnston Graham A. R. , Farrell Geoffrey C. 
Published: March 2007

Plasma γ-aminobutyric acid (GABA)-like activity, plasma GABA and the brain GABA-benzodiazepine receptor complex were studied in rats with chronic hepatic encephalopathy. Portal vein ligation (after prior subcutaneous transposition of the spleen) results in complete portal bypass of splanchnic blood. In addition, significant hepatocellular damage was superimposed on this model of portosystemic shunting by ligation of the common bile duct. Plasma GABA-like activity (determined by radioreceptor assay) and true plasma GABA concentrations (determined by high-performance liquid chromatography) were found to be significantly increased in both portal vein-ligated and portal vein and bile duct-ligated rats, compared with controls. However, plasma GABA-like activity was consistently greater than the concentration of true GABA in the plasma of all rats. This suggested the presence of a GABA-like factor in plasma that can inhibit [3H]GABA binding, but is not GABA itself. The concentration of this GABA-like factor was significantly increased in the plasma of rats with chronic hepatic encephalopathy
Despite the significant increase in plasma GABA-like activity and plasma GABA concentrations, there was no alteration in the affinity or density of the physiologically relevant, low-affinity brain GABA binding site in the rats with portal vein ligation, with or without bile duct ligation. There was also no significant alteration in brain benzodiazepine binding in these rats. GABA enhancement of benzodiazepine binding was unchanged in the portal vein-ligated rats. However, the maximal enhancement of benzodiazepine binding was decreased in the rats with portal vein and bile duct ligation.
There appears to be no substantial evidence that brain GABAergic neurotransmission is increased in these models of chronic hepatic encephalopathy.
Interaction of human liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels
Authors: Monteiro Alvaro N. A. , Borojevic Radovan 
Published: March 2007

Interactions of liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels in vitro were studied and compared.
Liver connective tissue cells showed the lowest rate of migration into the gel and the highest speed of gel contraction, reflecting their high adhesiveness to the substrate as compared to the other cell lines studied.
The analysis of their ultrastructural morphology showed that liver connective tissue cells and smooth muscle cells developed cytoskeletal and cytoplasmic organelle polarities, in response to the contact with gel surface. This polarity was lost when cells were embedded in the gel. Skin fibroblasts did not show this characteristic, neither on top nor in the gel.
Although liver connective tissue cells have been recognized as analogous to smooth muscle cells, they represent a defined cell population, present in fibrotic livers, with specific behavior and with particular relationship to the extracellular matrix.
The nature of cell death in piecemeal necrosis: Is order emerging from chaos?
Authors: Powell Lawrie W. 
Published: March 2007

Electron microscopic studies of acidophilic or Councilman-like bodies in the liver show that they are manifestations of apoptosis. The morphology and biochemistry of apoptosis suggest a process of active cellular self-destruction rather than degeneration. The incidence of apoptosis indicates that it is normally involved in the regulation of organ size and, in addition, may be triggered by specific pathological stimuli. Cell death produced in vitro by various types of cell-mediated immune injury occurs by apoptosis
The occurence of apoptosis in hepatic disease is illustrated and discussed. That it constitutes the only clearly identifiable mode of cell death in most types of acute and chronic hepatitis and in primary biliary cirrhosis is in accord with current concepts of the pathogenesis of these conditions. Furthermore, the morphological features of apoptosis may explain long-standing enigmas in the histology of hepatitis--the cryptic nature of the cell death in piecemeal “necrosis” and the apparent drop-out of large numbers of hepatocytes in many cases of acute hepatitis without overt evidence of necrosis. Apoptosis represents rapid budding of a cell to form numerous globules, the largest of which appear to be acidophilic bodies. All apoptotic fragments are quickly removed by adjacent cells without evident inflammation, permitting the process to occur inconspicuously.
Lack of hepatic transferrin receptor expression in hemochromatosis
Authors: Sciot Raf , Paterson Alan C. , Van Den Oord Joost J. , Desmet Valeer J. 
Published: March 2007

The major part of hepatocellular iron is derived from uptake of transferrin-bound iron by means of nonspecific fluid-phase endocytosis and specific, saturable binding on high-affinity transferrin receptors. We investigated the expression of transferrin receptors on hepatocytes in liver biopsies of 22 cases of hemochromatosis (21 primary hemochromatosis and 1 secondary hemochromatosis), using immunohistochemical demonstration of the human transferrin receptor with the specific monoclonal antibody OKT9. Fifty liver biopsies (normal and pathological) without demonstrable iron storage (Perls' stain negative) served as controls. In the controls, membranous and/or cytoplasmic transferrin receptor expression was always present on hepatocytes, albeit in variable numbers and patterns without obvious relation to the underlying liver disease. In 19 of 22 hemochromatosis cases with severe iron overload, OKT9 immunoreactivity on hepatocytes was completely absent. Three hemochromatosis cases showed few hepatocytes positive for OKT9. One showed mild iron overload, while the second, a successfully treated case, was free of iron. The remaining hemochromatosis case was a known alcoholic with severe iron overload. Since OKT9 binding to the transferrin receptor is not blocked by previous binding of transferrin, the findings show that in advanced hemochromatosis hepatocytes do not express transferrin receptors. This finding is in keeping with the inverse relation between transferrin receptor expression and exogenous iron supply in various cell cultures.
These results indicate that in hemochromatosis, apparently as a result of progressive iron overload, transferrin receptor expression on hepatocytes disappears. This leaves the hepatocytes with a nonsaturable mechanism for uptake of transferrin-bound iron (fluid-phase pinocytosis) and with uptake of potentially more toxic forms of nontransferrin-bound iron, which may represent up to 30% of serum iron in fully established hemochromatosis.
α1-Adrenergic effects and liver regeneration
Authors: Cruise Jennifer L. , Knechtle Stuart J. , Bollinger Randal R. , Kuhn Cynthia , Michalopoulos George 
Published: March 2007

The effects of several treatments involving α-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an α1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H] thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate.
The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, α1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.
Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: A prospective, randomized study†
Authors: Idéo Gaetanô , Bellati Giorgio , Fesce Edoardo , Grimoldi Daniela 
Published: March 2007

Propranolol has been reported to prevent the risk of hemorrhage in patients who survived episodes of variceal rupture. Since the first bleeding episode can be lethal, we did a prospective, randomized trial to see whether β-blockers could also prevent the first hemorrhage. Seventy-nine consecutive cirrhotics with large esophageal varices by endoscopy and who had never bled were randomly allocated to one of the following treatments: placebo; ranitidine (300 mg per day), or nadolol (40 to 120 mg per day)—which is not cardioselective, reduces portal hypertension and does not interfere with renal flow. Since no significant differences between ranitidine and placebo treatment were observed, the two groups were combined as the control group and compared with the nadolol group.
After a mean follow-up of 24 months, only 1 of the 30 patients in the nadolol group had bled, while 11 of the 49 patients in the control group had bled. The percentages of patients who had not bled 1 and 2 years after the inclusion-were 100 and 94.4% for the nadolol group and 81.2 and 70.2% for the control group (p < 0.02), respectively. There were no differences in the mortality rate.
In conclusion, nadolol significantly protects against the first gastrointestinal bleeding episode in cirrhotics.
The application of a numerical scoring system for evaluating the histological outcome in patients with chronic hepatitis B followed in long term
Authors: Lindh Gudrun , Weiland Ola , Glaumann Hans 
Published: March 2007

A numerical scoring system was applied and compared with conventional histological classification to assess the histological outcome in 42 patients with chronic hepatitis B followed for 16 to 162 months (mean = 75 months). Four histological categories in the biopsies were assessed and scored: (i) piecemeal necrosis; (ii) lobular necrosis; (iii) portal inflammation, and (iv) fibrosis and cirrhosis. The sum of all four categories was defined as the “Histological Activity Index.” Altogether, 102 liver specimens, including 2 to 4 repeats from each patient, were investigated. A good correlation was noted between a high value of the Histological Activity Index score and several liver histology as monitored by conventional terminology for chronic hepatitis. Among patients, with HBeAg persistence, 8 of 14 (57%) deteriorated during follow-up as judged by an increase in the Histological Activity Index score compared to 3 of 13 (23%) of the patients with HBeAg seroconversion (0.5 < p < 0.1). Piecemeal necrosis has been postulated to be a predictive marker for the eventual development of cirrhosis. Here, we found that a low score for piecemeal necrosis in the initial liver biopsy was significantly less predictive of a high fibrosis score in the follow-up biopsy than was a high score for initial piecemeal necrosis (p < 0.001).
It is concluded that the scoring system used can be applied to monitor the histological long-term follow-up, especially when separated into its four constituent categories. It also offers a means of predicting a chronic hepatitis outcome.
Interactions between isolated hepatocytes and kupffer cells in iron metabolism: A possible role for ferritin as an iron carrier protein
Authors: Sibille Jean-Claude , Kondo Hitoshi , Aisen Philip 
Published: March 2007

Like the rat peritoneal macrophage, the isolated Kupffer cell is capable of processing and releasing iron acquired by phagocytosis of immunosensitized homologous red blood cells. When erythrophagocytosis is restrained to levels which do not affect cell viability, about one red cell per macrophage, close to 50% of iron acquired from red cells is released within 24 hr in the form of ferritin. Immunoradiometric assay of the extracellular medium indicates that 160 ng ferritin are released by 106 Kupffer cells after 24-hr incubation at 37°C. Iron release is temperature-dependent, the rate at 37°C being nearly 5-fold greater than at 4°C. As estimated by sucrose-gradient ultracentrifugation, ferritin released by the erythrophagocytosing Kupffer cell averages 2,400 iron atoms per molecule.
When reincubated with isolated hepatocytes, this released ferritin is rapidly taken up by the cells. Via this process, hepatocytes may accumulate more than 160,000 iron atoms per cell per min. Such accumulation is not impeded by the presence of iron-loaded transferrin in the culture medium, but is markedly depressed by rat liver ferritin. In contrast to the conservation of transferrin during its interaction with hepatocytes, the protein shell of the ferritin molecule is rapidly degraded into trichloroacetic acid-soluble fragments. Ferritin-mediated transfer of iron from Kupffer cells to hepatocytes may help explain the resistance of the liver to iron deficiency as well as the liver’s susceptibility to iron overload.