bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of genetic differences in drug metabolism: Prediction of individual risk of toxicity or cancer
Authors: Nebert Daniel W. 
Published: March 2007

These two reports describe recombinant DNA tests that can identify individuals having a defect in the cytochrome P450IID6 (CYP2D6)-mediated oxidative metabolism of debrisoquine and more than two dozen other drugs that are commonly prescribed. The poor metabolizer (PM), representing 5% to 10% of the northern European white population is homozygous for an autosomal recessive trait. Compared with the extensive metabolizer (EM) phenotype, the PM individual is more prone to toxicity caused by some of these drugs. Curiously, the PM phenotype appears to be associated with a lower risk of lung and bladder cancer.
Gough and coworkers propose that the primary gene defect associated with the CYP2D6 polymorphism appears to be a G to A transition mutation affecting the splice junction of intron 3/exon 4 of the CYP2D6 gene. They offer a polymerase chain reaction (PCR) amplification method for diagnosing three variant alleles and claim to have predicted the phenotype of all normal and 34 of 42 (81%) PM individuals. Based on the known frequencies of those variant alleles detectable by this method, however, the assay would be expected to predict less than 60% of PM patients. Heim and Meyer, on the other hand, have combined allelespecific PCR with restriction fragment length polymorphism (RFLP) patterns to identify more than 95% of all mutant alleles, suggesting that their assay would accurately predict more than 90% of all PM individuals. Using this latter assay or a similar test with further improvements, especially in combination with family studies, it should soon be possible for the physician to determine the CYP2D6 phenotype of the patient, thereby avoiding toxic drug overdoses.
Increased expression of intercellular adhesion molecule 1 on bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis
Authors: Adams David H. , Hubscher Stefan G. , Shaw Jean , Johnson Gerald D. , Babbs Christopher , Rothlein Robert , Neuberger James M. 
Published: March 2007

It has been suggested that immunological mechanisms involving lymphocyte-mediated damage are important in the characteristic bile-duct damage that occurs in primary biliary cirrhosis and primary sclerosing cholangitis. Because adhesion is necessary for the interaction of lymphocytes with their target structures, we have studied the expression of intercellular adhesion molecule 1, a ligand for the leukocyte adhesion receptor lymphocyte function—associated antigen 1 in the liver of patients with primary biiary cirrhosis and primary sclerosing cholangitis. Strong expression of intercellular adhesion molecule 1 was seen on interlobular bile ducts and proliferating bile ductules in both conditions. In primary biliary cirrhosis, medium-sized ducts, which are spared by the disease, were negative. Minimal bile-duct staining was seen in conditions in which bile-duct damage is not a major feature, such as nonbiliary cirrhosis and acute liver diseases. In patients with cirrhosis from any cause, strong expression of intercellular adhesion molecule 1 was detected on the periseptal hepatocytes adjacent to new connective tissue. The intensity of immunohistochemical staining was recorded using a semiquantitative visual scoring system that was subsequently validated quantitatively by confocal laser scanning microscopy.
The expression/induction of intercellular adhesion molecule 1 on bile ducts may be important in the pathogenesis of bile-duct damage in primary biliary cirrhosis and primary sclerosing cholangitis and is further evidence to support an immune pathogenesis in these two conditions. Furthermore, the induction of intercellular adhesion molecule 1 on hepatocytes may be an important factor in the liver-cell damage and fibrosis that occur during the development of cirrhosis.
Transforming growth factor B and hepatic fibrosis: Cause or effect?
Authors: Brenner David A. 
Published: March 2007

Background.
Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation of unknown pathogenesis. Transforming growth factor (TGF) β1 induces the production of extracellular matrix proteins by liver cells and has been implicated in the pathogenesis of hepatic fibrosis in laboratory animals. TGFα is a hepatocyte mitogen that participates in liver regeneration.

Methods.
Using Northern blot analysis, we studied the expression of TGFβ1 messenger RNA (mRNA) in liver specimens from 42 patients with chronic hepatitis and cirrhosis and 12 subjects with either normal or fatty livers. The results were correlated with measurements of procollagen Type I mRNA in liver tissue, procollagen Type III peptide in serum, and the degree of histologic injury. We also investigated whether TGFα mRNA would be detectable in biopsy specimens of livers with proliferative activity.

Results.
TGFβ1 mRNA expression correlated closely with the expression of procollagen Type I mRNA (r = 0.94) and serum procollagen Type III peptide (r = 0.89) and with the histologic activity index (r = 0.73). All patients with increased fibrogenic activity (serum procollagen Type III peptide level, > 11.9 μg per liter) had increased levels of TGFβ1 mRNA (2 to 14 times the levels in the control group or in patients with normal fibrogenic activity), and both TGFα and H3 histone (a marker of DNA synthesis) mRNAs were detectable in patients with regenerative nodules. Six of eight patients with hepatitis C treated with interferon alfa for one year had sustained clinical responses with normalization of serum procollagen Type III peptide and aminotransferase activity. All these patients had normal levels of TGFβ1 mRNA in liver specimens obtained at the end of the year.

Conclusions.
TGFβ1 may have an important role in the pathogenesis of fibrosis in patients with chronic liver disease, and TGFα expression may be associated with liver regeneration in these patients.
Focusing in on P53 in hepatocellular carcinoma
Authors: Carbone David 
Published: March 2007

Human hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G→T transversion in seven HCC DNA samples and the G→C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5, 6, 8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains, which include codon 249. We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.

Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350:429-431.
Hepatocellular carcinoma (HCC) is a prevalent cancer in sub-Saharan Africa and eastern Asia. Hepatitis B virus and aflatoxins are risk factors for HCC, but the molecular mechanism of human hepatocellular carcinogenesis is largely unknown. Abnormalities in the structure and expression of the tumour-suppressor gene p53 are frequent in HCC cell lines, and allelic losses from chromosome 17p have been found in HCCs from China and Japan. Here we report on allelic deletions from chromosome 17p and mutations of the p53 gene found in 50% of primary HCCs from southern Africa. Four of five mutations detected were G→T substitutions, with clustering at codon 249. This mutation specificity could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1, a food contaminant in Africa, which is both a mutagen that induces G to T substitution and a liver-specific carcinogen.
Detection of proliferating liver cells in various diseases by a monoclonal antibody against DNA polymerase-α: With special reference to the relationship between hepatocytes and sinusoidal cells
Authors: Seki Shuichi , Sakaguchi Hiroki , Kawakita Nobuyoshi , Yanai Atsushi , Kuroki Tetsuo , Mizoguchi Yasuhiro , Kobayashi Kenzo , Monna Takeyuki 
Published: March 2007

Proliferating cells in liver specimens from patients with various diseases were detected by use of a monoclonal antibody against human DNA polymerase-α, which is present in the nuclei of cells in the G1, S, M and G2 phases of the mitotic cell cycle and absent in the G0 phase, to clarify the kinetics and morphological characteristics of these cells. This monoclonal antibody was supernatant derived from clone CL222-42B, and the peroxidase antiperoxidase method was used.
Not only epithelial cells (hepatocytes, biliary epithelial cells and hepatocellular carcinoma cells) but also nonepithelial cells (Kupffer cells and other macrophages, endothelial cells, fat-storing cells, lymphocytes and fibroblasts) were stained for DNA polymerase-α. In acute viral hepatitis with confluent necrosis, small hepatocytes with basophilic cytoplasm next to the necrosis accounted for most of the proliferating cells. In these areas, Kupffer cells and other macrophages and lymphocytes had often proliferated. Hepatocellular carcinoma cells were frequently stained for DNA polymerase-α, in addition to endothelial cells, macrophages and lymphocytes. These nonepithelial cells were stained more frequently in specimens with many stained carcinoma cells than in those with only a few cells stained. In fibrotic areas, fibroblasts were often stained for this enzyme. In proliferating bile ducts, both small epithelial cells and large mature cells were stained. The differences between stained and nonstained cells that were not hepatocytes could not be defined by their ultrastructural characteristics. From these findings, it seemed possible that sinusoidal cells, especially Kupffer cells and other macrophages, might be much involved in hepatocytic proliferation during regeneration of the liver and also in the occurrence of malignant tumors. (Hepatology 1991;14:781-788).
Effect of propranolol on portosystemic collateral circulation in patients with cirrhosis
Authors: Gaiani Stefano , Bolondi Luigi , Fenyves Daphna , Zironi Gianni , Rigamonti Alessandra , Barbara Luigi 
Published: March 2007

Propranolol has been demonstrated to be effective in lowering portal pressure in cirrhotic patients. This effect is mediated by a reduction of splanchnic arterial inflow and a consequent decrease of portal vein and portocollateral blood flow. Although experimental studies suggest a direct effect of the drug on portocollateral circulation, little information exists about relative flow changes occurring in the portal vein and in collateral veins feeding esophageal varices. This study addressed the problem in 12 cirrhotic patients selected on the basis of feasibility of Doppler flowmetry in both the portal and left gastric veins. Caliber, flow velocity and flow volume in both vessels were measured by Doppler ultrasound before and at 60, 120 and 180 min after an oral dose of 40 mg propranolol, together with heart rate and mean arterial pressure.
A significant decrease in heart rate (− 17.6% ± 1.1%, p < 0.001) and mean arterial pressure (− 10.6% ± 0.9%, p < 0.005) confirmed effective β-blockade. Baseline flow velocity was significantly lower in the portal vein than in the left gastric vein (12.4 ± 0.6 vs. 15.4 ± 1.5 cm/sec, p < 0.05). Maximal hemodynamic effect was reached at 120 min after administration of propranolol. The vessel caliber did not change significantly. Flow velocity fell from 12.4 ± 0.6 to 10.4 ± 0.7 cm/sec in the portal vein (p < 0.05) and from 15.4 ± 1.5 to 11.1 ± 0.9 cm/sec in the left gastric vein (p < 0.01). The percentage decrease in velocity and flow volume was significantly higher in the left gastric vein than in the portal vein (velocity = − 26.8% vs. − 15%, p < 0.05; flow = − 30.2 ± 4.4 vs. − 20.9 ± 3.3 cm/sec; p < 0.05). These data support the hypothesis of a direct effect of the drug on portocollateral resistance. (Hepatology 1991;14:824-829).
Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: A 30-month pilot study
Authors: O’brien Christopher B. , Senior John R. , Arora-Mirchandani Renu , Batta Ashok K. , Salen Gerald 
Published: March 2007

We investigated the effects of once-daily oral administration of 10 mg/kg ursodeoxycholic acid (generic name, ursodiol) on elevated serum enzyme activities, bilirubin, cholesterol, bile acids and symptoms in patients with primary sclerosing cholangitis. A 30-mo, open-label, pilot trial was designed to cover four periods: (a) 3 mo of pretreatment observation (period 1), (b) 6 mo on ursodiol (period 2), (c) 3 mo withdrawal of treatment (period 3) and (d) 18 mo of extended retreatment (period 4). Diagnosis was confirmed by cholangiography and liver biopsy specimens. We enrolled 12 patients with persistently elevated pretreatment alkaline phosphatase and γ-glutamyltransferase levels (at least twice the upper limit of normal), and observed them for a median of 37 mo.
Significant reductions in serum total cholesterol levels and in serum enzyme activities indicating cholestasis and hepatocellular injury occurred during ursodiol treatment in both treatment periods 2 and 4 and relapsed with treatment interruption in period 3. Elevated serum bilirubin and symptoms of disabling fatigue, pruritus and diarrhea were improved by ursodiol. Improvements have continued after 2 yr of treatment in 10 patients (1 patient had a transplantation after he relapsed on withdrawal of ursodiol therapy; another died of postoperative complications of colon resection for carcinoma). No other cases of clinical deterioration were observed in the retreatment period. The longer term reductions of alkaline phosphatase, transaminases, bilirubin and cholesterol after 2 yr of treatment were even greater than the initial reductions after 6 mo of treatment. These results justify initiation of larger, controlled clinical trials, with serial morphological evaluations of the liver and biliary tree. (Hepatology 1991;14:838-847).
Dexamethasone modulates α2-macroglobulin and apolipoprotein E gene expression in cultured rat liver fat-storing (Ito) cells
Authors: Ramadori Giuliano , Knittel Thomas , Schwögler Stefan , Bieber Florian , Rieder Hartmut , Büschenfelde Karl-Herrmann Meyer Zum 
Published: March 2007

Fat-storing (Ito) cells are perisinusoidal liver cells thought to play a central role in vitamin A metabolism and fibrogenesis. Glucocorticoids have been shown to be beneficial in the treatment of certain types of liver diseases by delaying the development of cirrhosis. To study the regulatory effects of dexamethasone on Ito cell gene expression, Ito cells were isolated from normal rat liver and primary cultures were established. The effect of dexamethasone on the synthesis of α2-macroglobulin, apolipoprotein E, fibronectin and actin was examined. Protein synthesis was studied both at the protein level and at the RNA level by means of biosynthetic labeling, immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blot analysis of total RNA.
After exposure to dexamethasone for 20 hr, α2-macroglobulin protein synthesis was increased threefold, whereas apolipoprotein E expression was decreased 80%. Biosynthesis of fibronectin remained unaffected by hormone treatment. The dexamethasone effect became detectable 5 hr after beginning the exposure. Deinduction kinetic experiments showed that the glucocorticoid effect was detectable more than 12 hr after the replacement of the dexamethasonecontaining culture medium by medium without the hormone.
Corresponding to the data obtained at the protein level, dexamethasone increased the steady-state levels of α2-macroglobulin-specific messenger RNA and reduced apolipoprotein E-specific transcripts, whereas fibronectin and actin messenger mRNA remained unchanged. These findings indicate that glucocorticoids can affect the Ito-cell gene expression in a differentiated manner. Because dexamethasone not only stimulates α2-macroglobulin but also fibronectin and apolipoprotein E gene expression in rat hepatocytes, it will be interesting to study the difference in regulation of those genes in both cell populations. (Hepatology 1991;14:875-882).
Effect of interferon-γ on hepatitis B viral antigen expression in primary hepatocyte culture†
Authors: Lau Johnson Y. N. , Bain Vincent G. , Naoumov Nikolai V. , Smith Heather M. , Alexander Graeme J. M. , Williams Roger 
Published: March 2007

Interferon-α has been shown recently to selectively enhance hepatocyte expression of HBsAg/pre-S2 in chronic hepatitis B virus infection in a way that may enhance immune recognition. To determine the effect of interferon-γ on hepatitis B virus antigen expression, hepatocytes isolated from patients with chronic hepatitis B virus infection were incubated in the absence or presence of interferon-γ and viral antigen expression was assessed by both radioimmunoassay and immunocytochemistry using appropriate monoclonal antibodies.
Interferon-γ inhibited the expression of all hepatitis B virus antigens tested. Intracellular HBsAg measured by radioimmunoassay of sonicated hepatocytes fell by 29% with 1 U/ml (p < 0.01) and 36% with 10 U/ml of interferon-γ (p < 0.001) compared with control treatment. Secreted HBsAg was reduced by 19% with 10 U/ml of interferon-γ (p < 0.01). Intracellular HBeAg was also decreased by 29% with 1 U/ml (p < 0.05) and 42% with 10 U/ml of interferon-γ (p < 0.05), but no significant change was found in the amount of secreted HBeAg. The proportion of hepatocytes containing various hepatitis B virus antigens and the intracellular viral antigen staining densities also fell significantly with interferon-γ incubation. Interestingly, the addition of interferon-γ abolished the augmenting effect of interferon-α on intracellular HBsAg.
These data indicate that interferon-γ, in contrast to interferon-α, has an inhibitory effect on hepatocyte expression of all hepatitis B virus antigens including HBsAg/pre-S2, suggesting that this may be one factor that accounts for their difference in clinical activity in patients with chronic hepatitis B virus infection. (Hepatology 1991;14:975-979.)
Plasma metallothionein concentration in patients with liver disorders: Special emphasis on the relation with primary biliary cirrhosis
Authors: Mulder Theo P. J. , Janssens Roelof A. , Verspaget Hein W. , Lamers Cornelis B. H. W. 
Published: March 2007

The plasma metallothionein concentration was evaluated in healthy subjects and in patients with several types of liver disorders. Plasma metallothionein concentrations in controls varied between 2.4 and 4.8 ng/ml. Patients with disorders associated with increased liver copper concentrations (i.e., primary biliary cirrhosis and primary sclerosing cholangitis) had significantly (both p <0.002) elevated plasma metallothionein concentrations (range = 1.8 to 52.2 ng/ml), and a considerable number of these were above the maximum control level (21 of 41 patients). In contrast, patients with liver disorders not associated with increased liver copper concentrations (alcoholic and cryptogenic cirrhosis, and acute viral and chronic active hepatitis) generally had normal plasma metallothionein concentrations and only a few were above the maximum control level (11 of 64 patients, maximum = 8.8 ng/ml). The metallothionein concentrations in plasma samples from patients in stage I or II primary biliary cirrhosis were within or slightly above the control range, whereas most patients in stage III had elevated levels (p <0.002), and almost all patients in stage IV had clearly elevated (p < 0.0001) concentrations. In primary biliary cirrhosis the plasma metallothionein concentration tended to increase during the evolution of the disorder, and the concentration correlated significantly with the serum total bilirubin concentration.
In conclusion, the plasma metallothionein concentration is significantly elevated in patients with primary biliary cirrhosis and in patients with primary sclerosing cholangitis. Although related to the histological stage of primary biliary cirrhosis, the measurement of plasma metallothionein concentrations contributes little to the diagnosis or the evaluation of the severity of these disorders. In patients with liver disorders not associated with increased liver copper concentrations the plasma metallothionein concentration is generally normal. (Hepatology 1991;14:1008-1012.)
Serum levels of short-chain fatty acids in cirrhosis and hepatic coma
Authors: Clausen Mette Rye , Mortensen Per Brøbech , Bendtsen Flemming 
Published: March 2007

Short-chain fatty acids cause reversible coma in animals and may contribute to the pathogenesis of the hepatic coma in humans. The concentrations of short-chain fatty acids in peripheral venous blood were significantly elevated in 15 patients with hepatic encephalopathy caused by cirrhosis (362 ± 83 μmol/L; mean ± S.E.M.) compared with 17 cirrhotic patients without encephalopathy (178 ± 57 μmol/L) and 11 normal individuals (60 ± 8 μmol/L). However, no correlation between the depth of coma and the level of short-chain fatty acids was found after repetitive measurements in the coma group. Compared with normal individuals, all short-chain fatty acids, except valerate, were elevated in patients with hepatic encephalopathy, whereas only the concentrations of isobutyrate and isovalerate were significantly elevated in cirrhotic patients without encephalopathy.
The concentrations of short-chain fatty acids in 21 nonencephalopathic cirrhotic patients who underwent catheterization were equally distributed in the aorta (187 ± 56 μmol/L), the hepatic vein (212 ± 75 μmol/L), the azygos vein (140 ± 37 μmol/L) and the renal vein (135 ± 43 μmol/L) compared with peripheral venous blood (178 ± 57 μmol/L).
This study does not support the idea that short-chain fatty acids are of major importance in the pathogenesis of hepatic coma in patients with cirrhosis. (Hepatology 1991;14:1040-1045.)
Insulin and glucagon infusion in acute alcoholic hepatitis: A prospective randomized controlled trial
Authors: Bird George , Lau Johnson Y. N. , Koskinas John , Wicks Claire , Williams Roger 
Published: March 2007

In a randomized, controlled trial to investigate the possible benefit of insulin and glucagon therapy in severe acute alcoholic hepatitis, 86 patients were randomized to receive 30 U insulin and 3 mg glucagon in 250 ml 5% dextrose over 12 hr each day for 3 wk or a similar regime of identical placebo. No significant differences were seen in patients’ clinical characteristics and disease severity in the treated and placebo groups.
Of the 43 patients receiving insulin and glucagon, 15 (35%) died within 4 wk of randomization, compared with 14 deaths (33%) in the control patients (p = not significant). When the patients surviving the first 4 wk were examined there were five more deaths in the treatment group, compared with one death in the control group at 6-mo follow-up (p = not significant). No significant differences in the frequency of short-term or long-term complications of alcoholic liver disease or relapse to alcohol were seen when the two groups were compared, although hypoglycemia was seen in six patients during infusion of insulin and glucagon. Similarly, no significant differences were seen in the improvement in clinical or biochemical features at 4 wk and at 6 mo in survivors when the insulin and glucagon-treated patients were compared with patients in the placebo group.
This study does not confirm previous reports that insulin and glucagon infusion improves the outcome of severe acute alcoholic hepatitis. (Hepatology 1991;14:1097-1101.)