Is ReO3 a mixed ionic-electronic conductor? A DFT study of defect formation and migration in a BVIO3 perovskite-type oxide.

Density-functional-theory (DFT) calculations within the generalised gradient approximation (GGA) were used to examine the behaviour of point defects in the cubic BVIO3 perovskite-type oxide, ReO3. Energies of reduction and of hydration were calculated, and the results are compared with literature data for ABO3 perovskite oxides. The activation energies of migration were determined for O2-, H+, Li+, Na+, K+ and H3O+. An occupied A site in ReO3 is found to be beneficial to oxide-ion migration by a vacancy mechanism as well as to proton migration by a Grotthuss mechanism. Na+, K+ and H3O+ exhibit activation energies of migration higher than 2 eV, whereas Li+ is characterised by a very low migration barrier of 0.1 eV. Reasons for this behaviour are discussed. Our results suggest that H+, O2-, and especially Li+, are highly mobile ions in ReO3.

Correlation of electrochromic properties and oxidation states in nanocrystalline tungsten trioxide.

Although tungsten trioxide (WO3) has been extensively studied since its electrochromic properties were first discovered, the mechanism responsible for the coloration or bleaching effect is still disputed. New insights into the coloration mechanism of electrochromic, nanocrystalline WO3 are provided in this paper by studying thin WO3 films combining the electrochemical and spectroscopic techniques. By employing in situ UV-Vis transmission spectroscopy at a fixed spectral band pass during electrochemical experiments, such as cyclic voltammetry, a two-step insertion process for both protons and lithium ions is identified, of which one step exhibits a significantly higher coloration efficiency than the other. To obtain a better understanding of the insertion process AxWO3 (A = H, Li,…) thin films were studied at different stages of intercalation using UV-Vis and X-ray photoelectron spectroscopy. The results show that the first step of the intercalation process represents the reduction from initial W(6+) to W(5+) and the second step the reduction of W(5+) to W(4+). We found that the blue coloration of this nanocrystalline tungsten trioxide is mainly due to the presence of W(4+) rather than that of W(5+).

Electrical transport properties of Ge-doped GaN nanowires.

The conductivity and charge carrier concentration of single GaN nanowires (NWs) doped with different concentrations of Ge were determined by four-point resistivity and temperature-dependent Seebeck coefficient measurements. We observed high carrier concentrations ranging from 9.1 × 10(18) to 5.5 × 10(19) cm(-3), well above the Mott density of 1.6 × 10(18) cm(-3), and conductivities up to 625 S cm(-1) almost independent of the NW diameter. The weak temperature dependence of the conductivity between 2 and 10 K could be assigned to the formation of an impurity band. For the sample with the highest conductivity metallic behaviour was found, indicated by a positive temperature coefficient of the resistivity. The near band edge emission analyzed by micro-photoluminescence spectroscopy showed only a small increase of the peak width up to 70 meV and no spectral shift for carrier concentrations up to 5.5 × 10(19) cm(-3). The latter was attributed to the simultaneous influence of band filling, band gap renormalization, and strain.

Downregulation of nuclear sex steroid receptor activity correlates with severity of alcoholic liver injury.

Chronic ethanol ingestion in rats and humans results in significant alterations in sex steroid levels and expression of sex hormone-dependent phenotype. In this study, we used the intragastric feeding model in male rats to determine hepatic sex hormone receptor activity under circumstances of chronic ethanol exposure and differing degrees of liver injury induced by type of dietary fat. Pathological analysis and quantitation of hepatic androgen receptor (AR) and estrogen receptor (ER) activity, serum sex hormones, and sex hormone-responsive protein and mRNA expression were performed. The activity of the physiologically relevant nuclear form of both AR and ER was significantly decreased with ethanol and correlated inversely with the severity of liver injury. Serum testosterone levels, as well as expression of an androgen-dependent hepatic mRNA, were decreased by ethanol and progressive liver injury. Serum estradiol increased with liver injury. We postulate that these changes in receptor activity may be due to the oxidative stress, reduced cellular energy, and/or altered cytokine milieu known to occur in this model.

Hypogonadism precedes liver feminization in chronic alcohol-fed male rats.

Men who chronically abuse alcohol may display a spectrum of endocrine abnormalities including hypogonadism and feminization, with elevated serum estradiol and low serum testosterone. We examined factors that may result in disruption of hepatic sex hormone homeostasis in alcohol-fed male rats and possible consequences of such changes. Rats were fed alcohol-containing or isocaloric diets for 30, 60, and 90 days. In alcohol-fed rats, serum testosterone levels and hepatic activity of 2 androgen-dependent estrogen metabolizing enzymes were reduced (P <.05) at all times, as was activity of androgen receptor. There was also a significant early and progressive decrease in testes/body ratio in alcohol-fed rats. Compared with this early decrease in testosterone-related parameters, there was a significant increase in serum estrogen levels (at 30 and 90 days, 132% and 168% of control values, respectively). An increase in serum ceruloplasmin, an estrogen-responsive liver protein, was apparent at 60 and 90 days, but not at 30 days of alcohol exposure, suggesting that hypogonadism precedes liver feminization. Hepatic estrogen receptor activity was decreased in alcohol-fed rats at 60 and 90 days, the latter despite elevated serum estrogen levels. Hepatic aromatase was slightly increased in alcohol-fed rats, an elevation probably not sufficient to account for observed increases in serum estrogen. Taken together, these data suggest that (1) alcohol induces profound reduction of serum testosterone, resulting in loss of androgen-regulated hepatic functions such as estrogen-metabolizing enzyme activity and activity of androgen receptors; and (2) such alcohol-induced hypogonadism precedes changes in hepatic sex hormone homeostasis and subsequent feminization.

Hepatic hyperplasia and cancer in rats: alterations in copper metabolism.

We previously demonstrated that rats exposed to the peroxisome proliferator (PP) diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxidase activity, which suggests tissue copper deposition. Copper is highly toxic in excess, and results in cellular damage and hepatocellular carcinomas (HCC). This study addresses changes in expression of copper-related genes and metal accumulation in hyperplastic liver and tumors induced by PP. Male rats were fed diets containing DEHP or clofibrate (CLF) for 3-60 days (hyperplasia) and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-beta-hydroxyethyl) acetamide for 10 months (HCC). During hyperplasia, an immediate and progressive decrease in serum CP activity was observed (P < 0.05), as were reductions in mRNA levels for both CP and Wilson's disease gene (WD gene, a P-type ATPase) (P < 0.05). Tumor-bearing rats had lower serum CP activity (P < 0.05), and CP and WD gene mRNA levels were reduced in tumors (P < 0.05), and in liver surrounding tumors (SL) (P < 0.05). Metallothionein mRNA showed no consistent changes during hyperplasia. Tumors showed a 2.5-fold induction of metallothionein mRNA (P < 0.05), and a 1.2-fold increase in SL. Temporal increases in liver copper content occurred during hyperplasia, with increases of 2-fold (DEHP) and 3.3-fold (CLF) at 60 days (P < 0.05). Copper content was 2.2-fold higher in tumors (P < 0.05) and 1.7-fold higher in SL; iron did not increase and zinc decreased temporally. Thus, copper accumulation and changes in copper-related gene expression may be contributing factors in liver neoplasia in PP-treated rats. Loss of CP results in decreased free radical scavenger capacity and thus may enhance oxidative damage induced by PPs.

Time to relief of episodic symptoms of gastro-oesophageal reflux disease. A crossover comparison of single doses of the effervescent and standard formulations of ranitidine.

BACKGROUND: The length of time until symptom relief and the consistency of response are important aspects of the management of episodes of gastro-oesophageal reflux disease (GORD). METHODS: In an open, randomized, crossover study 98 patients treated 3 episodes of GORD with ranitidine effervescent formulation and 3 with ranitidine standard formulation. The patients filled in a diary card during the 1st h after each study medication. Satisfaction with the formulations and the formulation of choice were determined at the end of the study. RESULTS: A higher percentage of episodes with acceptable symptom relief (82.4% versus 73.1% P=0.024) and a shorter time to acceptable symptom relief (27 min versus 36 min; P < 0.001) were achieved with the effervescent formulation. Sixty-five per cent preferred the effervescent formulation (P < 0.01). CONCLUSIONS: An increased consistency of response and a more rapid symptom relief were achieved with treatment with the ranitidine effervescent formulation, indicating it may be more appropriate for on-demand treatment in patients with episodes of GORD.

Overexpression of hepatic pancreatic polypeptide receptors in chronic pancreatitis.

Pancreatic polypeptide (PP) receptors have recently been demonstrated on liver microsomal membranes although the mechanisms of PP action on hepatocytes remain uncertain. The binding characteristics of these high affinity receptors under pathophysiologic conditions were studied in rats with oleic acid-induced chronic pancreatitis (CP), a state associated with diminished pancreatic PP content. Sixteen pancreatitic and 11 sham-operated control animals either were 16-h fasted or were given free access to food prior to organ removal. Competitive binding studies were performed by incubating hepatocyte microsomal preparation with 125I-labeled PP (20-40 pM) and increasing concentrations of nonlabeled PP (1 x 10(-10) to 1 x 10(-6) M). After total and nonspecific binding was quantified by gamma counting, coefficients of dissociation (Kd) and maximal binding sites (Bmax) were determined by Scatchard analysis of specifically bound radioactivity. Binding data were normalized to membrane protein content and expressed as means +/- standard error. Bmax was significantly greater in tissue from fed control animals than from fasted controls (4.46 +/- 0.36 versus 2.83 +/- 0.25, P < 0.05). Bmax was significantly greater under fasted conditions in tissue from CP animals than from controls (5.25 +/- 0.94 versus 2.83 +/- 0.25, P < 0.01). Under fed conditions, this differences was abolished by the increase in maximal binding in the control group. The fasting-associated decrease in maximal binding sites observed in controls did not occur in CP specimens. Increased Bmax in fed versus fasted control, as well as fasted CP versus fasted control, were associated with slight reciprocal decreases in receptor affinity. These data indicate that hepatic PP receptor concentration is upregulated in this model of chronic pancreatitis, most likely due to diminished exposure to ligand. Furthermore, normal PP receptor responses to the fed/fasted state are blunted in this condition. Regulatable PP receptor changes may play a role in altered hepatic metabolism previously observed in chronic pancreatitis.

Studies on the detection of tetracycline residues in poultry organs and tissues.

Oral and intramuscular administration of tetracycline to poultry resulted in a significant residue in muscles and organs. The highest concentration was detected after 6 hours of administration. The residues gradually decreased by time reaching around the minimum inhibitory concentration (MIC) after 24 hours. After 4 days no residue was detected in any organ. The results also revealed that the residues were higher in case of the intramuscular than the oral administration and disappeared earlier. Random samples from local markets showed that out of 50 samples examined for presence of antibiotic residues, only two chickens (4%) were positive in liver, and five samples (10%) were positive in kidney. No antibiotic residue was detected in any of the breast samples or thigh samples. Five days pre-slaughter withdrawal time is recommended to ensure complete withdrawal of antibiotics from all organs.

Hepatic hyperplasia and cancer in rats: metabolic alterations associated with cell growth.

BACKGROUND & AIMS: We showed previously that the peroxisome proliferators di(2-ethylhexyl)phthalate (DEHP), clofibrate, and 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyl)acetamide (BR931) alter hepatic sex steroid metabolism and receptor expression during induction of hepatic hyperplasia and hepatocellular carcinoma (HCC) in rats. The aim of this study was to identify metabolic changes associated with cell growth during hyperplasia and HCC. METHODS: Hepatic hyperplasia was induced in male rats by a diet containing DEHP and clofibrate for 3-60 days. HCC was induced by feeding a diet containing BR931, a more potent hepatocarcinogen, for 10 months. RESULTS: Cholesterol biosynthesis was depressed in hyperplastic livers but increased in HCC. Glucose-6-phosphate dehydrogenase (G6PD) activity was inhibited in hyperplastic liver as well as in HCC, whereas malic enzyme activity increased severalfold. Protein and messenger RNA (mRNA) levels for both G6PD and malic enzyme increased in hyperplastic livers and HCC. mRNA levels for 3-hydroxy-3-methylglutaryl-coenzyme A reductase decreased in hyperplasia and increased in HCC, whereas low-density lipoprotein receptor mRNA increased in hyperplasia and decreased in HCC. CONCLUSIONS: Neoplastic cells acquire a growth advantage by their capacity to synthesize cholesterol and obtain reduced nicotinamide adenine dinucleotide phosphate by the malic enzyme pathway when G6PD activity is inhibited by peroxisome proliferators.

Sex steroid metabolism and receptor status in hepatic hyperplasia and cancer in rats.

BACKGROUND & AIMS: Both androgenic and estrogenic steroids have been implicated in the development and course of several liver diseases, including hepatocellular carcinoma. The aim of this study was to investigate temporal changes in hepatic estrogen and androgen receptors and hormone metabolism in a rat model of liver hyperplasia and carcinogenesis. METHODS: Rats were fed hepatocarcinogenic peroxisome proliferator agents for 3 days to 10 months. Livers were examined for proliferation markers, activity and cellular distribution of sex steroid receptors, and key enzymes in sex hormone homeostasis. RESULTS: At all times, liver weight and proliferation markers in treated rats were increased. Early exposure resulted in increased nuclear estrogen and androgen receptor activity in treated rats. Tumors that developed after 9-10 months showed a marked decrease in estrogen receptor activity and, in contrast, an increase in androgen receptor activity, as did liver surrounding the tumors. Both short-term and long-term exposure to the carcinogens resulted in dramatic reductions in steroid metabolism. CONCLUSIONS: This study supports the thesis that, in preneoplastic stages such as hyperplasia, there is an elevation of both receptor activities and that the progression from hyperplasia to cancer results in suppression of estrogen receptor expression but maintenance of androgen receptor.

Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia.

Exposure to a common phthalate, di(2-ethylhexyl)phthalate (DEHP), is associated with liver hyperplasia prior to the development of hepatocellular carcinoma in rodents. The exact mechanism of liver hyperplasia as well as tumorigenesis by this agent is not known. Since other lines of evidence point to estrogens as mediators of liver hyperplastic changes, we investigated whether DEHP exposure might alter hepatic estrogen metabolism and induce hyperplasia. Male Fischer 344 rats were fed either control or 1.2% DEHP-containing diets and sacrificed after 4, 8 and 16 weeks of exposure; activities of several sex hormone-responsive markers were measured. Rats fed DEHP had significantly increased serum estradiol levels, but hepatic activity of both cytosolic and nuclear estrogen receptor (ER) was significantly reduced. The serum content of ceruloplasmin, an estrogen-responsive protein synthesized by the liver, was also reduced, perhaps as a consequence of loss of ER activity. The rise in serum estradiol in DEHP-treated rats may be explained by the observation that these rats showed significant losses in hepatic activity of both a major male estrogen-metabolizing enzyme, estrogen 2-hydroxylase, and a male-specific estrogen-sequestering protein. In contrast to reductions in these activities, the expression of proliferating cell nuclear antigen and mRNAs for both ER and fos increased significantly as a result of exposure to DEHP. Our results suggest that changes in estrogen metabolism, receptor activity and activation of genes for cell proliferation are among the earliest metabolic alterations induced by DEHP. These changes together with the induced hyperplasia could play a crucial role in hepatocellular carcinoma development as a result of continuous exposure to DEHP.

Androgen receptor in human liver: characterization and quantitation in normal and diseased liver.

Liver is responsive to sex hormones. The role of androgens in normal human liver function is not well understood, although androgens have been implicated in several liver diseases. Because the human hepatic androgen receptor has not been adequately characterized, we analyzed cytosolic and nuclear fractions from normal human liver of both sexes for androgen-binding activity using multipoint saturation analysis with the androgenic radioligand methyltrienelone (R1881). Both cytosolic and nuclear fractions of both sexes displayed high affinity R1881 binding (dissociation constants = nanomolar range). The R1881 binding in both fractions is highly specific in that potent androgens compete well, and the antiandrogens hydroxyflutamide and cyproterone acetate show partial competition; other nonandrogenic steroid hormones do not compete. The cytosolic R1881 receptor displays physicochemical characteristics of androgen receptors in other tissues in that it is retained by heparin-Sepharose and by DNA cellulose after activation, and it displays a molybdate-stabilized 8S form on sucrose gradients and a 7.3-nm species on gel filtration chromatography. Receptor activity was also quantitated in specimens of hepatic adenoma, focal nodular hyperplasia and metastatic carcinoma to the liver and in samples of adjacent histologically normal specimens when available. In general, both the diseased and normal portions of the livers from the patients with hepatic adenoma and metastatic carcinoma to the liver, but not focal nodular hyperplasia, demonstrated reduced total androgen-receptor activity as compared with liver from normal individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of estrogen and androgen receptors in hepatocellular carcinoma and adjacent normal human liver.

Sex hormones have been shown to influence the development and course of several liver diseases. The worldwide predominance of hepatocellular carcinoma (HCC) in males has led to the suggestion that this disease might be hormone-responsive. Therefore, the hepatic estrogen (ER) and androgen receptor (AR) status of liver specimens from such patients was investigated. Samples were obtained from three female and six males patients undergoing liver resection; in each case, a small sample of both the tumor and adjacent normal tissue was collected. All patients had primary hepatocellular carcinoma without cirrhosis. In most cases, the tumor and the normal specimen had an equivalent content of cytosolic ER; however, three of the tumor samples (one female and two male) displayed considerably elevated cytosolic ER levels as compared to that of the normal tissue. In every sample, the tumor contained less nuclear ER than did the normal liver. When AR was measured, tumors of three patients (one female and two male) demonstrated a twofold elevation in cytosolic AR as compared to adjacent normal tissue. In the two male patients, an approximately twofold greater nuclear AR was found. Two other samples from male patients showed a modest elevation of cytosolic AR in the tumors. The patients whose tumors showed elevations in ER were not the same patients as those in whom the AR was elevated. Thus, these studies indicate that certain, but not all, specimens of HCC demonstrate either elevated ER or AR and suggest that a determination of receptor content might be useful prior to initiation of certain antihormone therapies.

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats.

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy.

Effect of tamoxifen on hepatic regeneration in male rats.

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per se determines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli.

Liver regeneration in rats treated with the antiandrogen flutamide.

Previous studies have shown that male rat liver undergoes demasculinization during hepatic regeneration after partial hepatectomy. In the present study the effect of the antiandrogen flutamide on liver regeneration was assessed. Adult male Wistar rats were treated with flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for 3 days prior to and daily after partial hepatectomy. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. The rate of liver growth after partial hepatectomy in the three groups was similar at all time points examined. The increases in thymidine kinase activity and ornithine decarboxylase activity after partial hepatectomy were comparable throughout the study. Thus, administration of flutamide did not influence the regenerative response after partial hepatectomy.

Hepatic estrogen receptor in human liver disease.

Human liver contains estrogen receptors which render it sensitive to estrogen. Specific hormone binding to cytosol and nuclei from normal liver containing such receptors is of high affinity, low capacity, saturable, and specific for steroidal and nonsteroidal estrogens. Although estrogens alter metabolism and may produce disease, little data is available concerning estrogen receptor levels found in diseased liver. Herein we report estrogen receptor levels in human female liver containing diseases associated with oral contraceptives. Binding studies demonstrated cytosolic and nuclear estrogen receptors in human hepatic adenoma and focal nodular hyperplasia. Nuclear estrogen receptor levels in neoplastic tissue were greater than those in normal tissue. In addition, one hepatic adenoma resected from a patient taking tamoxifen contained no cytosolic estrogen receptor, and nuclear estrogen receptor levels were significantly lower than those found in normal tissue. These differences in binding capacity suggest a potential for greater hormone responsiveness in neoplastic liver tissue.

Characterization and quantitation of human hepatic estrogen receptor.

Because the liver is an estrogen-sensitive organ and such sensitivity necessitates the presence of an hepatic estrogen receptor, we assayed whole human liver cytosol for the presence of estrogen receptor. Scatchard plot analysis of specific [3H]diethylstilbestrol binding to whole human liver cytosol from both sexes demonstrated hormone binding that is of high affinity (Kd = 10(-10)M) and low capacity (1-10 fmol/mg cytosol protein), and that is saturable and specific for steroidal and nonsteroidal estrogens, but not for other steroids. The protein can be further characterized as an estrogen receptor by its binding to heparin-Sepharose. In addition, gel filtration chromatography of [3H]estrogen-labeled cytosol on Sephadex G-100 indicates that potentially contaminating proteins, such as albumin and sex-steroid-binding globulin, do not bind [3H]estrogen in whole cytosol. We conclude that human liver from both sexes has estrogen receptor and that the presence of estrogen receptor in human liver explains the sensitivity of the human liver to estrogen.