Phosphorus recovery from the sludge generated from a continuous bipolar mode electrocoagulation (CBME) system.

Phosphorus is known to be a limited non-renewable resource. Phosphorus is obtained from phosphate rock, which is likely to be depleted in the next few decades. Therefore, it is very important to find alternate sources of phosphorus from which phosphorus can be recycled and recovered. This study focuses on the recovery of phosphorus from the sludge generated from a continuous bipolar mode electrocoagulation (CBME) system, used for treating a palm oil mill effluent (POME). The sludge generated from the CBME system is leached with oxalic acid and sulphuric acid for phosphorus recovery with and without thermal treatment. Acid leaching was carried out at various time intervals using various liquid/solid (L/S) ratios of acids and sludge. The CBME system caused a 73% removal of phosphorus from POME, where phosphorus is precipitated in sludge as iron phosphates or adsorbed as phosphates depending on the pH in the system. Acid leaching resulted in nearly 85% recovery of phosphorus with both sulphuric acid and oxalic acid for sludge combusted at 900 °C. Statistical analysis was carried out to find the significance of the operational conditions on the phosphorus yield. Acid leaching results in the formation of orthophosphates, which can be used as a raw material for synthesis of chemical fertilizers.

The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses.

Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg-IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two-hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) (P < 0.0001). Multivariate logistic-regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002-1.139] and RVR (OR, 11.251; CI, 5.184-24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg-IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg-IFN (P = 0.795) nor ribavirin (P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg-IFN (0.77 +/- 0.10 microg/kg/week) and ribavirin (6.9 +/- 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients.

Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin.

The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given > or = 12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 microg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.

Pegylated interferon alpha-2b (Peg-IFN alpha-2b) affects early virologic response dose-dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg-IFN alpha-2b plus ribavirin.

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN alpha-2b during the first 12 weeks was the independent factor for c-EVR (P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving > or = 1.2 microg/kg/week of Peg-IFN, and declined to 38% at 0.9-1.2 microg/kg/week, and 22% in patients given <0.9 microg/kg/week (P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 (P < 0.0001) and SVR (P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.

Nipponium as a new element (Z=75) separated by the Japanese chemist, Masataka Ogawa: a scientific and science historical re-evaluation.

This review article deals with a new element 'nipponium' reported by Masataka Ogawa in 1908, and with its scientific and science historical background. Ogawa positioned nipponium between molybdenum and ruthenium in the periodic table. From a modern chemical viewpoint, however, nipponium is ascribable to the element with Z=75, namely rhenium, which was unknown in 1908. The reasons for this corrected assignment of nipponium are (1) its optical spectra, (2) its atomic weight when corrected, (3) its relative abundance in molybdenite, the same being true with rhenium. Recently some important evidence was found among the Ogawa's personal collection preserved by his family. Deciphering the X-ray spectra revealed that the measured spectra of the nipponium sample that Ogawa brought from University College, London clearly showed the presence of the element 75 (rhenium). Thus was resolved the mysterious story of nipponium, which had continued for almost a century. It is concluded that nipponium was identical to rhenium.

Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver.

This study was designed to investigate the mechanism for ethanol-induced hepatic vasoconstriction in isolated perfused rat liver. Upon initiation of ethanol infusion into the portal vein at concentrations ranging from 25 to 100 mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2-5 min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phenomenon). Endothelin-1 antiserum significantly inhibited this ethanol-induced hepatic vasoconstriction by 45-80%. Cessation of infusion of endothelin-1 antiserum was followed by a subsequent increase in portal pressure. On the other hand, when a nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the portal vein simultaneously with ethanol, the initial phase of the response of portal pressure to ethanol was not altered and the peak values of portal pressure remained unchanged. However, after the peak increase in portal pressure, the rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished the escape phenomenon and sustained the vasoconstriction. This study supports the hypothesis that two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide, regulate hepatic vascular tone in the presence of ethanol.

Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma.

Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its ability to promote vascular permeability and endothelial cell growth, and its role in tumor development has received considerable attention. In this report, we describe the elevation of VPF/VEGF transcript expression in human hepatocellular carcinoma. Surgical samples of 23 patients with hepatocellular carcinoma were studied using reverse transcription-PCR analysis. The oligonucleotide primers were designed to amplify all four known splicing variants that could be expressed in the samples studied. Sixteen cases showed VPF/VEGF transcript expression in the tumor (16/23, 69.6%), whereas only 9 of the 23 patients showed it in the corresponding nontumoral part. There was no difference between the pattern of expression of VPF/VEGF isoforms in tumoral and nontumoral tissues. VPF/VEGF mRNA expression in the liver tumors was associated with fibrous capsule formation and septal formation (P < 0.05 respectively, Fisher's exact P test). In situ hybridization confirmed the presence of VPF/VEGF mRNA expression in tumor cells and less intensely in hepatocytes of nontumoral liver. We also found that VPF/VEGF expression in the tumor cell was increased in the area adjacent to necrotic regions (presumably hypoxic regions). As a regulator of vascular permeability and endothelial cell growth factor, VPF/VEGF may play an important role in the development of hepatocellular carcinoma.

Chapter Seven - When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling.

Cell-surface receptors govern the critical information passage from outside to inside the cell and hence control important cellular decisions such as survival, growth, and differentiation. These receptors, structurally grouped into different families, utilize common intracellular signaling-proteins and pathways, yet promote divergent biological consequences. In rapid processing of extracellular signals to biological outcomes, posttranslational modifications offer a repertoire of protein processing options. Protein ubiquitination was originally identified as a signal for protein degradation through the proteasome system. It is now becoming increasingly recognized that both ubiquitin and ubiquitin-like proteins, all evolved from a common ubiquitin structural superfold, are used extensively by the cell and encompass signal tags for many different cellular fates. In this chapter we examine the current understanding of the ubiquitin regulation surrounding the insulin-like growth factor and insulin signaling systems, major members of the larger family of receptor tyrosine kinases (RTKs) and key regulators of fundamental physiological and pathological states.

A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.

BACKGROUND: Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. RESULTS: We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TR beta over TR alpha. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. CONCLUSIONS: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TR beta selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms.

Selective thyromimetics: tissue-selective thyroid hormone analogs.

Thyroid hormone coordinates a diverse array of physiological events in development and homeostasis. Many of the actions of thyroid hormone are tissue-specific and are primarily mediated by a panel of thyroid hormone receptor isoforms that are expressed in different ratios in different tissues. Because these tissue-specific hormone signaling pathways are linked to a number of metabolic diseases, the development of synthetic thyroid hormone analogs that have tissue-selective hormone actions (i.e., selective thyromimetics) is highly desirable. There is a powerful collection of tools available today for this pursuit including efficient receptor binding and activation assays, receptor structures and a variety of thyroid hormone receptor knockout mice. The medicinal chemistry efforts in this area demonstrate that selective thyromimetics can be produced from a variety of approaches. These compounds are proving useful as probes to better define thyroid hormone actions and may one day find use in the clinic for the treatment of metabolic disorders.

Ethanol-induced disturbance of hepatic microcirculation and hepatic hypoxia.

The hypothesis was tested whether ingestion of ethanol might disturb the hepatic microcirculation with resulting hepatic hypoxia. Infusion of ethanol increased the portal pressure concentration-dependently in rat livers perfused with Krebs-Henseleit buffer at a constant flow rate (Emax = 11.5 cm H2O, EC50 = 90 mM). This increase in portal pressure was due to hepatic vasoconstriction, since it diminished in the presence of sodium nitroprusside, a direct acting vasodilator. The regional hepatic tissue hemoglobin concentration after perfusion with added erythrocyte suspension (hematocrit 1%), measured by tissue-reflectance spectrophotometry, was significantly diminished by the infusion of ethanol, indicating the impairment of the microcirculation of the superficial layer of the liver. When the absorption spectrum of the liver was examined by reflectance spectrophotometry, infusion of ethanol caused a parallel reduction of all the mitochondrial respiratory cytochromes in a concentration-dependent fashion, concomitant with the increase of portal pressure, indicating a marked reduction of oxygen concentration in superficial liver tissue. The reduction of the respiratory cytochromes was also associated with the decrease in oxygen consumption of the liver, indicating that the hepatic hypoxia was due to the reduction of oxygen delivery to hepatocytes rather than the increased oxygen consumption of the liver. The reduction of the respiratory cytochromes was correlated with the increase in portal pressure and was inhibited by sodium nitroprusside. These data indicate that the ethanol-induced hepatic vasoconstriction disturbs hepatic microcirculation, resulting in hepatic hypoxia and reduction of mitochondrial respiratory cytochromes.

FK506-associated limbic injury following umbilical cord blood transplantation.

A 5-year-old girl with Ph-positive chronic myelogenous leukemia, who underwent umbilical cord blood transplantation, developed two episodes of electrical status epilepticus while receiving tacrolimus (FK506) then cyclosporin A (CsA), as treatment against graft-versus-host disease. MRI including diffusion weighted MR imaging of the brain revealed abnormalities in the hippocampus and posterior white matter following FK506 and CsA treatment, respectively. While posterior white matter injury has been described with both FK506 and CsA, no previous report describes hippocampal injury from either drug. The MRI changes in the hippocampus in our case suggest possible increased susceptibility to hippocampal injury with FK506.

cDNA sequencing of mouse alpha 1-microglobulin/inter-alpha-trypsin inhibitor light chain and its expression in acute inflammation.

A cDNA encoding alpha 1-microglobulin (alpha 1mG)/inter-alpha-trypsin inhibitor light chain (ITI-LC) was cloned from mouse liver by reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. Sequence analysis of the cDNA showed that the basic molecular structure of the proprotein was similar to that in other animals, so that two mature proteins, alpha 1mG and ITI-LC, could be produced from the proprotein translated from the mRNA. Since ITI-LC is known as a positive acute phase reactant and since ITI-LC is genetically identical with mast cell proteinase inhibitor, trypstatin, we examined the mRNA level in the liver of parasite-infected mice showing extensive mastocytosis. The mRNA level was, however, not significantly changed during inflammatory processes, except for a slight increase on day 8 post-infection.

Changes in coagulation and fibrinolysis occurring in dogs during hypothermia.

Changes in fibrinolysis, platelets and coagulation during hypothermia were investigated in anesthetized dogs. Strong activation of plasma fibrinolysis was observed in the hypothermia group. The maximum fibrinolytic activity determined with standard fibrin plates was markedly higher than that of the control sample (mean values: 67 and 15 mm2/0.03 ml plasma, respectively). On the other hand, no fibrinolysis was observed by the plasminogen free plate method. Activation was not observed in the control group or the hypothermia group premedicated with chlorpromazine. The platelet count was decreased from 100% to 14.7% and the collagen induced platelet aggregability from 61% to 2.3% during hypothermia. Recovery from both reductions occurred on rewarming. In the control and premedicated groups, the recalcification time was reduced progressively (from 93.6 to 60.9 sec and from 101.1 to 71.8 sec as mean times, respectively). The tendency towards shortening of the recalcification time was not related to the core temperature.

Cellulose acetate electrophoretic determination of bone alkaline phosphatase activity in healthy subjects and diabetic patients with and without osteopenia.

We adapted the electrophoretic method of bone alkaline phosphatase (ALP) determination using neuraminidase from Vibrio cholerae to separate bone and liver ALP on cellulose acetate membrane. Treatment of separator plus serum (1:8, neuraminidase 111 U/l in final) for 10 min at room temperature (25 +/- 1 degree C) and subsequent electrophoresis made it possible to quantify bone ALP activity simply and rapidly. The precision of the data was at the level of CV of 1.6% (within-day) and 4.7% (day-to-day), with recovery rates of 97-103%. The normal range of bone ALP activity depended on age and sex. Seventy-eight diabetes mellitus (DM) patients, excluding those with renal failure, were divided into two groups of those with and without osteopenia with matching of age (+/- 3 years) and sex. Bone ALP (P < 0.001) and total ALP (P < 0.05) activities and urine calcium/creatinine ratio (P < 0.05) were significantly higher in DM with osteopenia than in DM without osteopenia. Therefore, bone formation and absorption may be accelerated in DM with osteopenia in comparison with DM without osteopenia.

Acid stable trypsin inhibitor in bile.

Acid stable trypsin inhibitor having the same antigenicity as urinary trypsin inhibitor was first identified in the bile of patients with malignant tumors (biliary tract carcinoma or pancreas head carcinoma) and gallstones. Bile trypsin inhibitor from malignant tumor patients was partially purified by DEAE cellulose ion exchange column chromatography. Two molecular forms of the inhibitor were identified. The main form had a molecular weight of about 86,000 and the minor one a molecular weight of 31,000 as determined by gel filtration. Using isoelectric focussing, the larger molecular form gave a pI value of 2.0 and the smaller form, a pI value of 5.1. The isolated larger form migrated on the slightly cationic side of human serum albumin by analytical polyacrylamide gel electrophoresis. The larger form reacted and fused with anti-urinary trypsin inhibitor serum and strongly inhibited trypsin, partially inhibited chymotrypsin and plasmin, but did not inhibit urokinase. The clinical significance of acid stable trypsin inhibitor is discussed.

Menadione causes selective toxicity to periportal regions of the liver lobule.

Infusion of increasing concentrations (0.2-1 mM) of the quinone, menadione, caused step-wise increases in oxygen uptake in perfused livers from fasted rats presumably due to oxygen-dependent redox cycling. Maximal increases in oxygen uptake of about 40 mumol/g/h were observed with 0.8 to 1.0 mM menadione. This increase in oxygen uptake was confined to periportal areas of the liver lobule suggesting that redox cycling due to menadione occurs exclusively in cells localized around the portal triad. After 60 min of infusion of menadione (1 mM), lactate dehydrogenase was released from the liver at rates between 60 to 70 U/g/h. Under these conditions, trypan blue was taken up by virtually all hepatocytes in periportal regions of the liver lobule. In contrast, dye was not taken up by cells in pericentral areas. It is concluded that menadione is selectively toxic to hepatocytes located in oxygen-rich periportal regions of the liver lobule.

Low Km ALDH isozyme and alcoholic liver injury.

To assess the relationship between the polymorphism of aldehyde dehydrogenase (ALDH) isozyme and alcoholic liver injury, ALDH isozyme was analyzed by isoelectric focusing electrophoresis in hair roots from normal volunteers and alcoholics with chronic liver disease. Liver biopsy specimens from alcoholics and non-alcoholics with chronic liver disease were also analyzed. It was found that (1) the frequency of low Km ALDH isozyme in hair roots from chronic alcoholics with liver injury was 90%, which was significantly higher than those from normal volunteers (44%) and from non-alcoholics with chronic liver disease (56%); (2) the isozyme pattern of liver specimens analyzed coincided with that of hair roots; (3) the low Km ALDH isozyme-positive subjects including alcoholics showed no facial flushing, and negative subjects showed facial flushing after drinking alcohol. It is concluded that a much higher frequency of low Km ALDH isozyme was found in chronic alcoholics with liver injury. There was no apparent difference in hepatic biochemical and histological findings between chronic alcoholics with and without low Km ALDH isozyme, suggesting that acetaldehyde does not play a primary role in the pathogenesis of alcoholic liver injury.