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PubMed2005

Nonalcoholic fatty liver disease: a clinical review.

Nonalcoholic fatty liver disease may be the most common liver disease in the United States, with a high prevalence in the obese, type 2 diabetic population, and it is probably underestimated as a cause for cirrhosis. Clinicopathologically, it represents a wide spectrum of histologic abnormalities and clinical outcomes, ranging from benign hepatic steatosis to cirrhosis. Pathophysiologically, insulin resistance is thought to be pivotal in the development of steatosis, after which a second oxidative stressor produces lipid peroxidation and nonalcoholic steatohepatitis (NASH). Liver biopsy is the gold standard for diagnosis and prognosis. The need for an effective treatment is both clear and urgent, yet in the absence of proven therapies, treatment is directed toward weight loss and comorbidity management. For patients with NAFLD at risk of disease progression, there is a lack of large, randomized, placebo-controlled trials of adequate treatment duration, with baseline stratification according to histologic severity.

Fatty Liver↗

PubMed2005

A clinical-morphological study on cholestatic presentation of nonalcoholic fatty liver disease.

To determine the association among the clinical, biochemical, and histological features of cholestasis, we analyzed all the relevant data of the patients recorded in our non-alcoholic fatty liver disease (NAFLD) database. We selected 20 NAFLD patients with abnormal transaminase levels, with both alkaline phosphatase >500 U/L and gamma-glutamyl transpeptidase >250 U/L. Their histological features were compared with those of a group of patients with NAFLD matched for sex, age, and body mass index and of a group of patients matched for sex, body mass index and histological NAFLD grading/staging. Cases and controls satisfied, on histology, the criteria for NASH. The presence of cholestasis in our patients was correlated with injury of the bile duct epithelium, characterized by cholangitis, swelling, variable bile duct loss, and bile stasis. Compared to NAFLD patients of similar age, sex, and body mass index, the cholestatic group had total and severe histological liver impairment. When we analyzed the group of patients histologically identified on the basis of identical stage and grade severity, we could not find any evidence of significant bile damage, compared to cases, despite the control group's significantly older age. NAFLD patients with biochemical cholestasis have a histological picture of bile damage; they have more advanced histological impairment than patients matched for age, sex and body mass index.

Aged↗

PubMed1990

Oxidation of glycerol to formaldehyde by rat liver microsomes. Effects of cytochrome P-450 inducing agents.

Glycerol was shown recently to be metabolized to formaldehyde by microsomes from chowfed control rats (Winters et al., Biochem Biophys Res Commun 153: 612-617, 1988). In the present study, experiments were carried out to evaluate the oxidation of glycerol by microsomes isolated from rats treated with inducers of different isozymes of cytochrome P-450. The oxidation of glycerol to formaldehyde was increased in microsomes from rats treated with pyrazole, ethanol or acetone relative to their respective controls, but not after treatment with phenobarbital or 3-methylcholanthrene. This reaction was sensitive to inhibition by carbon monoxide and was inhibited by compounds known to be effective substrates for P-450j, e.g. aniline, ethanol, pyrazole and 4-methylpyrazole. Treatment with pyrazole caused an increase in Vmax for glycerol oxidation but did not affect affect the Km (about 15 mM) for glycerol, as compared to saline controls. Evidence that the product of glycerol metabolism is formaldehyde was provided by the observation that this product served as a substrate for the glutathione-dependent formaldehyde dehydrogenase, and the amount of formaldehyde detected was identical to that detected by the Nash reaction. By utilizing [14C]glycerol, and coupling the formaldehyde dehydrogenase reaction to the formate dehydrogenase reaction, 14CO2 could be detected, indicating that the formaldehyde produced was derived from the added glycerol. These results suggest that that glycerol is not metabolically inert when added to microsomes but serves as an effective substrate for the cytochrome P-450j isozyme, extending the alcohol substrate specificity of this enzyme to poly-ols. The production of formaldehyde from glycerol may require caution since glycerol is often present in microsomal or reconstituted systems.

Acetone↗

PubMed1990

Percutaneous ablation of gallstones.

The purpose of this study was to determine if gallstones could be safely and effectively ablated in the pig using a proprietary percutaneous rotor-tipped catheter, the Kensey-Nash Lithotrite (KNL). All gallstones in a single human gallbladder were defined as a gallstone set. Human gallstone sets not meeting current treatment criteria for extracorporeal shock wave lithotripsy (ESWL) were placed in the gallbladder (GB) of male pigs (N = 8; 80-100 kg). A percutaneous transhepatic guide wire was put into the GB and the abdomen closed. The KNL was then introduced under fluoroscopy using the Seldinger technique and activated. Gallstone ablation was monitored by tactile and auditory feedback to the operator and by fluoroscopy. Once completed the device was withdrawn, the GB irrigated, and the 9F sheath removed. Animals were sacrificed immediately (Group 1, N = 4) and at 28 +/- 5 days (Group 2, N = 4). Gallstones were ablated in 26 +/- 8 min. No pig had significant hemorrhage, GB perforation, or pancreatitis. One acute animal had stone fragments greater than 2 mm in the gallbladder. No other animals had any fragments greater than 1 mm present in the GB, cystic duct, common duct, ampulla, or duodenum. Histologic examination of the GB showed acute hemorrhagic mucosal injury in Group 1 and extensive mucosal regeneration with some stone fragment granulomata and mural fibrosis in Group 2. We conclude that percutaneous gallstone ablation with the KNL is safe and effective in this short-term pig model and appears to be a safe procedure for gallstone ablation. Long-term safety and effectiveness remain to be demonstrated. This device should be useful for treatment of symptomatic gallstones in patients not treatable by ESWL.

Animals↗

PubMed1983

A game-theoretical model of parasite virulence.

The evolution of parasitic reproductive rates, relative infectiousness and severity of disease are considered using a game-theoretical model in which parasites compete within hosts. Each parasite's fitness is assumed to be directly proportional to the product of its reproductive rate (lambda) and the length of time (T) over which it reproduces. An increase in a parasite's reproductive rate is assumed to increase its host's disease-induced mortality rate (alpha) and consequently, through host death, to decrease T. By maximizing the total number of propagules that individuals produce with respect to their individual reproductive rates, we show that competitors within a host may be favored by natural selection to reproduce at rates below their maximum potential rates. Whether competitors behaving with such restraint can coexist at a Nash equilibrium is shown to depend on the functional form of alpha (lambda) and on the number of competitors within a host. While an individual's restraint benefits its within-host competitors through increased host longevity, the model does not invoke group selection. In the model, selection favors an individual's restraint when such behavior increases the individual's total number of propagules. Concurrent increases in the absolute and relative fitness of an individual's within-host competitors can be consequences of such individual selection.

Animals↗

PubMed1991

Optimal growth schedule of pathogens within a host: switching between lytic and latent cycles.

We have studied the optimal growth schedule of a pathogen, which maximizes the total number of transmissions from an infected host to other individuals until host death or recovery. It is assumed that both transmission rate f(N) and host mortality increase with the number of pathogens, N. The model predicts that the optimal growth schedule of pathogens strongly depends on the curvature of f(N): If f(N) increases faster than linearly with N, the pathogens should always reproduce at the maximum speed. By contrast, if f(N) saturates with N, the optimal schedule is composed of (1) a brief initial stage of infection, in which the pathogens proliferate at the maximum speed (productive cycle), (2) followed by the long latent period with the "stationary infection level," N* (latent cycle), (3) which may end when the pathogens start rapid proliferation triggered either by the host's senescence ("programmed break") or by the sudden rise in the host's mortality ("incidental break"). The latter may be caused by the double infection of another strain. We also examine the Nash equilibrium schedule of pathogen growth in the presence of multiple infections.

Age Factors↗

PubMed1992

Pay-as-you-go public pensions with endogenous fertility.

A 1986 "model of public pensions is generalized to allow for endogenous fertility. We show that gifts to the old, which can be viewed as social security contributions, are always positive in the steady state. An optimal stationary allocation is sustainable if savings are zero and fertility is exogenous. However, the optimal allocation is in general not sustainable. In particular, if a government enforces a social security plan setting the pension level at the optimal gifts and individuals optimize under the pension constraint, the resulting sustainable outcome is in general different from either the optimal or Nash outcome." The geographical focus is on developed countries.

Demography↗

PubMed1991

Enzymic synthesis of steroid sulphates. XVII. On the structure of bovine estrogen sulphotransferase.

Estrogen sulphotransferase plays a major role in controlling intracellular levels of 17 beta-estradiol in human mammary cancer cells and human endometrium. Bovine estrogen sulphotransferase c-DNA has recently been cloned; the encoded protein having a maximum Mr of 35,000 (Nash, A.R. et al. (1988) Aust. J. Biol. Sci. 41, 507-516). Enzyme of Mr 35,000 by SDS-PAGE has now been isolated and cyanogen bromide-cleaved peptides sequenced. The latter were identified in the c-DNA-predicted amino acid sequence which confirms that the active enzyme (Mr approximately 70,000) exists as a dimer of identical subunits. Sequence data on similar peptides isolated from an enzyme preparation containing a protein of Mr 74,000 as the major species on SDS-PAGE, which was previously thought to represent the enzyme, suggested that this protein was transferrin. This was confirmed by PAGE, SDS-PAGE, susceptibility to neuraminidase and reaction with bovine transferrin antibody. Isoelectric focusing experiments show that active enzyme exists in two or three polymorphic forms (pI values 5.3, 5.7 and possibly 5.9) having similar physicochemical properties of polymorphic forms of transferrin so that they overlap on ion-exchange chromatography and PAGE. The enzyme shows some homology to the amino acid sequence close to the Fe-binding site in lactoferrin and the question is raised as to the possible presence of a tightly bound metal in estrogen sulphotransferase involved in the binding of adenosine 3'-phosphate 5'-phosphosulphate.

Amino Acid Sequence↗

PubMed1993

The old-age security hypothesis revisited.

"Children's altruism toward parents is allowed in a two-overlapping-generations model with endogenous fertility. Parents raise children because, when retired, they expect gifts from their children who are essentially a capital good. Individuals' behavior between generations is examined by analyzing a Nash equilibrium, which is then compared with a social planner's optimal allocation. The pay-as-you-go public pension program is viewed as the optimal gifts from the optimal allocation when the latter is implemented. The effect on fertility of the introduction of a capital market is also analyzed. The validity of the old-age security hypothesis is shown to depend on the parameters of utility and cost functions."

Behavior↗

PubMed1990

NADPH-dependent reaction of paraquat in mouse brain microsomes.

When paraquat was incubated with mouse brain microsomes in the presence of NADPH, a Nash-reagent-reactive substance (NRRS) (but not formalin) was produced. It was found that NRRS production was decreased in a dose-dependent manner by N-ethylmaleimide, a sulfhydryl reagent, which also inhibited NADPH-cytochrome P-450 reductase in parallel with the decrease in NRRS production. NRRS production was reduced by radical scavengers (catechin, glutathione, mannitol, superoxide dismutase and catalase), or under anaerobic conditions. In addition, inhibitors of adrenal cortex mitochondrial cytochrome P-450 (metyrapone, aminoglutethimide and amphenone B) inhibited NRRS production without causing a significant decrease in NADPH-cytochrome P-450 reductase activity. These findings suggest that active oxygen species and the mixed-function oxidase system may play important roles in NRRS production from paraquat in brain microsomes.

Animals↗

PubMed1987

Spectrophotometric determination of obidoxime chloride as its Pd(II) complex in water and injections.

It has been established that obidoxime chloride reacts with palladium(II) chloride in the pH range 3.9-8.0 and forms a yellow water-soluble (1:1) complex with maximum absorbance at 355 nm. By applying the methods of Sommer, Nash and Job involving non-equimolar solutions the conditional stability constant of the complex, at the optimum pH of 6.3 and an ionic strength mu = 0.55 M, is found to be 10(5.3). The molar absorptivity at 355 nm is 3.16 x 10(4) l mol(-1) cm(-1) at pH 6.3. Beer's law is obeyed up to 20 mumol l(-1) obidoxime chloride concentration. The detection limit of the method is 0.36 mug ml(-1). The relative standard deviation (n = 10) varies over the range 1.10-2.66%. The proposed method was found to be suitable for the accurate and sensitive analysis of obidoxime chloride in water and injection solutions.

Journal Article↗

PubMed1989

Spectrophotometric determination of oxytetracycline in pharmaceutical preparations using sodium molybdate as analytical reagent.

A spectrophotometric method is proposed for the determination of oxytetracycline in pharmaceutical preparations. The method is based on the measurement of the absorbance of the molybdate-oxytetracycline complex at 404 nm (pH 5.50; mu = 0.1 M; 20 degrees C). The composition of the complex (1:1) was determined by the application of the spectrophotometric methods of Job and Bent-French (pH 5.50; lambda = 390 nm; mu = 0.1 M). The relative stability constant (K' = 10(4.6) of the complex was obtained by the methods of Sommer and Nash (pH 5.50; lambda = 390 nm; mu = 0.1 M; 20 degrees C). The molar absorptivity of the complex was 9.5 x 10(3) l mol-1 cm-1. Beer's law was obeyed over the concentration range 2.48-34.78 micrograms ml-1. The relative standard deviation RSD (n = 10) was 0.27-0.39%. The method proposed can be applied to the assay of oxytetracycline in capsules. The detection limit of oxytetracycline is 2.5 micrograms ml-1.

Capsules↗

PubMed2003

Hepatitis C virus infection and liver steatosis.

The mechanism by which the hepatitis C virus (HCV) causes chronic, progressive liver damage is unknown. Factors other than the virus itself have been implicated. The role of liver steatosis has been recently studied. Hepatic steatosis is a common histological finding occurring in more 50% of patients with chronic hepatitis C. Both host and viral factors have been demonstrated to play an important role in its development. In those patients infected with genotype 1, steatosis appears to be due to the co-existence of Non-Alchoholic SteatoHepatitis (NASH) with HCV and associated with an increased body mass index (BMI). Some recent observations suggest that steatosis may be of viral origin and related to genotype 3. This fact raises the possibility of a direct effect of specific viral sequences on the pathogenesis of lipid accumulation. Furthermore, hepatic steatosis attributed to genotype 3 correlates directly with serum and intrahepatic titters of HCV RNA. The resolution of steatosis after successful antiviral therapy as well as steatosis being a sign of recurrent HCV infection in patients with genotype 3 add convincing evidence that steatosis is viral related. The pathogenic mechanism induced by genotype 3 is speculative. A correlation between steatosis, intrahepatic HCV RNA and core protein expression suggest a direct effect. Further support is provided by the finding that HCV core protein induces steatosis in transgenic mice. Another possibility relates to interaction with hepatic triglyceride turnover. In conclusion, for patients infected with genotype 1, BMI has a role in the pathogenesis of steatosis while in those infected with genotype 3, steatosis may be due to a virus-specific cytopathic effect. Regardless of etiology, the contribution of both to liver fibrosis progression seems accepted.

Animals↗

PubMed2006

High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: comparison to C3H and C57 mice.

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases.

BACKGROUND: Fibrosis is a common consequence of chronic liver diseases irrespective of aetiology. Metalloproteinases play an important role in the fibrotic process participating in the balance between collagen synthesis and degradation. We examined whether matrix gelatinases and stromelysins are similarly involved in the development of viral (HCV, HBV) and non-viral (NASH) liver diseases. METHODS: Hepatic mRNA levels of matrix metalloproteinase MMP-2, MMP-9, MMP-10 and MMP-11 isolated from liver biopsies were measured by semi-quantitative RT-PCR. Seventy-three patients were examined in this study: non-diseased controls (10), patients with chronic hepatitis B (14), chronic hepatitis C (33) and non-alcoholic steatohepatitis (16). RESULTS: A significant increase of MMP-9 and MMP-10 expression was found in patients with non-viral (non-alcoholic steatohepatitis) liver disease. Patients with chronic hepatitis B and hepatitis C showed an increase in MMP-2 mRNA expression compared to controls. Moreover, chronic hepatitis B and hepatitis C patients had significantly different mRNA expression patterns. CONCLUSIONS: These findings indicate that matrix metalloproteinases are differentially involved in the fibrotic process of viral and non-viral chronic liver diseases. Differences exist between HBV and HCV chronic hepatitis. Differences between early and late fibrosis indicate that in future studies, careful staging of patients is mandatory for interpretation of results.

Biopsy↗

PubMed2005

Report on antibodies submitted to the stromal cell section of HLDA8.

The paradigm for tissue specific homing of leukocytes is the "area code" hypothesis, which predicts that a specific combination of adhesive interactions and chemokine signals from the endothelium directs leukocyte migration into specific tissue sites. This area code hypothesis has been supported by studies from previous HLDA workshops where endothelial specific cell antigens have been studied. Similarly, a clear haematopoietic "stem cell code" comprising the chemokine SDF-1 (CXCL12) and the adhesion receptor VCAM-1 (CD106) has been shown to contribute to the stem cell niche within bone marrow [K. Tokoyoda, T. Egawa, T. Sugiyama, B.I. Chai, T. Nagasawa, Cellular niches controlling B lymphocyte behaviour within bone marrow during development, Immunity 20 (2004) 707-718]. HLDA 7 included a section devoted to stem cell antigens, which began to define additional antigens important in these processes. During the course of HLDA 8 we have extended these observations to determine whether a more global stromal address code defined by fibroblasts, exists in variety of different tissues [G. Parsonage, A.D. Filer, O. Haworth, G.B. Nash, G.E. Rainger, M. Salmon, C.D. Buckley, A stromal area postcode defined by fibroblasts, Trends Immunol. 26 (2005) 150-156]. The stromal cell section in HLDA 8 was designed to complement the malignant cell, endothelial cell, and stem cell/progenitor cell sections. Seven new CD numbers were assigned to antibodies included in this section at the HLDA 8 Workshop meeting held during December 2004.

Antibodies, Monoclonal↗

PubMed2006

Growth and lead accumulation by the grasses Vetiveria zizanioides and Thysanolaena maxima in lead-contaminated soil amended with pig manure and fertilizer: a glasshouse study.

Bo Ngam lead mine soils contain high concentrations of lead (up 1% total Pb) and low amounts of organic matter and major nutrients (N, P, K). A glasshouse study was conducted to compare growth performance, metal tolerance and metal uptake by two grasses, Thysanolaena maxima (Roxb.) O. Kuntze and four ecotypes of Vetiveria zizanioides (L.) Nash, syn. Chrysopogon zizanioides (L.) Roberty (three from Thailand: Surat Thani, Songkhla and Kamphaeng Phet, and one from Sri Lanka) and to study the effects of pig manure (20% and 40% w/w) and inorganic fertilizer (75 and 150 mg kg(-1)) amendments to this lead mine soil. The results showed that both T. maxima and V. zizanioides (Surat Thani and Songkhla) could tolerate high Pb concentrations in soil (10750 mg kg(-1)) and had very good growth performance. Application of pig manure increased electrical conductivity (EC) and reduced DTPA-extractable Pb concentration in the soils. Pig manure application improved the growth of vetiver, especially at 20%, application dosage. Vetiver had the highest biomass. T. maxima could not tolerate high EC values. The uptake by roots and transport of Pb to shoots of both species was reduced when soils were amended with pig manure. Application of inorganic fertilizer did not improve growth of vetiver but did improve that of T. maxima. Fertilizer application did not have any great influence on the Pb uptake in vetiver while T. maxima took up more Pb as a result of the fertilizer enhancing its biomass yield. Both species transported low Pb concentrations to shoots (8.3-179 mg kg(-1)) and accumulated higher concentrations in roots (107-911 mg kg(-1)). In summary, both species may be species well suited for phytostabilization in tropical lead mine areas.

Animals↗

PubMed2006

Capillary electrophoresis with electrochemiluminescence detection for measurement of aspartate aminotransferase and alanine aminotransferase activities in biofluids.

A new sensitive assay for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in biofluids was developed, based on the separation and detection of alanine, glutamate, and aspartate using capillary electrophoresis (CE) with electrochemiluminescence (ECL) detection. The three amino acids were separated in 5 mM phosphate of pH 2.1 as background electrolyte, and detected on a 500 microm platinum disk electrode at 1.2V (versus Ag/AgCl) in the presence of 10 mM tris(2,2'-bipyridyl)ruthenium(II) dissolved in 80 mM phosphate of pH 10.5. A mass detection limit of 37.3 fmol (or 81.5 fmol) for glutamate, corresponding to the product in the enzyme reaction catalyzed by 1.24 x 10(-9)U AST (or 2.72 x 10(-9)U ALT) in a 30 min reaction period, was achieved. This assay was applied to investigate the cytotoxicity effect of ethanol on HepG2 cells and differentiating nonalcoholic steatohepatitis (NASH) from alcoholic liver disease, indicating that the technique is promising for the application in the cell biological and clinical fields.

Alanine↗