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PubMed2006

Nonalcoholic steatohepatitis--a histological perspective.

Nonalcoholic Steatohepatitis (NASH) is a progressive liver disease that has gained recognition in the last two decades. It may even account for some of the cases previously diagnosed as cryptogenic cirrhosis. Association of this entity,with obesity, insulin resistance and type II diabetes is well documented. In this review we clarify the terminology and describe the histological features associated with NASH. Criteria for diagnosis, grading and staging systems and role of liver biopsy is also discussed.

Adult↗

PubMed2006

[Effects of pentoxifylline on hepatic nuclear factor-kappa B signaling pathway and insulin resistance in nonalcoholic steatohepatitis rats induced by fat-rich diet].

OBJECTIVE: To explore the effects of pentoxifylline (PTX) on nuclear factor-kappa B (NF-kB) signaling pathway, insulin receptor substrates (IRSs) and glucose transporter 2 (GLUT2) expressions in livers in a rat model of nonalcoholic steatohepatitis (NASH). METHODS: Rats fed a fat-rich diet for 4 weeks were randomly allocated into two groups; the model group rats (n = 12) were fed a high-fat diet alone and the PTX group rats (n = 12) were fed a high-fat diet plus PTX (100 mg x kg(-1)/d(-1)) in drinking water. Meanwhile, rats (n = 6) fed a standard diet from the start served as controls. All the rats were sacrificed at the end of the 24th week. Hepatic NF-kappaB binding activity was measured by electrophoretic mobility shift assay (EMSA). The expression of tumor necrosis factor (TNF) alpha and inhibitor kappaB (IkappaBalpha) proteins in livers were determined by Western blot. Messenger RNA of IRS-1, IRS-2 and GLUT2 expressions were examined by RT-PCR. RESULTS: NF-kappaB binding activity was higher in the model group than that in the controls, while it was lower in the PTX group compared with that in the model group. The expression of TNFalpha protein was markedly increased in the model group (vs. the control group) but decreased in the PTX group (vs. the model group). The expression of IkappaBaalpha protein was decreased in the model group (vs. the control group) but increased in the PTX group (vs. the model group) to a certain extent. IRS-2 mRNA expression was markedly increased in the model group, and significantly decreased in the PTX group when compared with the model group (P less than 0.01). CONCLUSIONS: PTX could influence NF-kappaB signaling pathway and IRS expression in livers of NASH rats, which might be involved in the improvement of hepatic insulin resistance.

Animals↗

PubMed1989

Possible catabolism of paraquat in mouse brain microsomes.

Whether formalin would be formed from paraquat (PQ) was studied in vitro using subcellular fractions of the mouse tissues. When Nash's method was used, a detectable increase of the OD at 412 nm was obtained only in the brain microsomal fraction in the presence of NADPH. The OD was increased by the addition of 0.1 mM EDTA. It disappeared when NADPH was omitted or when microsomes were denatured. However, when the brain microsomes were incubated with [3H]PQ in the presence of NADPH and EDTA, no [3H] formalin was detected. These results suggest that PQ may be catabolized in the mouse brain microsomes, though not demethylated, resulting in the production of the Nash reagent-reactive substance.

1-Methyl-4-phenylpyridinium↗

PubMed1994

[Non alcoholic steatohepatitis].

A prospective study of 21 patients with the diagnosis of non-alcoholic steatohepatitis (NASH) was carried out. All patients had hepatomegaly and in 10 (48%) image studies were consistent with steatosis and/or fibrosis. Biochemically, there was increase of AST, ALT and cholesterol in 48%, of GGT in 52% and of alkaline phosphatase in 38%. 18 patients were obese, 2 of them diabetic, 2 others had a history of exposure to drugs (amiodarone and isopropilic alcohol) and the last one presented hypothyroidism. Liver biopsies were studied using a semiquantitative scale to evaluate the degree of steatosis, inflammation and fibrosis in a scale from 1 to 3. Results showed a medium score of 2.6 for steatosis, 1.5 for inflammation and 1.8 for fibrosis. Four patients had cirrhosis and Mallory bodies were found in 11 cases (52%). NASH is an oligosymptomatic disease that can be found in different clinical conditions, mainly obesity, and is more frequent in women. It is histologically indistinguishable from alcoholic steatohepatitis. It is frequently underdiagnosed clinically and must be taken into account as a possible cause of cryptogenetic cirrhosis.

Adult↗

PubMed1993

Sexual abuse, family environment, and psychological symptoms: on the validity of statistical control.

M. R. Nash, T. L. Hulsey, M. C. Sexton, T. L. Harralson, and W. Lambert (1993) reported on the effects of controlling for family environment when studying sexual abuse sequelae. Sexual abuse history was associated with elevated Minnesota Multiphasic Personality Inventory and Rorschach scores in a sample of 105 women, but many of the reported differences disappeared when a Family Functioning Scale score was used as a covariate. The present article considers the findings of Nash et al. in terms of the theoretical and statistical constraints placed on analysis of covariance and other partializing procedures. Because family dysfunction is not always causally antecedent to sexual abuse, and given the quasi-experimental quality of most abuse research, the use of covariate techniques to test hypotheses about the causal role of family environment in the impacts of sexual abuse may be ill advised. Analyses of a 2,964-subject data set illustrate these concerns.

Adaptation, Psychological↗

PubMed1997

Development of a selective culture medium for Fusarium moniliforme.

Nash and Snyder medium and malachite green agar 2.5 ppm medium, a new selective culture medium designed in our laboratory, were challenged with pure cultures of Fusarium moniliforme strains and two different mixed-conidium suspensions, which included rapidly spreading fungi, for their utility in the isolation and enumeration of F. moniliforme. From the results of this comparative study, malachite green agar 2.5 ppm allowed only the selective growth of F. moniliforme whereas Nash and Snyder medium allowed both the growth of F. moniliforme and other species not belonging to Fusarium spp. The enumeration of F. moniliforme propagules was similar in both culture media.

Agar↗

PubMed1998

Diagnosis and interpretation of steatosis and steatohepatitis.

Steatosis--accumulation of triacylglycerol in hepatocytes--is a common finding in liver biopsy specimens. The commonest form is macrovesicular change, which occurs in response to a wide range of insults. In the absence of other features, the pathologist cannot ascertain the likely cause on morphological features alone but can give an indication of the severity of steatosis. Close clinicopathological correlation is required to establish the cause. In most instances, macrovesicular steatosis is at least potentially reversible. Although it may be thought of as a benign condition, it may be associated with the development of necroinflammation and fibrosis--so-called steatohepatitis. The classic example of this is alcoholic hepatitis, but there is increasing awareness of steatohepatitis occurring in nonalcoholics: NASH. Distinction between alcoholic hepatitis and NASH on purely histological grounds may be impossible; careful clinicopathological discussion is mandatory. Microvesicular steatosis is generally a more severe disease than the macrovesicular form and is seen in a variety of conditions in which there is either an inherited or an acquired defect in beta-oxidation of fatty acids; the former includes mitochondrial cytopathies and disorders of ureagenesis, and the latter includes acute fatty liver of pregnancy and Reye's syndrome. This review describes the morphological features of steatosis and steatohepatitis, considers their pathogenesis, and outlines the clinical significance of the different patterns of injury.

Fatty Liver↗

PubMed1981

Erythrocyte membrane elasticity during in vivo ageing.

Changes in the ability of senescent erythrocytes to pass through the microcirculation may cause them to be trapped in the spleen and removed from the blood. To help understand this process we have measured erythrocyte membrane elasticity, to see whether it changes during in vivo ageing. Human and rabbit red cells were fractionated by isopycnic sedimentation to obtain samples of aged and young cells. These were subjected to micropipette analysis in order to determine their membrane shear elastic modulus. We found that the membrane rigidity did not significantly alter as red cells aged. Previously we have also demonstrated that the changed size and shape of aged cells is unlikely to explain their removal from the circulation (Nash, G.B. and Wyard, S.J. (1981) Biorheology, in the press). Thus we conclude that the lifespan of erythrocytes is not determined by factors related to membrane flexibility or cell shape but may depend on changes in their viscous properties (as suggested by Williams, A.R. and Morris, D.R. (1980), Scand. J. Haematol. 24, 57--62).

Animals↗

PubMed1992

Surface antigen variability and variation in Giardia lamblia.

Recent studies show that Giardia isolates are heterogeneous but fall into at least three groups as determined by a number of complementary techniques. Giardia undergoes surface antigenic variation, both in vitro, and in humans and other animal model infections. Many of the characteristics of antigenic variation and the proteins involved, called variant-specific surface proteins (VSPs), are unique. The sequences of five VSPs reveal a family of cysteine-rich proteins. Here Theodore Nash reviews the relationship between antigenic variation and Giardia heterogeneity.

Journal Article↗

PubMed1998

The molecular mechanisms of giardia encystation.

The protozoan parasite Giardia lamblia is transmitted as an environmentally resistant cyst. The encystation process is attracting attention not only from the viewpoint of disease transmission, but also as a model for differentiation. Here, Hugo Luján, Michael Mowatt and Theodore Nash discuss molecular events underlying this process, including the induction of expression and transport of cyst wall proteins and the induction of Golgi-like activity. They also propose that the signal for encystation derives from cholesterol deprivation in the lower small intestine.

Journal Article↗

PubMed1996

A transient precursor of the HIV-1 protease. Isolation, characterization, and kinetics of maturation.

Recently, the mechanism of autoprocessing of the protease (PR) of the human immunodeficiency virus type 1 from the model polyprotein, MBP-DeltaTF-PR-DeltaPol, which contains the protease linked to short native flanking sequences (DeltaTF and DeltaPol) fused to the maltose binding protein (MBP) of Escherichia coli, was reported (Louis, J. M., Nashed, N. T., Parris, K. D., Kimmel, A. R., and Jerina, D. M. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 7970-7974). According to this mechanism, intramolecular cleavage of the N-terminal strands of the dimeric MBP-DeltaTF-PR-DeltaPol protein leads to the formation of the PR-DeltaPol intermediate, which is subsequently converted to the mature protease by cleavage of the C-terminal strands. We now report the purification and characterization of the PR-DeltaPol intermediate and the kinetics of its processing to the mature protease. Unlike the MBP-DeltaTF-PR-DeltaPol precursor, PR-DeltaPol has proteolytic activity similar to that of the mature enzyme at pH 5.0. The pH rate profile for kcat/Km is similar to that of the mature protease above pH 4.0. Although the PR-DeltaPol is more sensitive than the mature protease toward denaturing reagents, both the enzymatic activity and the intrinsic fluorescence of PR-DeltaPol are linearly dependent on the protein concentration, indicating that the protein is largely in its dimeric form above 10 nM. In contrast to the first-order kinetics observed for the proteolytic reaction at the N terminus of the protease, the proteolytic reaction at the C terminus of the protease is second order in protein concentration. These results are discussed in terms of a mechanism in which the C-terminally located DeltaPol peptide chains are cleaved intermolecularly to release the mature protease.

Amino Acid Sequence↗

PubMed2003

Role of Ca2+ feedback on single cell inositol 1,4,5-trisphosphate oscillations mediated by G-protein-coupled receptors.

The dynamics of inositol 1,4,5-trisphosphate (Ins (1,4,5)P3) production during periods of G-protein-coupled receptor-mediated Ca2+ oscillations have been investigated using the pleckstrin homology (PH) domain of phospholipase C (PLC) delta1 tagged with enhanced green fluorescent protein (eGFP-PHPLCdelta1). Activation of noradrenergic alpha1B and muscarinic M3 receptors recombinantly expressed in the same Chinese hamster ovary cell indicates that Ca2+ responses to these G-protein-coupled receptors are stimulus strength-dependent. Thus, activation of alpha1B receptors produced transient base-line Ca2+ oscillations, sinusoidal Ca2+ oscillations, and then a steady-state plateau level of Ca2+ as the level of agonist stimulation increased. Activation of M3 receptors, which have a higher coupling efficiency than alpha1B receptors, produced a sustained increase in intracellular Ca2+ even at low levels of agonist stimulation. Confocal imaging of eGFP-PHPLCdelta1 visualized periodic increases in Ins(1,4,5)P3 production underlying the base-line Ca2+ oscillations. Ins(1,4,5)P3 oscillations were blocked by thapsigargin but not by protein kinase C down-regulation. The net effect of increasing intracellular Ca2+ was stimulatory to Ins(1,4,5)P3 production, and dual imaging experiments indicated that receptor-mediated Ins(1,4,5)P3 production was sensitive to changes in intracellular Ca2+ between basal and approximately 200 nM. Together, these data suggest that alpha1B receptor-mediated Ins(1,4,5)P3 oscillations result from a positive feedback effect of Ca2+ onto phospholipase C. The mechanisms underlying alpha1B receptor-mediated Ca2+ responses are therefore different from those for the metabotropic glutamate receptor 5a, where Ins(1,4,5)P3 oscillations are the primary driving force for oscillatory Ca2+ responses (Nash, M. S., Young, K. W., Challiss, R. A. J., and Nahorski, S. R. (2001) Nature 413, 381-382). For alpha1B receptors the Ca2+-dependent Ins(1,4,5)P3 production may serve to augment the existing regenerative Ca2+-induced Ca2+-release process; however, the sensitivity to Ca2+ feedback is such that only transient base-line Ca2+ spikes may be capable of causing Ins(1,4,5)P3 oscillations.

Animals↗

PubMed1983

Gemfibrozil in combination with other drugs for severe hyperlipidemia. Preliminary study comprising four cases.

In this very early report, Dr Nash shares his insights into a newly developing approach to hyperlipidemia therapy. Four severely hyperlipidemic patients in whom maximum dietary therapy had proved ineffective showed a dramatic reduction in cholesterol and triglyceride levels when treated with multiple drugs, including gemfibrozil. These cases demonstrate that maximally effective polypharmacy can have striking results in selected patients. These provocative findings should encourage other investigators to verify or refute them.

Adult↗

PubMed1990

Lowering cholesterol naturally.

Patients today are more likely than ever to seek advice about reducing cholesterol levels. Physicians can help by teaching patients how to cut down on saturated fats. However, as Dr. Nash points out, eating habits are difficult to change, especially for those who think that healthy foods have an unpleasant taste. This article discusses several dietary interventions that have been proven to reduce cholesterol levels and thus the risk of coronary artery disease.

Cholesterol↗

PubMed2004

Estimate of the annual number of percutaneous injuries among hospital-based healthcare workers in the United States, 1997-1998.

OBJECTIVE: To construct a single estimate of the number of percutaneous injuries sustained annually by healthcare workers (HCWs) in the United States. DESIGN: Statistical analysis. METHODS: We combined data collected in 1997 and 1998 at 15 National Surveillance System for Health Care Workers (NaSH) hospitals and 45 Exposure Prevention Information Network (EPINet) hospitals. The combined data, taken as a sample of all U.S. hospitals, were adjusted for underreporting. The estimate of the number of percutaneous injuries nationwide was obtained by weighting the number of percutaneous injuries at each hospital by the number of admissions in all U.S. hospitals relative to the number of admissions at that hospital. RESULTS: The estimated number of percutaneous injuries sustained annually by hospital-based HCWs was 384,325 (95% confidence interval, 311,091 to 463,922). The number of percutaneous injuries sustained by HCWs outside of the hospital setting was not estimated. CONCLUSIONS: Although our estimate is smaller than some previously published estimates of percutaneous injuries among HCWs, its magnitude remains a concern and emphasizes the urgent need to implement prevention strategies. In addition, improved surveillance could be used to monitor injury trends in all healthcare settings and evaluate the impact of prevention interventions.

Hospitalization↗

PubMed1985

Murine sarcoma virus ts110 RNA transcripts: origin from a single proviral DNA and sequence of the gag-mos junctions in both the precursor and spliced viral RNAs.

Our previous studies have argued persuasively that in murine sarcoma virus ts110 (MuSVts110) the gag and mos genes are fused out of frame due to a approximately 1.5-kilobase (kb) deletion of wild-type murine sarcoma virus 349 (MuSV-349) viral information. As a consequence of this deletion, infected cells grown at 39 degrees C appear morphologically normal, producing a 4-kb viral RNA and a truncated gag gene product, P58gag. At 33 degrees C, however, MuSVts110-infected cells appear transformed, producing two viral RNAs, about 4 and 3.5 kb in length, and two viral proteins, P58gag and P85gag-mos. Recent S1 nuclease analyses (Nash et al., J. Virol. 50:478-488, 1984) suggested strongly that at 33 degrees C about 430 bases surrounding the out-of-frame gag-mos junction and bounded by consensus splice donor and acceptor sites are excised from the 4-kb RNA to form the 3.5-kb RNA. As a result of this apparent splicing event, the gag and mos genes seemed to be fused in frame and allowed the translation of P85gag-mos. In the present study, DNA primers hybridizing to the MuSVts110 4- and 3.5-kb RNAs just downstream of the gag-mos junction points were used to sequence these junctions by the primer extension method. We observed that, relative to wild-type MuSV-349 5.2-kb RNA, the MuSVts110 4-kb RNA had suffered a 1,488-base deletion as a result of the fusion of wild-type gag gene nucleotide 2404 to wild-type mos gene nucleotide 3892. This gag-mos junction is out of frame, containing both TAG and TGA termination codons in the reading frame 42 and 50 bases downstream of the gag-mos junction, respectively. Thus, the MuSVts110 4-kb RNA can only be translated into a truncated gag precursor containing an additional C-terminal 14 amino acid residues derived from an alternate mos gene reading frame. Similar analyses of the MuSVts110 3.5-kb RNA showed a further loss of both gag and mos sequences over those deleted in the original 1,488-base deletion. In the MuSVts110 3.5-kb RNA, we found that gag nucleotide 2017 was fused to mos nucleotide 3936 (nucleotide 2449 in the MuSVts110 4-kb genome). This 431-base excised fragment is bounded exactly by in-frame consensus splice donor and acceptor sequences. As a consequence of this splice event, the TAG codon is excised and the restoration of the original mos gene reading frame allows the TGA codon to be bypassed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

mRNA stability plays a major role in regulating the temperature-specific expression of a Tetrahymena thermophila surface protein.

Synthesis of the serotype H3 (SerH3) surface antigen is temperature dependent and responds within 1 h to a change in incubation conditions (G.A. Bannon, R. Perkins-Dameron, and A. Allen-Nash, Mol. Cell. Biol. 6:3240-3245, 1986). Recently, a Tetrahymena thermophila cDNA clone (pC6; D.W. Martindale and P.J. Bruns, Mol. Cell. Biol. 3:1857-1865, 1983) has been shown to be homologous to a portion of the SerH3 mRNA (F.P. Doerder and R.L. Hallberg, personal communication), and it was shown that the cellular levels of this RNA rapidly decreased when cells were shifted from 30 to 41 degrees C (R.L. Hallberg, K.W. Kraus, and R.C. Findly, Mol. Cell. Biol. 4:2170-2179, 1984). These observations indicate that synthesis of the SerH3 protein is highly regulated in response to temperature and led us to initiate studies to determine the mechanism(s) by which SerH3 gene expression is controlled. Using pC6 as a hybridization probe for the SerH3 mRNA, we have determined that (i) the level of SerH3 protein synthesis is directly correlated with the amount of SerH3 message available for translation; (ii) there is, at most, a twofold difference between the relative transcription rates of SerH3 genes at 30 and 40 degrees C; (iii) the SerH3 mRNA half-life in cells incubated at 30 degrees C is greater than 1 h, whereas the half-life in cells incubated at 40 degrees C is only approximately 3 min. These results demonstrate that Tetrahymena SerH3 surface protein expression is regulated by mRNA abundance. Furthermore, the major mechanism controlling mRNA abundance is a dramatic temperature-dependent change in SerH3 mRNA stability.

Animals↗

PubMed1989

Experimental percutaneous gallstone lithotripsy: results in swine.

The Kensey-Nash device is used to fragment gallstones percutaneously. It is inserted into the gallbladder through an 8-F introducer sheath, a cage is expanded to protect the gallbladder, and the impeller is activated. A strong vortex automatically pulls the stones into the basket. The device was tested in 24 pigs in which human gallstones (5-19 mm, bilirubin and cholesterol types) had been implanted and in two control pigs with no gallstones. All pigs except two were killed immediately after the procedure (acute studies); the two were followed up for 36 days and then killed. Fragments (1-3 mm) were similar in size to those seen in current extracorporeal shock wave lithotripsy studies. A complication occurred in one animal, and technical failures occurred in two, causing these three studies to be aborted.

Animals↗