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PubMed2006

[Nonalcoholic steatohepatitis--current treatment options].

Nonalcoholic steatohepatitis (NASH) is the term used to describe the distinct clinical entity in which the liver biopsy findings are similar to that observed in alcoholic hepatitis, but patients lack a history of significant alcohol consumption. The most widely supported theory implicates insulin resistance as the key mechanism leading first to hepatic steatosis, and next to steatohepatitis. In spite of lacking proof by EBM (evidence based medicine) and effective therapy for NASH, modification of risk factors, such as obesity, hyperlipidemia, and good diabetic control is generally recommended. Although there is no consensus of treatment form, the new drugs which can be useful in NASH treatment are continously tested. The aim of our study is to present current knowledge about nonalcoholic steatohepatitis, focusing on present and being in various phases of clinical trials treatment options.

Adult↗

PubMed2006

The role of cytokines in non-alcoholic steatohepatitis. A review.

The pathogenesis of NASH is being unraveled by studies of animal models and humans with this disorder. The necro-inflammatory component of NASH appears to be modulated by interactions among various factors (for example cytokines, hormones, neurotransmitters) that regulate the biological activity of TNF- and other proinflammatory (Th-1) cytokines. Hepatic necroinflammation is necessary, but not sufficient, for progression to cirrhosis. Factors such as leptin inducible factors (for example, noradrenaline), that regulate the activity of profibrogenic cytokines, such as IL-10 and TGF-beta, dictate the extent of fibrosis that occurs during liver injury. A better understanding of how these and other soluble and cell associated factors regulate the phenotypes of different types of liver cells should help us to develop rationale treatments for NASH and other disorders in the metabolic syndrome.

Adipocytes↗

PubMed1991

[Non alcoholic steatohepatitis. Mid-term clinical and histologic course in 10 patients].

BACKGROUND: The progressive character of the hepatic lesions in nonalcoholic steatohepatitis (NASH) has not been well established. In the present study, the clinical and histological course of this condition was evaluated at medium term. METHODS: Then patients (6 females and 4 males) with NASH, in a non-cirrhotic stage at the time of diagnosis, were followed up during 58 +/- 7 months (range 24 to 88 months). RESULTS: Nine patients were obese, but a significant reduction of body weight was found at the end of the study (p = 0.0072). Other clinical, physical or laboratory changes were not found, although in two cases hepatic biochemical tests were within normal limits when the follow-up biopsy was performed. Changes in the characteristic hepatic features were also absent, although fat infiltrates disappeared in three cases. Six patients had increased fibrosis and a progression of the hepatic architectural distortion; four reached the stage of cirrhosis. The evolution of the hepatic lesion correlated with the interval between diagnostic and follow-up biopsies (r = 0.69; p less than 0.05) and with the reduction in body weight (r = 0.64; p less than 0.05). CONCLUSIONS: In most cases, NASH results in a progressive hepatic distortion with can end in cirrhosis, although the change is slow and silent.

Adult↗

PubMed1998

Psychopathology associated with sexual abuse: the importance of complementary designs and common ground.

In their recent longitudinal study of youth victimization and consequent traumatization, S. Boney-McCoy and D. Finkelhor (1996) contrast their position with previous retrospective research (S. Harter, P. Alexander, & R. A. Neimeyer, 1988; M. R. Nash, T. C. Hulsey, M. C. Sexton, T. L. Harralson, & W. Lambert, 1993a), arguing that their data support the impact of victimization per se, independent of the moderating effect of family environment. Because Boney-McCoy and Finkelhor's argument may misrepresent the results of such studies, this article (a) clarifies the actual findings of previous retrospective studies of abuse, (b) suggests methodological limitations both in Boney-McCoy and Finkelhor's research and in that of S. Harter et al., 1998, and M. R. Nash et al., 1993a, that should be remedied by future investigators, and (c) argues that both retrospective clinical research and prospective community surveys converge on a common ground, namely, that specific abuse experiences can best be understood and investigated in the context of the prior, contemporaneous, and subsequent family environments in which they occur.

Adolescent↗

PubMed2026

Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.

BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

Humans↗

PubMed1978

The Labor Reform Act of 1977: a detailed analysis.

As a former General Counsel of the NLRB, Peter Nash enjoyed a vantage point from which to observe the procedures of the Board and evaluate how the provisions of the NLRA itself operated. Nou in private practice, he has made a detailed analysis of the labor reform legislation pending in Congress and strongly supported by organized labor. Writing from management's point of view, Mr. Nash concludes that the bills now pending are designed solely to assist unions in their organizing efforts; will not expedite the processing of Board cases; and contain harsh, unfair, and unnecessary deterrent remedies against employers.

Civil Rights↗

PubMed2004

Success that lasts.

Pursuing success can feel like shooting in a landscape of moving targets: Every time you hit one, five more pop up from another direction. We are under constant pressure to do more, get more, be more. But is that really what success is all about? Laura Nash and Howard Stevenson interviewed and surveyed hundreds of professionals to study the assumptions behind the idea of success. They then built a practical framework for a new way of thinking about success--a way that leads to personal and professional fulfillment instead of feelings of anxiety and stress. The authors' research uncovered four irreducible components of success: happiness (feelings of pleasure or contentment about your life); achievement (accomplishments that compare favorably against similar goals others have strived for); significance (the sense that you've made a positive impact on people you care about); and legacy (a way to establish your values or accomplishments so as to help others find future success). Unless you hit on all four categories with regularity, any one win will fail to satisfy. People who achieve lasting success, the authors learned, tend to rely on a kaleidoscope strategy to structure their aspirations and activities. This article explains how to build your own kaleidoscope framework. The process can help you determine which tasks you should undertake to fulfill the different components of success and uncover areas where there are holes. It can also help you make better choices about what you spend your time on and the level of energy you put into each activity. According to Nash and Stevenson, successful people who experience real satisfaction achieve it through the deliberate imposition of limits. Cultivating your sense of "just enough" can help you set reachable goals, tally up more true wins, and enjoy lasting success.

Achievement↗

PubMed2002

A comparison of consensus and nonconsensus approaches to modeling contraceptive choice behavior.

This paper develops a more general model of contraceptive choice, taking into account a fundamental difference between the condom and the contraceptive pill, the two most commonly used reversible contraceptives in the US. The pill produces a single output of pregnancy prevention, but the condom is an input into a joint production for both pregnancy prevention and disease protection. Since the condom is ultimately used by the male, and the pill by the female, noncooperative game theory is used to model the separate male and female utility functions. Using both Stackelberg and Nash as solution concepts, econometric specifications are derived and the models are compared with the specifications derived from a consensus model of the household. Simultaneous-move Nash best describes the behavior of unmarried and noncohabiting sexual partners, and female-leader Stackelberg outperforms the other models for married or cohabiting couples.

Adolescent↗

PubMed2005

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention.

Adult↗

PubMed2006

Long-term follow-up of patients with NAFLD and elevated liver enzymes.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

Alkaline Phosphatase↗

PubMed2006

Glutathione-enhancing agents protect against steatohepatitis in a dietary model.

UNLABELLED: Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). RESULTS: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups (p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-alpha1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, and TGF-beta) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients.

Animals↗

PubMed1999

Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation.

Recurrence of hepatopulmonary syndrome (HPS) after orthotopic liver transplantation (OLT) in an adult has never been reported. We describe a 23-year-old woman who initially underwent OLT because of debilitating and severe HPS associated with nonalcoholic steatohepatitis (NASH). Although the clinical resolution of HPS was well documented day 117 post-OLT, the reappearance of NASH was documented by liver biopsy. Severe hypoxemia because of recurrent HPS rapidly evolved beginning approximately day 700 post-OLT. Retransplantation was attempted, but the patient died post-OLT of sepsis and/or multiorgan failure.

Acute Disease↗

PubMed1999

Dilemma of the equality: an all-pay contest with individual differences in resource holding potential

An all-pay contest in which many players compete for an indivisible resource and each player continuously maintains a different resource holding potential (RHP) is analysed. There exists the unique pure ESS function, which is common sense; that is, a higher RHP induces a higher level of investment, and, as a consequence, a player with a greater RHP always wins. As the variance in distribution of RHP converges to zero, the ESS becomes equal to the symmetric mixed Nash-equilibrium reported by Rose, which does not satisfy the condition of ESS. This suggests that some unstable symmetric Nash equilibria change to ESS functions in some games when we extend the games by assuming one more random continuous parameter of the player's condition. Moreover, the smaller the individual differences in RHP, the more intense the competition becomes, and the smaller becomes the expected payoff for almost all individuals as well as the average payoff of the population. This negative correlation between equality in RHP and the payoff in the population was first found by Kura & Kura in a war-of-attrition game and named the "dilemma of equality". Its biological implications are also discussed. Copyright 1999 Academic Press.

Journal Article↗

PubMed2002

Are there really no evolutionarily stable strategies in the iterated prisoner's dilemma?

The evolutionary form of the iterated prisoner's dilemma (IPD) is a repeated game where players strategically choose whether to cooperate with or exploit opponents and reproduce in proportion to game success. It has been widely used to study the evolution of cooperation among selfish agents. In the past 15 years, researchers proved over a series of papers that there is no evolutionarily stable strategy (ESS) in the IPD when players maintain long-term relationships. This makes it difficult to make predictions about what strategies can actually persist as prevalent in a population over time. Here, we show that this no ESS finding may be a mathematical technicality, relying on implausible players who are "too perfect" in that their probability of cooperating on any move is arbitrarily close to either 0 or 1. Specifically, in the no ESS proof, all strategies were allowed, meaning that after a strategy X experiences any history H, X cooperates with an unrestricted probability p (X, H) where 0< or =p (X, H)< or =1. Here, we restrict strategies to the set S in which X is a member of S [corrected] if after any H, X cooperates with a restricted probability p (X, H) where e< or =p (X, H)< or =1-e and 0<e<1/2. The variables e and 1-e may be thought of as the biological limits to how perfect (pure) a strategy can be. In S, we first prove that an ESS must be a Nash equilibrium and boundary strategy of S where a boundary strategy has allowable probabilities of cooperating of e or 1-e after any history. We then prove that X is an ESS in S if and only if X is a Nash equilibrium in the set consisting of only S's boundary strategies. Thus, in searching for ESSs in S, we only need to consider what happens when boundary strategies interact with one another. This greatly simplifies the search for ESSs. Using these results, we finally show that when e is sufficiently small, exactly three one-move memory ESSs exist in S: [1] Pavlov-e which generally cooperates (i.e. cooperates with maximum probability 1-e) after both players either simultaneously cooperated or simultaneously defected; otherwise, Pavlov-e generally defects (i.e. cooperates with minimum probability e). [2] Grudge-e which generally cooperates after both players simultaneously cooperated; otherwise, Grudge-e generally defects. [3] ALLD-e which generally defects after all histories.

Animals↗

PubMed2007

[Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis].

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome. Since the prevalence of obesity and consequently of the metabolic syndrome is steadily increasing, the different types of NAFLD are nowadays the most common cause of liver injury in North America. The development of NASH and fatty liver cirrhosis occurs after a "two-hit-theory", in which hepatic steatosis is followed by lipid peroxidation, the production of cytokines and the induction of Fas ligand. A standardized drug based therapy does not exist so far, but glitazones have emerged as a promising treatment option. However, since the disease is related to Western lifestyle, treatment should be based on prevention and changes in lifestyle.

Fatty Liver↗

PubMed1998

Identification of mitochondria in liver biopsies. A study by immunohistochemistry, immunogold and Western blot analysis.

Hepatocytes are rich in mitochondria, which play an important role in hepatic metabolism. In certain pathologic conditions (most often alcoholic liver disease) mitochondria became enlarged; nevertheless, even in these conditions they are hardly detectable on light microscopy. Recently an antimitochondrial antibody (mAM), which recognizes a 60-kDa protein, has been characterized. The purpose of the present study was to study immunoreactivity of this antibody in a series of liver biopsies. We studied 146 liver biopsies using an mAM. In 8 cases an ultrastructural study was also done, and in 2 cases Western blot analysis was performed. Cases were divided as follows: alcoholic liver disease (ALD, 31); steatosis (8); nonalcoholic steatohepatitis (NASH, 1); hepatitis C virus (HCV)-related hepatitis (83); hepatitis B virus (HBV)-related hepatitis (6); primary biliary cirrhosis (1); sclerosing cholangitis (1); haemosiderosis (1); sarcoidosis (1); alpha-1-antitrypsin deficiency (1); nonspecific findings (12). All the patients were investigated for alcohol or drug abuse, pharmacological treatment, hyperlipidaemia, hypercholesterolaemia and diabetes. Immunoreactivity was diffuse in cases of ALD, NASH and steatosis, and in patients with drug abuse. Electron microscopic immunogold and Western blot analysis confirmed that in the conditions examined the protein recognized by the mAM showed greater expression. Immunohistochemical staining was helpful in demonstrating a toxic or a metabolic insult even in cases in which the histological picture was blurred by viral infection.

Adult↗

PubMed2004

What limits herb biomass in grasslands: competition or herbivory?

Competition and herbivory are two of the main forces shaping plant communities. Although several studies have investigated their impact on plant populations separately, few investigations have examined how they might interact. With the purpose of clarifying the combined roles of competition and herbivory on herb biomass in a grassland, we assessed the effects of different herbivores with reduced grass competition. We conducted a field experiment in 2000-2001 in a British acid grassland (Oak Mead), where we experimentally reduced grass biomass and excluded rabbits, insects and molluscs in a factorial design. Removing the grasses from Oak Mead dramatically increased herb biomass and total above-ground biomass. Herbivore exclusions (i.e. rabbits, insects and molluscs) did not affect total above-ground biomass, but they altered relative abundance of several species. Grass removal and rabbit exclusion had positive interactions on biomass of several herb species, and there were some subtle interactions between different herbivore groups: monocots benefitted when both rabbits and molluscs were excluded, and some herb species had greater biomass when insects and rabbits were absent. We then compared the results with a 10-year experiment that manipulated similar variables in neighbouring grassland (Nash's Field). The comparison between Oak Mead and Nash's Field showed that cessation of herbicide application returns the system to its previous state of grass dominance after 3 years. Therefore, even when herbs were more abundant, they could not prevent reinvasion of the grasses once external factors were removed.

Analysis of Variance↗

PubMed2004

Nonalcoholic steatohepatitis associated with psoriasis vulgaris.

A 24-year-old man was admitted to our hospital because of liver dysfunction. He had been diagnosed as having psoriasis vulgaris at 18 years of age. Physical examination demonstrated obesity, general erythema, and hepatomegaly. Laboratory data revealed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glucose. A histological examination of the liver revealed macrovesicular fatty change and infiltration of inflammatory cells, including lymphocytes and polymorphonuclear cells, within the liver lobules. Pericentral fibrosis and pericellular fibrosis were also recognized. He was diagnosed as having nonalcoholic steatohepatitis (NASH), based on the fact that he had no habit of drinking alcohol, as well as psoriasis vulgaris and diabetes mellitus. We herein report a very rare case of NASH associated with psoriasis vulgaris.

Adult↗