Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia

OBJECTIVE: This study aims to evaluate the risk of esophagectomy in the elderly compared with younger patients and to determine whether results of esophagectomy in the elderly have improved in recent years. SUMMARY BACKGROUND DATA: An increased life expectancy has led to more elderly patients presenting with carcinoma of the esophagus in recent years. Esophagectomy for carcinoma of the esophagus is associated with significant morbidity and mortality, and advanced age is often considered a relative contraindication to esophagectomy despite advances in modern surgical practice. METHODS: The perioperative outcome and long-term survival of 167 elderly patients (70 years or more) with esophagectomy for carcinoma of the esophagus were compared with findings in 570 younger patients with esophagectomy in the period 1982 to 1996. Changes in perioperative outcome and survival between 1982 to 1989 and 1990 to 1996 were separately analyzed. RESULTS: The resection rate in the elderly was 48% (167/345), lower than the 65% (570/874) resection rate in younger patients (p < 0.001). There were significantly more preoperative risk factors and postoperative medical complications in the elderly, but no significant differences were observed in surgical complications. The 30-day mortality rate was higher in the elderly (7.2%) than in younger patients (3.0%) (p = 0.02), but the hospital mortality rate was not significantly different in the elderly (18.0%) and younger age groups (14.4%) (p = 0.27). The long-term survival after curative resection in elderly patients was worse than younger patients (p = 0.01). However, when deaths from unrelated medical conditions were excluded from analysis, survival was similar between the two age groups (p = 0.23). A comparison of data for the periods 1982 to 1989 and 1990 to 1996 revealed that the resection rate had increased from 44% to 54% in the elderly, with significantly fewer postoperative complications and lower 30-day and hospital mortality rates. Long-term survival has also improved, although this has not reached a statistically significant level. CONCLUSIONS: With current surgical management, esophagectomy for carcinoma of the esophagus can be carried out with acceptable risk in the elderly, but intensive perioperative support is required. The improved results of esophagectomy in the elderly in recent years are attributed to increased experience and better perioperative management. Long-term survival was similar to that of younger patients, excluding deaths caused by unrelated medical conditions.     

Differential expression of superoxide dismutases containing Ni and Fe/Zn in Streptomyces coelicolor

Streptomyces coelicolor contains two distinct superoxide dismutase (SOD) activities detected on native PAGE. The level of each changed differently depending on growth media and scarcely responded to paraquat, a superoxide-generating agent. The total SOD activity doubled in late exponential phase compared with that in mid-exponential phase and less than double upon treatment with plumbagin, another superoxide-generating agent. The two SODs from S. coelicolor ATCC 10147 (Müller) strain were purified to near homogeneity. SOD1, a tetramer of 13.4-kDa subunits, was found to be a novel type of SOD containing 0.74 mol nickel/mol subunit as determined by atomic absorption spectroscopy. SOD2, a tetramer of 22.2-kDa subunits, was found to contain 0.36 mol iron and 0.26 mol zinc/mol subunit. The N-terminal amino acid sequences of both SODs were determined. SOD2 is similar to manganese-containing superoxide dismutases (MnSODs) and iron-containing superoxide dismutases (FeSODs) from other organisms, whereas SOD1 is less similar to known SODs but still contains a few conserved amino acids. The effects of metals and chelating agents on the expression of these two SODs were examined. The presence of nickel at micromolar concentrations in growth media induced the expression of SOD1 (nickel-containing superoxide dismutase; NiSOD), whereas the expression of SOD2 (iron/zinc-containing superoxide dismutase; FeZnSOD) was repressed. The changes in SOD activities were positively correlated with the amount of each enzyme as determined by immunoblotting, suggesting that metals do not modulate the activity per se but the amount of each protein.     

Hepatic artery resistance in alcoholic liver disease

This first known case of concurrent congenital dyserythropoietic anaemia (CDA) and autoimmune haemolytic anaemia (AIHA) which occurred in a hispanic male and spanned 6 years from the age of 2. Light and electron microscopy of bone marrow erythroblasts and immunophenotyping confirmed CDA; serum/eluate warm autoantibodies and positive direct antiglobulin tests (DAT) associated with severe, episodic anaemias established AIHA. Cytogenetic analysis of bone marrow cells and peripheral blood lymphocytes ascertained sex chromosome aneuploidy (48 XY,+ Y,+ Y). Recurrent, life-threatening episodes of transfusion-dependent anaemia refractory to steroids and intravenous immune globulin, were put into stable remission at age 8 years when splenectomy successfully managed both disorders.     

Aetiology and pathogenesis of alcoholic liver disease

Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.     

Dietary and nutritional abnormalities in alcoholic liver disease: a comparison with chronic alcoholics without liver disease

OBJECTIVE: To document the profile and role of malnutrition in alcoholic hepatitis, compared with chronic alcoholics and nonalcoholic chronic liver disease. METHODS: To this end, we studied 67 patients with alcoholic liver disease (ALD) (group I), 52 chronic alcoholics without histological evidence of liver disease (group II), 44 nonalcoholic cirrhotics (group III), and 52 healthy controls (group IV). Alcoholic and nonalcoholic calories were calculated and percentage dietary and nutritional deficiencies computed. Anthropometric indices, nitrogen balance, and immune status of the patients were assessed. RESULTS: Alcohol constituted about 48% of daily caloric intake in patients with ALD. The percentage mean intake of carbohydrate, protein, and energy was decreased in all three study groups compared with controls. The deficiencies were more pronounced in patients with severe than with moderate ALD. These deficiencies were more severe in the group III patients. Whereas body fat stores were maintained in groups I and II, reduction in lean body mass and serum transferrin was significant in patients in groups I and III. In group II patients compared to group I patients, the body mass index (19.9 +/- 4.0 vs. 22.3 +/- 3.4) and triceps skinfold thickness (6.1 +/- 4.8 vs. 10.2 +/- 5.6 mm) were significantly lower. CONCLUSIONS: 1) protein energy malnutrition is common in both alcoholic and nonalcoholic cirrhotics, but is more pronounced in the latter; 2) the degree and profile of malnutrition in chronic alcoholics and in alcoholic cirrhotics are comparable; 3) based on our results, we hypothesize that malnutrition may not play a primary role in the pathogenesis of ALD.     

Acetaldehyde/protein interactions: are they involved in the pathogenesis of alcoholic liver disease?

Alcohol abuse is a major cause of liver disease. While ethanol itself has been shown to be hepatotoxic, its primary metabolite acetaldehyde has also been implicated in the pathogenesis of alcoholic liver disease. The majority of ethanol metabolism occurs in the liver and high concentrations of acetaldehyde accumulate during chronic ethanol abuse. Acetaldehyde has been shown to react with many proteins in vitro, forming stable covalent adducts. These modifications can act as neoantigens and may also alter biological function. Acetaldehyde-modified proteins have been detected in the livers of ethanol-fed rats and human alcoholics. Circulating antibodies reactive with modified proteins have also been detected. A direct linkage between acetaldehyde-modified proteins, antibodies and liver damage has yet to be established, but current research should clarify the picture in the next few years.     

Circulating neutrophils and liver injury in rat models of experimental alcoholic liver disease

The present study examined the effects of progesterone (P4) treatments on estrous cyclicity and the loss of ovarian follicles during aging. Young rats received repeated treatments with P4 or empty implants between 3.5 and 8 mo of age. At 8 mo, ovaries were obtained from some animals to determine the numbers of resting follicles, and estrous cycle patterns and hormone levels were determined from other groups of treated females. In contrast to the cyclic increases in P4, estradiol (E2), LH, and FSH in control animals, P4-implanted rats exhibited elevated serum P4 but low E2, LH, and FSH levels. After implant treatments, the follicular reserve was significantly (p < 0.05) larger in P4-treated females (2012 +/- 297 resting follicles per ovary, n = 5 rats per group) than in regularly cyclic control rats (713 +/- 226 follicles per ovary, n = 7). The effects of P4 implants on the follicular reserve were associated with a subsequently higher incidence of regular estrous cycles after P4 treatment. These results demonstrate that P4 prevents cyclic increases in E2 secretion and is associated with a conservation of the ovarian follicular reserve and the maintenance of regular estrous cycle patterns, indicating a protective effect of P4 on the age-related loss of ovarian follicles.     

The interaction of alcoholic liver disease and hepatitis C

The following article reviews available data of the interaction of alcohol related liver disease and hepatitis C viral infection as well as special considerations for the treatment of these patients. Alcohol worsens the degree and accelerates the progression of hepatic injury, enhances the risk of developing hepatocellular carcinoma and decreases response to interferon therapy. Patients with hepatitis C should avoid alcohol ingestion.     

Giant mitochondria in hepatocytes: a diagnostic hint for alcoholic liver disease

One hundred and sixty-five coded liver biopsy specimens were studied by light microscopy to evaluate the occurrence and diagnostic significance of giant mitochondria, which have been identified as periodic acid-Schiff-negative globular hyaline cytoplasmic inclusions of regular outline, clearly distinguishable from Mallory bodies. In 4 cases, electron microscopy confirmed that these globules were in fact enlarged mitochondria. The incidence of giant mitochondria was significantly higher in patients with high alcohol consumption (72%) than in those with low or no alcohol intake (10%). Their presence was related to the amount of daily ethanol consumption and to the shortness of abstinence before the biopsy. It was independent of other changes in the liver, and was detected with similar frequency in biopsies showing different alcoholic liver diseases. Our study emphasizes that giant mitochondria may be detected by light microscopy in a high proportion of alcoholics, and rarely in nonalcoholic liver diseases. Although less specific, they are much more frequent than Mallory bodies. Consequently they should be considered as a diagnostic hint of recent and heavy alcoholsm.     

Serum IgA antibodies to human gut luminal aspirates and human liver in alcoholic liver disease

BACKGROUND: Elevation of serum IgA is a characteristic feature of alcoholic liver disease. It has been proposed that this occurs partly as an antigenic response to gut-derived proteins or acetaldehyde-modified liver proteins, but the principal antigens responsible remain unknown. AIMS: The goal of this study was to determine if serum IgA antibodies were present against human gut luminal antigens or liver antigens in alcoholic liver disease. PATIENTS AND METHODS: Twenty-nine patients with alcoholic liver disease, 10 with primary biliary cirrhosis, 12 with "other" liver diseases, 8 alcoholics, and 20 healthy subjects were studied. Western blotting was used to examine the reactivity of sera from these groups against human small and large bowel aspirates and liver tissue from alcoholic liver disease patients. RESULTS: Serum IgA antibodies to a 140 kDa colonic luminal protein were found in 22 (76%) patients in the alcoholic liver disease group (p < 0.0001), and 7 (24%) patients had serum IgA antibodies to a 40 kDa colonic luminal protein (p = 0.04). These responses were confined to colonic aspirates and not observed in other disease groups, alcoholics or healthy subjects. There was no significant serum IgA response to human liver proteins in alcoholic liver disease. CONCLUSIONS: Serum IgA antibodies to a human 140 kDa colonic luminal protein are frequently found in alcoholic liver disease. This novel antigen may contribute to the increased levels of circulating IgA in alcoholic liver disease.     

P-450-dependent metabolism of lauric acid in alcoholic liver disease: comparison between rat liver and kidney microsomes

Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.     

Renal tubular acidosis and alcoholic liver disease (author''s transl)

Report on 8 cases of congenital atresia or severe stenosis of the choanae. In 2 cases early transnasal surgery followed by canulation was necessary. One child died of pleuropneumonia and sepsis following asphyxia on the 10th day, when mouth-breathing had already been established.     

Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease

Formalin-fixed sections from the brains of 36 patients (30 alcoholic and 6 nonalcoholic) with autopsy-proven cirrhosis who died while in a hepatic coma were stained with hematoxylin and eosin, and examined for the presence of diencephalic, cerebellar, pontine, and basal ganglia lesions. Significant neuropathology was identified in 23 of 36 cases consisting of mammillary body and thalamic lesions characteristic of Wernicke encephalopathy (WE) (9 cases, all alcoholic patients) and cerebellar degeneration (20 cases, 17 alcoholic and 3 nonalcoholic patients). Clinical diagnosis of WE had been entertained during life in only 2 of these patients. All cases, alcoholic and nonalcoholic, manifested mild to severe Alzheimer's type II astrocytosis. No cases of central pontine myelinolysis nor acquired (non-Wilsonian) hepatocerebral degeneration were found. These findings show that the brains of a high proportion of cirrhotic patients with end-stage liver disease manifest concomitant unsuspected diencephalic and cerebellar pathology. The high incidence of WE underscores the need for early sustained treatment of alcoholic cirrhotic patients with vitamin B1. Evaluation of the neurological sequelae of liver transplantation, particularly of alcoholic patients with end-stage liver disease, may require a careful neurological and radiological assessment both before and after surgery.     

Characteristics of serum hyaluronate concentrations in patients with alcoholic liver disease

It has been reported that serum hyaluronate [hyaluronic acid (HA)] concentrations are increased in liver diseases, especially in alcoholic liver disease (ALD). However, the characteristics of serum HA concentration in patients with ALD have not been studied. In this study, first, we measured serum HA concentrations in patients with different stages of both ALD and non-ALD to clarify the characteristics of serum HA concentration in patients with ALD. Second, we measured serum HA concentrations in patients with ALD sequentially after abstinence. We also measured serum HA concentrations in patients with chronic type C hepatitis before and after treatment with interferon. Finally, we analyzed the relationship between serum HA concentrations and the contents of type IV collagen and laminin in the livers of both ALD and non-ALD patients. Serum HA concentrations in liver disease were higher than the cut-off value, and increased significantly (p < 0.001) in parallel with the progression of hepatic fibrosis in both ALD and non-ALD patients. Serum HA concentrations in patients actively drinking with ALD were significantly higher (p < 0.001) than those in non-ALD. After 4 weeks of abstinence, these concentrations fell to the levels of non-ALD. Although serum ALT levels were decreased in 80% of patients treated with interferon, serum HA concentrations were not changed or increased. A significant correlation between serum HA concentrations and hepatic type IV collagen and laminin content was present in ALD, but not in non-ALD. These results clearly suggest that the increase of serum HA concentrations in ALD may be associated with not only hepatic fibrosis, but also alcohol drinking.     

Enhanced cyclooxygenase-2 gene expression in alcoholic liver disease in the rat

BACKGROUND & AIMS: Inflammatory stimuli and lipid peroxidation up-regulate cyclooxygenase (COX)-2. This study evaluated the relationship between inflammatory mediators, COX expression, and pathological changes in experimental alcoholic liver disease. METHODS: Rats (5 per group) were fed ethanol and a diet containing saturated fat, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In the first set of experiments, whole livers were analyzed. In the second set of experiments, Kupffer cells, endothelial cells, and hepatocytes were isolated from rats in each group. Pathological analyses and measurements of lipid peroxidation, tumor necrosis factor (TNF)-alpha, COX-1 and COX-2 messenger RNA (mRNA), endotoxin, and liver and plasma thromboxane were performed. RESULTS: Increased expression of COX-2 mRNA was detected in the livers of rats showing necroinflammatory changes. The Kupffer cell was the cell primarily responsible for the increase in COX-2 mRNA level. Increased expression of COX-2 was associated with increased levels of endotoxin, TNF-alpha mRNA, lipid peroxidation, and synthesis of thromboxane. COX-1 mRNA was decreased in Kupffer cells in rats with the most severe liver injury. CONCLUSIONS: Up-regulation of COX-2 in alcoholic liver injury occurred in the presence of proinflammatory stimuli and resulted in increased synthesis of inflammatory and vasoactive eicosanoids. Down-regulation of COX-1 may result in decreased synthesis of cytoprotective eicosanoids and additionally exacerbate liver injury.     

Expression of manganese superoxide dismutase in esophageal and gastric cancers

The tumor-killing activity of radiotherapy and chemotherapy for cancer is closely associated with the production of active oxygen, and the relation between therapeutic resistance and active oxygen scavengers produced by the tumor itself is gaining more attention. It is considered that manganese superoxide dismutase (MnSOD) protects host cells from oxidative stress, in synergy with other antioxidant enzymes. In this study, we used a quantitative polymerase chain reaction assay to measure MnSOD mRNA in resected specimens from patients with esophageal and gastric cancers. In both esophageal and gastric cancers, the level of MnSOD mRNA was significantly elevated in cancer tissue compared to non-cancer tissue (P < 0.01). In gastric cancer tissue, the MnSOD mRNA level was significantly higher than in esophageal cancer tissue (P < 0.01). The significance of MnSOD in cancer tissue was investigated further by measuring MnSOD content in resected specimens using an enzyme-linked immunosorbent assay, and by examining its location by an immunohistochemical method. Upregulation of MnSOD in cancer tissue most likely serves as a protective mechanism against anti-cancer therapies known to produce superoxide radicals as a key component of their tumor-killing activity.