Metallothionein-independent zinc protection from alcoholic liver injury

Previous studies using metallothionein (MT)-overexpressing transgenic mice have demonstrated that MT protects the liver from oxidative injury induced by alcohol. The mechanism of action of MT is unknown. Because MT primarily binds to zinc under physiological conditions and releases zinc under oxidative stress and zinc is an antioxidant element, it is likely that zinc mediates the protective action of MT. The present study was undertaken to determine the distinct role of zinc in hepatic protection from alcoholic injury. MT I/II-knockout (MT-KO) mice along with their wild-type controls were treated with three gastric doses of ethanol at 5 g/kg at 12-hour intervals. Zinc sulfate was injected intraperitoneally in a dosage of 5 mg/kg/day for 3 days before ethanol treatment. MT concentrations in MT-KO mice were very low and zinc concentrations in MT-KO mice were lower than in wild-type mice. Zinc treatment significantly elevated hepatic MT concentrations only in wild-type mice and increased zinc concentrations in both MT-KO and wild-type mice. Ethanol treatment caused degenerative morphological changes and necrotic appearance in the livers of MT-KO mice. Microvesicular steatosis was the only ethanol-induced change in the liver of wild-type mice. Ethanol treatment decreased hepatic glutathione concentrations and increased hepatic lipid peroxidation, and the concentrations of lipid peroxide products in the wild-type mice were lower than in the MT-KO mice. All of these alcohol-induced toxic responses were significantly suppressed by zinc treatment in both MT-KO and wild-type mouse livers. These results demonstrate that zinc, independent of MT, plays an important role in protection from alcoholic liver injury. However, MT is required to maintain high levels of zinc in the liver, suggesting that the protective action of MT in the liver is likely mediated by zinc.     

Non-invasive diagnostic and prognostic evaluation of liver cirrhosis and portal hypertension

Cirrhosis is the final stage of most of chronic liver diseases, and is almost invariably complicated by portal hypertension, which is the most important cause of morbidity and mortality in these patients. This review will focus on the non-invasive methods currently used in clinical practice for diagnosing liver cirrhosis and portal hypertension. The first-line techniques include physical examination, laboratory parameters, transient elastography and Doppler-US. More sophisticated imaging methods which are less commonly employed are CT scan and MRI, and new technologies which are currently under evaluation are MR elastography and acoustic radiation force imaging (ARFI). Even if none of them can replace the invasive measurement of hepatic venous pressure gradient and the endoscopic screening of gastroesophageal varices, they notably facilitate the clinical management of patients with cirrhosis and portal hypertension, and provide valuable prognostic information.     

Quantitative real-time PCR tests for diagnostic and prognostic purposes in cases of legionellosis

The usefulness of two quantitative real-time PCR assays (qrt-PCRmip targeting Legionella pneumophila, and qrt-PCR16S targeting all Legionella species) performed on lower respiratory tract (LRT) samples for diagnostic and prognostic purposes in 311 patients hospitalized for community-acquired pneumonia (CAP) in Rhône-Alpes (France) was evaluated. The Now Legionella urinary antigen test (UAT) from Binax (Portland, ME, USA) was used as a reference test. Samples were divided into two groups. Group A included 255 CAP patients admitted to Chambery hospital in 2005 and 2006. The Now Legionella UAT was positive in 14 patients. Sensitivities, specificities, positive predictive and negative predictive values for both qrt-PCR tests were 63.6, 98.7, 77.7 and 97.4%, respectively. Group B included 56 consecutive legionellosis patients diagnosed during a 4-year period (2003–2006) at the Grenoble University Hospital. The qrt-PCR16S and qrt-PCRmip displayed a sensitivity of 82.14 and 80.4%, respectively. Among the 70 legionellosis cases, L. pneumophila serogroup 1 was isolated in 15; qrt-PCRmip was positive in another 36, suggesting L. pneumophila infection, whereas the Legionella species involved could not be determined in the remaining 19 cases. The Legionella burden in LRT samples at the time of admission was determined in 46 patients using qrt-PCR16S tests, 44 for qrt-PCR mip groups A and B patients. It varied from 1.9 to 8.35 log¹⁰ DNA copies/mL of LRT sample for qrt-PCR16S and from 1.9 to 8.11 log¹⁰ DNA copies/mL of sample for qrt-PCRmip. High bacterial loads in LRT samples at hospital admission were significantly associated with higher Fine classes, the need for hospitalization in an intensive care unit and for prolonged hospitalization.     

Mosquito allergy: recombinant mosquito salivary antigens for new diagnostic tests

In patients with mosquito allergy, lack of a readily available, sensitive, specific, safe test is the major obstacle to accurate diagnosis. Three recombinant mosquito salivary antigens, rAed a 1 (68 kD), rAed a 2 (37 kD) and rAed a 3 (30 kD), from Aedes aegypti have been cloned, expressed, purified and characterized. All three recombinant antigens are shared by Aedes vexans and other mosquito species, and all have been found to have biologic activity in humans. In recent studies, 43% of 28 mosquito bite test-positive subjects had a positive skin test to rAed a 1, 11% to rAed a 2 and 32% to rAed a 3. The sizes of the skin test reactions to the recombinant antigens correlated with the sizes of the A. aegypti bite test reactions. None of 15 A. aegypti bite test-negative subjects had a positive skin test to any of the recombinant antigens. Recombinant mosquito salivary antigens will facilitate the diagnosis of mosquito allergy.     

Clinical efficacy assessment of diagnostic tests: from the standpoint of analysis of prognostic factors

The usefulness of laboratory tests has been assessed by indices such as diagnostic sensitivity, specificity and predictive values. This paper describes the means by which usefulness is evaluated by analysis of prognostic factors, including risk factors and clinical outcome of therapy. It is essential to follow appropriate research designs and to make use of appropriate statistical analyses. Some of the efficient means for analyzing prognostic values include prospective investigation, as represented by cohort studies which follow characteristics of groups for a period of time, and retrospective investigation, as represented by case-controlled studies which evaluate characteristics of groups in a retrospective manner. The appropriate method of analysis for sample data which contain time factors and a relationship between cause and outcome may be multiple logistic regression analysis. This analytical method can present the effects of each factor on a given disease by odds ratios, and can also calculate the occurrence probability of the disease for each case. For example, we analyzed the prognostic factors that govern the effects of interferon therapy on hepatitis type C. We found that the genetic type and quantity of the virus are the major prognostic factors determining the efficacy of interferon therapy, which is in good accord with previous studies. Furthermore, we were able to identify some factors which have not been recognized before. Thus, appropriate research designs not only provide new insights into therapeutic approaches but can also improve the usefulness of laboratory tests.     

IgA deposition in liver in alcoholic liver disease. An index of progressive injury

A retrospective study was done to evaluate the prognostic importance of the patterns of IgA deposition in the liver in alcoholic liver disease. The patterns of IgA deposition in the liver were determined by direct immunofluorescence with fluorescein conjugated rabbit antihuman IgA. Twenty of 40 patients showed a characteristic continuous pattern, and 20 patients showed the nonspecific discontinuous pattern of IgA deposition in the liver. Alcoholic liver disease progressed considerably in 14 (70%) of the 20 patients with an initial continuous pattern and in three (15%) of the 20 patients with an initial discontinuous pattern. Alcoholic liver disease did not progress in six (30%) of 20 patients with an initial continuous pattern and in 17 (85%) of the 20 patients with an initial discontinuous pattern of IgA deposition in the liver.     

Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress

Objective and design  

The present investigation was designed to determine the effects of caffeine on alcohol-induced hepatic injury in mice.     

A new diagnostic immunoassay for proximal tubule injury

Adenosine deaminase binding protein (AdAbp), a glycoprotein found in the epithelial cells of the brush border of the proximal tubule, is shed into urine following kidney damage. A sandwich enzyme immunoassay is described that uses two monoclonal antibodies, URO-4 (S27) and URO-4a (S23), which react with different epitopes on AdAbp (2, 24). Release of AdAbp into the urine appears to reflect the severity of the insult to the nephron and its measurement may assist in distinguishing between tubular disease and glomerular disease and may be useful in indicating renal toxicity.     

Clusters of alcohol use disorders diagnostic criteria and predictors of alcohol use after liver transplantation for alcoholic liver disease

BACKGROUND: Establishing the correct alcohol use disorder diagnosis is clinically relevant because several reports of post-transplant alcohol use suggest that a pre-transplant diagnosis of alcohol dependence (rather than abuse) predicts relapse to alcohol use. Numerous combinations of specific symptoms are possible to achieve diagnostic significance. OBJECTIVE: The authors hypothesized that there would be distinct clusters of liver transplant recipients who showed specific combinations of alcohol-related symptoms and that these clusters would be predictive of alcohol-abuse outcome after transplant. METHOD: A group of 120 ALD liver transplant recipients received the Structured Clinical Interview for DSM-IV (SCID) module for alcohol abuse/dependence, and a cluster analysis was performed. RESULTS: Within the clusters of those with alcohol dependence, cluster assignment did not predict those more likely to drink. However, those assigned to the alcohol abuse cluster were significantly less likely to drink than those with alcohol dependence. CONCLUSION: Results therefore suggest that the prognosis regarding continued abstinence posttransplant is much more positive for individuals with a diagnosis of abuse than for those who meet criteria for alcohol dependence.     

Increased severity of alcoholic liver injury in female verses male rats: a microarray analysis

Alcoholic liver disease (ALD) is an increasingly recognized condition that may progress to end-stage liver disease. In addition to alcohol consumption, genetic factors, dietary fatty acids, gender and viral infection potentiate the severity of alcoholic liver injury. In humans, significant gender differences in susceptibility to ALD are observed. In the intragastric infusion rat model of ALD, female rats developed more severe liver injury than males. To understand the effect of gender on the development of more severe ALD in female rats, we performed a microarray based expression profiling of genes in rats fed with fish oil and ethanol diet. A large number of genes showed significant changes in female livers compared to males. The upregulated genes in female liver were involved in proteosome endopeptidase activity, catalytic activity, lipid metabolism, alcohol metabolism, mitochondrial and oxidoreductase activity. The downregulated genes were involved in oxidoreductase activity, chaperone activity, and electron transport activity in the female liver as demonstrated by biological theme analysis. Ingenuity computational pathway analysis tools were used to identify specific regulatory networks of genes operative in promoting liver injury. These networks allowed us to identify a large cluster of genes involved in lipid metabolism, development, cellular growth and proliferation, apoptosis, carcinogenesis and various signaling pathways. Genes listed in this article that were significantly increased or decreased (expression two fold or more) were assigned to pathological functional groups and reviewed for relevance to establish hypotheses of potential mechanisms involved in ALD in female liver injury.     

On the process for evaluating Proposed new diagnostic EEG tests

Summary Assessment of new technology is an important part of the evolving art of medicine. For a variety of reasons, it is appropriate to restrict clinical applications of new technology to those tests which have been shown to be safe and effective. Efficacy of new EEG technology can be assessed through a variety of standard procedures, generally based on controlled, well organized clinical studies. Scientific reports using new EEG technology all too often fail to meet the standards traditionally expected for such clinical trials. Many such studies were never designed to be clinical trials. Misunderstandings occur when reports of scientific studies and informal clinical series become confused with formal clinical trials of efficacy. Based upon examples given during the 1991 ISBET meeting symposium on discriminant analysis, examples are discussed regarding how well individual kinds of presentations can be used to help clarify the generic clinical efficacy of the presented diagnostic tests.     

Role of chemokines in metastatic niche: new insights along with a diagnostic and prognostic approach

Chemokines are cytokines that are involved in the movement of leukocytes and the occurrence of immune responses. It has recently been noted that these cytokines play a role in the movement of cancer cells to different parts of the body and create a suitable environment [i.e. (pre) metastatic niche] for their growth and proliferation. We studied the role of chemokines in the metastasis of cancer cells, as well as their involvement in the proliferation and growth of these cells. Relevant literature was identified by a PubMed search (2005–2017) of English language papers using the terms ‘chemokine,’ ‘metastasis niche,’ and ‘organotropism.’ Based on the nature of cancer cells, the expression of chemokine receptors on these cells leads to metastasis to various organs, which ultimately causes changes in different signaling pathways. Finally, the targeting of chemokines on cancer cells could prevent the metastasis of cancer cells toward different organs.     

Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress

Alcoholic liver disease is associated with zinc decrease in the liver. Therefore, we examined whether dietary zinc supplementation could provide protection from alcoholic liver injury. Metallothionein-knockout and wild-type 129/Sv mice were pair-fed an ethanol-containing liquid diet for 12 weeks, and the effects of zinc supplementation on ethanol-induced liver injury were analyzed. Zinc supplementation attenuated ethanol-induced hepatic zinc depletion and liver injury as measured by histopathological and ultrastructural changes, serum alanine transferase activity, and hepatic tumor necrosis factor-alpha in both metallothionein-knockout and wild-type mice, indicating a metallothionein-independent zinc protection. Zinc supplementation inhibited accumulation of reactive oxygen species, as indicated by dihydroethidium fluorescence, and the consequent oxidative damage, as assessed by immunohistochemical detection of 4-hydroxynonenal and nitrotyrosine and quantitative analysis of malondialdehyde and protein carbonyl in the liver. Zinc supplementation suppressed ethanol-elevated cytochrome P450 2E1 activity but increased the activity of alcohol dehydrogenase in the liver, without affecting the rate of blood ethanol elimination. Zinc supplementation also prevented ethanol-induced decreases in glutathione concentration and glutathione peroxidase activity and increased glutathione reductase activity in the liver. In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways.