Ethanol Feeding Causes Inactivation of Both State 1 and State 2 Rat Hepatic Asialoglycoprotein Receptors

Previous studies have shown that ethanol feeding in rats causes inactivation and redistribution of ˜50% of the total asialoglycoprotein receptors (ASGPRs) in hepatocytes (Tworek et al., J. Biol. Chem. 271:2531, 1996), and that two equal populations of hepatic ASGPRs mediate ligand uptake and processing via two functionally different pathways (Weigel in Glycoconjugates: Composition, Structure and Function , Marcel Dekker, 1992, p. 421). The purpose of this study was to determine if ethanol feeding causes preferential inactivation of only one of these two ASGPR populations, which have been designated state 1 and state 2 ASGPRs. The state 2, but not state 1, ASGPRs are inactivated in isolated hepatocytes by a variety of drugs and inhibitors. State 2 ASGPRs can also be inactivated in permeable cells by ATP treatment and then reactivated by treatment with fatty acyl coenzyme As. In the present study, permeable cell assays for state 2 ASGPR inactivation and reactivation were used to assess whether hepatocytes from ethanol-fed rats contain inactive state 2 ASGPRs. The results show that preferential inactivation of one ASGPR population does not occur after ethanol feeding. That inactive ASGPRs could not be reactivated by treatment with palmitoyl-coenzyme A to a greater extent in ethanol-fed versus control cells indicates there is not a larger pool of inactivated state 2 ASGPRs in treated cells. We conclude that ethanol feeding causes equal inactivation of both state 1 and state 2 ASGPRs. Ethanol feeding may represent the first treatment found to inactivate state 1 ASGPRs.     

Executive cognitive deficits in primary dystonia.

Primary dystonia is a disorder of movement for which no consistent pathophysiology has been identified; in the absence of evidence to the contrary, it is assumed to be cognitively benign. We have studied a clinically heterogeneous group of 14 patients with primary dystonia on a battery of neuropsychological tests. Despite well-preserved speed of information processing, language, spatial, memory and general intellectual skills relative to normal controls, we have identified a constellation of attentional-executive cognitive deficits on the Cambridge Neuropsychological Test Automated Battery (CANTAB). Specifically, patients demonstrated significant difficulties negotiating the extra-dimensional set-shifting phase of the IED task. The implications of these findings for the pathophysiology of primary dystonia are discussed. This is, to the best of our knowledge, the first report of a significant cognitive deficit in patients with primary dystonia.     

Tuimorigenic activity of fluoranthene, 2-methylfluoranthene and 3-methylfluoranthene in newborn CD-I mice

Fluoranthene (FA) is frequently among the more abundant componentsdetected in environmental mixtures of polycyclic aromatic hydrocarbons.Several methylated fluoranthenes, although less prevalent thanFA, have also been detected as environmental pollutants. WhileFA is inactive as a tumorigenic agent on mouse skin, it doesinduce lung and liver tumors in newborn mice. Among the fiveisomers of methylfluoranthene, only 2-methylfluoranthene (2-MeFA)and 3-methylfluoranthene (3-MeFA) are active as tumor initiatorson mouse skin. A comparative bioassay was performed to determinethe relative tumorigenic activity of FA, 2-MeFA and 3-MeFA innewborn CD-1 mice. All three compounds were assayed at dosesof 3.46 and 17.3 µmol. The bioassay was terminated whenmice were 1 year old. At a dose of 17.3 µmol, FA and 2-MeFAinduced a similar incidence of lung tumors (65–96%) inboth male and female mice. However, tumor multiplicity in thelung was different between FA and 2-MeFA. At a dose of 17.3µmol, the multiplicity of lung tumors observed for miceadministered 2-MeFA ranged from 3.04 to 3.94 tumors per mouse.In contrast, animals treated with FA developed only an averageof 1.12–2.45 tumors per mouse. 3-MeFA did not induce astatistically significant incidence of lung tumors in eithermale or female mice. All three compounds when administered tonewborn mice did induce a significant incidence of liver tumorsamong male mice. The relative tumorigenic potency observed wasFA 5     

Evidence-based medicine for nutrition support: an overview of the process.

On a daily basis, clinicians make decisions regarding therapies to result in the best outcome for their patients. These decisions should be based on the evidence in the literature, indicating a therapy will cause the best outcome. To facilitate this, many professional societies and scientific journals have published technical and scientific reviews, as well as evidence-based standards of care focused on many issues of nutrition support practice. This paper provides an overview of how these reviews and standards of care are derived to promote both the understanding of what they can and cannot do to enhance clinical practice.     

Liver transplantation for erythropoietic protoporphyria liver disease.

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival.