Methionine-induced hepatic coma in dogs.

Oral methionine is noncomatogenic in normal dogs, but it is consistently comatogenic in dogs with portacaval shunts in the presence of elevated ammonia levels. Such action appears to be enhanced by the ammonia itself, since relatively small doses of oral methionine can induce coma when baseline levels of ammonia are above 1,000 mug/100 ml; much higher doses are nesessary for near normal ammonemia. The methionine-induced coma closely reproduces the clinical and electroencephalographic picture of coma in other canine models. Oral methionine does not significantly increase the ammonia levels, but its action is probably mediated by the release of methanethiol (and other less active compounds) from the bowel. Methanethiol levels tend to increase in proportion to the amount of methionine administered, and its comatogenic action may be amplified, up to one hundredfold, by high ammonia levels. Methanethiol levels in comatose patients and the concept of the synergistic effect with ammonia may lead to a clearer understanding of certain enterogenous and dietetic forms of hepatic encephalopathy in cirrhotic patients. The lowering of ammonia levels by hemodialysis or methanethiol levels by activated charcoal hemoperfusion, as attempts to reverse such forms of coma, warrants further investigation.     

Effects of two different hydroxyethyl starch solutions (HES200/0.5 vs. HES130/0.4) on the expression of platelet membrane glycoprotein

BACKGROUND: There are various hydroxyethyl starch (HES) solutions with different degrees of hydroxylation and different molecular weights. HES200/0.5 solution is most commonly used. HES130/0.4 is a new HES solution and is the 'state-of-the-art' in volume substitution. However, the mechanism of the observed anticoagulation action of HES has not been fully delineated. The objective of this study was to further investigate the effect of HES200/0.5 and HES130/0.4 on platelet coagulation. METHODS: Sixty ASA I-II patients undergoing elective minor surgery were randomly allocated to receive an intravenous infusion (20 ml/kg) of lactated Ringer's solution (group L), HES200/0.5 (group H) or HES130/0.4 (group V) after the induction of anesthesia. The expression of CD42b, CD41/61 and CD62p in vivo was assessed on non-stimulated platelets and adenosine diphosphate (ADP) agonist-activated platelets using flow cytometry. RESULTS: Resting glycoprotein expression of the non-stimulated platelets was observed. HES200/0.5 and HES130/0.4 reduced the CD42b, CD41/61 and CD62p expression of ADP-agonist-activated platelets at 15 min after intravenous infusion. At 6 h after intravenous infusion, the trend of decreasing expression of activated CD42b, CD41/61 and CD62p was maintained in group H. However, CD42b, CD41/61 and CD62p expression returned to the pre-operative level in group V. CONCLUSION: This study showed that both HES200/0.5 and HES130/0.4 can inhibit platelet coagulation. Platelet dysfunction experienced a faster recovery after the infusion of HES130/0.4 than after HES200/0.5. Liquid resuscitation with HES130/0.4 may decrease the risk of hemorrhage in the operative period.     

Solubilization of an active opiate receptor from Bufo marinus

The effect of veratridine on in vitro release of noradrenaline (NA) from ligand cat hypogastric nerve was investigated. After in vivo ligation for 24–48 h, large amounts of NA and dopamine-β-hydroxylase (DBH) accumulated in the nerve segment immediately proximal to the ligature (P₁). In vitro incubation of ligated nerves (segments P₁ and P₂) in oxygenated Krebs solution at 37°C in the presence of veratridine caused a marked and dose-dependent release of endogenously accumulated NA into the incubation medium. The release continued to occur for a considerable time, even after washout of the drug. Veratridine-induced depletion of tissue NA was accounted for by its release, as NA, into the incubating medium. The secretory response to veratridine was readily blocked by tetrodotoxin (TTX). Veratridine-induced release was dependent on calcium and abolished by high magnesium. On the basis of the similarity between the NA secretory response to veratridine in this preparation and in adrenergically innervated organs, the results favour the view that the in vivo-ligated cat hypogastric nerve may serve as a useful model of adrenergic nerve terminals free of effector cells.     

Parietal cell vagotomy for intractable and obstructing duodenal ulcer

Parietal cell vagotomy can be accomplished with minimal morbidity and mortality. Symptoms and signs of delayed gastric emptying early after operation are common and occur more frequently in patients with preoperative gastric outlet obstruction than in those without, a difference that is statistically significant. These symptoms are generally mild and transient. Dumping and diarrhea were not problems in our series. In patients with preoperative gastric outlet obstruction, parietal cell vagotomy with pyloroduodenal dilatation achieved good or excellent results in 79 percent of patients; however, the possibility of a higher recurrence rate requires further evaluation and suggests caution and selectivity in the use of this procedure. The recurrence rate of 3 percent in patients without gastric outlet obstruction and a very good or excellent clinical result in 91 percent of these patients appear acceptable and encourage us to continue to use parietal cell vagotomy as the procedure of choice in patients with intractable duodenal ulcer. Most patients with recurrent ulcer have been treated medically with success. Close long-term clinical follow-up studies will be required to assess better the success of this procedure.     

Parenteral nutrition-induced gallbladder disease: a reason for early cholecystectomy

Patients who receive long-term parenteral nutrition have an increased incidence of both calculous and acalculous cholecystitis. In an attempt to establish guidelines for the clinical management of patients with TPN-induced gallbladder disease, we have reviewed the records of 35 patients who have undergone cholecystectomy for this problem since 1976 at the UCLA Medical Center. The mean age of the 23 adult and 12 children who had cholecystectomy was 29.1 years. Forty percent of these patients required emergency cholecystectomy. The overall operative morbidity was 54 percent, and the hospital mortality was 11 percent. Significant factors contributing to this high rate of complications included a delay in diagnosis, especially in the young children, and increased operative difficulty due to extensive adhesions and intraoperative hemorrhage. Our analysis suggests that patients receiving long-term TPN should have a program of ultrasound surveillance for gallstone formation, elective cholecystectomy when stones first appear, and consideration of cholecystectomy at the time of laparotomy performed for other reasons. Whether TPN-induced gallstones can be prevented through daily stimulated gallbladder emptying awaits the results of future studies.     

Increased activity of matrix metalloproteinase-2 in human glial and neuronal cell lines treated with HIV-1 gp41 peptides

Part of the neurodegenerative cascade in AIDS dementia may involve overexpression of matrix metalloproteinases (MMPs). Here, we examined the possible effect of HIV-1 gp41, which has been shown as a key determinant associated with pathogenesis of AIDS dementia, on the activity of MMPs using human neuronal and glial cell lines. Zymographic analysis revealed that treatment with the gp41 peptide (aa 583–599) for 24 h markedly elevated the activity of MMP with Mr 66 kDa in the cultured media of glioblastoma cell line T98G in a concentration-dependent manner as well as of neuroblastoma cell line SK-N-SH despite of lower magnitude of the activity. In contrast, the immediately adjacent gp41 peptide (aa 598–613) as well as the reverse peptide (aa 598–583) had a little effect. Recombinant gp41 protein containing extracellular domain also elicited a similar effect, although with a lesser extent. This 66 kDa MMP was confirmed as gelatinase A (MMP-2) based on the results of its activity dependent on Ca²⁺ and inhibited in the presence of 1,10-phenanthroline or EDTA, as well as its specific immunoreactivity on the Western blot.N-acetyl cysteine (NAC) downregulated this gp41 peptide-induced MMP-2 activity in T98G. The soluble form of amyloid precursor protein (sAPP), which is synthesized in theEscherichia coli system, also inhibited the MMP-2 activity in vitro. Taken together, these results implicate that high production of HIV-1 gp41 or its metabolites containing aa 583–599 within central nervous system (CNS) could result in the increased activity of MMP-2 and that the extracellular deficiency of reducing agent or decreased level of sAPP within CNS could exacerbate this gp41-induced MMP-2 activity.     

Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance

A rare pathway of HIV-1 resistance to small molecule CCR5 inhibitors such as Vicriviroc (VCV) involves changes solely in the gp41 fusion peptide (FP). Here, we show that the G516V change is critical to VCV resistance in PBMC and TZM-bl cells, although it must be accompanied by either M518V or F519I to have a substantial impact. Modeling VCV inhibition data from the two cell types indicated that G516V allows both double mutants to use VCV-CCR5 complexes for entry. The model further identified F519I as an independent determinant of preference for the unoccupied, high-VCV affinity form of CCR5. From inhibitor-free reversion cultures, we also identified a substitution in the inner domain of gp120, T244A, which appears to counter the resistance phenotype created by the FP substitutions. Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors.