Modulation of trenimon-induced cytotoxicity by DT-diaphorase in isolated rat hepatocytes under aerobic versus hypoxic conditions.

Trenimon belongs to a class of aziridinylbenzoquinone anticancer drugs that cross the blood-brain barrier. In this study we have investigated the molecular mechanisms for trenimon-induced toxicity in aerobic versus hypoxic conditions with the use of freshly isolated rat hepatocytes. The following evidence suggests the mechanisms for trenimon detoxification involves reduction by DT-diaphorase, while the cytotoxic mechanism involves macromolecular alkylation under hypoxic conditions as well as oxidative stress under aerobic conditions. (a) Hepatocyte cytotoxicity induced by trenimon (250 microM) under aerobic conditions ensued following an initial induction of cyanide-resistant respiration and partial oxidation of glutathione to oxidized glutathione. Trenimon reduction to the hydroquinone by the hepatocytes was rapid. Inhibition of hepatocyte DT-diaphorase by dicumarol increased trenimon-induced cytotoxicity by approximately 10-fold, and markedly inhibited hydroquinone formation. Furthermore, both cyanide-resistant respiration and oxidized glutathione formation were markedly increased, resulting in depletion of oxygen in the media. Trenimon reduction to the hydroquinone then occurred. This suggests that DT-diaphorase in normal hepatocytes prevents the formation of the semiquinone that causes cytotoxic protein alkylation and oxidative stress. (b) Hepatocyte cytotoxicity induced by trenimon (350 microM) under hypoxic conditions ensued following glutathione depletion without oxidized glutathione formation. Inactivation of hepatocyte DT-diaphorase by dicumarol under hypoxic conditions increased trenimon-induced cytotoxicity by approximately 3.5-fold and increased semiquinone radical levels 2-fold without affecting its reduction rate. This suggests that the cytotoxic mechanism involves protein alkylation by semiquinone radicals formed by reductases catalyzing a one-electron reduction of trenimon.     

Various manifestations of hyperthyroidism in an ambulatory clinic: case studies

This study reviews five cases of women with hyperthyroidism, three black women and two Hispanic women. Initially, two patients presented with voice changes, weight loss, and increased appetite. Only two patients presented with classical symptoms of hyperthyroidism. Examination showed all patients had diffusely enlarged thyroids and exaggerated reflexes. Two patients showed Graves'' opthalmopathy.     

Staphylococcal toxins: screening of burn wound isolates and evidence for alphahaemolysin production in the burn wound

Culture filtrates of Staphylococcus aureus strains isolated from burn patients were examined for cytotoxic activities. A large molecular weight cytotoxin (MW=253000 daltons) that exhibited cytotoxicity for human foreskin cells and haemolytic activity against human and rabbit erythrocytes was identified. The cytotoxic activity could be completely neutralized by antiserum formed against the cytotoxin. Further characterization of the molecule by isoelectric focusing revealed that the cytotoxin was composed of at least two toxic factors of smaller molecular weight. Both factors exhibited cytotoxicity to tissue-culture cells. however, one factor lysed rabbit but not human erythrocytes whereas the other factor had the opposite haemolytic pattern. The cytotoxicity of each factor was neutralized by the antiserum formed against the cytotoxin. A cytotoxic factor that exhibited haemolytic activity for rabbit erythrocytes, and that was neutralized by the cytotoxin antiserum, was identified in burn wound extracts of mice infected with Staph. aureus. On the basis of molecular weight and isoelectric focusing data, we conclude that the large molecular weight cytotoxin was composed of an aggregation of alpha-haemolysin and another presently unidentified toxic molecule, possibly delta-toxin. Alpha-haemolysin appears to be produced in vivo during experimental staphylococcal burn wound infection.     

Direct solution to an optimal control problem of econometric systems

A direct solution is proposed to an optimal control problem of linear econometric systems with a quadratic welfare loss function when there are linear equality constraints on the control variables. The direct solution proposed here eliminates the problem of non-uniqueness of the optimal solution, which is present when this optimal control problem is solved using the recursive algorithm proposed by Chow,¹ Pindyck² and Tan.³ If a unique solution to the optimal control problem exists, then the direct solution and the recursive solution coincide.     

Zur Acylierung von Hydroxy- und Mercapto-carbonsäureestern nach dem Carbodiimid/Acylierungskatalysator-Verfahren

On the Acylation of Hydroxy- and Mercaptocarboxylic Acid Esters Using the Carbodiimide/Acylation Catalyst Method Acylation of esters of hydroxycarboxylic acids can be carried out easily and in good yields by using the carbodiimide/acylation catalyst method. The reaction has also been applied to dihydroxy- and mercaptocarboxylic acid esters. The compounds formed from certain esters of hydroxycarboxylic acids are unstable to heat and decompose easily to the free carboxylic acid. No racemization is observed when using enantiomeric hydroxycarboxylic acids. Use of racemic carboxylic acids leads to diastereomers, whose ¹H-NMR shifts for characteristic protons are different as expected. Five drugs are among the carboxylic acids investigated in this context.     

Release of 2-thiobarbituric acid reactive products from glutamate or deoxyribonucleic acid by 1,2,4-benzenetriol or hydroquinone in the presence of copper ions

Cytotoxic effects of various quinone compounds are thought to be due to the formation of semiquinone free radicals. Hydroquinone and 1,2,4-benzenetriol in the presence of copper ions release from glutamate or DNA aldehydic products capable of reacting with 2-thiobarbituric acid (TBA). The formation of TBA reactive products (TBAR) was greater in the presence of 1,2,4-benzenetriol in comparison with hydroquinone. Complete inhibition of formation of TBAR from glutamate by 1,2,4-benzenetriol and copper was observed in the presence of catalase, thiourea and mannitol. Albumin and superoxide dismutase offered substantial protection. Complete protection of formation of TBAR from DNA was observed in the presence of catalase and thiourea. Presence of albumin, mannitol and superoxide dismutase caused only partial inhibition. The formation of TBAR from glutamate or DNA is dependent on copper ion concentration. The present data indicate that hydroquinone and 1,2,4-benzenetriol in the presence of copper ions can lead to the formation of reactive hydroxyl radicals which can release TBAR from glutamate or DNA.     

Prosthetic joint infectionsin the elderly

Total joint arthroplasty is among the most remarkable advances in orthopaedic surgery for the elderly, enabling themto regain physical function and be free of pain. Although uncommon, infection of the prosthetic joint causes serious morbidity leading to poor functional outcome with a mortality approaching 8% in the elderly. Most infections occur through inoculation of the prosthesis at the time of implantation and are due to Gram-positive cocci, although a third of the episodes are due to Gram-negative bacilli from a secondary focus. The management presents a major clinical and therapeutic challenge due to systemic and local comorbid conditions in the elderly. Medical and surgical treatment decisions for infected joint prosthesis are complex and should be individualized in each case. Optimal nutrition is essential for a successful outcome. Adverse reactions to medications are more common in the elderly due to end organ dysfunction and drug-drug interactions.     

Changes in selected biochemical parameters in the kidney and blood of the fish,Tilapia mossambica (Peters), exposed to heptachlor

Bulletin of Environmental Contamination and Toxicology -