Role of Tumour Necrosis Factor in the Enhanced Sensitivity of Mice to Endotoxin After Exposure to Lead

Heavy metals administered to animals, at doses which appear relatively innoxious by themselves, enhance susceptibility to endotoxin. The mechanisms which underly this phenomenon are not yet fully understood. In this study we investigated the role of the cytokine Tumour Necrosis Factor (TNF), an important mediator of the effects of endotoxin, in this phenomenon.

First it was studied whether Lead enhances sensitivity of mice to endotoxin and to TNF. Lead appeared to enhance sensitivity to both endotoxin and TNF resulting in mortality of mice at low endotoxin and TNF doses. Next we studied the influence of lead on serum TNF levels after stimulation by endotoxin. Lead treated mice showed lower TNF blood levels two hours after injection of endotoxin and lead. Six and eight hours after injection TNF levels of lead treated mice were higher compared to those of mice injected with endotoxinonly. In the last part of our investigation, we studied the influence of a monoclonal hamster anti TNF antibody on the effect of combined lead-endotoxin exposure. Administration of the antibody prevents lethality completely.

Our data indicate that TNF plays a central role in the phenomenon of the enhanced susceptibility of animals to endotoxin after exposure to lead. The enhanced susceptibility to endotoxin is caused by an enhanced susceptibility to TNF and possibly by a prolonged exposure to a higher level of TNF.     

Breast specimen radiography: evaluation of a compression device

The irregular shape and uneven tissue thickness of excised breast specimens makes radiographic evaluation difficult, especially when calcifications are not present. Xeroradiographs before and after compression of 20 separate excised breast specimens were compared, and 17 of the same specimens were compared after compression combined with immersion in water. Specimen compression improved visibility of the lesion on average in 88% of cases, and visibility was equal in 12%. Combined compression/immersion further improved visibility of the lesion on average in 37% of cases. More significantly, evaluation of the compressed specimen led to a change in interpretation of the radiographs in 45% of cases. Compression of the specimen in specimen radiography is recommended in all cases in which pre-biopsy localization is performed.     

Congenital dyserythropoietic anaemia: Report of three cases

Between January 1985 and June 1992, the Paediatric Department of Hospital Universiti Sains Malaysia has diagnosed congenital dyserythropoietic anaemia in three children, two of whom were siblings. The age of onset ranged from 1 to 3 years. All of them became transfusion-dependent before the age of 4 months. One of them was successfully treated with bone marrow transplantation.     

Evidence of involvement of tumor necrosis factor in adverse reactions during treatment of kidney allograft rejection with antithymocyte globulin

Serial plasma concentrations of the pyrogenic cytokines tumor necrosis factor and interleukin-1 beta were measured during treatment of acute renal allograft rejection with antithymocyte globulin in 7 consecutive kidney transplant recipients. TNF and IL-1 beta were measured with specific enzyme-linked immunosorbent assays. In 6 of 7 patients TNF could not be detected in the plasma before the start of the ATG infusion. During the first ATG infusion, which was accompanied by fever and other side effects in all patients, plasma TNF levels were shown to be elevated, ranging between 100 and 700 pg/ml. During the second ATG infusion, when side effects were minimal or absent, plasma TNF levels were only slightly raised. Circulating IL-1 beta could not be detected in any of the patients before or during ATG infusion. Additional experiments showed that TNF is rapidly secreted in cultures of peripheral blood mononuclear cells incubated with both ATG and the monoclonal antibody OKT3. These findings suggest that side effects, including fever and chills, during antilymphocyte antibody infusion are related to increased plasma levels of the pyrogenic cytokine TNF.     

Pressure erosions of bone in rheumatoid arthritis: a subject review

Pressure, or compressive, erosions of bone in various locations in patients with rheumatoid arthritis are described. Possible pathophysiologic mechanisms that account for the appearance and distribution of these erosions include osteopenia, soft-tissue laxity, soft-tissue pressure on bone, bone pressure on bone, and muscular forces.     

Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation

L-Methylmalonyl-CoA mutase (MUT) is an adenosylcobalamin (AdoCbl)- requiring mitochondrial matrix enzyme that catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA. Inherited defects in the gene encoding this enzyme result in the mut forms of methylmalonic acidemia. Expression of mature human MUT cDNA in Escherichia coli at a post- induction cultivation temperature of 12 degrees C, rather than 37 degrees C, led to the folding of the majority of the synthesized protein to a soluble form, with an activity of 0.2-0.3 U/mg protein in the cell-free extract, 10-15 times higher than that in human liver homogenate. Six missense mutations, producing the amino acid changes G94V, Y231N, R369H, G623R, H678R and G717V, were detected in MUT cDNA of patients suffering from the mut- form of methylmalonic acidemia, resulting from defective AdoCbl binding. Two (G623R and G717V) had been reported in other patients. Three (G94V, Y231N and R369H) are the first changes in the NH2-terminal part of the enzyme reported to cause the mut- phenotype. Enzymes with the mutations were individually expressed, and their kinetic parameters were generally in accord with published biochemical data from extracts of fibroblasts from these patients. The mutations increased the K(m) for AdoCbl by 40- to 900-fold, while V(max) values varied from 0.2% to nearly 100% of that of wild-type protein. In one case of a doubly heterozygous cell line, however, neither of the constituent mutant enzymes had a K(m) corresponding to the lower of the two estimated from the extract data. This finding may reflect the natural occurrence of interallelic complementation in vivo in this cell line.