'Hemorrhagic' and microvascular phenomena within the arterial wall.

OBJECTIVE: To study microvasculature and hemorrhage within the arterial wall. DESIGN: Human autopsy specimens of the arch of the aorta, the carotid, brachiocephalic, subclavian and coronary arteries perfused with liquid casting material and maintained at physiological pressure until the material had set. MAIN RESULTS: Evidence of dense microvasculature and other phenomena which have the morphological appearance of 'hemorrhage' within the arterial wall, coupled with calcified matter and other impressions made on the cast by atherosclerotic plaques. CONCLUSIONS: The findings lend support to suggestions in the literature that neovascularization may play a role in the pathogenesis of coronary atherosclerosis and its sequelae, that hemorrhage into the intima may be due to rupture of capillaries which are derived from the coronary lumen, and that an increase in microvasculature occurs in the immediate vicinity of localized atherosclerotic lesions.     

Congenital toxoplasmosis—prenatal aspects of Toxoplasma gondii infection

Toxoplasma gondii (T. gondii) is the cause of toxoplasmosis. Primary infection in an immunocompetent person is usually asymptomatic. Serological surveys demonstrate that world-wide exposure to T. gondii is high (30% in US and 50–80% in Europe). Vertical transmission from a recently infected pregnant woman to her fetus may lead to congenital toxoplasmosis. The risk of such transmission increases as primary maternal infection occurs later in pregnancy. However, consequences for the fetus are more severe with transmission closer to conception. The timing of maternal primary infection is, therefore, critically linked to the clinical manifestations of the infection. Fetal infection may result in natural abortion. Often, no apparent symptoms are observed at birth and complications develop only later in life. The laboratory methods of assessing fetal risk of T. gondii infection are serology and direct tests.Screening programs for women at childbearing age or of the newborn, as well as education of the public regarding infection prevention, proved to be cost-effective and reduce the rate of infection.The impact of antiparasytic therapy on vertical transmission from mother to fetus is still controversial. However, specific therapy is recommended to be initiated as soon as infection is diagnosed.     

Effect of the glucocorticoid receptor antagonist RU 38486 on muscle protein breakdown in sepsis

The role of glucocorticoids in muscle catabolism during sepsis was tested with the glucocorticoid receptor antagonist RU 38486. Sepsis was induced in male Sprague-Dawley rats (40 to 60 gm) by cecal ligation and puncture (CLP). Other animals underwent sham operation. Two hours before CLP or sham operation, rats received RU 38486 (5 mg/kg) or a corresponding volume of vehicle by gavage. Sixteen hours after CLP or sham operation, protein synthesis rate was determined by measuring incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus muscles. Total and myofibrillar protein breakdown rates were determined by measuring net release of tyrosine and 3-methylhistidine, respectively. The protein synthesis rate was approximately 30% lower in rats with sepsis than in sham operated rats and was not affected by treatment with RU 38486. The total protein breakdown rate was increased by approximately 70% and myofibrillar protein degradation was increased more than fivefold in muscle from rats with sepsis. Treatment with RU 38486 resulted in a 28% reduction of total and a 44% reduction of myofibrillar protein breakdown in rats with sepsis but did not affect proteolysis in muscle from sham-operated animals. The results support a role of glucocorticoids in accelerated muscle proteolysis during sepsis. It is not clear whether glucocorticoids are the only required mediator or they interact with other substances to induce muscle protein breakdown during sepsis.     

De novo amplification within a "silent" human cholinesterase gene in a family subjected to prolonged exposure to organophosphorous insecticides

A 100-fold DNA amplification in the CHE gene, coding for serum butyrylcholinesterase (BtChoEase), was found in a farmer expressing the "silent" CHE phenotype. Individuals homozygous for this gene display a defective serum BtChoEase and are particularly vulnerable to poisoning by agricultural organophosphorous insecticides, to which all members of this family had long been exposed. DNA blot hybridization with regional BtChoEase cDNA probes suggested that the amplification was most intense in regions encoding central sequences within BtChoEase cDNA, whereas distal sequences were amplified to a much lower extent. This is in agreement with the "onion skin" model, based on amplification of genes in cultured cells and primary tumors. The amplification was absent in the grandparents but present at the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to the long arm of chromosome 3, close to the site where we previously mapped the CHE gene. Altogether, these observations suggest that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning was indicated to be physiologically necessary. Our findings demonstrate a de novo amplification in apparently healthy individuals within an autosomal gene producing a target protein to an inhibitor. Its occurrence in two generations from a family under prolonged exposure to parathion indicates that organophosphorous poisons may be implicated in previously unforeseen long-term ecological effects.     

Human monoclonal anti-DNA antibodies react as lymphocytotoxic antibodies

Two out of 25 monoclonal anti-DNA autoantibodies that were produced by human-human hybridoma were found to have lymphocytotoxic activity. The antibodies reacted with normal B and T lymphocytes at cold (4 degrees C) as well as at warm (37 degrees C) temperatures. The lymphocytotoxic activity of the monoclonal anti-DNA antibodies could be inhibited by prior incubation of the antibodies with either polynucleotides, e.g. poly(I), poly(dT) or anti-idiotypic antibodies, that had been raised against a dominant anti-DNA antibody. The cross-reactivity between nuclear material and lymphocyte membrane raises the question whether these apparently diverse materials have a shared epitope. The cross-reactivity between anti-DNA antibodies and lymphocyte membrane may account in part for the lymphopenia observed in systemic lupus erythematosus patients.     

Influence of sepsis in rats on muscle protein turnover in vivo and in tissue incubated under different in vitro conditions

We studied the influence of sepsis on muscle protein synthesis and degradation in vivo and in muscles, incubated flaccid or at resting length. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham-operated. A flooding dose of 14C-phenylalanine was used to determine muscle protein synthesis rate in vivo, and protein breakdown was calculated from the difference between protein synthesis and growth rates. Protein synthesis rate in vitro was assessed by determining incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus (EDL) and soleus (SOL) muscles. Total and myofibrillar protein breakdown rates were determined from release into incubation medium of tyrosine and 3-methylhistidine (3-MH), respectively. Muscle protein synthesis rate in vivo was reduced by 35%, similar to the reduction observed in muscles incubated flaccid or at resting length. The calculated protein breakdown rate in vivo was increased by 31% in septic rats. In incubated muscles, the increase in total protein breakdown (ie, tyrosine release) during sepsis was almost identical in muscles incubated flaccid or at resting length, ie, 83% to 88% in EDL and 47% to 49% in SOL. Myofibrillar protein degradation in vitro (ie, 3-MH release) was increased approximately 10-fold in EDL muscles incubated flaccid or at resting length, but was not significantly affected by sepsis in SOL. Results suggest that sepsis-induced changes in protein synthesis observed in muscles incubated either flaccid or at resting length reflect changes in vivo. Changes in protein breakdown were qualitatively similar in vivo and in vitro, but results in incubated muscles may overestimate the increase in muscle proteolysis caused by sepsis.