Cytotoxic activity of platelets and peripheral blood mononuclear cells from oncology patients and healthy donors

Testicular germ cell tumour is said to be a model for curable neoplasm. However, the prognosis of primary extragonadal germ cell tumour does not appear to be as promising. Though similar in histology, the biology of primary extragonadal germ cell tumour is different as exemplified by the patients in this review. Eight patients with primary mediastinal germ cell tumours were treated with intensive cisplatin-based chemotherapy. All, except one, had non-seminomatous components. The poor prognosis of mediastinal germ cell tumour is due to a combination of poor treatment results with the cisplatin-based regimen and the development of non-germ cell and haematological malignancies.     

Asymptomatic myocardial ischemia before and after surgical revascularization in patients with multivessel occlusive coronary disease

INTRODUCTION: The objective of this study was to examine the occurrence of asymptomatic myocardial ischemia prior to and after myocardial revascularization in patients with multivessel occlusive coronary disease. Asymptomatic ischemia can be described as real ischemia without anginal pain or other ischemic symptoms in patients with coronary disease or coronary artery spasm. Our study examined silent ischemia after myocardial revascularization. Early detection of silent ischemia is important for prevention of cardiac incidents. MATERIAL AND METHODS: We have examined patients with multivessel coronary disease with occurrence of continued preoperative silent ischemia. All patients have undergone ECG examination, exercise stress test and Holter-monitoring prior to and after myocardial revascularization. RESULTS: The investigation comprised 27 patients and their average age was 54.5 years. All patients with silent ischemia had a multivessel occlusive coronary disease and have undergone myocardial revascularization managed with triple or quadruple aortocoronary bypass surgery. Exercise stress test was performed postoperatively in elder patients, as well as ECG and Holter-monitoring. Silent ischemia was established in 21.6% of patients, while in 87.5% untreated diabetes mellitus was diagnosed. Silent ischemia most often occurred in the early morning hours and it was frequently associated with heart rhythm disturbances (VES) whereas these rhythm disturbances depended on the length of the ischemic episode. Intermittent 2nd degree atrioventricular block was found in one patient. CONCLUSION: Silent myocardial ischemia occurred in 21% of patients after myocardial revascularization. It is most often detected in the early morning hours and is associated with ventricular rhythm disorders. Silent ischemia is easily detected by simple examination procedures providing adequate therapy and prevention of cardiac incidents.     

Lacrimal canaliculitis due to Arachnia (Actinomyces) propionica

The clinical and microbiological findings in a chronic case of lacrimal canaliculitis due to Arachnia propionica are described. Bacterial culture and identification should be performed in the investigation of the disease in order to establish the role of A. propionica and other specific actinomycetes at the acute as well as at the chronic stage.     

Rapid postmortem changes in the cellular localisation of amino acid transmitters in the retina as assessed by immunocytochemistry

We have assessed by means of immunocytochemistry, the cellular distributions of the amino acid transmitters GABA, glycine and glutamate, and the free-radical scavenger taurine, in the retinae of adult rabbits at various times after death. Within 10 min of death, horizontal cells began to display immunoreactivity for GABA, whilst displaced amacrine cells began to display immunoreactivity for glycine. By 40 min postmortem, GABA was present in glial cells. Glutamate, which is not normally detectable in retinal glia, was detected in such glia by 20 min postmortem. By contrast immunocytochemically detectable glycine did not accumulate in glia. There was a gradual diminution of immunoreactivity for taurine in glial cells and photoreceptors. By 2 h postmortem, most immunoreactivity had disappeared from the retina. We conclude that amino acid transmitters show rapid changes in their distributions immediately after death, which may be related to changes in the patterns of transmitter release and uptake, and changes in degradation mechanisms. The rapid changes in cellular localisation of amino acid immunoreactivity illustrated in this study, indicate that the fixation of nervous tissues must be performed rapidly. Moreover, the massive loss of immunoreactivity by 2 h postmortem suggests that any assays for content of these transmitters at this, and subsequent time-points, will bear little resemblance to the values obtained at the time of death.     

Specific glucocorticoid binding at different levels of human motor activity

We studied the number of glucocorticoid receptors and dissociation constant in isolated human lymphocytes as well as blood concentrations of hormones produced by the hypothalamic-hypophyseal-adrenocortical system in three experimental series: at normal (17 subjects), decreased (10 subjects, a 360-d head-down bed rest) and increased (8 subjects, physical exercise on bicycle ergometer) levels of motor activity. In the first series we found that the number of glucocorticoid receptors and dissociation constant did not depend on the season, on the age of subjects nor on cortisol concentrations in blood. In the second series we observed the following: at the end of the first month of bed rest the number of glucocorticoid receptors and receptor affinity significantly increased; at the beginning of the third month of bed rest specific glucocorticoid binding significantly decreased and circadian rhythms of adrenocorticotropin and cortisol in blood varied markedly; at the end of the sixth month of bed rest the number of glucocorticoid receptors returned to prebed rest levels and dissociation constant decreased. In the third series physical exercises that induced an activation of the hypothalamic-hypophyseal-adrenocortical system (maximal physical exercises and prolonged submaximal exercises at 70% of maximal oxygen uptake) led to a significant increase in the number of glucocorticoid receptors without changes of dissociation constant. These results indicate that both a decrease and an increase of human motor activity resulted in significant changes of specific glucocorticoid binding which were not influenced by changes of circulating hormone concentrations in blood but by some other factors affected by physical activity.     

Farnesyl diphosphate-based inhibitors of Ras farnesyl protein transferase

The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described. Compound 3, wherein a beta-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 microM) and mevalonate kinase (I50(MK) = > 200 microM). A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken. Both the carboxylic and phosphonic acid groups of the beta-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 microM). The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 microM), substitution by a dodecyl fragment (14, I50 = 9 microM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 microM). Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 microM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM). FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.