Early developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure decreases chick embryo heart chronotropic response to isoproterenol but not to agents affecting signals downstream of the beta-adrenergic receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes cardiovascular toxicity in laboratory animals, including alteration in several processes in which beta-adrenergic receptor (beta-AR) signaling plays important roles. Thus, our laboratory investigated the effects of TCDD on beta-AR expression and signal transduction. Fertile chicken eggs were injected with vehicle (corn oil), 0.24 or 0.3 pmol TCDD/g egg on incubation day 0 (D0) or D5. On D10, heart function was assessed by ECG in ovo. Exposure to TCDD increased the incidence of arrhythmias and decreased the positive chronotropic responsiveness of the heart to isoproterenol. The reduced beta-AR responsiveness was, in part, independent of any overt morphological changes in the heart as chick embryos exposed to TCDD on D5 displayed an intermediate responsiveness to beta-AR agonist in the absence of the dilated cardiomyopathy observed in chick embryos exposed to TCDD on D0. TCDD did not decrease the chronotropic response of the heart to agents that stimulate signals downstream of the beta-AR. In fact, TCDD-exposed embryos were more sensitive than controls to forskolin, increasing heart rates (HR) 21.8 +/- 3.5 beats per min (bpm) above baseline versus control values at 6.3 +/- 2.7 bpm above baseline. TCDD exposure also augmented the negative chronotropic response of the heart to verapamil, decreasing HR -23.2 +/- 7.4 bpm relative to baseline versus control embryos at -12.7 +/- 5.9 bpm below baseline. Finally, the mean cardiac beta1-AR mRNA expression in D10 embryos was not significantly altered by exposure to TCDD on D0. These findings establish that a functional end point of the developing chick heart is sensitive to TCDD exposure and that the TCDD-induced reduction in beta-AR responsiveness may result from alterations in signal transduction upstream of adenylyl cyclase.     

A randomized trial of two types of adjuvant chemotherapy in radiotherapy-treated patients with clinical stages I and II high-grade non-Hodgkin's lymphoma

Summary This paper reports the 8-year results of comparing the use of two types of adjuvant chemotherapy following involved field radiotherapy for clinical stages I and II high-grade non-Hodgkin's lymphoma. Twenty-four patients received 6 weeks of VAP plus 2 years of oral maintenance chemotherapy, and 30 had six cycles of CMOPP. Four patients were not in complete remission at completion of i. v. chemotherapy (CR rate 91%). Ten patients (18.5%) have relapsed (VAP/M=5; CMOPP=5), with only two of these remaining alive, both of them being disease free. There have been three deaths from intercurrent causes, one from malignant melanoma and the other two from myocardial infarction. The relapse-free survivals at 2, 5 and 8 years were 80%, 76% & 76% respectively. The overall survivals at the same time points were 86%, 72% & 68%. There were no significant differences in either relapse-free or overall survival for either of the two treatment groups. The shorter period of weekly intravenous chemotherapy (VAP/M) was better tolerated than 36 weeks of CMOPP, and the former appears to produce equivalent results.     

Radionuclide ventriculography (equilibrium gated blood pool scanning) —its present clinical position and recent development

Myocardial scanning (MS) and radionuclide ventriculography (RNV) are the foundation of nuclear cardiology. These procedures aim in two completely different directions: RNV tries to image heart motion, that is, mechanical (pump) function, and therefore belongs to the group of first-order functional imaging (FI, imaging mechanical function), whereas MS is based on myocardial metabolism, and therefore can be attributed to third-order functional imaging (metabolism). This statement is relevant for the assessment of the clinical position of RNV: Third-order (metabolism) functional imaging is the domain of nuclear medicine (NM), whereas first-order FI has to face the competition of alternative noninvasive procedures such as ultrasound (US), digital subtraction angiography (DSA), computer tomography (CT), and nuclear magnetic resonance (NMR). The domain of RNV includes stages two (acute infarction) and three (postinfarction period) of coronary arterial disease (CAD). The advantageous combination of quantitative data on global, left ventricular (LV) function and imaging of regional motion ensures the superiority of RNV over US. However, RNV is inferior to MS in physical examinations in the preinfarction stage of CAD, whereas US is clearly inferior to both NM procedures. Recent progress could be attained by gated SPECT (GASPECT). A proposal is presented for simplification of this time-consuming procedure. Technetium-labeled isonitriles offer the chance for the combination of perfusion-motion imaging of the myocardium. However, even standard RNV offers new possibilities. The multitude of parameters produced by quantitation has not yet been exploited completely. This can be done by discriminant analysis. The computer finds out an optimal subset from the whole set of parameters for the solution of a significant clinical problem. The software learns to find the label of a special pathognomonic entity. This computer work is supported by a relational data bank (Oracle) and an optical disk. Two examples for the effectiveness of the computer in problem solving are presented. It is concluded that RNV, even in the very competitive class of first-order functional imaging, enjoys a preferred position. The future indeed seems brighter because labeled isonitriles offer the chance for the combination of perfusion-motion imaging of the myocardium.Dedicated to Prof. Heinz Hundeshagen on the occasion of his 60th birthday     

Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas

A prospective, randomized trial evaluates the effects of two postoperative treatment regimens on survival in 198 adult patients with supratentorial gliomas. All patients were irradiated with 6 000 rads after possibly radical removal of tumors. CCNU administration in the dosis of 100 mg/sq m of body surface every 6–8 weeks following surgery proved to have no significant effect on the survival of patients. The median survival time in patients receiving radiation therapy alone was 61±7 weeks, while in those receiving additional chemotherapy was 56±4 weeks. Tumor histological malignancy and patients age were found to be the only important prognostic factors, irrespective of the treatment modality. Address for offprints: T Trojanowski, Department of Neurosurgery, Medical School, Jaczewskiego 8, 20-950 Lublin, Poland     

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors

One hundred sixty-two patients with Stages III and IV non-Hodgkin's lymphoma of low-grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow-up alone or "maintenance" chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow-up, 74 months). Multivariate analysis revealed stage (P less than 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P less than 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse-free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.     

Effects of chemical mediators of anaphylaxis on ciliary function

We assessed the effects of selected chemical mediators of anaphylaxis on CBF in vitro. Ciliated epithelial cells were obtained from the trachea of conscious sheep with a cytology brush and suspended in a perfusion chamber containing KH. Ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of CBF. Prostaglandin E1 (10(-8) M to 10(-6) M), prostaglandin E2 (10(-10) M to 10(-6) M), and leukotriene-C4 (10(-8) M) increased CBF between 7% and 33%. Histamine caused ciliostimulation only at the relatively high concentrations above 10(-5) M (7% increase in CBF), whereas prostaglandin F2 alpha (10(-10) M and 10(-6) M) was without effect. In no preparation was ciliary discoordination observed. These findings indicate that several chemical mediators of anaphylaxis stimulate CBF and that the previously described impairment of mucociliary transport in stable allergic asthma or antigen-induced bronchoconstriction is probably not caused by a primary alteration of ciliary function.     

Response of human peripheral blood lymphocytes in the presence of cord sera: relationship of lymphocyte transformation with number of pregnancies and levels of alpha-fetoprotein

Peripheral blood lymphocytes were stimulated with various mitogens (PHA, Con A and PWM) and allogenic cells in the presence of cord serum. The cord sera suppressed more effectively certain T cell populations. This immunoregulatory response of cord serum was compared with nonpregnant and pregnant sera from different gestations. Although the cord sera showed significantly higher inhibition compared to normal adult serum but the serum from gravidae in late gestation proved more inhibitory compared to cord serum. No correlation was found between the levels of alpha-fetoprotein (AFP) in the cord sera and the degree of inhibition observed in the cultures. As previously described for pregnant sera the cord serum obtained from women with different numbers of pregnancies did not correlate with the inhibition of cellular proliferation. Our results suggest a possible different suppressor factor in pregnant and cord sera and also excludes the possibility of AFP in cord sera as a suppressor agent of cell-mediated immunity.