Disposition and Elimination of Three Polychlorinated Dibenzofurans in the Liver of the Rat

Disposition and Elimination of Three Polychlorinated Dibenzofuransin the Liver of the Rat. VAN DEN BERG, M., DE JONGH, J., ECKHART,P., AND VAN DER WIELEN, F. W. M. (1989). Fundam. Appl. Toxicol.12, 738–747. The disposition and elimination of 1,2,3,6,7,8-HxCDF(HxCDF), 1,2,3,7,8-PnCDF (1-PnCDF), and 2,3,4,7,8-PnCDF (4-PnCDF)were studied in liver of female Sprague-Dawley rats after administrationof a single oral dose of 3.5–6.3 µg/kg. The dispositionof these PCDF congeners was structure and vehicle dependent.Administration in peanut oil caused the highest liver retention,compared with administration through the standard diet. Half-livesin liver for 1-PnCDF, 4-PnCDF, and HxCDF were 3.3, 108, and73 days, respectively. 4-PnCDF showed very high liver retention:70% of the dose in the first days after administration. To studykinetic interaction in the liver, mixtures of 1-PnCDF and 4-PnCDF(Experiment I) and of 4-PnCDF and HxCDF (Experiment II) wereadministered. The presence of 4-PnCDF in Experiment I did notsignificantly influence the half-life of I-PnCDF. In ExperimentII the estimated half-life of 4-PnCDF was again 108 days, butfor HxCDF an increased half-life was found, 156 days. It isconcluded that PCDFs with a chlorine substituent(s) adjacentto the oxygen bridge (4- and 6-positions) are eliminated vcryslowly with 14 much greater than that of TCDD.     

Effect of captopril on prostacyclin and nitric oxide formation in healthy human subjects: Interaction with low dose acetylsalicylic acid

1Angiotensin converting enzyme inhibitors have been suggested to act in part by potentiating the stimulatory effect of bradykinin on endothelial prostacyclin and/or nitric oxide (NO) formation. This may give rise to interaction with cyclo-oxygenase inhibiting drugs like acetylsalicylic acid, which is most often used in low doses in patients with cardiovascular diseases. 2We investigated the effects of captopril (2×25 mg day⁻¹), or ASA (1×100 mg day⁻¹), or the combination of both drugs for 7 days, on blood pressure, prostanoid and NO formation rates in a double-blind, double dummy, randomized crossover study in 13 healthy female subjects. The urinary metabolites of thromboxane A₂ (2,3-dinor-TXB₂) and prostacyclin (2,3-dinor-6-keto-PGF_1α), and PGE₂ were measured by gas chromatography/tandem mass spectrometry in urine on days 1, 6 and 7 of each medication. NO formation was assessed using urinary NO3− and cyclic GMP as indicators. 3Urinary 2,3-dinor-6-keto-PGF_1α excretion was not significantly changed by either captopril, ASA, or their combination. Urinary 2,3-dinor-TXB₂ excretion was inhibited by >80% by ASA alone or in combination with captopril (each P<0.05), but was not affected by captopril alone. Urinary PGE₂ excretion was not significantly changed by either of the treatments. Urinary NO3− and cyclic GMP excretion rates were not significantly changed by captopril, ASA, or their combination. 4Blood pressure was slightly reduced by captopril. ASA had no effect on blood pressure when given alone, nor did it modulate the effect of captopril on blood pressure during co-administration. Angiotensin II/angiotensin I ratio (index of ACE activity) was significantly decreased by captopril alone or in combination with ASA, but was unaffected by ASA alone. 5Captopril does not stimulate prostacyclin formation in healthy human subjects in a dose sufficient to substantially inhibit ACE activity. Co-administration of ASA significantly inhibits 2,3-dinor-TXB₂ excretion, but does not interfere with the blood pressure lowering effect of captopril in healthy human subjects.     

Rise of oxygenation in cervical lymph node metastasis during the initial course of radiochemotherapy

It has been hypothesized that during radiation treatment a reoxygenation of hypoxic tumor tissue takes place. To test this hypothesis, we have investigated whether reoxygenation in lymph node metastases could be determined by invasive PO (2) measurements. Through a hypodermic needle inserted transcutaneously into tumor-positive lymph nodes, polarographic oxygen determinations were made in 18 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx. These measurements were performed before therapy and a week after the onset of radiotherapy or radiochemotherapy, respectively. Low PO (2) values before treatment (mean value of the patient's median was 12.6 mm Hg PO (2)) and a mean hypoxic fraction (PO (2) < 5 mm Hg) of 39.6% indicated manifest tumor hypoxia. After 1 week of treatment, a significant increase in the median PO (2) (mean value of shift: 7.3 mm Hg) and a reduction in the hypoxic fraction (mean value of shift: 13.4% PO (2) < 5 mm Hg, P < 0.03) were observed after both radiotherapy and radiochemotherapy. Thus invasive PO (2) histography fulfills the requirements for a method to confirm tumor hypoxia in head and neck tumors. The results obtained indicate that reoxygenation occurs during the initial phases of radiotherapy and radiochemotherapy, and they will form the basis for future comparative investigations on the possible influence of hypoxic parameters on tumor responsiveness toward radiation and radiochemotherapy.     

Screening for breast cancer in Catalonia: Which policy is to be preferred?

Background: the effects and costs of different policies forbreast cancer screening in Catalonia (Spain) were analysed,to give a basis for setting priorities and deciding on the introductionof a screening programme. Methods: the MISCAN (MIcrosimulationSCreening ANalysis) model of the natural history of breast cancerwas used. The epidemiology of breast cancer in Catalonia andthe demography of the Catalan population was taken into accountas well as the results on mortality reduction from a Swedishoverview of breast cancer screening trials. Results: the reductionin breast cancer mortality in the total female population dueto a screening programme for the age group 50–64 yearswould be 16, 12 and 9%, with screening intervals of one, twoand three years respectively. The cost-effectiveness ratios(CE ratios) for these scenarios were 924,000, 730,000 and 719,000pesetas (P_t) per life-year gained respectively (5% discounting).The most cost-effective screening scenario is the one in whichwomen aged 50–69 years are screened with an interval ofthree years with a mortality reduction of approximately 12%in the total female population (CE ratio = 694,000 P_t). Screeninguntil the age of 69 years (two year interval) was almost ascost-effective as screening the age group 50–64 yearswith a two year interval, with a reduction in breast cancermortality of 15%. Extension to under the age of 50 years resultedin diverging results depending on the assumptions for improvementin prognosis for younger women (40–49 years). Conclusion:if the extension of a two yearly screening programme for womenaged 50–64 years is considered (mortality reduction of12%), extension to older women would be more advisable, basedon proven benefits and costs, than extension to younger agegroups.     

Approaches to the space-time modelling of infectious disease behaviour

A new approach to the space-time modelling of infectious diseasesis considered. A modulated heterogeneous Poisson process withintensity defined as a function of a two-dimensional susceptibilityfield is proposed. The model is fitted to a measles epidemicusing a proportional hazards approximation.     

Cholestyramine treatment of type IIa hypercholesterolaemia normalizes platelet reactivity against prostacyclin

Abstract. The effect of lowering total plasma and low density lipoprotein (LDL) cholesterol in heterozygous familial hypercholesterolaemia type IIa (FH) on platelet function, thromboxane (TX) formation and platelet sensitivity against iloprost, a stable prostacyclin mimetic, was studied in platelet-rich plasma ex vivo . Seven FH patients were treated with cholestyramine (12 g day^-1) for 8–11 months and were compared with eight untreated FH patients and 11 healthy control subjects. In comparison with platelets from healthy controls, platelets from untreated FH patients exhibited a significantly increased aggregation response and TX formation, and a reduced reactivity against inhibition of platelet aggregation by prostacyclin. Treatment with cholestyramine for 8–11 months resulted in a 21% reduction in total serum and LDL-cholesterol. This was not accompanied by any change in platelet hyperreactivity or TX formation. However, cholestyramine treatment normalized the platelet reactivity of FH patients against iloprost, being no more different from healthy controls. It is concluded that reduction in plasma cholesterol by cholestyramine results in normalization of the reduced platelet sensitivity against prostacyclin. This might contribute to beneficial effects of cholestyramine treatment in preventing thrombembolic complications of atherosclerosis.     

Oversensing in a Cardioverter Defibrillator System Caused by Interaction Between Two Endocardial Defibrillation Leads in the Right Ventricle

A 53-year-old male patient underwent implantable Cardioverter defibrillator (ICD) implantation with a single lead (Endotak ®) transvenous system due to recurrent episodes of drug refractory ventricular tachycardia. After pulse generator replacement, inappropriate ICD shocks were observed due to muscle potential sensing. Intraoperatively, the old Endotak ® lead could not be extracted; therefore, it was transsected and capped. A new lead was inserted and tested without any problems. At the predischarge test, VF was induced and was followed by ICD shocks during sinus rhythm. In another surgical procedure, the old Endotak ® lead was explanted using a special instrument. The present report demonstrates that two endocardial Endotak ® leads should be avoided, because the leads may disturb each other and be followed by inappropriate ICD discharges.