Hepatic Uptake and Metabolism of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-Tetrachlorodibenzofuran

The pharmacokinetics of TCDD and related compounds is congener,dose, and species specific, with urinary and biliary excretionbeing dependent on the metabolism of these compounds. Isolatedhepatocytes and liver slices in suspension culture and hepaticmicrosomes were used as in vitro models to assess the hepaticuptake and metabolism of [³H]- and [¹⁴C]- TCDD and [³H]TCDF(0.01–1.0 µM) in control and induced (5 µgTCDD/kg, 3 days earlier) male Sprague-Dawley rats. TCDD pretreatment,with an increase in cytochromes P450 1A1 and 1A2 (CYP1 Al, CYP1A2),produced an increase in the hepatic uptake of TCDD, while noincrease in the hepatic uptake of TCDF was observed. The resultsare consistent with CYP1A2 serving as a hepatic binding proteinfor TCDD but not for TCDF. The rates of metabolism of TCDD andTCDF were directly proportional to their concentrations, indicatingthat the reaction follows first order kinetics at concentrationsfrom 0.01 to 1.0 µM. Very limited metabolism of TCDD andTCDF was observed in control rat liver (0.45 and 3.2 pmol/hr/ghepatocyte wet wt at 0.1 µm, respectively). TCDD inducedits own rate of metabolism about two- to fivefold at 1.0 µMbut no induction was observed at 0.01 and 0.1 µM. In contrast,TCDD markedly induced the rate of TCDF metabolism at all substrateconcentrations. While the results support the role of rat CYP1A1in TCDF metabolism, the data suggest that CYP1 Al or CYP1A2may not metabolize TCDD. These results also support the hypothesisthat the more rapid metabolism and excretion of TCDF accountsfor the relative resistance of the rat to the acute toxicityof TCDF. Comparative studies in rat and human liver microsomesfound that TCDF metabolism exhibited first order kinetics inboth species. Furthermore, the rate of TCDF metabo-lism in humanliver microsomes was similar to that of control rat liver microsomes.Together the results suggest that TCDF will be far more persistentin rats, and possibly humans, following exposure at low doseswhich do not significantly induce cytochrome P450 1A1 and/or1A2.     

The estimation of the lymphocyte percentage by the Coulter Counter Model S Plus III

Summary. The accuracy of the Coulter Counter Model S Plus III in determining lymphocyte percentage was assessed. In ‘routine’ adult blood counts accuracy was satisfactory but in infectious mononucleosis, and in chronic lymphocytic leukaemia and other lymphoproliferative disorders, there was a high rejection rate and an often considerable underestimation of the lymphocyte percentage. The S Plus III lymphocyte percentage was of no use in neonates because of inaccuracy and a high rejection rate. In infants the relationship with lymphocyte percentages based on manual differential counts was non-linear, and there was underestimation of some high percentages. The white cell size histogram was useful in alerting staff to abnormalities, and also suggested that lymphocytes of neonates and infants were larger than those of adults, with plots being very similar to those of some adults with lymphoproliferative disorders. The S Plus III lymphocyte percentage was useful in reducing the need for differential counts in adult patients but did not replace examination of a blood film or a manual lymphocyte percentage in patients with chronic lymphocytic leukaemia or a lymphoproliferative disorder.     

VITAMIN D NUTRITION AND VITAMIN D METABOLISM IN THE PREMATURE HUMAN NEONATE

The effect of supplementation with daily doses of vitamin D2 (1000 IU or 3000 IU, 25-75 micrograms, 63-189 nmol) has been studied in 39 premature neonates, initial gestational age 25-32 weeks. The initial mean plasma 25-hydroxyvitamin D was 25.8 nmol/l (10.3 ng/ml) but in 12 infants, most of whom were born in the winter months, the level was less than 15 nmol/l (6 ng/ml), and in seven babies plasma 1,25-dihydroxyvitamin D was less than 48 pmol/l (20 pg/ml). These findings suggest a considerable degree of maternal vitamin D-deficiency. Maximum attained concentrations of 25-hydroxyvitamin D on treatment were 77.3 nmol/l (30.9 ng/ml), high dose and 86.8 nmol/l (34.7 ng/ml), low dose, the mean rate of increase was greatest during the first two weeks (2.2 nmol/l/d; 0.88 ng/ml/d) and declined over the next 4 weeks. Mean maximum concentrations of 1,25-dihydroxyvitamin D2 were 283 pmol/l, (121 pg/ml), high dose and 309 pmol/l (129 pg/ml), low dose. Apart from a minor contribution to the initial plasma 1,25-dihydroxyvitamin D concentration, no effect of gestational age could be discerned in any of the measured variables. The endogenous pool of 1,25-dihydroxyvitamin D3 decayed with a T 1/2 of 22.5 d, indicating that vitamin D supplementation of these infants was necessary to avoid vitamin D-deficiency.     

REDIRECTING T LYMPHOCYTE SPECIFICITY USING T CELL RECEPTOR GENES

Redirecting T cells by transferring T cell receptor (TCR) genes from tumor-associated antigen (TAA)-reactive T cell clones into human peripheral blood lymphocytes (PBL) has therapeutic potential for the treatment of diseases, including cancer. T cell specificity can be altered using retroviruses encoding TCR &#102 and TCR &#103 chain genes, or chimeric immunoglobulin (cIg) genes containing signaling domains of CD3 &#145 or Fc &#108 RI- &#110. This review evaluates recent studies using TCRs and cIgs to redirect T cell specificity and discusses some of the technical and biological hurdles that need to be addressed before these approaches can be successfully used to treat patients.     

Hemodynamic Effect of Propafenone and the Experience in Patients with Congestive Heart Failure

The effects of propafenone on left ventricular function and hemodynamics are presented in this study. In one group of 13 patients who underwent electrophysiological testing and subsequent chronic oral therapy with propafenone, eight had left ventricular ejection fractions determined by nuclear study before and during therapy with the drug. Initial measurements ranged from 22% to 39% (mean 30%), while those on chronic therapy showed no statistical difference and ranged from 22% to 48% (mean 30%). In a separate dose titration study of 14 patients, left ventricular ejection fraction showed a modest but significant decrease (52%± 9% to 48%± 11%; p < 0.05). This change was more marked in patients with an initial low ejection fraction. Propafenone appears to be safe in these patients but should be administered with caution in patients with particularly low ejection fractions.     

Phonological development: a normative study of British English‐speaking children

This paper reports a normative study on the phonological development of British English‐speaking children. Speech samples of 684 children, aged between 3;0 and 6;11 years, randomly selected from nurseries and schools in eight different areas throughout the UK, were collected and analysed to obtain normative data. This paper reports on two aspects of speech development: the age of acquisition of sounds (phonetic acquisition) and the age that error patterns were suppressed (phonemic acquisition). It discusses the effects of age, gender and socio‐economic status on speech sound development. The study found that older children had more accurate production and fewer error patterns in their speech. It found no gender differences in the younger age groups. However, in the oldest age group, it found the phonological accuracy measures of girls' better than boys. It found no significant effects of socio‐economic status on any of the phonological accuracy measures.