Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD-1 Mice

Coumarin, a naturally occurring substance most frequently usedas a fragrance enhancer and stabilizer, was administered inthe diet of Sprague-Dawley rats at dose levels of 0, 333, 1000,2000, 3000, and 5000 ppm or in the diet of CD-1 mice at doselevels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000,and 2000 ppm coumarin were exposed to these dose levels in uteroand during the lactational period, then chronically followingweaning. Rats in the 3000- and 5000-ppm dose groups and allmice received only postweanlng chronic exposure. All male ratswere terminated after 104 weeks of postweaning exposure; femalerats were terminated after 110 weeks. Male mice were terminatedat Week 101 and female mice at Week 109. Among rats, survivalwas decreased at 333 ppm, but signilicantly increased amongrats in the 3000- and 5000-ppm dose groups. Dramatic dose-relateddecreases in body weight gain were recorded for rats receiving2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximumtolerated dose, as indicated by a body weight decrement of greaterthan 10–15%) was exceeded. Food consumption also was decreasedat the three highest dose levels, although body weight decrementwas disproportionately large compared to changes in food consumption.Treatment-related decreases in hemoglobin were recorded fromWeek 6 onward. Minimal treatment-related changes in he matologyand clinical chemistry were recorded. Increased liver weightswere observed for male and female rats receiving 3000 or 5000ppm and for females only at 1000 and 2000 ppm. Increased incidencesof cholanglofibroma, cholangiocarcinoma, and parenchymal livercell tumors were observed among male and female rats receiving5000 ppm. One male rat receiving 3000 ppm devel oped a cholangiocarcinoma;no tumor increase was observed in males or females at 2000 ppmor below. Coumarin, at a dose clearly exceeding the MTD can,therefore, induce liver tumors in rats, although survival, relativeto controls, was increased at the same dose levels. Among mice,a decrease in body weight gain was reported for males in the1000- and 3000-ppm dose groups during the first 52 weeks ofthe study. No dose-related abnormalities in clinical signs,clinical pathology, hematology, or gross or microscopic pathologywere noted.     

Malignant Ventricular Tachycardia During Propafenone Treatment in a Child with Junctional Automatic Tachycardia: Effectiveness of Intravenous Molar Sodium Lactate

Propafenone may aggravate the preexisting arrhythmia or induce another one. Usually, such proarrhythmic effects occur in patients with spontaneous ventricular arrhythmias and/or coronary heart disease with poor left ventricular function. We report the case of a 5-year-old girl with Junctional automatic tachycardia and no structural heart disease, in whom malignant ventricular tachycardia occurring during propafenone treatment could be terminated by molar sodium lactate (MSL) infusion. The serum propafenone level obtained before MSL infusion was within the therapeutic range. Two hypothesis could explain the beneficial effects of MSL in our patient: (1) alkalinization facilitates the cell membrane hyperpolarization and thus can decrease the voltage-dependent effect of Class Ic drugs, (2) alkalinization could displace propafenone from its tissue receptor sites by an increase in the nonionized fraction.     

Local structural differences between α and β-elicitins shown by circular dichroism and ultraviolet difference spectroscopy

In order to investigate differences in the conformation of elicitins exhibiting different levels of activity (toxicity to tobacco plants). the environment of the tyrosyl residues in four elicitins has been compared by different spectroscopic methods (difference absorption and circular dichroism). We compared two α-elicitins (capsicein and parasiticein) and two β-elicitins (β-cryptogein and β-cinnamomin), that are 50–100 times more toxic than the α-ones. Thermal difference UV spectroscopy and titration experiments clearly showed the exposure of Tyr-85 by comparison of parasiticein lacking Tyr-85 and the accessibility of its hydroxyl group to the solvent. The adjacent Ty-87 was also suggested to be located at the surface. In β-cryptogein, β-cinnamoniin and capsicein the pK was measured at between 10.5 and 10.8, while in parasiticein it is higher (11.5) owing to a difference in the local environment. Thermal difference UV spectroscopy showed one more exposed tyrosine in β-elicitins than in α-ones. This difference was attributed to Tyr-12, considering the more hydrophilic characteristic of the sequence around residue 13 in β-elicitins and the role of this region in the toxicity. However, no difference in titration behaviour was noted among elicitins concerning Tyr-12. The other two tyrosines also presented an abnormal pK of titration (> 12). In all elicitins Tyr-47 was probably exposed, while Tyr-33 was probably buried and not titrated, except in β-cinnamomin at very alkaline pH.     

Atrioventricular Interval Optimization and Exercise Tolerance

Modern pacemakers offer many programming options regarding the AV interval including the ability to vary AV intervals depending on whether atrial activity is paced or spontaneous and to shorten AV intervals with increasing rates. To determine if optimization of these features improves exercise tolerance, 14 patients with intact sinus node function and AV block treated with dual chamber pacemakers were enrolled in a randomized double-blind crossover trial. Doppler echocardiographic measurements of cardiac index and mitral flow were assessed over a range of programmable AV intervals at rest to determine each patient's optimal AV interval. Eleven patients completed serial graded exercise tests with spiroergometry after randomly programming the AV interval three ways in a crossover manner: fixed AV interval = 150 ms without rate adaptation (150/Fixed), fixed AVinterval = 150 ms with rate adaptation (150/R), or optimized AV interval with rate adaptive AV interval shortening (optimized/R). Exercise capacity was determined by maximum oxygen uptake. Ten men and four women, age 64 +/- 8 years, were enrolled. At rest, optimization of the AVintervalimproved the cardiac index by 21% (P < 0.001) and mitral flow by 13.4% (P < 0.001) when compared to least-favorable AV intervals. During exercise, no differences in maximum heart rates were noted. Maximum oxygen uptake was increased in both groups with rate adaptive AVinterval shortening when compared tofixed AVinterval without rate adaptation: 13.9% (adjusted P < 0.04) and 14.6% (adjusted P < 0.02) in optimized/R and 150/R, respectively. No differences were noted between optimized/R and 150/R. In conclusion, rate adaptive AV interval shortening improved exercise tolerance independent of changes in heart rate. However, optimization of the AV interval with Doppler echocardiography at rest did not further improve exercise capacity.     

Autotumour reactive T-cell clones among tumour-infiltrating T lymphocytes in B-cell non-Hodgkin's lymphomas

Summary. Seventy-three T-cell clones (TCC) were established from tumour-infiltrating lymphocytes-T (TIL-T) derived from lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) in nine patients with different histological subtypes and clinical stages. 40 TCC (55%) expressed the CD25 Ag and were also able to proliferate in the presence of irradiated autologous B-NHL cells. Among them, 23 autotumour (AuTu) proliferative TCC were found not to proliferate to autologous EBV-transformed B-cell lines, indicating that the proliferative reactivity of these TCC was preferentially directed at autologous B-NHL cells. Tested against autologous B-NHL cells, only three AuTu prolifera- tive TCC (CD8 ⁺) showed a significant level of cytotoxicity (specific lysis > 15%). In blocking experiments, the AuTu proliferative reactivity of three TCC from one patient was strongly inhibited by anti-DR and anti-DQ mAbs, whereas that of three TCC from another patient was not affected by either anti-MHC class I or class II (DR., DP, DQ) mAbs. These findings suggest that the recognition of autologous B-NHL cells by AuTu proliferative TCC may occur through MHC-restricted as well as MHC-unrestricted mechanisms.     

Pain assessment by children and adolescents during intraosseous anaesthesia using a computerized system (QuickSleeper™)

Background.  Intraosseous (IO) anaesthesia has been shown to be effective in children. However, the pain associated with anaesthetic injections, and its acceptance by children, have never been studied.
Aim.  The aim of this study was to assess the pain associated with the IO injection of 4% articaine with 1 : 200 000 epinephrine using the computerized QuickSleeper' system in a population of children and adolescents.
Design.  IO anaesthesia was performed on patients aged 10.4 ± 2.6 years of age. The patients assessed their pain on a faces pain scale (FPS) and on a visual analogue scale (VAS). The operators were also asked to assess signs of patient pain/discomfort.
Results.  No pain or mild discomfort was reported by, respectively, 81.8% (FPS) and 83.9% (VAS) of the patients. Some 58.9% of children with previous experience of dental anaesthesia reported that computerized IO anaesthesia was more comfortable than traditional infiltration methods. Operators noted signs of discomfort during penetration and injection in 18.3% and 25.3% of the patients, respectively.
Conclusions.  This study showed that the majority of children reported no pain or mild pain when anaesthetic was administered by computerized needle rotation and solution deposition. This technique holds promise for use by trained paediatric dentists.     

DISTRIBUTION OF α1(IV) AND α3(IV) CHAINS OF TYPE IV COLLAGEN IN LUNG TUMOURS

Tumour invasion is associated with strong remodelling of the extracellular matrix, including the basement membrane (BM). The major structural component of BMs is type IV collagen, which is composed of an association of three α chains. In this study, the distribution of the α1 and α3 chains in both normal and neoplastic lung tissues has been examined by immunohistochemistry, using specific monoclonal antibodies. In normal tissues, the α1(IV) chain was found in all BMs, whereas the α3(IV) chain was only found in alveolar BMs. In 36 lung tumours, the α1(IV) chain was detected in all cases, with irregular positivity around tumour clusters and in the stroma. It was noteworthy that this stromal distribution was particularly associated with the presence of cancer cells, whatever their invasive properties. In contrast, in 22 tumours out of 36, the α3(IV) chain was only found at the interface between invasive tumour clusters and stroma, with a linear and disrupted pattern. These data show a distinctive distribution of type IV collagen chains in lung tumours, with expression of α1(IV) chain and likely neosynthesis of the α3(IV) chain around some invasive tumour clusters. The results suggest the involvement of these BM components in the process of tumour invasion. © 1997 John Wiley & Sons, Ltd.     

CONVERSION OF ANGIOTENSIN I IN PULMONARY AND SYSTEMIC VASCULAR BEDS OF CHILDREN1

The systemic pressor response to bolus injections of Angiotensin I (A-I) into the pulmonary artery (PA) and the aortic root (Ao) was compared in 11 children during routine left and right heart catheterization; five had a left-to-right shunt and 6 had no hemodynamic abnorm'alities. An additional 4 children with normal hemodynamics were tested with Angiotensin I1,(A-II). Systemic pressor peaks to PA injections of A-I were slightly higher than those resulting from Ao injections. A study of the time course of the pressor responses showed that the intervals from the injection to onset of response, and from injection to half peak, were significantly prolonged after injection of A-I into the aorta, as compared with injections of A-I1 by the same route. Such a difference was not observed when A-I and A-I1 were given into the PA. These results indicate that conversion occurs to a considerable degree in the peripheral circulation, with a delay that is most probably due to the process of activation. When this peripheral conversion is maximal, the systemic pressor response assay is unable to detect pulmonary conversion solely on the basis of the height of pressor peaks, because the responses are equal after PA and Ao injections. PA injections of Angiotensin I and I1 had no effect on pulmonary artery pressure. It is concluded that: (1) pulmonary conversion occurs in all children with and without shunt; (2) peripheral (systemic) conversion occurs to a considerable degree and can account for most of the overall conversion of Angiotensin I, so that the role of the lung in the renin-angiotensin system seems unlikely.