In vitro schedule-dependency of myelotoxicity and cytotoxicity of Ecteinascidin 743 (ET-743)

Background: Ecteinascidin (ET-743) is a marine derived compound with an interesting preclinical profile currently completing phase I clinical trials. The present study was undertaken to compare the toxicity of different schedules of ET-743 against human hemopoietic progenitors and tumour cell lines.Materials and methods: Human hemopoietic progenitors and solid tumour cell lines were incubated with ET-743 for one hour, 24 hours and one hour daily for five consecutive days to define by comparison an in vitro therapeutic index. Additional experiments were set up to assess whether incubation for 24 hours or five days could change either the sensitivity of cells or the activity of ET-743.Results: Prolonged or repeated exposures were more toxic than a single one hour exposure (P < 0.001), but due to the higher sensitivity to prolonged exposure of several tumor cell lines, prolonged treatment yielded a more favorable in vitro therapeutic index. After incubation for 24 hours, ET-743 showed a significantly (P < 0.01) lower inhibiting capacity. Incubation before treatment rendered progenitors more resistant, but incubation after treatment increased their sensitivity, so that overall the toxicity of ET-743 on hemopoietic cells appears to be close to AUC dependency.Conclusions: Despite the possible effect of some experimental artefacts, prolonged exposure could represent the best schedule of administration of ET-743.     

Closing the theory—practice gap: a model of nursing praxis

Summary

• ? Despite the efforts of nursing theorists, educationalists and practitioners, the theory-practice gap continues to defy resolution. This paper argues that only by reconsidering the relation between theory and practice can the gap be closed.
• ? Drawing upon ideas from teaching and other practice-based disciplines, including nursing, the article suggests that the current model of viewing theory as informing and controlling practice should give way to a mutually enhancing model in which theory is derived from practice, and in turn influences future practice.
• ? This coming together of theory and practice is referred to as nursing praxis, and suggests that informal theory should be unique to each individual encounter with each patient.
• ? The clinical nurse is thus not only a practitioner, but a theorist and researcher, who responds to patients not according to some grand, inflexible theory, but by the process of reflection-in-action, drawing upon their expertise and a repertoire of past experiences and encounters.

     

Comparison of in situ hybridization and immunocytochemistry for the detection of residual beta cells in the pancreas of streptozotocin-treated diabetic rats

The relative efficacy of immunocytochemistry versus in situ hybridization in identifying residual beta cells was studied in rats with streptozotocin-induced diabetes. Consecutive sections of pancreas of streptozotocin-treated diabetic rats and control animals were alternately subjected to in situ hybridization (synthetic oligonucleotides complementary to rat preproinsulin mRNA) and immunocytochemistry (monoclonal antibodies to insulin). The results obtained with both methods were quantitated with the use of computer-assisted image analysis, and the ratio of cells positive by immunocytochemistry to those positive by in situ hybridization was determined. Under normoglycaemic conditions the values obtained by immunocytochemistry correlated well with those obtained by in situ hybridization (immuno/in situ > 95%). In the streptozotocin diabetic animals, however, immunocytochemistry resulted in a distinct underestimation of the number of residual beta cells (immuno/in situ < 80%). This difference was even more striking in small islet cell clusters (<100 m) immuno/in situ 20%). These results suggest that in situ hybridization for prohormone mRNA is the method of choice for the identification of residual or regenerating beta cells with very low insulin content. Caution should be used when interpreting quantitative data in diabetic conditions that are based exclusively on immunocytochemical detection methods.     

Excretion of modified nucleosides during development of malignant lymphomas in mice after whode body irradiation

Summary During x-ray-induced development of malignant lymphomas in mice their urinary excretion of eight modified nucleosides was monitored and the values were compared to the results of the histological examination of the animals at time of their sacrifice.It was found that the pathologically augmented excretion of modified nucleosides begins as much as several weeks before the malignant lymphomas can be diagnosed clinically. Thus some mice had increased levels of modified nucleosides even 10 weeks before sacrifice, though at the time of sacrifice the histological investigation reveled only some small foci of reticulum cell neoplasm in their spleen.It is therefore stressed that the usefulness of the determination of urinary modified nucleosides as an early noninvasive screening test for cancer in man and as an in vivo carcinogenicity test should be evaluated.Abbreviations pseudouridine - m¹A 1-methyladenosine - m⁵C 5-methylcytidine - m¹I 1-methylinosine - m¹G 1-methylguanosine - m²G N ²-methylguanosine - m²G N ²,N²-dimethylguanosine - ac⁴C N ⁴-acetylcytidine - mt⁶A N-(9--d-ribofuranosylpurine-6-yl)N-methylcarbamoyl) threonine - acp³U 3-(3-amino-3-carboxypropyl) uridine - SD standard deviation     

Placental transfer of lead,mercury and cadmium in women living in a rural area

Summary The influence of the lead content of drinking water on the transplacental transfer of lead was investigated in 70 pregnant women living in a rural area of Belgium. The mothers were divided into 2 groups: group A: morning water lead below 50 g/liter; group B: morning water lead above this value. In group A, the mean lead content of water was 11.8 g/liter and in group B it amounted to 247.4 g/liter.The difference in the mean lead concentration between the two groups were for maternal blood: 3.2 g/100 ml, for umbilical cord blood: 3.3 g/100 ml, and for placenta: 3.6 g/100 g. These differences are statistically significant.There were significant correlations between water lead and lead concentration in blood (mother, newborn) or placenta. An increment of water lead concentration from 50 to 500 g/liter increases blood lead concentration in mother and in newborn by about 3 g/100 ml and in placenta by about 2.5 g/100 g (wet weight).     

Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations

According to linear pharmacokinetics, the time course of plasma concentration of a drug, C_p,is expressed by a sum of exponential functions, C_p= _i=1 ⁿ a_i .This article describes a statistical technique to estimate the number of exponential terms, n,for the time course of drug by the application of Akaike's information criterion (AIC). Plasma concentrations of ethoxybenzamide, sulfisoxazole, bishydroxycoumarin, and diazepam measured following bolus intravenous injection were used as clinical examples for this method. Selection of models is compared between the AIC method and an Ftest method at significance levels of 5% and 1%.     

Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.     

Blutverteilungsmuster in der Lunge beim plötzlichen Säuglingstod

Zusammenfassung Bei 67 Fällen von plötzlichem Säuglingstod (SIDS) wurde die Blutverteilung in den Lungen mit Hilfe der Benzidin-Färbung an 50 dicken histologischen Schnitten untersucht. Es besteht ein fokales, akutes Emphysem und häufig ein diffuses, alveoläres und auch interstitielles Emphysem. In allen Lungenabschnitten finden sich z.T. ausgedehnte Atelektasen und Dystelektasen. Die Atelektasen und Dystelektasen zeigen eine hochgradige Hyperämie bei weitgestellten Alveolarkapillaren, während der Blutgehalt in den von Emphysem betroffenen Bezirken vermindert ist. Die mögliche funktionelle Bedeutung der gestörten Blutverteilung in der Lunge für eine zunehmende Hypoxie und den Todesmechanismus wird diskutiert.Als Vortrag auf der 56. Tagung der Deutschen Gesellschaft für Rechtsmedizin gehalten. Graz 17.–20.9.1977     

Tetrahydronorharmane (Tetrahydro-β-carboline), a physiologically occurring compound of indole metabolism

Summary In the present paper a sensitive method is described to measure tetrahydronorharmane (THN) in the urine of man and rats as well as in the forebrain of rats. The compound is extracted into diethyl ether, separated by thin layer chromatography (TLC), acetylated with radiolabelled acetic anhydride and further isolated by two-dimensional TLC development. The existence of THN in urine of man was proven by using chromatography with different solvent systems, cocristallisation, isotope dilution technique as well as mass-spectrometry. The amount of THN in the urine varied over a wide range.With the same method it was demonstrated that THN occurs also in the forebrain of rats. The concentration increases after loading with tryptamine.The findings are discussed in view of the hypothesis that THN acts as a compound modulating neuronal mechanism.     

6. Die Chirurgie in der Entscheidung — 20 Jahre Berufsverband der Deutschen Chirurgen

Zusammenfasung 1. Chirurgische Arbeit erfordert Wissen und Können, aber auch Reife und Verantwortungs-Fähigkeit. Gewährleisten die derzeitigen Aus- und Weiterbildungsgänge und unsere Haltung dem Nachwuchs gegenüber dieses Erziehungs-Ziel? 2. Die Bewältigung zentrifugaler Kräfte und die Integration autonomer Teile in der Chirurgie gelingt nur mit Hilfe der Teilgebiets-Idee, die Abwehr von Tendenzen, die Chirurgie wieder zum operierenden Werkzeugo zu degradieren, nur durch verstärkte Interaktion mit den Nachbardisziplinen. 3. Die Überwindung der vielfältigen auf die Arbeit des Chirurgen ausgeübten Pressionen ist nur durch Bewahrung einer sich selbst verptlichteten Freiheit als Grundlage aller chirurgischen Berufstätigkeit erreichbar.