The determination of 4-methyl-2-thiouracil in animal blood, urine and faeces

A method is described for the determination of 4-methyl-2-thiouracil in blood, human urine and hen's excreta. In the determination in the excreta a suspension of these excreta is dialysed for 12–24 hours against acid water and the determination is carried out in this acid water, as always with the aid of Grote's reagent. This method was applied with good results in later studies on the metabolism of methylthiouracil in poultry

The metabolism of orally administered 4-methyl-2-thiouracil in cockerels

The metabolism of orally administered methylthiouracil (= MTU) was studied by chemical determinations in the excrements, the contents of the digestive tract, blood plasma, muscle tissue and the thyroids. Daily doses of 40, 50, 80, 100 and 120 mg MTU were used. From the results the following conclusions are drawn: 1. About half of the amount of MTU may be recovered from the excrements within 24 hours after the administration; 2. The excretion rate is maximal about 2–6 hours after the administration. Most of the excretion takes place within 12 hours, excretion is almost complete after 24 hours; 3. In blood plasma and muscle tissue the maximal concentrations (2–4 mg%) are reached in 2–5 hours, after which a rapid decline occurs and no or very little MTU may be found after 20–24 hours; 4. Concentrations of MTU in thyroid tissue are markedly higher than those in muscle tissue. The differences, however, are much smaller than those found by other investigators; 5. MTU is very rapidly absorbed from the gastro-intestinal tract. MTU is only excreted by way of the kidneys, no direct passage through the digestive tract into the excrements occurs; 6. No cumulation of MTU in muscle tissue takes place. All these facts favour the opinion that MTU may very easily penetrate into and be just as readily eliminated from body tissue

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(–/– and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg−1. Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration–time curve of doxorubicin in it>mdr1a(–/–) mice were 1.6- and 1.2-fold higher respectively.The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(–/–) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(–/–) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of oxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(–/–) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin. © 1999 Cancer Research Campaig

Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes

© 2017 The Authors Human astrocytes network with neurons in dynamic ways that are still poorly defined. Our ability to model this relationship is hampered by the lack of relevant and convenient tools to recapitulate this complex interaction. To address this barrier, we have devised efficient coculture systems utilizing 3D organoid-like spheres, termed asteroids, containing pre-differentiated human pluripotent stem cell (hPSC)-derived astrocytes (hAstros) combined with neurons generated from hPSC-derived neural stem cells (hNeurons) or directly induced via Neurogenin 2 overexpression (iNeurons). Our systematic methods rapidly produce structurally complex hAstros and synapses in high-density coculture with iNeurons in precise numbers, allowing for improved studies of neural circuit function, disease modeling, and drug screening. We conclude that these bioengineered neural circuit model systems are reliable and scalable tools to accurately study aspects of human astrocyte-neuron functional properties while being easily accessible for cell-type-specific manipulations and observations. In this article, Krencik and colleagues show that high-density cocultures of pre-differentiated human astrocytes with induced neurons, from pluripotent stem cells, elicit mature characteristics by 3–5 weeks. This provides a faster and more defined alternative method to organoid cultures for investigating human neural circuit function.This work has been supported by the Paul G. Allen Family Foundation Award, SFARI Award 345471, NIMH ( R01MH099595-01 ), That Man May See, NIH-NEI ( EY002162 ) Core Grant for Vision Research, and the Research to Prevent Blindness Unrestricted Grant

The lower prevalence of female genital mutilation in the Netherlands: a nationwide study in Dutch midwifery practices

OBJECTIVES: To determine the prevalence of female genital mutilation (FGM) in women giving birth in 2008 in the Netherlands. METHOD: A retrospective questionnaire study was conducted. The study covered all 513 midwifery practices in the Netherlands. The data were analysed with SPSS 17.0. RESULTS: The response from midwifery practices was 93% (n = 478). They retrospectively reported 470 circumcised women in 2008 (0.32%). The expected prevalence in the Netherlands based on the estimated prevalence of FGM in the country of birth was 0.7%. It is likely that there was underreporting in midwifery practices since midwives do not always enquire about the subject and may not notice the milder types of FGM. Midwives who checked their records before answering our questionnaire reported a prevalence of 0.8%. CONCLUSION: On the basis of this study, we can conclude that FGM is a serious clinical problem in Europe for migrant women from risk countries for FGM. These women should receive extra attention from obstetricians and midwives during childbirth, since almost half are mutilated and FGM involves a risk of complications during delivery for both women and children.Public Health and primary car

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers:A nationwide cohort study

AIM: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. RESULTS: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). CONCLUSION: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers

The development of an online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making: a usability and pilot study

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples’ decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest–posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision