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•Male survivors of HL treated with chest radiotherapy have an increased risk of developing BC compared with the general population.•Although the occurrence of male BC is an uncommon event, clinicians should be alert to BC symptoms in male survivors of HL.

Een belangrijk deel van de huidige alleenstaande minderjarige vreemdelingen komt in aanmerking voor gezinshereniging. Voordat er sprake is van een hereniging, heeft het kind lang gewacht en veel meegemaakt. En als het dan eindelijk zover is en ouders en kind elkaar weerzien, is de blijdschap groot. Maar de hereniging en het als één gezin bij elkaar wonen kan ook leiden tot nieuwe en onbekende spanningen en bij het kind enige paniek veroorzaken.

The authors discuss European case law and the VAT Implementing Regulation with regard to the concept of the fixed establishment and question whether, thirty years after it was introduced into the field of VAT, all the mysteries surrounding the fixed establishment have now been solved. [ABSTRACT FROM AUTHOR]

The extremely knowledge-intensive sector of the tool and die industry is forced to reduce costs due to raising international competition. This paper deals with the development and implementation of a knowledge transfer system in order to reduce costs by avoiding mistakes in the tool making process and cutting costs of rework. It constitutes typical weak points concerning shared information and explains a systematic knowledge feedback chain. Additionally it describes the application of supporting knowledge distribution tools, for example mobile tablet apps, and gives examples regarding an improved information flow along the process chain of the tool and die industry.

Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the "gold standards" for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestis isolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestis in in vitro and animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestis in an in vitro pharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestis and with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the Cmax(maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestis in 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitro pharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestis infections in humans. Studies of moxifloxacin in animal models of plague are warranted.

ABSTRACTYersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the “gold standards” for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestisisolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestisin in vitroand animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestisin an in vitropharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestisand with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the Cmax(maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestisin 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitropharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestisinfections in humans. Studies of moxifloxacin in animal models of plague are warranted.

ABSTRACTSimulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for ≥700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthraciswithout resistance selection. Linezolid at ≤600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at ≥500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthraciswas predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (Cmax)/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg·h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg·h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracisand prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

ABSTRACTRespiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosainfection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ± 7.8 kg) and 26 healthy volunteers (WT, 71.1 ± 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (≥90%) probability-of-target attainment (PTA) for MICs of ≤12 mg/liter in CF patients and ≤16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of ≤16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosainfection in CF patients, based on susceptibility data from two German CF clinics.

The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam (2 mg orally), clearance of midazolam (1 mg i.v.), apparent clearance of tolbutamide (125 mg orally), urinary excretion of 4′-hydroxymephenytoin 0 to 8 h postdose (50 mg of mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 h postdose (150 mg of caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days of treatment with 15 mg of propiverine (test) or placebo (reference) twice daily. All phenotyping drugs were quantified by liquid chromatography-tandem mass spectrometry. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively [90% confidence interval (CI) for test/reference ratios 0.85–0.93 and 0.72–0.89], with the combined effect resulting in a 1.46-fold increase in area under the curve of oral midazolam (90% CI 1.36–1.57). Propiverine had no relevant effect on CYP2C9, CYP2C19, and CYP1A2 (90% CI for test/reference ratios 0.93–1.00, 0.84–0.96, and 0.97–1.07, respectively). All study drugs were well tolerated. In conclusion, propiverine has a minor potential to cause drug-drug interactions.

AbstractThe objective of this study was to determine serum bactericidal titers (SBT, the highest dilution of serum showing no growth) and the serum bactericidal activity (SBA, i.e. duration of SBT greater than 1:2) as well as the serum bactericidal rate of gemifloxacin and clarithromycin after single doses in healthy male volunteers against Streptococcus pneumoniae. Strains tested had various degrees of susceptibility to penicillin as well as different susceptibility to quinolones due to a different QRDR mutation pattern (parC, gyrA). Serum samples from volunteers (n=12) who had received a single oral dose of either 320 mg gemifloxacin or 500 mg clarithromycin in an open-label crossover study were obtained over a 24-hour period. SBA was determined, using the microdilution method. SBA of wildtype strains for gemifloxacin ranged from 8.9 to 15.4 h (mean 12.6 h). For gemifloxacin, 2 strains with solitary gyrAmutation had an SBA from 4.5 to 4.7 h (median 4.5 h). One of the 2 strains with a single QRDR mutation in parCdisplayed an SBA of 4.5 h, comparable to the gyrA mutation strains, whereas the second strain had a nearly twice as long SBA of 8.9 h. Two strains with two mutations (parCand gyrA) did not display any SBA. For clarithromycin, the duration of SBA ranged from 11.3 to 15.5 h (mean 13.6 h) for 6 of the 12 strains with an MIC ≤0.06 mg/L (no SBA was found for the remaining strains, with an MIC of 0.25 mg/L or higher). In conclusion, a correlation between individual serum concentrations and SBA was found for both antibiotics.

Drug absorption within urinary diversions has been reported to cause prolonged and higher grade toxicity. Therefore, continuous urine drainage has been recommended during chemotherapy in patients with continent urinary diversion. We developed an animal model in which to examine the significance of drug absorption in normal rabbit bladders compared with ileal augmented bladders.

The parental effects on progenies from potato 4x.2x(FDR) crosses were analyzed to determine anether and to what extent selection criteria used for selecting tetraploid breeding lines have to be adjusted when selecting diploid breeding lines. For vine maturity and chip colour multiple regression analysis of progeny means on means of diploid and tetraploid parents revealed high coefficients of determination (R2) for both characters, indicating good predicting power of the performance of both diploid and tetraploid parents on the performance of their 4x.2x progenies. For vine maturity the multiple regression slope for the tetraploid perents was significantly larger than for the diploid parents, and progeny means were towards the tetraploid parents. This indicates that selection criteria for vine maturity may be less stringent at the diploid level. However, diploids may be earlier maturing than tetraploids and therefore selection criteria can better be similar at both ploidy levels. For chip colour, multiple regression slopes for diploid and tetraploid parents were similar and progeny means were towards the darkest coloured parent irrespective of its ploidy level. This indicates that selection of breeding lines for chip colour can be conducted similarly at both ploidy levels.

Selection criteria for agronomic characters in a potato breeding program at the diploid (2x) level may differ from selection criteria used when selecting breeding lines at the tetraploid (4x) level. Differences between selection criteria are expected, (1) when expression of the characters is different at both ploidy levels and/or (2) when the effect of diploid breeding lines on agronomic characters of tetraploid progenies is different from the effect of tetraploid breeding lines. In this investigation sets of diploid and tetraploid progenies, each set derived from the same 2x.2x cross, were compared as to the expression of six agronomic characters. Diploid progenies had significantly lower yields (due to smaller tubers) and significantly higher under water weights than tetraploid progenies. Vine maturity and chip colour were similarly expressed at both ploidy levels. Correlations between yield and yield components, and between under water weight and chip colour were similar at both ploidy levels. The lower yields and higher under water weights found in diploids point to the need of different selection criteria for selecting diploid and tetraploid breeding lines.

Numerically unreduced (2n) gametes from first division restitution (FDR) are considered to be superior to 2n-gametes from second division restitution (SDR) because they transfer a larger proportion of the total parental heterozygosity and epistasis intact to the tetraploid progeny. This supposed superiority was investigated by comparing 12 sets of reciprocal 4x-2x crosses. Each diploid parent used in a reciprocal set produced 2n-pollen by FDR and 2n-eggs by SDR. Six agronomic characters were investigated. FDR progenies (from 4x.2x) were found to have higher mean yields due to more and bigger tubers. With respect to underwater weight, the overall progeny mean of FDR progenies was significantly higher than that of SDR progenies (from 2x.4x). However, the absolute difference found between both overall progeny means was too small to be of practical significance. No differences between FDR and SDR progeny means were found for vine maturity and chip colour. In addition to the progeny mean, within-progeny variation is important in potato breeding. For vine maturity a higher within-progeny variation was detected in SDR progenies, whereas within-progeny variations for yield, underwater weight and chip colour were not different in FDR and SDR progenies. With regard to vine maturity, we conclude that SDR 2n-gametes are superior to FDR 2n-gametes because, with the same progeny means of FDR and SDR progenies, the within-progeny variation was higher in SDR progenies. Therefore the assumed superiority of FDR 2n-gametes was confirmed for yield but was not observed for vine maturity, underwater weight and chip colour.

Its broad antibacterial spectrum qualifies the combination of piperacillin and tazobactam for therapy of nosocomial bacterial central nervous system (CNS) infections. Since these infections sometimes are accompanied by only minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 9; age range, 48 to 75 years). After administration of the first dose of piperacillin (6 g)-tazobactam (0.5 g) over 30 min intravenously, serum and CSF were drawn repeatedly and analyzed by high-performance liquid chromatography. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations of piperacillin in CSF ranged from 8.67 to <0.37 mg/liter (median, 3.42 mg/liter), and those of tazobactam ranged from 1.37 to 0.11 mg/liter (median, 0.45 mg/liter). CSF maxima were observed, in median, 1.5 and 2 h after the end of the infusion. Elimination in CSF was considerably slower than in serum (median half-life at beta phase for piperacillin, 5.9 h in CSF versus 1.47 h in serum; for tazobactam, 6.1 h versus 1.34 h). For tazobactam, the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in serum was approximately three times as high as that for piperacillin (medians, 0.106 versus 0.034). In view of the tazobactam concentrations in CSF observed in this study, the practice of using a constant concentration of 4 mg of tazobactam per liter for MIC determination is inadequate for intracranial infections. Larger amounts of tazobactam than the standard dose of 0.5 g three times daily may be necessary for CNS infections.

Im Serum von Carcinompatienten wiesen wir in allen Fällen mit erhöhter Phosphataseaktivität eine Substanz nach, die sich bei der von uns angewandten Methode wie Cholin verhält, im Gegensatz zu Cholin jedoch durch Kochen mit n-HCl zerstört wird. Sie läßt sich auch in Seren, die längere Zeit gestanden haben, nicht mehr nachweisen, ebensowenig wie in Seren von Carcinomkranken mit normaler Serumphosphataseaktivität. Die Substanz steht in keinem unmittelbaren Zusammenhang zum Cholinstoffwechsel. Versuche, sie zu identifizieren, waren bisher erfolglos.

1.In der embryonalen Lunge von Gallus dom. finden sich unspezifische Esterasen zunächst nur im Epithel der Bronchialverzweigungen, später auch im sich differenzierenden oder schon ausgebildeten Muskelgewebe der Bronchialwände der Anlage.2.Die mit verschiedenen Substraten nachgewiesene Aktivität unspezifischer Esterasen nimmt während der Ontogenese zu, vor allem im Muskelmaterial der Bronchien. Man erhält die Reaktion auch in der Auskleidung der Atrien, aus denen die Luftkapillaren hervorgehen. Letztere reagieren dagegen nicht, ebensowenig wie das undifferenzierte Mesenchym, aus dem sich das Stroma der Parabronchialläppchen bildet.3.Bei der Züchtung von Lungenanlagen in toto oder ihrer Fragmente in vitro auf verschiedenen Entwicklungsstadien konnte bestätigt werden, daß der morphogenetische Prozeß keinen wesentlichen Änderungen unterliegt. Auch die normale Aktivität unspezifischer Esterasen kann man in unveränderter Stärke dort beobachten, wo sie in vivo auftritt.4.In der Lichtung des Bronchialbaumes findet man eine kolloidähnliche Substanz, die sich bei der Trichromfärbung nach Mallory blau färbt, die Parabronchiallichtung und die Lichtung der Atrien ausdehnt und sich bei der Reaktion auf unspezifische Esterasen nicht anfärbt.

For N-acetyltransferase type 2 (NAT2) phenotyping, urinary ratios of caffeine metabolites are determined after a caffeine test dose. It is not known how these ratios change with postdose time, and which urine collection interval is best for phenotyping.Therefore, 16 healthy male Caucasians collected urine before and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, and 16-24 h after a 150 mg caffeine test dose. The test was repeated after 10 days. Concentrations of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X) and 1-methylurate (1U) were measured with LC-MS/MS (LOQ, 100 ng/mL). As a NAT2 metric, the molar ratio (AFMU+AAMU)/(1X+1U+AFMU+AAMU) was determined.In both periods, urinary ratios were stable from 4 until 24 hours postdose. The arithmetic means for the collection periods ranged from 0.152 to 0.169 and from 0.163 and 0.186, respectively, the CV was <6 % in all cases. Intraindividual CVs were between 9 and 16% starting 4 hours postdose, while interindividual variability reached values between 58 and 66%, respectively. There was no statistically significant difference in CV between the respective collection periods or between study periods. Hence, urine for NAT2 phenotyping may be collected at any time between 4 and 24 hours after caffeine dosing. The low intraindividual CVs enable the conductance of interaction studies assessing the effect of drugs on NAT2 activity with a sample size as low as n=12 subjects.Clinical Pharmacology & Therapeutics (2004) 75, P69–P69; doi: 10.1016/j.clpt.2003.11.259