Despite intervention campaigns, complete covering of the baby, prone position and heavy maternal smoking are still major risk factors for cot death. Except for sleeping on cushions, all major epidemiological risk factors for cot death act independently. Despite encouraging success in the reduction of risk factors for cot death, there is still substantial need for future endeavours towards a further reduction of modifiable risk factors for SID.
Objectives: The effect of ceftazidime dosing increments and frequency of dosing on the selection of ceftazidime-resistant Enterobacter cloacae in the intestine was studied in rats, during treatment of a pulmonary infection caused by Klebsiella pneumoniae.Methods: Rats with pulmonary infection (n 5 10 per group) received therapy with doses of ceftazidime at 3.1 to 400 mg/kg per day at a frequency of every 6,12 or 24 h for 18 days, starting 24 h after bacterial inoculation of the lung. Emergence of resistance in intestinal E. cloacae was monitored by culturing fresh stool specimens at days 0, 8, 15, 22, 29, 36 and 43 on agar plates with (6.4 mg/L) and without ceftazidime. Pharmacodynamic indices and time within the mutant selection window (MSW) were assessed in infected rats for each regimen. Ceftazidime-resistant E. cloacae mutants were characterized by determination of the b-lactamase activity under cefoxitin-induced and non-induced conditions.Results: A reduction of intestinal ceftazidime-susceptible E. cloacae was observed and showed a significant correlation with the fAUC/MIC at days 8, 15 and 22 and with the fC max on days 8, 15, 22, 29 and 36. More rats treated with 12-25 and 50-100 mg/kg per day every 6 h were found colonized with ceftazidime-resistant E. cloacae mutants than animals treated every 12 h or every 24 h. The proportion of rats colonized with ceftazidime-resistant E. cloacae mutants at days 15, 36 and 43 correlated with the time during which ceftazidime plasma concentrations were within the boundaries of the MSW. Only at day 15 was a correlation demonstrated between the fC max and significantly fewer rats colonized with ceftazidime-resistant E. cloacae. Ceftazidime-resistant E. cloacae mutants (MIC ! 128 mg/L) were characterized as stable derepressed mutants.Conclusions: Colonization with stable derepressed ceftazidime-resistant E. cloacae mutants particularly occurred when rats were exposed to moderate doses of ceftazidime (12-25 or 50-100 mg/kg per day) administered every 6 h. Emergence of resistance was correlated with time within the MSW.
Most Genotyping-by-Sequencing (GBS) strategies suffer from high rates of missing data and high error rates, particularly at heterozygous sites. Tunable genotyping-by-sequencing (tGBS®), a novel genome reduction method, consists of the ligation of single-strand oligos to restriction enzyme fragments. DNA barcodes are added during PCR amplification; additional (selective) nucleotides included at the 3'-end of the PCR primers result in more genome reduction as compared to conventional GBS methods. By adjusting the number of selective bases different numbers of genomic sites can be targeted for sequencing. Because this genome reduction strategy concentrates sequencing reads on fewer sites, SNP calls are based on more reads than conventional GBS, resulting in higher SNP calling accuracy (>97-99%) even for heterozygous sites and less missing data per marker. tGBS genotyping is expected to be particularly useful for genomic selection, which requires the ability to genotype populations of individuals that are heterozygous at many loci.
The establishment of polarity in cells and tissues is one of the first steps in multicellular development. The 'eternal embryo' hydra can completely regenerate from a disorganised cell cluster or a small fragment of tissue of about 10, 000 cells. During regeneration, the cells first form a hollow cell spheroid, which then undergoes de-novo symmetry breaking to irreversibly polarise. Here, we address the symmetry-related shape changes. Prior to axis establishment, the spherical aggregates of regenerating cells show highly coordinated mechanical oscillations on several timescales that are isotropic in space. There are transient periods of fluctuations in defined arbitrary directions, until these undergo a clearly identified irreversible transition to directed fluctuations along the future main axis of the regenerating hydra. Stabilised cytosolic actin structures disappear during the de-novo polarisation, while polymerised microtubules remain. Drugs that depolymerise actin filaments accelerate the symmetry breaking process, while drug-stabilised actin filaments prevent it. Nocodazole-depolymerised microtubules prevent symmetry breaking, but it can be rescued by the microtubule-stabilising drug paclitaxel at concentrations where microtubular structures start to reappear. We discuss the possibility that these mechanical fluctuations induce the orientation of the microtubules, which contribute to β -catenin nuclear translocation, to increase the organiserforming-potential of the cells. Our data suggest that in regenerating hydra spheroids, the biomechanical shape fluctuations are an integral part of the cooperative polarisation of the self-organising hydra, during which microtubules play a pivotal role.
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