Two conflicting hypotheses for chromosome replication in the Volvocaceae, one postulating multiple rounds of replication prior to cell division (endoreduplication) and the other claiming a canonical ...sequence of one round of nuclear DNA replication preceding each cell division, have been tested experimentally. Competitive PCR of the single‐copy actin gene (target) of Volvox carteri f. nagariensis Iyengar and a shortened gene version (competitor) containing the same primer binding sites were used to assess the genome equivalents present in a given number of cells. Determining the molar ratio of the PCR products generated from target DNA (extracted from a known number of cells) and defined numbers of competitor molecules revealed that Volvox embryos between the one‐ and 16‐cell stages possess an average of between one and two—but never more than two—copies of the actin gene. This led us to conclude that the number of genome equivalents per nucleus in dividing Volvox embryos varies only between one and two and that, unlike the case predicted by endoreduplication, the nuclear genome undergoes only one round of replication prior to each cell division.
Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical ...success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100% T->MIC, 50% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100% T->MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.
This study aimed at investigating sensitizing and hazardous effects of a new acid anhydride, pyromellitic dianhydride (PMDA), in addition to those of phthalic anhydride, maleic anhydride and ...trimellitic anhydride, in a group of 92 exposed workers in two German chemical plants. Of the 92 workers, 56 reported work-related complaints with a predominance of phlegm and dyspnoea in those exposed to anhydride dust for less than 1 year. Haemorrhagic rhinitis occurred only after a prolonged exposure of more than 15 years. Specific IgE antibodies to anhydride-HSA conjugates could be detected in 15 exposed subjects, 12 of whom had work-related symptoms. The IgE-positive group had significantly more impaired lung function parameters than the IgE-negative group. The proportion of IgE-positive subjects was highest in the groups with dyspnoea (5/18), cough (6/24) and rhinitis (11/44) whereas only 1 of 11 workers with haemorrhagic rhinitis had such antibodies. A follow-up study of 23 affected workers was performed after 10 months to assess clinical symptoms, lung function and IgE antibody levels. This follow-up study showed the absence of obstructive ventilation patterns in three out of six subjects in addition to cessation of symptoms in most initially affected workers who were no longer exposed. On the other hand, 14 workers under continuous exposure had comparable pathological findings on re-examination. Our results confirm that anhydrides including the lesser known PMDA, behave as respiratory irritants and as immediate-type sensitizers. They predominantly induced reversible symptoms in workers whose exposure stopped after a working period of about 0.7 years. Abnormal lung function parameters normalized in nearly 50% of these subjects.
Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, ...systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.
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