Functional Compromise Cohort Study (FCCS): Sarcopenia is a Strong Predictor of Mortality in the Intensive Care Unit.

BACKGROUND: Functional compromise in elderly patients is considered to be a significant contributing factor in increased postoperative morbidity and mortality. It is described as a state of reduced physiologic reserves including, e.g., sarcopenia, cachexia, malnutrition and frailty with increased susceptibility to adverse health outcomes. Aim of this study was to investigate the association of sarcopenia with mortality in ICU patients. METHODS: A retrospective analysis of a total of 687 patients admitted to the ICU from January 2013 until December 2014 was performed. Indirect measurements of functional compromise in these patients were conducted. Sarcopenia was assessed using the L3 muscle index by using Osirix© on computed tomography scans. Groningen Frailty Indicator (GFI) and Short Nutritional Assessment Questionnaire (SNAQ) scores were extracted from the digital patient filing system and were used to assess frailty and nutritional status. These factors were analyzed using logistic regression analysis as predictor for in-hospital mortality and 6-month mortality, which was the primary endpoint along with other secondary outcome measures. RESULTS: Age was an independent predictor of in-hospital mortality, OR 1.043 (95% CI 1.030-1.057, p < 0.001). Analysis of sarcopenia showed OR 2.361 (95% CI 1.138-4.895, p = 0.021), for GFI OR 1.012 (95% CI 0.919-1.113, p = 0.811) and for SNAQ OR 1.262 (95% CI 1.091-1.460, p = 0.002). CONCLUSION: This study shows a promising role for the sarcopenia score as a predictor of mortality on the ICU, based upon CT imaging at L3 level and SNAQ score. Further research is necessary to test this in larger cohorts and to develop a possible instrument to predict mortality in the intensive care unit.

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 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 doxorubicin. 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.

High-performance liquid chromatographic bio-analysis of PSC 833 in human and murine plasma.

We have developed a rapid, sensitive and selective method for the determination of the cyclosporin analog PSC 833 in human and mouse plasma using cyclosporin A as internal standard. The assay uses liquid-liquid extraction with diethyl ether for sample clean-up followed by reversed-phase high-performance liquid chromatography with UV detection at 210 nm. Good peak shapes were obtained using a NovaPak Phenyl column operating at 72 degrees C. Good selectivity from endogenous compounds was achieved using a mobile phase composed of methanol-acetonitrile-water (34:34:32). The retention times of cyclosporin A and PSC 833 were approximately 7.8 and 11.7 min, respectively, with two major endogenous peaks at 9.2 and 16.7 min. Selective decreasing of the retention times of cyclosporin A and PSC 833 relative to these interferences occurring upon aging of the column was balanced by increasing the percentage of methanol relative to acetonitrile. No other late eluting peaks were present, resulting in a total analysis time of 20 min per sample. The assay performance in human plasma was good. The absolute recovery of PSC 833 after the sample clean-up step was 48+/-6%. The lower limit of quantitation was 0.05 microM using 500 microl of sample. Within the linear dynamic range of the assay (0.10-5.0 microM) the accuracy was close to 100% and within-day and between-day variation less than 7%. Because of the limited availability of blank mouse plasma, the concentration in samples from mice were determined using calibration curves constructed in human plasma. The lower limit of quantitation in mouse was 0.25 microM using 200 microl of sample. Overall, the performance of the assay in mouse plasma was somewhat less than in human plasma but accuracy and precision were within the ranges that are considered acceptable for bio-analytical assays.

The cell cycle of Bacillus subtilis as studied by electron microscopy.

Bacillus subtilis strain Marburg was grown exponentially with a doubling time of 65 min. To follow the time course of various cell cycle events, cells were collected by agar filtration and were then classified according to length. The DNA replication cycle was determined by a quantitative analysis of radioautograms of tritiated thymidine pulse labeled cells. The DNA replication period was found to be 45 min. This period is preceded and followed by periods without DNA synthesis of about 10 min. The morphology and segregation of nucleoplasmic bodies was studied in thin sections. B. subtilis contains two sets of genomes. DNA replication and DNA segregation seem to go hand in hand and DNA segregation is completed shortly after termination of DNA replication. Cell division and cell separation were investigated in whole mount preparations (agar filtration) and in thin sections. Cell division starts about 20 min after cell birth; cell separation starts at about 45 min and before completion of the septum.