Impact of depth of propofol anaesthesia on functional residual capacity and ventilation distribution in healthy preschool children

Background Propofol is commonly used in children undergoing diagnostic interventions under anaesthesia or deep sedation. Because hypoxaemia is the most common cause of critical deterioration during anaesthesia and sedation, improved understanding of the effects of anaesthetics on pulmonary function is essential. The aim of this study was to determine the effect of different levels of propofol anaesthesia on functional residual capacity (FRC) and ventilation distribution. Methods In 20 children without cardiopulmonary disease mean age (sd) 49.75 (13.3) months and mean weight (sd) 17.5 (3.9)kg, anaesthesia was induced by a bolus of i.v. propofol 2mgkg−1 followed by an infusion of propofol 120µgkg−1min−1 (level I). Then, a bolus of propofol 1mgkg−1 was given followed by a propofol infusion at 240µgkg−1min−1 (level II). FRC and lung clearance index (LCI) were calculated at each level of anaesthesia using multibreath analysis. Results The FRC mean (sd) decreased from 20.7 (3.3)mlkg−1 at anaesthesia level I to 17.7 (3.9)mlkg−1 at level II (P < 0.0001). At the same time, mean (sd) LCI increased from 10.4 (1.1) to 11.9 (2.2) (P = 0.0038), whereas bispectral index score values decreased from mean (sd) 57.5 (7.2) to 35.5 (5.9) (P < 0.0001). Conclusions Propofol elicited a deeper level of anaesthesia that led to a significant decrease of the FRC whereas at the same time the LCI, an index for ventilation distribution, increased indicating an increased vulnerability to hypoxaemi

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min−1 were excluded. Study treatment consisted of docetaxel 75 mg m−2 (day 8) and gemcitabine 1000 mg m−2 (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42–74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3–4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1–9.2 months) and the median overall survival was 15 months (95% CI 11.2–18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

A randomised phase III trial of MVAC (methotrexate, vincristine, doxorubicin, cisplatin) vs gemcitabine and cisplatin (GC) (G 1000 mg m(-2) days 1, 8, and 15 plus C 70 mg m(-2) day 2, q 4 wks) indicated GC had similar efficacy and lower toxicity (JCO 2000). Significant haematologic toxicities in the GC arm occurred on day 15, necessitating dose adjustments in 37% of cycles. We conducted a phase I/II dose escalation trial using GC on a 21-day cycle, with G and C split between days 1 and 8. The objective of the study to define maximum-tolerated dose and dose-limiting toxicity (DLT), objective response rate, and overall survival. In all, 32 patients with locally advanced, relapsed, or metastatic disease received: dose level 1, G/C 1000/35; level 2, 1100/35; level 3, 1200/35; level 4, 1200/45 mg m(-2) (G and C given on days 1 and 8 every 3 wks). A total of 19 patients had glomerular filtration rate <60 ml min(-1) and 19 patients had metastatic disease. Dose-limiting toxicity was haematologic (grade 4 thrombocytopenia) at dose level 2. Of 151 cycles, at day 15, platelets were <100 in 61 cycles; neutrophils <0.5, platelets <50 in 26 cycles. Only seven cycles were deferred due to haematological toxicity; four for renal toxicity (chemotherapy instituted posthydration). Overall response rate was 65.5% on an intention-to-treat analysis (75% [21/28] for assessable patients), with four complete responses (12.5%) and 17 partial responses (53%). After the median follow-up of 17.2 months (range 13.1-32.4 months), 12 patients remain alive. The overall median survival was 16 months (range 10.1-26.6 months). G plus C every 3 weeks is active and well tolerated in an outpatient setting, even in patients receiving prior platinum-based regimens and with poor renal reserve

Experiential learning and the acquisition of managerial tacit knowledge

Tacit knowledge is believed to be one factor that distinguishes successful managers from others. We sought to determine whether levels of accumulated managerial tacit knowledge (LAMTK) were associated with managers' dominant learning styles. Instruments used in the study, involving 356 Malaysian public sector employees, included Sternberg et al.'s (2000) Tacit Knowledge Inventory for Managers and a normative version of Kolb's (1999a) Learning Styles Inventory (LSI-Ill). Findings suggest that LAMTK is independent of the length of subjects' general work experience, but positively related to the amount of time spent working in a management context. Learning styles also had a significant relationship. Subjects who spent most of their time performing management functions and whose dominant learning styles were accommodating had significantly higher LAMTK than those with different learning styles. We also found support for the belief that learners with a strong preference for all four different abilities defined in Kolb's learning theory may be critical for effective experiential learning

Avoiding degenerate coframes in an affine gauge approach to quantum gravity

In quantum models of gravity, it is surmized that configurations with degenerate coframes could occur during topology change of the underlying spacetime structure. However, the coframe is not the true Yang--Mills type gauge field of the translations, since it lacks the inhomogeneous gradient term in the gauge transformations. By explicitly restoring this ``hidden" piece within the framework of the affine gauge approach to gravity, one can avoid the metric or coframe degeneracy which would otherwise interfere with the integrations within the path integral. This is an important advantage for quantization.Comment: 14 pages, Preprint Cologne-thp-1993-H