The Response of RIF-1 Fibrosarcomas to the Vascular-Disrupting Agent ZD6126 Assessed by In Vivo and Ex Vivo1H Magnetic Resonance Spectroscopy

AbstractThe response of radiation-induced fibrosarcoma1 (RIF-1) tumors treated with the vascular-disrupting agent (VDA) ZD6126 was assessed by in vivo and ex vivo1H magnetic resonance spectroscopy (MRS) methods. Tumors treated with 200 mg/kg ZD6126 showed a significant reduction in total choline (tCho) in vivo 24 hours after treatment, whereas control tumors showed a significant increase in tCho. This response was investigated further within both ex vivo unprocessed tumor tissues and tumor tissue metabolite extracts. Ex vivo high-resolution magic angle spinning (HRMAS) and 1H MRS of metabolite extracts revealed a significant reduction in phosphocholine and glycerophosphocholine in biopsies of ZD6126-treated tumors, confirming in vivo tCho response. ZD6126-induced reduction in choline compounds is consistent with a reduction in cell membrane turnover associated with necrosis and cell death following disruption of the tumor vasculature. In vivo tumor tissue water diffusion and lactate measurements showed no significant changes in response to ZD6126. Spin-spin relaxation times (T2) of water and metabolites also remained unchanged. Noninvasive 1H MRS measurement of tCho in vivo provides a potential biomarker of tumor response to VDAs in RIF-1 tumors

The DALI study: defining antibiotic levels in intensive care unit patients: prolonged infusion of beta-lactam antibiotics in critically ill patients

Background – The aim of this study was to determine whether there is any pharmacokinetic and/or clinical advantage associated with the administration of beta-lactam antibiotics by prolonged infusion (PI; continuous or extended-infusion) compared to intermittent bolus (IB) dosing in critically ill patients. Methods - This report is part of the multi-national DALI study which included 68 intensive care units (ICU) throughout Europe. This study was a pharmacokinetic point-prevalence study, that was performed to describe concentrations of 3 beta-lactam antibiotics at two specified time-points. Differences in plasma antibiotic concentrations and clinical outcomes between PI and IB were assessed by using univariate and multivariate analyses. Results – This study included 224 critically ill patients whereby 63% and 37% of them received beta-lactam antibiotics via IB and PI dosing, respectively. IB dosing was preferred for piperacillin (IB 61% vs. PI 39%) and meropenem (IB 70% vs. PI 30%). The frequency of use of PI differed significantly between countries. PI demonstrated consistently higher drug concentrations compared to IB dosing. Clinical cure (IB 66% vs. PI 62%, p = 0.63), mortality (IB 28% vs. PI 30%, p = 0.87) and infection-related mortality rates (IB 22% vs. PI 17%, p = 0.288) were similar between PI and IB. Multiple regression analyses suggested that mortality was significantly predicted by SOFA score (OR = 1.10, 95% CI 1.00-1.21) and clinical cure (OR = 0.12, 95% CI 0.06-0.28). Only SOFA score predicted clinical cure (OR = 0.89, 95% CI 0.82-0.96). Conclusions – PI of beta-lactams is as effective as the traditional IB dosing in critically ill patients

Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. European Paediatric Lipodystrophy Group

Objectives: To estimate prevalence of body fat redistribution and dyslipidaemia in HIV-infected children and to assess associated risk factors, ultimately to inform the definition of lipodystrophy in children. Design: Cross-sectional observational study. Methods: During a 2-3 month period, 477 HIV-infected children aged ≥ 3 years (median 9.78; range, 3-18) in 30 paediatric HIV clinics were assessed at their first visit. Sociodemographic, clinical and immunological data were recorded and the presence or absence of clinical signs of fat redistribution (peripheral lipoatrophy and central lipohypertrophy) determined according to an agreed protocol. Laboratory indicators of lipid/glucose metabolism were recorded for all children in 18 centres. Results: Prevalence was 26.0% [95% confidence interval (CI), 22.1-30.2] for any fat redistribution, 8.81% (95% CI, 6.42-11.7) for central lipohypertrophy, 7.55% (95% CI, 5.34-10.3) for peripheral lipoatrophy and 9.64% (95% CI, 7.15-12.7) for the combined subtype (more than one sign of each). Independent predictors of fat redistribution included Centers for Disease Control and Prevention class C disease, female gender, ever used versus never use of protease inhibitors and of stavudine. Increasing time since initiation of antiretroviral therapy was associated with increased severity of fat redistribution. In the metabolic assessment subgroup, 27% (95% CI, 21.6-32.7) of children had hypercholesterolaemia and 21% (95% CI, 16.4-26.6) hypertriglyceridaemia; however, significantly more children had fat redistribution in this subgroup than overall (31%). Conclusions: Approximately a quarter of children and adolescents could be taken to have signs of lipodystrophy, with clinical presentation and risk factors similar to those described in adults

Long-term clinical effects of a chlorhexidine varnish implemented treatment strategy for chronic periodontitis

Background: Scaling and root planing in combination with oral hygiene monitoring are still considered the therapeutic standards for periodontitis. Although this treatment concept customarily results in satisfactory clinical improvements, treatment outcome may become less favorable predominantly when full access to periodontal defects is compromised, thereby leaving accretions behind. The purpose of this study was to investigate, over a 9-month period, the clinical benefits of a treatment strategy for chronic periodontitis based on a combination of sequential scaling and root planing and subgingival chlorhexidine varnish administration. Methods: This randomized controlled, single blind, parallel trial included 26 volunteers with chronic periodontitis. The control group received oral hygiene instructions and was scaled and root planed in two sessions. The test group received the same instructions and treatment; however, all pockets were additionally disinfected using a highly concentrated chlorhexidine varnish. Clinical response parameters were recorded at baseline and at 1, 3, 6, and 9 months. The impact of the initial strategy on the decision-making process for supplementary therapy at 9 months was investigated based on treatment decisions made by five independent clinicians. Results: Both treatment strategies showed significant reductions in probing depth and gains in clinical attachment at study termination in comparison with baseline (P = 7 mm) around multirooted teeth seemed to benefit most from the combination strategy, resulting in an additive pocket reduction of 1.06 mm (P= 0.009) and a clinical attachment gain of 0.54 mm (P = 0.048) in comparison to scaling and root planing alone. A trend toward a reduction of surgical treatment needs following the varnish-implemented strategy was found (P= 0.076). Conclusion: These findings suggest that the outcome of initial periodontal therapy may benefit from the adjunctive subgingival administration of a highly concentrated chlorhexidine varnish