Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure?

Mitochondrial functions include production of energy, activation of programmed cell death, and a number of cell specific tasks, e.g., cell signaling, control of Ca2+ metabolism, and synthesis of a number of important biomolecules. As proper mitochondrial function is critical for normal performance and survival of cells, mitochondrial dysfunction often leads to pathological conditions resulting in various human diseases. Recently mitochondrial dysfunction has been linked to multiple organ failure (MOF) often leading to the death of critical care patients. However, there are two main reasons why this insight did not generate an adequate resonance in clinical settings. First, most data regarding mitochondrial dysfunction in organs susceptible to failure in critical care diseases (liver, kidney, heart, lung, intestine, brain) were collected using animal models. Second, there is no clear therapeutic strategy how acquired mitochondrial dysfunction can be improved. Only the benefit of such therapies will confirm the critical role of mitochondrial dysfunction in clinical settings. Here we summarized data on mitochondrial dysfunction obtained in diverse experimental systems, which are related to conditions seen in intensive care unit (ICU) patients. Particular attention is given to mechanisms that cause cell death and organ dysfunction and to prospective therapeutic strategies, directed to recover mitochondrial function. Collectively the data discussed in this review suggest that appropriate diagnosis and specific treatment of mitochondrial dysfunction in ICU patients may significantly improve the clinical outcome

The influence of quasi resonant internal waves on the radar imaging mechanism of shallow sea bottom topography

During previous field experiments in the North Sea it was often assumed that the water column in such shallow coastal tidal waters is vertically well mixed and stratification was neglected when discussing the Normalized Radar Cross Section modulation caused by the sea floor. In this paper the influence of quasi resonant internal waves with the sea bed on the radar imaging mechanism of submarine sand waves itself is investigated. In situ data of the tidal cur-rent velocity and several water quality parameters such as sea surface temperature, fluorescence. and beam transmittance were measured in the Southern Bight of the North Sea in April 1991. Simulations of the total NRCS modulation caused by sand waves and internal waves as a function of the current gradient or strain rate induced by the internal wave current field at the sea surface have been carried out using the quasi-steady approximation and linear internal wave theory. As a first approximation the strain rate depending on stratification was calculated using the two-layer model. These simulations demonstrate that at least a density difference between the two layers of the order of Delta(Q) approximate to 1 kg m(-3) is necessary for a sinusoidal thermocline to effect the total NRCS modulation considerably. The NRCS modulation as a function of wind friction velocity has been calculated independently and is discussed with regard to the strain rate of the surface current field caused by the superimposed imaging mechanisms of sand waves and internal waves. It turned out that the existence of a surface roughness-wind stress feedback mechanism cannot be excluded. (C) 2002 Ifremer/CNRS/IRD/Editions scientifiques et medicales Elsevier SAS. All rights reserved.Précédemment, en mer du Nord, la stratification, pratiquement inexistante dans cette région peu profonde et à fortes marées, a été négligée lors de la discussion de la modulation par le fond marin de la section efficace normalisée du radar. Dans le présent article, nous examinons l'influence des vagues internes quasi-résonantes et du fond sous-marin sur les images radar du fond sableux. Les données in situ ont été recueillies en avril 1991 dans la partie sud de la mer du Nord : vitesse du courant de marée, température de surface, fluorescence et transmission. Des simulations de la modulation de la section efficace normalisée du radar produite par les ondulations du fond sableux et les ondes internes en fonction du gradient de courant ou de la tension induits par le champ de courants des ondes internes à la surface de mer ont été réalisées. L'approximation quasi-stationnaire et la théorie linéaire des vagues internes ont été utilisées. En première approximation, la tension dépendant de la stratification a été calculée en utilisant un modèle à deux couches. Ces simulations montrent une différence de densité entre les deux couches d'au moins Δρ ≈ 1 kg m–3 est nécessaire pour une thermocline sinusoïdale pour modifier fortement la section efficace normalisée du radar. Cette modulation, fonction de la vitesse de friction du vent, a été calculée séparément et est discutée en fonction de la tension du champ de courant superficiel produit par les images superposées des ondulations du sable et des ondes internes. L'existence d'un mécanisme de rétroaction de tension du vent ne peut pas être exclue

First Results of the Viers-1 Experiment

In February 1988, cornbined measurements of microwave backscatler, wind, waves and gas exchange have been carried out in the large Delft lHydraulics wind/rwave tank. This experiment was the first in a series of experimeuts in the frame of the VIERS-1 project. In this project a number of Dutch and German laborabories cooperate. Main objective is to come to a physical descriplion of the processes involved in wind scatterometry and, from that point, to an improvement of the algorithms used for determination of wind speed and direction from satellite borne microwave scatterometers. A second objective is to study the relation between the gas exchange at the water surface and the microwave backscatter. To achieve these objectives two wind/wave tank experiments and one ocean based platform experiment are scheduled. In this paper, the VIERS-1 programme will be outlined. The Delft wind/wave tank experiment will be described and some first results of a preliminary comparison of backscatter and wave slope measurements will be shown