Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

The sub-lethal effects and tissue concentration of the human pharmaceutical atenolol in rainbow trout (Oncorhynchus mykiss).

Atenolol is a highly prescribed anti-hypertensive pharmaceutical and a member of the group of β-blockers. It has been detected at concentrations ranging from ng L(-1) to low μg L(-1) in waste and surface waters. The present study aimed to assess the sub-lethal effects of atenolol on rainbow trout (Oncorhynchus mykiss) and to determine its tissue-specific bioconcentration. Juvenile rainbow trout were exposed for 21 and 42 days to three concentration levels of atenolol (1 μg L(-1) - environmentally relevant concentration, 10 μg L(-1), and 1000 μg L(-1)). The fish exposed to 1 μg L(-1) atenolol exhibited a higher lactate content in the blood plasma and a reduced haemoglobin content compared with the control. The results show that exposure to atenolol at concentrations greater than or equal to 10 μg L(-1) significantly reduces both the haematocrit value and the glucose concentration in the blood plasma. The activities of the studied antioxidant enzymes (catalase and superoxide dismutase) were not significantly affected by atenolol exposure, and only the highest tested concentration of atenolol significantly reduced the activity of glutathione reductase. The activities of selected CYP450 enzymes were not affected by atenolol exposure. The histological changes indicate that atenolol has an effect on the vascular system, as evidenced by the observed liver congestion and changes in the pericardium and myocardium. Atenolol was found to have a very low bioconcentration factor (the highest value found was 0.27). The bioconcentration levels followed the order liver>kidney>muscle. The concentration of atenolol in the blood plasma was below the limit of quantification (2.0 ng g(-1)). The bioconcentration factors and the activities of selected CYP450 enzymes suggest that atenolol is not metabolised in the liver and may be excreted unchanged.

Continuous milking of dairy cows disrupts timing of peak IgG concentration appearance in mammary secretions

The length of the dry period in commercial dairy production is under close scrutiny. While the main concern is the composition and volume of milk produced, the evaluation of colostrum quality under these new paradigms has suggested a decline in IgG concentrations, while some reports indicate no change. Colostrum quality has been defined as an adequate concentration (>50 mg/ml) of immunoglobulin in the secretions to provide the newborn with maximal disease resistance. We investigated the appearance of IgG in mammary pre- and post partum secretions in cows without a dry period (continuously milked, Dry0) and compared the secretions with cows that experienced a dry period of 60 d (Dry60). Blood was collected during the experimental period and plasma analysed for progesterone (P4) and prolactin (Prl). Approximately -6 d relative to parturition, the Dry0 animals exhibited increased concentration of IgG in their secretions to an average of ∼35 mg/ml that remained rather constant through subsequent pregnancy and following parturition. Dry0 cows were producing an average IgG concentration in parturition colostrum of 44·2±17·6 mg/ml that was not different than that of controls (66·86±16·8 mg/ml). However, Dry0 cows exhibited high variation, different peak times (day) of IgG concentration including times that occurred both pre and post parturition. IgG mass of the Dry0 cows remained rather constant pre- and post partum and did not show the same declining mass following parturition that was shown for the Dry60 cows. The change in plasma P4 and Prl were shown to have no timing effect on colostrum IgG concentration.

Lactate dehydrogenase concentration in nasal wash fluid indicates severity of rhinovirus-induced wheezy bronchitis in preschool children.

The clinical course of rhinovirus (RV)-associated wheezing illnesses is difficult to predict. We measured lactate dehydrogenase concentrations, RV load, antiviral and proinflammatory cytokines in nasal washes obtained from 126 preschool children with RV wheezy bronchitis. lactate dehydrogenase values were inversely associated with subsequent need for oxygen therapy. lactate dehydrogenase may be a useful biomarker predicting disease severity in RV wheezy bronchitis.

The role of seasonality of mineral dust concentration and size on glacial/interglacial dust changes in the EPICA Dronning Maud Land ice core

We present a record of particulate dust concentration and size distribution in subannual resolution measured on the European Project for Ice Coring in Antarctica (EPICA) Dronning Maud Land (EDML) ice core drilled in the Atlantic sector of the East Antarctic plateau. The record reaches from present day back to the penultimate glacial until 145,000 years B.P. with subannual resolution from 60,000 years B.P. to the present. Mean dust concentrations are a factor of 46 higher during the glacial (~850–4600 ng/mL) compared to the Holocene (~16–112 ng/mL) with slightly smaller dust particles during the glacial comparedto the Holocene and with an absolute minimum in the dust size at 16,000 years B.P. The changes in dust concentration are mainly attributed to changes in source conditions in southern South America. An increase in the modal value of the dust size suggests that at 16,000 years B.P. a major change in atmospheric circulation apparently allowed more direct transport of dust particles to the EDML drill site. We find a clear in-phase relation of the seasonal variation in dust mass concentration and dust size during the glacial (r(conc,size) = 0.8) but no clear phase relationship during the Holocene (0 concentration from the glacial to the Holocene.

Large-scale land acquisitions in Peru: Land (re)-concentration, agrarian change and reactions from rural communities

More than 40 years after the agrarian reform, Peru is experiencing a renewed process of concentration of land ownership in the hands of large-scale investors, favoring the development of a sugar cane production cluster along the northern coast. The expansion of the agricultural frontier by means of large irrigation projects – originally developed to benefit medium- and small-scale farmers – is carried out today in order to be sold to large-scale investors for the production of export crops. In the region of Piura the increasing presence of large-scale biofuel investors puts substantial pressure on land and water resources, not only changing the use of and access to land for local communities, but also generating water shortages vis-à-vis the multiple water demands of local food producers. The changes in land relations and the agro-ecosystem, the altering food production regime as well as the increasing proletarization of smallholders, is driving many locals – even those which (initially) welcomed the investment – into resistance activities against the increasing control of land, water and other natural resources in the hands of agribusinesses. The aim of this presentation is to discuss the contemporary political, social and cultural dynamics of agrarian change along the northern Peruvian coast as well as the «reactions from below» emanating from campesino communities, landless laborers, brick producers, pastoralists as well as other marginalized groups. The different strategies, forms and practices of resistance with the goal of the «protection of the territory» shall be explored as well as the reasons for their rather scattered occurrence and the lack of alliances on the land issue. This input shall make a contribution to the on-going debate on individual and communal property rights and the question of what is best in terms of collective defense against land grabbing.

Effect of nonsurgical periodontal treatment in conjunction with either systemic administration of amoxicillin and metronidazole or additional photodynamic therapy on the concentration of matrix metalloproteinases 8 and 9 in gingival crevicular fluid in patients with aggressive periodontitis.

BACKGROUND To evaluate in patients with aggressive periodontitis (AgP) the effect of nonsurgical periodontal treatment in conjunction with either additional administration of systemic antibiotics (AB) or application of photodynamic therapy (PDT) on the gingival crevicular fluid (GCF) concentration of matrix metalloproteinases 8 and 9 (MMP-8 and -9). METHODS Thirty-six patients with AgP were included in the study. Patients were randomly assigned to treatment with either scaling and root planing (SRP) followed by systemic administration of AB (e.g. Amoxicillin + Metronidazole) or SRP + PDT. The analysis of MMP-8 and -9 GCF concentrations was performed at baseline and at 3 and 6 months after treatment. Nonparametric U-Mann-Whitney test was used for comparison between groups. Changes from baseline to 3 and 6 months were analyzed with the Friedman's ANOVA test with Kendall's index of consistency. RESULTS In the AB group, patients showed a statistically significant (p = 0.01) decrease of MMP-8 GCF level at both 3 and 6 months post treatment. In the PDT group, the change of MMP-8 GCF level was not statistically significant. Both groups showed at 3 and 6 months a decrease in MMP-9 levels. However, this change did not reach statistical significance. CONCLUSIONS Within the limits of the present study, it may be suggested that in patients with AgP, nonsurgical periodontal therapy in conjunction with adjunctive systemic administration of amoxicilin and metronidazole is more effective in reducing GCF MMP-8 levels compared to the adjunctive use of PDT.

Stand scale variability of topsoil organic matter composition in a high-elevation Norway spruce forest ecosystem

Our knowledge about the effect of single-tree influence areas on the physicochemical properties of the underlying mineral soil in forest ecosystems is still limited. This restricts our ability to adequately estimate future changes in soil functioning due to forest management practices. We studied the stand scale spatial variation of different soil organic matter species investigated by 13C NMR spectroscopy, lignin phenol and neutral sugar analysis under an unmanaged mountainous high-elevation Norway spruce (Picea abies L.) forest in central Europe. Multivariate geostatistical approaches were applied to relate the spatial patterns of the different soil organic matter species to topographic parameters, bulk density, oxalate- and dithionite-extractable iron, pH, and the impact of tree distribution. Soil samples were taken from the mineral top soil. Generally, the stand scale distribution patterns of different soil organic matter compounds could be divided into two groups: Those compounds, which were significantly spatially correlated with topography/altitude and those with small scale spatial pattern (range ≤ 10 m) that was closely related to tree distribution. The concentration of plant-derived soil organic matter components, such as lignin, at a given sampling point was significantly spatially related to the distance of the nearest tree (p ≤ 0.05). In contrast, the spatial distribution of mainly microbial-derived compounds (e.g. galactose and mannose) could be attributed to the dominating impact of small-scale topography and the contribution of poorly crystalline iron oxides that were significantly larger in the central depression of the study site compared to crest and slope positions. Our results demonstrate that topographic parameters dominate the distribution of overall topsoil organic carbon (OC) stocks at temperate high-elevation forest ecosystems, particularly in sloped terrain. However, trees superimpose topography-controlled OC biogeochemistry beneath their crown by releasing litter and changing soil conditions in comparison to open areas. This may lead to distinct zones with different mechanisms of soil organic matter degradation and also stabilization in forest stands.

Seasonal Distributions of Satellite-Measured Phytoplankton Pigment Concentration Along the Chilean Coast

Five years (1979-1983) of Coastal Zone Color Scanner satellite ocean color data are used to examine seasonal patterns of phytoplankton pigment concentration along the Chilean coast from 20 degrees S to 45 degrees S. Four kilometer resolution, 2-4 day composites document the presence of filaments of elevated pigment concentration extending offshore throughout the study area, with maximum offshore extension at higher latitudes. In three years, 1979, 1981, and 1983, sufficient data exist in monthly composites to allow recreation of portions of the seasonal cycle. Data in 1979 are the most complete. Near-shore concentrations and cross-shelf extension of pigment concentrations in 1979 are maximum in austral winter throughout the study area and minimum in summer. Available data from 1981 and 1983 are consistent with this temporal pattern but with concentrations approximately double those of 1979. Seasonal, spatial patterns within 10 km of shore and 50 km offshore indicate a latitudinal discontinuity both in absolute concentration and in the magnitude of the seasonal cycle at approximately 33 degrees S in both 1979 and in the climatological time series. The discontinuity is strongest ill fall-winter and weakest in summer. South of this latitude, concentrations are relatively high (2-3 mg m(-3) in 1979), a strong seasonal cycle is present, and patterns 50 km offshore are correlated with those within 10 km of shore. North of 33 degrees S, concentrations are < 1.5 mg m(-3) (in 1979), and the seasonal cycle within 10 km of shore is present but much weaker and less obviously correlated with that 50 km offshore. The seasonal cycle of pigment concentrations is 180 degrees out of phase with monthly averaged upwelling favorable winds. Noncoincident Pathfinder sea surface temperature data show that over most latitudes, coastal low surface temperatures lag wind forcing by 1-2 months, but these too are out of phase with the pigment seasonal cycle. These data point to control of pigment patterns along the Chilean coast by the interaction of upwelling with circulation patterns unconnected to local wind forcing.

Regional-Scale Mean Copepod Concentration Indicates Relative Abundance of North Atlantic Right Whales

Management plans to reduce human-caused deaths of North Atlantic right whales Eubalaena glacialis depend, in part, on knowing when and where right whales are likely to be found. Local environmental conditions that influence movements of feeding right whales, such as ultra-dense copepod patches, are unpredictable and ephemeral. We examined the utility of using the regional-scale mean copepod concentration as an indicator of the abundance of right whales in 2 critical habitats off the northeastern coast of the United States: Cape Cod Bay and Great South Channel. Right whales are usually found in Cape Cod Bay during the late winter and early spring, and in the Great South Channel during the late spring and early summer. We found a significant positive relationship between mean concentration of the copepod Calanus finmarchicus in the western Gulf of Maine and the frequency of right whale sightings in the Great South Channel. In Cape Cod Bay we found a significant positive relationship between the mean concentration of other copepods (largely Pseudocalanus spp. and Centropages spp.) and the frequency of right whale sightings. This information could be used to further our understanding of the environmental factors that drive seasonal movement and aggregation of right whales in the Gulf of Maine, and it offers a tool to resource managers and modelers who seek to predict the movements of right whales based upon the concentration of copepods.

Kinetics and Mechanism of Oxygen Delignification

Considerable research has been conducted into the kinetics and selectivity of the oxygen delignification process to overcome limitation in its use. However most studies were performed in a batch reactor whereby the hydroxide and dissolved oxygen concentrations are changing during the reaction time in an effort to simulate tower performance in pulp mills. This makes it difficult to determine the reaction order of the different reactants in the rate expressions. Also the lignin content and cellulose degradation of the pulp are only established at the end of the experiment when the sample is removed from the batch reactor. To overcome these deficiencies, we have adopted a differential reactor system used frequently for fluid-solid rate studies (so-called Berty reactor) for measurement of oxygen delignification kinetics. In this reactor, the dissolved oxygen concentration and the alkali concentration in the feed are kept constant, and the rate of lignin removal is determined from the dissolved lignin content in the outflow stream measured by UV absorption. The mass of lignin removed is verified by analyzing the pulp at several time intervals. Experiments were performed at different temperatures, oxygen pressures and caustic concentrations. The delignification rate was found to be first order in HexA-free residual lignin content. The delignification rate reaction order in caustic concentration and oxygen pressure were determined to be 0.42 and 0.44 respectively. The activation energy was found to be 53kJ/mol. The carbohydrate degradation during oxygen delignification can be described by two contributions: one due to radicals produced by phenolic delignification, and a much smaller contribution due to alkaline hydrolysis. From the first order of the reaction and the pKa of the active lignin site, a new oxygen delignification mechanism is proposed. The number 3 carbon atom in the aromatic ring with the attached methoxyl group forms the lignin active site for oxygen adsorption and subsequent electrophic reaction to form a hydroperoxide with a pKa value similar to that of the present delignification kinetics. The uniform presence of the aromatic methoxyl groups in residual lignin further support the first order in lignin kinetics.