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IntroductionOnly limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.MethodsThirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.ResultsThe following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.ConclusionsThe results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.Trial RegistrationClinicalTrials.gov: NCT00747721

The metabolic modifications of birch (Betula pubescens Ehrh.) leaf phenolics in the digestive tract of its major defoliator, larvae of the autumnal moth Epirrita autumnata, were studied. The main phenolic acids of birch, i.e. chlorogenic and p-coumaroylquinic acids, were isomerised in the alkaline digestive tract. Moreover, only 16 to 92% of the ingested amounts of chlorogenic acid were found in the faeces of individual larvae; the missing portion is possibly being used in the formation of reactive o-quinones. Water-soluble flavonoid glycosides were mostly excreted unaltered. In contrast, lipophilic flavonoid aglycones were not excreted as such, but as glycosides after being detoxified by E. autumnata via glycosylation. When the larvae were fed with leaf-painted acacetin and kaempferide, i.e. two naturally occurring birch leaf flavonoid aglycones, acacetin-7-O-glucoside and kaempferide-3-O-glucoside appeared in larval faeces as major metabolites. However, the efficiency of aglycone glycosylation varied, ranging from 17 to 33%, depending on the aglycone and its dietary level. There was also large variation in the efficiency of glycosylation Ð from 2 to 57% Ð among individual larvae. These results demonstrate a compound-specific metabolism of phenolic compounds, leading to different phenolic profiles in the insect gut compared to its leaf diet.

We review the evidence for the earliest agriculture in Finland. The claims are all based on pollen analysis. Some claims go back to the Neolithic period. We contest these claims critically and argue that the ‘early cereal-type’ pollen grains may in fact come from large-grained wild grasses, and cannot be taken as clear evidence for cultivation in the absence of other lines of evidence. Cultivation of cereals in Finland may have started as late as the start of the Iron Age in c. 500 BC.

Experiments on pollination were carried out in a border population of the terrestrial orchid Spiranthes spira/is (L.) Chevall. in the southern part of The Netherlands, one of the two remaining sites in the country. Experiments revealed that S. spiralis is a non-autogamous species. Visiting insects, mainly bumblebees, are needed for seed production, either by geitonogamy or cross-pollination. Insect-pollinated plants had 35% fruit set compared to 75'% for fiowers geitonogamously pollinated by hand. Removal of fiowers of other species surrounding clumped fiowering stalks of S. spiralis increased fruit set, indicating interspecific competition for pollinators. Fruit set was independent of the number of fiowers per infiorescence. Since the number of seeds per fruit increased with the number of fruits per infiorescence, available resources do not limit the seed production. This is probably a result of the phenology of this species. Insect pollination does not appear to be a bottle-neck in the sustainability of this border population of the rare and endangered S. spiralis. Appropriate vegetation management of the site is probably essential if the population is to persist.

Abstract-The surface of birch leaves contains glandular trichomes that secrete exudates containing flavonoid aglycones. We investigated the biological activities of white birch (Betula pubescens) leaf surface exudates against larvae of the autumnal moth, Epirrita autumnata, a common insect pest of birch. We found that tree-specific mortality (up to 100%) of first instar larvae correlated strongly with the tree-specific contents of surface flavonoid aglycones (r s = 0.905) in emerging leaves. We also found that first instars clearly preferred birch buds from which surface exudates had been removed. In addition, the duration of the first instar was shortened by 29%, and the weights and relative growth rates of first instars improved by 8% and 52%, respectively, as a result of removal of the exudates from their leaf diet. The correlation of tree-specific foliar contents of flavonoid aglycones, especially 5-hydroxy-4 ,7-dimethoxyflavanone, with changes in larval performance, suggests that flavonoid aglycones are responsible for the changes observed in first instar larval performance. The results show that chemical characteristics of birch leaves are effective against neonate E. autumnata larvae. However, the removal of leaf surface exudates from fully expanded leaves did not affect the leaf acceptance for the voracious fifth instars. This is probably a result of reduction in contents of flavonoid aglycones compared to those of emerging leaves.

A stable isotope investigation of a large Medieval population buried in Iin Hamina, northern Finland, has been used to reconstruct palaeodiet. Iin Hamina is situated approximately 30 km away from the modern city Oulu, in close proximity to the Bothnian Bay coast and the river Ii. The material used in this study is human skeletal material from an Iin Hamina cemetery dated as 15 to 17th centuries AD and animal bones excavated in Northern Ostrobothnia from pre-industrial contexts. Stable isotope analysis of well-preserved collagen indicate that both freshwater and marine fish was the dominant protein source for the people buried at the Iin Hamina cemetery.

The strontium isotope composition of human tissues is widely used in archaeological mobility studies. However, little attention is paid to the relative contributions of terrestrial versus marine sources of strontium in these studies. There is some debate over the role of a solid diet versus drinking water as the most important source of strontium for the human body, with related possibilities of misinterpretation of the archaeological record if only strontium isotope compositions of the biosphere are studied. However, there is a third component, marine strontium, which is commonly not assumed to contribute towards the strontium isotope composition of archaeological skeletal remains, especially in locations that are not directly coastal. To illustrate the potentially obfuscating effects of mixed Sr sources in a human population, we present a case study of twelve individuals from the medieval Finnish site Iin Hamina with a known dietary history. Our study shows that marine consumption is a significant factor explaining the strontium isotope composition of the Iin Hamina human remains, with implication of erroneous conclusions about immigration without prior knowledge of diet composition. Thus, future studies should always incorporate a rigorous analysis of dietary history, with special regard to potential consumption of aquatic resources, when strontium isotope analysis is used as a method in the study of palaeomobility.