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Selected AbstractsMethylone and mCPP, two new drugs of abuse?ADDICTION BIOLOGY, Issue 4 2005M. Bossong Recently, two new ecstasy-like substances, methylone and mCPP, were found in street drugs in the Netherlands by the Drugs Information and Monitoring System (DIMS). Methylone (3,4-methylenedioxymethcathinone) is the main ingredient of a new liquid designer drug that appeared on the Dutch drug market, called ,Explosion'. mCPP (meta-chlorophenylpiperazine) is a substance often used as a probe for the serotonin function in psychiatric research, and has now been found in street drugs, both in tablets and powders. Methylone as well as mCPP act on monoaminergic systems, resembling MDMA (3,4-methylenedioxymethamphetamine), with mCPP mainly affecting the serotonin system. The subjective effects of both new substances exhibit subtle differences with those of MDMA. Only little is known about the harmfulness of both methylone and mCPP. However, because of similarities between these substances and MDMA, risks common to MDMA cannot be excluded. [source] Phytogeographical evidence for post-glacial dispersal limitation of European beech forest speciesECOGRAPHY, Issue 6 2009Wolfgang Willner The post-glacial migration of European beech Fagus sylvatica has been addressed by many studies using either genetic or fossil data or a combination of both. In contrast to this, only little is known about the migration history of beech forest understorey species. In a review of phytosociological literature, we identified 110 plant species which are closely associated with beech forest. We divided the distribution range of European beech forests into 40 geographical regions, and the presence or absence of each species was recorded for each region. We compared overall species numbers per region and numbers of narrow-range species (species present in <10 regions). A multiple regression model was used to test for the explanatory value of three potential diversity controls: range in elevation, soil type diversity, and distance to the nearest potential refuge area. A hierarchical cluster analysis of the narrow-range species was performed. The frequency of range sizes shows a U-shaped distribution, with 42 species occurring in <10 regions. The highest number of beech forest species is found in the southern Alps and adjacent regions, and species numbers decrease with increasing distance from these regions. With only narrow-range species taken into consideration, secondary maxima are found in Spain, the southern Apennines, the Carpathians, and Greece. Distance to the nearest potential refuge area is the strongest predictor of beech forest species richness, while altitudinal range and soil type diversity had little or no predictive value. The clusters of narrow-range species are in good concordance with the glacial refuge areas of beech and other temperate tree species as estimated in recent studies. These findings support the hypothesis that the distribution of many beech forest species is limited by post-glacial dispersal rather than by their environmental requirements. [source] Response of collembolan communities to land-use change and grassland successionECOGRAPHY, Issue 2 2007Matthieu Chauvat This study focuses on the long-term changes of collembolan communities occurring after the conversion of arable land to managed grassland. We analysed collembolan communities at grassland sites of different age that had been gradually converted over a period of 50 yr. Abundance and biomass responded rapidly and very positively to the conversion of arable land to grassland, while species richness was not affected. Collembolan assemblages changed only little during grassland maturation. The impact of land-use change on community structure was more obvious at the functional level because the colonization processes observed in our study mostly relied on hemiedaphic species. Vegetation and soil parameters were good predictors of collembolan community structure during development of managed grassland. The present study demonstrated that past landscape patterns and processes like land-use conversion and subsequent succession had a considerable impact on the present day pattern of species richness and community composition of Collembola within a landscape. Our results strongly differ from those obtained for other invertebrate groups, highlighting on the one hand the very diverse reactions of invertebrates to a common factor, and on the other hand the need to survey more than one taxa in order to draw conclusions on effects of land-use change on faunistic communities. [source] Care provision for patients with eating disorders in Europe: what patients get what treatment where?EUROPEAN EATING DISORDERS REVIEW, Issue 3 2005Matthias Richard Abstract In this paper, we report on the similarities and differences between patients with eating disorders and the services provided to them across 80 centres participating in a European collaboration (COST Action B6). Differences in patient characteristics as well as differences in treatment regimen, especially length of treatment, are described. The relationship between patient characteristics, treatment setting and length of treatment is investigated by multilevel analysis. The findings show a rich diversity in service conditions and traditions across European countries. Patients with anorexia nervosa are mostly treated in inpatient settings, patients with bulimia nervosa are treated mostly as outpatients,with the exception of German-speaking countries. Day-patient settings were generally rare. Clinical characteristics of the patients,e.g. severity of symptoms or illness duration,contributed only little to the differences in treatment length (within as well as between centres), whereas organizational factors explained the largest proportion of between centre variability. The findings are discussed from a service research perspective. Copyright © 2005 John Wiley & Sons, Ltd and Eating Disorders Association. [source] Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008K. J. Aichberger ABSTRACT Background, Systemic mastocytosis (SM) is a mast cell neoplasm in which neoplastic cells usually display the D816V-mutated variant of KIT. Cladribine (2CdA) and dasatinib are two drugs that counteract the in vitro growth of neoplastic mast cells in SM. However, only little is known about the in vivo effects of these drugs in SM. Patient and methods, We report on a patient with highly aggressive interferon-alpha-resistant SM who was treated with 2CdA and dasatinib. In vitro pretesting revealed a response of neoplastic mast cells to both compounds with reasonable IC50 values. Results, The patient was treated with six cycles of 2CdA (0·13 mg kg,1 intravenously daily on 5 consecutive days). Despite a short-lived major clinical response and a decrease in serum tryptase, the patient progressed to mast cell leukaemia after the sixth cycle of 2CdA. The patient then received two further courses of 2CdA followed by treatment with dasatinib (100 mg per os daily). However, no major response was obtained and the patient died from disease progression after 2 months. Conclusions, In a patient with rapidly progressing aggressive SM, neither 2CdA nor dasatinib produced a long-lasting response in vivo, despite encouraging in vitro results. For such patients, alternative treatment strategies have to be developed. [source] Cold-Induced Recruitment of Brown Adipose Tissue ThermogenesisEXPERIMENTAL PHYSIOLOGY, Issue 1 2003Martin Klingenspor Non-shivering thermogenesis in brown adipose tissue is the main mechanism for thermoregulatory heat production in small mammals and newborns. During cold acclimation the sympathetic innervation triggers the recruitment of brown adipose tissue by hyperplasia, which involves the proliferation and differentiation of precursor cells, and by hypertrophy of mature brown adipocytes. Mitochondrial biogenesis and increased synthesis of the uncoupling protein 1 (UCP-1) are hallmarks of the thermogenic recruitment process. The severalfold increase of mitochondrial protein content during cold acclimation recruits a large capacity for oxidative phosphorylation. However, UCP-1 increases proton leakage across the inner membrane of brown adipocyte mitochondria and thereby dissipates proton motive force as heat instead of ATP synthesis. During recent years considerable progress has been achieved in the analysis of transcriptional mechanisms controlling Ucp1 gene expression. However, so far only little is known about the molecular basis of cold-induced mitochondrial biogenesis in brown adipose tissue. [source] Feeding rates, assimilation efficiencies and growth of two amphipod species on biodeposited material from zebra musselsFRESHWATER BIOLOGY, Issue 12 2008RENÉ GERGS Summary 1. Accumulation of organic material by the zebra mussel Dreissena polymorpha is assumed to be the source of a biodeposition-based food web. However, only little is known about the importance of the biodeposited material as a food source and its contribution to increased abundances of macroinvertebrates in the presence of D. polymorpha. 2. Feeding, assimilation and growth of the amphipods Gammarus roeselii and Dikerogammarus villosus on food sources directly and indirectly associated with D. polymorpha (biodeposited material and chironomids) and on conditioned alder leaves were measured. The stoichiometry of carbon, nitrogen and phosphorus of the diets was measured as an important determining factor of food quality. 3. Chironomids had the highest nitrogen and phosphorus contents, alder leaves were depleted in nitrogen and phosphorus, and the stoichiometry of biodeposited material was intermediate. 4. Both amphipod species had highest feeding rates and assimilation efficiencies on chironomids. Gammarus roeselii fed more on biodeposited material than on alder leaves, but assimilation efficiencies were similar; D. villosus also had similar feeding rates and assimilation efficiencies on the two diets. 5. Both amphipod species had highest growth rates on chironomids and lowest growth rates on alder leaves. Both grew at intermediate rates on biodeposited material of D. polymorpha. The growth rates of the amphipod species were related to food stoichiometry. Overall, the invasive D. villosus grew faster than the indigenous G. roeselii. 6. Food resources directly and indirectly associated with D. polymorpha are potential diets for amphipods, providing further evidence for a D. polymorpha biodeposition-based food web. [source] Modulation of astrocyte P2Y1 receptors by the carboxyl terminal domain of the gap junction protein Cx43GLIA, Issue 2 2008Eliana Scemes Abstract Gap junction proteins, connexins, provide intercellular channels that allow ions and small signaling molecules to be transmitted to adjacent coupled cells. Besides this function, it is becoming apparent that connexins also exert channel-independent effects, which are likely mediated by processes involving protein,protein interactions. Although a number of connexin interacting proteins have been identified, only little is known about the functional consequences of such interactions. We have previously shown that deletion of the astrocytic gap junction protein, connexin43 (Cx43) causes a right-ward shift in the dose-response curve to P2Y1R agonists and decreased P2Y1R expression levels. To evaluate whether these changes were due to reduced gap junctional communication or to protein,protein interactions, Cx43-null astrocytes were transfected with full-length Cx43 and Cx43 domains, and P2Y1R function and expression levels evaluated. Results indicate that restoration of P2Y1R function is independent of gap junctional communication and that the Cx43 carboxyl terminus spanning the SH3 binding domain (260,280) participates in the rescue of P2Y1R pharmacological behavior (shifting to the left the P2Y1R dose-response curve) without affecting its expression levels. These results suggest that the Cx43 carboxyl-terminus domain provides a binding site for an intracellular molecule, most likely a member of the c-Src tyrosine kinase family, which affects P2Y1R-induced calcium mobilization. It is here proposed that a nonchannel function of Cx43 is to serve as a decoy for such kinases. Such modulation of P2Y1R is expected to influence several neural cell functions, especially under inflammation and neurodegenerative disorders where expression levels of Cx43 are decreased. © 2007 Wiley-Liss, Inc. [source] A general non-linear optimization algorithm for lower bound limit analysisINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 2 2003Kristian Krabbenhoft Abstract The non-linear programming problem associated with the discrete lower bound limit analysis problem is treated by means of an algorithm where the need to linearize the yield criteria is avoided. The algorithm is an interior point method and is completely general in the sense that no particular finite element discretization or yield criterion is required. As with interior point methods for linear programming the number of iterations is affected only little by the problem size. Some practical implementation issues are discussed with reference to the special structure of the common lower bound load optimization problem, and finally the efficiency and accuracy of the method is demonstrated by means of examples of plate and slab structures obeying different non-linear yield criteria. Copyright © 2002 John Wiley & Sons, Ltd. [source] Genetic polymorphisms of chitotriosidase in Caucasian children with bronchial asthmaINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2006S. Bierbaum Summary In humans, two types of chitinases have been identified: chitotriosidase I (CHIT1) and acid mammalian chitinase (AMCase). They are enzymes that cleave chitin, a polysaccharide contained in many different human parasites. So far, only little is known about their function in human and especially in human diseases. Recently we have described association of polymorphisms of AMCase with bronchial asthma in a pediatric population. In this study we were interested in whether CHIT1 is also involved in the genetics of asthma. The amino acid variants Gly102Ser and Ala442Gly, as well as a 24 bp duplication within CHIT1, were typed by means of restriction fragment length polymorphisms on 322 children with asthma and 270 randomly chosen adult controls. Statistical analyses made use of the Armitage's trend test; haplotypes were calculated by famhap and fastehplus. The amino acid variants showed no association with bronchial asthma. The 24 bp duplication, previously shown to completely demolish CHIT1 activity, was also evenly distributed between asthmatics and controls. Finally, the haplotype showed no association with the disease. We conclude from our results that CHIT1 does not play a major role in the development of bronchial asthma in Caucasian children. The results might also imply that the two human chitinases that have been identified so far have quite distinct functions in human diseases even though they have the same substrate. [source] Soluble carbohydrates in the nutrition of house longhorn beetle larvae, Hylotrupes bajulus (L.) (Col., Cerambycidae): from living sapwood to faecesJOURNAL OF APPLIED ENTOMOLOGY, Issue 9 2002W. Höll Living sapwood contains high amounts of sucrose, glucose, fructose and starch. These carbohydrates seem to be hydrolysed and metabolized during the production of the sapwood blocks. The faeces contain carbohydrates which are not present either in living sapwood or in the sapwood blocks: xylose and an oligosaccharide of uncertain composition. This oligosaccharide is the dominant water-soluble carbohydrate in the faeces. In contrast to living sapwood and sapwood blocks, the faeces contain considerable amounts of soluble ,-glucans. The results show that the composition and the amounts of carbohydrates differ significantly from that in the sapwood blocks (fodder for the larvae). The ,-glucans (starch) present in the wood are not significantly utilized by the larvae. Regarding soluble carbohydrates, diet wood has only little in common with the living wood of the standing tree. [source] Retail oligopoly power, dairy compact, and Boston milk pricesAGRIBUSINESS : AN INTERNATIONAL JOURNAL, Issue 4 2005Benaissa Chidmi This paper assesses the impacts of the Northeast Dairy Compact (NEDC) and retail oligopoly power on fluid milk prices in Boston. Empirical results reveal that price increases due to oligopoly power outweighed those caused by the NEDC by nearly seven times. In fact, markups are estimated at approximately 25% of the retail milk price, translating into approximately a little less than $0.75/gallon. We also estimated that only around two-thirds of the raw milk price changes were passed forward to consumers. This helps explain why consumer prices have come down only little after elimination of the NEDC. In fact, the new milk income-loss contract program, which basically provides partial price subsidies to farmers, has contributed to low raw milk prices that have generated substantial benefits to milk processors and retailers, modest benefits to farmers and consumers, all at the expense of taxpayers. [JEL classification: L66, L11, L13]. © 2005 Wiley Periodicals, Inc. Agribusiness 21: 477,491, 2005. [source] Oligohis-tags: mechanisms of binding to Ni2+ -NTA surfacesJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2009Steven Knecht Abstract Since immobilized metal ion affinity chromatography (IMAC) was first reported, several modifications have been developed. Among them, Ni2+ immobilized by chelation with nitrilotriacetic acid (NTA) bound to a solid support has become the most common method for the purification of proteins carrying either a C - or N -terminal histidine (His) tag. Despite its broad application in protein purification, only little is known about the binding properties of the His-tag, and therefore almost no thermodynamic and kinetic data are available. In this study, we investigated the binding mechanism of His-tags to Ni2+ -NTA. Different series of oligohistidines and mixed oligohistidines/oligoalanines were synthesized using automated solid-phase peptide synthesis (SPPS). Binding to Ni2+ -NTA was analyzed both qualitatively and quantitatively with surface plasmon resonance (SPR) using commercially available NTA sensor chips from Biacore. The hexahistidine tag shows an apparent equilibrium dissociation constant (KD) of 14,±,1,nM and thus the highest affinity of the peptides synthesized in this study. Furthermore, we could demonstrate that two His separated by either one or four residues are the preferred binding motifs within hexahis tag. Finally, elongation of these referred motifs decreased affinity, probably due to increased entropy costs upon binding. Copyright © 2009 John Wiley & Sons, Ltd. [source] Isotopic compositions of different presolar silicon carbide size fractions from the Murchison meteoriteMETEORITICS & PLANETARY SCIENCE, Issue 5 2000Sachiko AMARI Ratios of 12C/13C range from 37 to 42 and 14N/15N ratios from 370 to 520, within the range of single-grain measurements on coarser samples and in agreement with an asymptotic giant branch (AGB) star origin of most of the grains. Variations among size fractions do not show any simple trend and can be explained by varying contamination with isotopically normal material. Silicon isotopic ratios vary only little and, with one exception, lie to the right of the singlegrain mainstream correlation line. This might indicate a higher percentage of the minor populations Y and Z among finer grain-size fractions. All bulk samples have large 26Mg excesses attributed to the presence of short-lived 26Al at the time of grain formation. Inferred 26Al/27Al ratios are much larger than those measured in single larger mainstream grains. This is probably because of the presence of SiC grains of type X; we obtain an estimate of 0.4 for their 26Al/27Al ratio. Our Ca-isotopic measurements, the first made on presolar SiC grains, show excesses in 42Ca and 43Ca, which is in general agreement with theoretical expectations for AGB stars. Calcium-44 excesses are much larger than expected and are probably because of X grains, which have high44Ca excesses because of the decay of short-lived 44Ti produced in supernova explosions. We arrive at an estimate of 0.014 for the initial 44Ti/48Ti ratio of the X grains, within the range obtained from previous single X grain measurements. The Ti-isotopic ratios of the bulk samples show a V-shaped pattern with excesses of all isotopes relative to 48Ti. Isotopes 46Ti, 47Ti, and 50Ti show excesses relative to the correlation between Ti and Si ratios for single grains and are in general agreement with theoretical models of s-process nucleosynthesis in AGB stars. In contrast, 49Ti does not show any excess relative to the singlegrain data; it also fails to agree with theory, which predicts much larger excesses than observed. Measured 53Cr/52Cr and 57Fe/56Fe ratios are normal within errors. The first result is expected even for Cr in AGB star envelopes, but the second result suggests that most of the Fe analyzed originates from contamination. We have found no simple trends in isotopic composition with respect to grain size that can be interpreted in terms of nucleosynthetic origin, unlike the results for Kr, Xe, Ba, and Sr. [source] Neurogenic mechanisms in bronchial inflammatory diseasesALLERGY, Issue 11 2004D. A. Groneberg Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi-directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene-related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD. [source] Hydrolytic enzymes as virulence factors of Candida albicansMYCOSES, Issue 6 2005Martin Schaller Summary Candida albicans is a facultative pathogenic micro-organism that has developed several virulence traits enabling invasion of host tissues and avoidance of host defence mechanisms. Virulence factors that contribute to this process are the hydrolytic enzymes. Most of them are extracellularly secreted by the fungus. The most discussed hydrolytic enzymes produced by C. albicans are secreted aspartic proteinases (Saps). The role of these Saps for C. albicans infections was carefully evaluated in numerous studies, whereas only little is known about the physiological role of the secreted phospholipases (PL) and almost nothing about the involvement of lipases (Lip) in virulence. They may play an important role in the pathogenicity of candidosis and their hydrolytic activity probably has a number of possible functions in addition to the simple role of digesting molecules for nutrition. Saps as the best-studied member of this group of hydrolytic enzymes contribute to host tissue invasion by digesting or destroying cell membranes and by degrading host surface molecules. There is also some evidence that hydrolytic enzymes are able to attack cells and molecules of the host immune system to avoid or resist antimicrobial activity. High hydrolytic activity with broad substrate specificity has been found in several Candida species, most notably in C. albicans. This activity is attributed to multigene families with at least 10 members for Saps and Lips and several members for PL B. Distinct members of these gene families are differentially regulated in various Candida infections. In future, prevention and control of Candida infections might be achieved by pharmacological or immunological tools specifically modulated to inhibit virulence factors, e.g. the family of Saps. [source] Can ant-eating Zodarion spiders (Araneae: Zodariidae) develop on a diet optimal for euryphagous arthropod predators?PHYSIOLOGICAL ENTOMOLOGY, Issue 2 2009STANO PEKÁR Abstract Little attention is paid to the behavioural and physiological adaptations of ant-eating predators. It is expected that there should be a strong selection for traits related to prey handling, leading to the evolution of morphological, behavioural and nutritional adaptations. Such adaptations may then entail trade-offs in handling and utilization of alternative prey. To investigate behavioural as well as nutritional adaptations and the occurrence of the corresponding trade-offs in two ant-eating spiders of the genus Zodarion [Zodarion atlanticum Pekár & Cardoso and Zodarion germanicum (C. L. Koch)], spiders are reared on two diets: ants (i.e. their preferred prey) and fruit flies (i.e. an alternative prey that is nutritionally optimal for euryphagous spiders). Food consumption is observed and several fitness-related life-history parameters are measured. Although spiders readily accept ants, more than one-third of 35 spiders refuse to consume fruit flies and starve. Furthermore, severe hunger does not induce these individuals to accept fruit flies. Starving spiders die before moulting to the second stadium. Spiders that eat fruit flies increase only little and slowly in weight, and all of these die during the first two stadia. By contrast, spiders on an ant diet increase dramatically in weight, and develop up to the fourth stadium. These data indicate that fruit flies are not suitable for Zodarion, supporting the hypothesis that there are behavioural and nutritional trade-offs. Taking into account the results of previous studies, it is suggested that nutritional trade-offs are generally important for stenophagous spiders. [source] Mast cells in the seminal plasma of infertile men as detected by flow cytometryANDROLOGIA, Issue 1 2009J.-P. Allam Summary Increased numbers of mast cells (MCs) in the testis have been associated with testicular dysfunction, where accumulation of MCs occurs. Furthermore, it has been reported that MCs might affect sperm function as it has been demonstrated that MC-derived tryptase in the seminal fluid might reduce sperm motility. Although MCs have been detected in rat epididymis, only little is known about the presence of MCs in human seminal plasma. Thus, we analysed MC numbers in the ejaculate of men during routine semen analysis of male patients suspected for infertility (n = 100). MCs were detected by c-kit (CD117) expression using flow cytometry. Thereby, we detected significant numbers of MCs in the ejaculate of most patients (559 ± 525 MCs ml,1, mean ± SD). However, we could neither detect a correlation with respect to MCs and sperm count, motility or morphology nor to the seminal inflammatory markers like polymorphonuclear elastase. Nevertheless, a significant correlation of MCs to spermatozoa-bound IgA (r = 0.5; P = 0.03; n = 21) was observed. It is concluded that significant numbers of MCs can be detected in the human ejaculate without necessarily influencing sperm function. A potential role of MCs in seminal plasma as well as the association between MCs and IgA on spermatozoa remains to be elucidated. [source] Reduktion der Frosthebungen bei der künstlichen BodenvereisungBAUTECHNIK, Issue 9 2009Guoqing Zhou Prof. Dr.-Ing. Geotechnik; Bodenmechanik; Geotechnical Engineering; Soil Mechanics Abstract Mit dem Ziel der Reduktion der Frosthebungen bei der künstlichen Bodenvereisung wurden die Einflüsse des Temperaturgradienten, der Temperaturänderung sowie der Temperaturänderungsamplitude und -periode der Vereisungstemperatur auf die Frosthebungen bei der eindimensionalen Frosteindringung in feinkörnige Böden experimentell im Labor untersucht. Bei der Frosteindringung in feinkörnige Böden ist die Frosthebung infolge der Bildung der untersten Eislinse (letzte Eislinse bei Frostung von oben nach unten) im thermodynamisch stationären Zustand maßgebend. Der Temperaturgradient beeinflusst zwar die Frosteindringtiefe, die Größe der Frosthebung dagegen nur in geringem Maße. Durch zyklische Veränderungen der Vereisungstemperatur kann das Wachstum der letzten Eislinse beschränkt und dadurch die Frosthebung vermindert werden. Die zyklische Veränderung der Vereisungstemperatur bereits vor der Bildung der letzten Eislinse führt dagegen zu einer großen Frosthebung. Zur Minimierung der Frosthebung müssen die Temperaturveränderungsamplitude und -periode während der Vereisung auf die Eislinsenbildung abgestimmt werden. Decreasing frost heaves of artificial frozen soils by intermission freezing. For decreasing the frost heaves of artificially frozen soils the influences of temperature gradient, its changes as well as the amplitude and period of changing freezing temperature on the one-dimensional frost heaves of fine-grained soils were investigated by experiments in the laboratory. During the frost penetration into the fine-grained soils the frost heaves due to the formation of the final ice lens under thermodynamic stationary condition is decisive. The gradient of temperature influences strongly the depth of frost penetration but only little the total frost heave. Cyclical changes of the freezing temperature can confine the growth of the final ice lens and thereby the frost heave decreases. However, the cyclical changes of the freezing temperature before the formation of the final ice lens can cause a heavy frost heave. For decreasing frost heaves the amplitude und period of changing the freezing temperature must be controlled properly. [source] Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Rob Ter Heine WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS , We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l,1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK,PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance. [source] WTO Constraints on Domestic Support in Agriculture: Past and FutureCANADIAN JOURNAL OF AGRICULTURAL ECONOMICS, Issue 1 2009Lars Brink The domestic support provisions in the WTO Agreement on Agriculture originate in the 1958 Haberler Report. Economic analysis often overlooks the agreement's legally important distinctions. Few domestic support issues lead to dispute settlement proceedings. The Doha negotiations would result in more constraints on domestic support than the sole commitment on Total Aggregate Measurement of Support (AMS) in the present agreement: ceilings on overall trade-distorting support and blue box payments, and also product-specific caps. Some 18 members would reduce their Total AMS commitments, and 25 would reduce the de minimis percentages. Most members would not reduce their constraints at all or only little. If today's developing countries continue to grow as they did in recent decades, their capacity to support agriculture increases significantly. If they then choose to support agriculture as today's developed countries did at the same stage of economic development, the future WTO constraints on trade-distorting domestic support would allow them to provide considerably more such support than developed countries. Les règles sur le soutien interne de l'Accord sur l'agriculture de l'OMC tirent son origine du rapport ,Haberler, de 1958. L'analyse économique oublie souvent les distinctions d'importance juridique de l'accord. Peu de questions en soutien interne entraînent des procédures de règlement des différends. Les négociations de Doha se solderaient par plus de contraintes sur le soutien que le seul engagement de l'accord actuel, celui sur la mesure globale de soutien (MGS) totale. Ces contraintes comprennent des plafonds sur le soutien interne global ayant des effets de distorsion des échanges et sur les paiements dans la boîte bleue, ainsi que des plafonds par produit. Environ 18 membres réduiraient leurs engagements sur la MGS totale, et 25 membres réduiraient les pourcentages de minimis. La plupart des membres ne réduiraient pas leurs engagements ou les réduiraient seulement un peu. Si la croissance économique des pays, qui aujourd'hui sont en voie de développement, continue au même taux que dans les décennies récentes, leur capacité de soutenir leur agriculture augmente. S'ils choisissaient dans l'avenir de soutenir leur agriculture, comme l'ont fait les pays qui sont aujourd'hui les pays développés lorsqu'ils se trouvaient au même stage de développement, les contraintes futures de l'OMC sur le soutien interne faussant les échanges permettraient aux pays en voie de développement d'accorder de tel soutien dans des montants considérablement plus importants que ceux des pays développés. [source] | ||||||||||||||||||||||||||||||||||