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Deep Neural Networks (DNN) are increasingly used as components of larger software systems that need to process complex data, such as images, written texts, audio/video signals. DNN predictions cannot be assumed to be always correct for several reasons, among which the huge input space that is dealt with, the ambiguity of some inputs data, as well as the intrinsic properties of learning algorithms, which can provide only statistical warranties. Hence, developers have to cope with some residual error probability. An architectural pattern commonly adopted to manage failure-prone components is the supervisor, an additional component that can estimate the reliability of the predictions made by untrusted (e.g., DNN) components and can activate an automated healing procedure when these are likely to fail, ensuring that the Deep Learning based System (DLS) does not cause damages, despite its main functionality being suspended. In this paper, we consider DLS that implement a supervisor by means of uncertainty estimation. After overviewing the main approaches to uncertainty estimation and discussing their pros and cons, we motivate the need for a specific empirical assessment method that can deal with the experimental setting in which supervisors are used, where the accuracy of the DNN matters only as long as the supervisor lets the DLS continue to operate. Then we present a large empirical study conducted to compare the alternative approaches to uncertainty estimation. We distilled a set of guidelines for developers that are useful to incorporate a supervisor based on uncertainty monitoring into a DLS., Accepted for publication at the Journal of Software: Testing, Verification and Reliability. arXiv admin note: substantial text overlap with arXiv:2102.00902

In the homotopical study of spaces of smooth embeddings, the functor calculus method (Goodwillie–Klein–Weiss manifold calculus) has opened up important connections to operad theory. Using this and a few simplifying observations, we arrive at an operadic description of the obstructions to deforming smooth immersions into smooth embeddings. We give an application which in some respects improves on recent results of Arone–Turchin and Dwyer–Hess concerning high-dimensional variants of spaces of long knots.

Patients undergoing hip or knee replacement therapy are routinely pretreated with antibiotics before they enter the operation theater. This treatment intends to reduce the incidence of peri- or postsurgical infections. Here, we calculated the uptake kinetics of levofloxacin into bone to see whether levofloxacin could be obtained from the trabecular and cortical bone and at what time concentrations are sufficiently high to inhibit the usual hospital infections. Patients (n = 42) undergoing routine surgery were treated with 500 mg levofloxacin intravenously immediately prior to the operation. Plasma samples were taken before and at 3 points after termination of drug infusion. After replacement of the bones, extracts were obtained from them. Levofloxacin was quantified using high-performance liquid chromatography. The kinetics of levofloxacin and its distribution into bone were analyzed using a population approach (ADAPT5). Clearance was 14.0 L/h, and distribution volume was 77 L. Bone uptake t½ was calculated as 4.2 and 5.4 hours for cortical bone and trabecular bone, respectively. In knee samples (but not in hip samples), we noted that the cortical bone contained higher levels of levofloxacin than the trabecular bone. From our data, we can conclude that levofloxacin might be useful for prophylactic use in bone surgery.

20 I 21 II 21 III 23 IV 29 V 33 VI 35 36 36 References 36 SUMMARY: Root endophytism and mycorrhizal associations are complex derived traits in fungi that shape plant physiology. Sebacinales (Agaricomycetes, Basidiomycota) display highly diverse interactions with plants. Although early-diverging Sebacinales lineages are root endophytes and/or have saprotrophic abilities, several more derived clades harbour obligate biotrophs forming mycorrhizal associations. Sebacinales thus display transitions from saprotrophy to endophytism and to mycorrhizal nutrition within one fungal order. This review discusses the genomic traits possibly associated with these transitions. We also show how molecular ecology revealed the hyperdiversity of Sebacinales and their evolutionary diversification into two sister families: Sebacinaceae encompasses mainly ectomycorrhizal and early-diverging saprotrophic species; the second family includes endophytes and lineages that repeatedly evolved ericoid, orchid and ectomycorrhizal abilities. We propose the name Serendipitaceae for this family and, within it, we transfer to the genus Serendipita the endophytic cultivable species Piriformospora indica and P. williamsii. Such cultivable Serendipitaceae species provide excellent models for root endophytism, especially because of available genomes, genetic tractability, and broad host plant range including important crop plants and the model plant Arabidopsis thaliana. We review insights gained with endophytic Serendipitaceae species into the molecular mechanisms of endophytism and of beneficial effects on host plants, including enhanced resistance to abiotic and pathogen stress.

BACKGROUND Single-incision laparoscopy (SIL) has been developed to reduce surgical trauma, whereas technical difficulties in bleeding control limit the broad acceptance for hepatectomy. A novel minimized invasive strategy combining inline radiofrequency pre-coagulation and transumbilical SIL is presented herein. METHODS A cohort of 21 selected patients underwent transumbilical SIL hepatectomies (segmentectomies II-VI) utilizing inline radiofrequency pre-coagulation for hepatic transection (Habib 4X). Bleeding control, postoperative complications and positive resection margins in malignant diseases served as primary and secondary outcome parameters, respectively. RESULTS Single-incision laparoscopy was successfully completed in all patients. A total of 33 segments were retrieved: mean resection time was 66 ± 35 min, including 11 anatomical (52.38%) and 10 non-anatomical (47.62%) resections. Sixteen patients (76.19%) underwent concomitant abdominal surgery. No substantial blood loss occurred. Neither additional staplers nor clips were necessary to control any bleeding or bile leakage. One pleural effusion counted for the only postoperative complication. Free margins could be achieved in all but one resection (12/13 patients with malignancies; 92.31%). Ninety-day mortality was zero. CONCLUSIONS The combination of SIL and inline radiofrequency pre-coagulation proved to be a simple, efficacious and safe technique in minor hepatectomy.

Heterozygous disruptions of the Forkhead transcription factor FoxP2 impair acquisition of speech and language. Experimental downregulation in brain region Area X of the avian ortholog FoxP2 disrupts song learning in juvenile male zebra finches. In vitro, transcriptional activity of FoxP2 requires dimerization with itself or with paralogs FoxP1 and FoxP4. Whether this is the case in vivo is unknown. To provide the means for future functional studies we cloned FoxP4 from zebra finches and compared regional and cellular coexpression of FoxP1, FoxP2, and FoxP4 mRNA and protein in brains of juvenile and adult male zebra finches. In the telencephalic song nuclei HVC, RA, and Area X, the three investigated FoxPs were either expressed alone or occurred in specific combinations with each other, as shown by double in situ hybridization and triple immunohistochemistry. FoxP1 and FoxP4 but not FoxP2 were expressed in RA and in the HVCRA and HVCX projection neurons. In Area X and the surrounding striatum the density of neurons expressing all three FoxPs together or FoxP1 and FoxP4 together was significantly higher than the density of neurons expressing other combinations. Interestingly, the proportions of Area X neurons expressing particular combinations of FoxPs remained constant at all ages. In addition, FoxP-expressing neurons in adult Area X express dopamine receptors 1A, 1B, and 2. Together, these data provide the first evidence that Area X neurons can coexpress all avian FoxP subfamily members, thus allowing for a variety of regulatory possibilities via heterodimerization that could impact song behavior in zebra finches.

The EU legislature has used the last two and a half years to negotiate a modernised framework for cross-border insolvencies largely outside the spotlight of public debate. The revised Insolvency Regulation introduces new rules on secondary proceedings and innovative provisions on insolvency proceedings for groups of companies. Some parts of the final reform package were not originally envisaged by the European Commission, and it was the European Parliament and the Council that, in an unusual display of unity, agreed on more ambitious steps than the EU executive had proposed. However, not all that glitters is gold. The legislature missed the opportunity to clarify the concept of Centre of Main Interest, and it is still for the courts to establish international jurisdiction on the basis of rather vague criteria. It will soon be time to give life to the rules and ensure that cross-border insolvencies are conducted more effectively than they are today. The new rules entered into force on 25 June 2015 and apply from 26 June 2017. Copyright © 2015 INSOL International and John Wiley & Sons, Ltd

Objectives: Up to now, vascular indicator-dilution curves have been analyzed by numerical integration or by fitting empirical functions to the data. Here, we apply a recently developed mechanistic model with the goal to quantitatively describe flow distribution in the sinusoidal network of normal rat livers and those with high-fat emulsion-induced NASH. Methods: Single-pass outflow concentration data of sucrose were obtained from in situ perfused rat livers after impulse injection. The model fitted to the data consists of a continuous mixture of inverse Gaussian densities assuming a normal distribution of regional flow. It accounts for the fractal flow heterogeneity in the organ and has three adjustable parameters with a clear physiological interpretation. Results: The model fitted the data well and revealed that the intrahepatic flow dispersion of 49.6 % in the control group increased significantly to 87.2 % in the NASH group (p

Male songbirds often maintain territories throughout the breeding season, and one of the main functions of song is to deter invaders. Therefore, the distance of an unknown singing rival should play a crucial role within territorial singing interactions of males. This distance is expected to be assessed as more threatening the closer the rival approaches. Here, we tested this assumption by conducting nocturnal playbacks from two different distances in territorial Common nightingales (Luscinia megarhynchos). Immediate vocal responses of birds were examined by analysing changes in song structure as well as temporal response features. The next morning, follow-up playbacks from an intermediate distance allowed us to investigate longer-lasting effects of nocturnal playbacks. We found that the distance of a simulated rival had an effect on both immediate and later vocal responses of territorial male nightingales with different song parameters being affected during nocturnal and diurnal singing. This indicates that birds perceive intruder distances and adjust their response behaviour both immediately and in later interactions.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cisatracurium is a non-depolarizing neuromuscular blocking drug used in anaesthesia and intensive care. • Cisatracurium degrades at physiological pH via Hofmann elimination. Therefore, the elimination of cisatracurium may be from both plasma and tissues. • Critically ill patients may have or develop resistance to non-depolarizing neuromuscular blocking drugs. • Pathophysiological changes in critically ill patients with sepsis can cause changes in both pharmacokinetics (PK) and pharmacodynamics (PD). WHAT THIS STUDY ADDS • This is the first study to characterize PK and PD of cisatracurium in intensive care patients with severe sepsis following a single bolus dose. • This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. • The resistance to cisatracurium in these patients is more attributed to altered PD as pharmacokinetic parameters were similar to those described in other patient populations. AIM To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis. METHODS Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg−1. Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis. RESULTS Steady-state volume of distribution was determined to be 111 ± 71 ml kg−1 and plasma clearance was 5.2 ± 1.8 ml min−1 kg−1 in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml−1) was larger than previously described. CONCLUSIONS This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.

An increase in the area under the curve (AUC) after oral digoxin due to coadministration of drugs known as P-glycoprotein (P-gp) inhibitors has been reported in several studies, but there is very little information on the rate of absorption after P-gp inhibition. Based on an inverse Gaussian density absorption model and using a population approach, the authors reanalyzed data showing an increase in oral digoxin AUC in healthy volunteers after coadministration of talinolol. The model fitted the data well, and the results revealed that the maximum rate of digoxin absorption increased nearly 2-fold, whereas bioavailability increased only by 21%. It is concluded that the increase in the rate of absorption seems to be a better indicator of intestinal P-gp inhibition than the increase in extent of absorption. Furthermore, the authors use a simulation study to demonstrate the ability of the method to estimate bioavailability based on the population characteristics of digoxin disposition kinetics obtained from a different group of healthy volunteers.

Piriformospora indica is a basidiomycete of the order Sebacinales, representing a model for the study of mutualistic symbiosis and, beyond that, the plant immune system. The fungus colonizes the roots of a wide range of vascular plants, increasing their growth, seed yield and adaptation to abiotic and biotic stresses. The fungal colonization of roots begins with a biotrophic growth phase, in which living cells are colonized, and continues with a cell death-dependent phase, in which root cells are actively killed by the fungus. The complexity of sebacinalean symbiosis is further enhanced by the presence of endocellular bacteria which may represent significant determinants for a successful outcome of the symbioses. Molecular ecological analyses have revealed an exceptional relevance of sebacinoid fungi in natural ecosystems worldwide. This natural competence could be rooted in their phenotypic adaptability, which, for instance, allows P. indica to grow readily on various synthetic media and to colonize distinct hosts. In molecular and genetic studies, P. indica's mutualistic colonization strategy has been partly unravelled, showing that the jasmonate pathway is exploited for immune suppression and successful development in roots. Research on P. indica supports efforts to make the bioprotective potential of the fungus accessible for agricultural plant production. The decoding of P. indica's genome has revealed its potential for application as bioagent and for targeted improvement of crop plants in biotechnology-based approaches.

BACKGROUND AND PURPOSE It is well established that cytochrome P450 2J (CYP2J) enzymes are expressed preferentially in the heart, and that ebastine is a substrate for CYP2J, but it is not known whether ebastine is metabolized in myocardium. Therefore, we investigated its pharmacokinetics in the rat isolated perfused heart. EXPERIMENTAL APPROACH Rat isolated hearts were perfused in the recirculating mode with ebastine for 130 min. The concentrations of ebastine and its metabolites, hydroxyebastine and carebastine, were measured using liquid chromatography with a tandem mass spectrometry. The data were analysed by a compartmental model. The time course of negative inotropic response was linked to ebastine concentration to determine the concentration–effect relationship. KEY RESULTS Ebastine was metabolized to an intermediate compound, hydroxyebastine, which was subsequently further metabolized to carebastine. No desalkylebastine was found. The kinetics of the sequential metabolism of ebastine was well described by the compartmental model. The EC50 of the negative inotropic effect of ebastine in rat isolated heart was much higher than free plasma concentrations in humans after clinical doses. CONCLUSIONS AND IMPLICATIONS The kinetics of ebastine conversion to carebastine via hydroxyebastine resembled that observed in human liver microsomes. The results may be of interest for functional characterization of CYP2J activity in rat heart.

Afferent proprioceptive information from the knee joint may be altered due to a reconstruction of the anterior cruciate ligament (ACL), which could result in changes of cortical activity. The aim of the study is to look if force sensation and cortical activation measured by EEG are influenced by an ACL-reconstruction when performing a force reproduction task. Nine patients after ACL reconstruction and nine healthy controls were asked to reproduce 50% of their maximal voluntary isometric contraction (MVIC) reproduction. EEG power values related to frequency bands and the error in reproduction were collected while performing the force reproduction. The aberration error demonstrated no significant differences between groups. The cortical activity results in significant higher frontal Theta power during the force reproduction task with the reconstructed limb (F3 and Fz: p

1. The present study sought to explain the mechanism leading to reduced availability of propranolol when given after a priming dose in the single-pass perfused rat liver. 2. Extracellular sucrose space (as a measure of sinusoidal relaxation) in perfused rat liver before and after propranolol or propranolol and N(G)-nitro-L-arginine methyl ester (L-NAME; nitric oxide (NO) synthase inhibitor) treatment were examined. The results showed that propranolol induces sinusoidal relaxation in the perfused liver and this effect could be abolished by NO synthase inhibitor L-NAME. 3. Two bolus injections of propranolol were given to the isolated perfused rat liver and outflow concentration-time profiles of intact propranolol were determined. A two-phase physiologically based organ pharmacokinetic model was applied to estimate hepatocellular influx, efflux, binding, ion-trapping and metabolic elimination pharmacokinetic parameters for propranolol. The recovery of propranolol in the second injection was approximately 54% of that in the first injection. The permeability-surface area product, the binding and the intrinsic clearance all increased significantly after prior exposure of the rat liver to the first bolus of propranolol (P < 0.05). 4. Based on the findings of the present study, we propose that the most likely explanation for the reduced availability of a second propranolol dose (after administration of a priming dose) in the perfused liver is a consequence of the NO-mediated sinusoidal relaxation effect of propranolol, arising from the priming dose. This observation supports the view that the pharmacokinetics of some drugs might be altered by the pharmacodynamic effects of the same drug given earlier in the perfused liver.

Mashups combine data and services provided by third parties through open APIs (such as Google Maps and Flickr), as well as internal data sources owned by users. The creation of mashups is supported by a complex ecosystem of interconnected data providers, mashup platforms, and users. In this paper, we examine the structure of the mashup ecosystem and its growth over time. Several observations follow from our analysis. First, we can conclude that while the number of new APIs and mashups over time follows a linear growth pattern, the distribution of mashups over APIs is not uniform but follows a power law. This implies that a small number of APIs provides the basis for the majority of mashups, and the other APIs are only used in certain application niches. Second, our analysis suggests that mashup platforms were introduced in response to the increasing complexity of mashups, as mashups evolved from one-feature mashups (widgets). Third, we observe that complementary relationships between open APIs are formed based on the position of the APIs in the ecosystem. The propensity of two APIs to be used together in the same mashup depends on the existing number of mashups to which they both contribute. The growth of the mashup ecosystem follows a pattern where keystone data providers or ‘powerful hubs’ attract niche data providers as complementors, and the positions of keystones in the ecosystem are mutually reinforcing.

Background and purpose: In order to use the transient response to an antagonist (prazosin) to evaluate properties of agonist interactions with the α1-adrenoceptor system, an integrative mechanistic model of cardiac uptake of prazosin and its competitive interaction with phenylephrine at the receptor site was developed. Based on the operational model of agonism, the aim was to evaluate both the receptor binding and signal transduction process as determinants of the inotropic effect of phenylephrine. Experimental approach: In Langendorff-perfused rat hearts, prazosin outflow concentration and left ventricular developed pressure were measured, first in the presence of 12.3 µmol·L−1 phenylephrine following a 1 min infusion of 1.27 nmol [3H]-prazosin, and second, when after 30 min the phenylephrine concentration in perfusate was reduced to 6.1 µmol·L−1, the 1 min infusion of 1.27 nmol [3H]-prazosin was repeated. Key results: The kinetic model accounted for cardiac uptake and receptor binding kinetics of prazosin (dissociation constant, mean ± SD: 0.057 ± 0.012 nmol·L−1), assuming that the competitive displacement of phenylephrine (dissociation constant: 101 ± 13 nmol·L−1) reduced the receptor occupation by the agonist and, consequently, contractility. This competitive binding process appeared to be the rate-determining step in response generation. The relationship between receptor occupancy and inotropic response was described by an efficacy parameter (τ, ratio of receptor density and coupling efficiency) of 4.9. Conclusions and implications: Mechanistic pharmacodynamic modelling of the kinetics of antagonism by prazosin allows quantitative assessment of the α1-adrenoceptor system both at the receptor and post-receptor levels.

Formation of ectomycorrhizas, a symbiosis with fine roots of woody plants, is one way for soil fungi to overcome carbohydrate limitation in forest ecosystems. Fifteen potential hexose transporter proteins, of which 10 group within three clusters, are encoded in the genome of the ectomycorrhizal model fungus Laccaria bicolor. For 14 of them, transcripts were detectable. When grown in liquid culture, carbon starvation resulted in at least twofold higher transcript abundances for seven genes. Temporarily elevated transcript abundance after sugar addition was observed for three genes. Compared with the extraradical mycelium, ectomycorrhiza formation resulted in a strongly enhanced expression of six genes, of which four revealed their highest observed transcript abundances in symbiosis. A function as hexose importer was proven for three of them. Only three genes, of which just one was expressed at a considerable level, revealed a reduced transcript content in mycorrhizas. From gene expression patterns and import kinetics, the L. bicolor hexose transporters could be divided into two groups: those responsible for uptake of carbohydrates by soil-growing hyphae, for improved carbon nutrition, and to reduce nutrient uptake competition by other soil microorganisms; and those responsible for efficient hexose uptake at the plant-fungus interface.

Because conventional absorption models often fail to describe plasma concentration-time profiles following oral administration, empirical input functions such as the inverse Gaussian function have been successfully used. The purpose of this note is to extend this model by adding a first-order absorption process and to demonstrate the application of population analysis using maximum likelihood estimation via the EM algorithm (implemented in ADAPT 5). In one example, the analysis of bioavailability data of an extended-release formulation, as well as the mean dissolution times estimated in vivo and in vitro with the use of the inverse Gaussian function, is well in accordance, suggesting that the inverse Gaussian function indeed accounts for the in vivo dissolution process. In the other example, the kinetics of trapidil in patients with liver disease, the absorption/dissolution parameters are characterized by a high interindividual variability. Adding a first-order absorption process to the inverse Gaussian function improved the fit in both cases.

After reconstruction of the anterior cruciate ligament (ACL) afferent proprioceptive information from the knee joint may be altered. In order to examine changes in central activation patterns, spectral features of the electroencephalography (EEG) were measured. Patients after ACL reconstruction and healthy controls carried out an knee-angle reproduction task in a groups x limbs x trials design. Cortical activity was recorded using international standards. FFT were conducted to determine power at Theta, Alpha-1, Alpha-2 and Beta-1. Statistics show significantly larger aberrations in the reconstructed limbs compared with the controls whereas there are no differences between the uninvolved land controls. Brain activity demonstrates significantly higher frontal Theta-power (F3, F4, F8) in both limbs of the ACL group vs the controls and a significantly higher Alpha-2 power was shown in the ACL-reconstructed limb compared with controls at parietal positions (P3, P4). No such differences were found between the uninvolved side and the controls. The EEG was able to measure a change in joint position sense at the cortical level after the reconstruction of the ACL. The results of these findings might indicate differences in focused attention with involvement of the anterior cingulate cortex (frontal Theta) and sensory processing in the parietal somatosensory cortex (Alpha-2).

Cavendishia nobilis var. capitata is an endemic member of the Ericaceae growing as a hemiepiphyte in the tropical mountain rain forest of southern Ecuador. Mycorrhizas were collected from 20 individuals along an altitudinal gradient between 1850 and 2300 m. Transmission electron microscopy was used to study the symbiotic association in detail, and phylogenetic analyses based on nuclear rDNA coding for the ribosomal large subunit (nucLSU) were carried out to identify the associated mycorrhizal fungi. Microscopic and ultrastructural investigations showed the formation of a hyphal sheath, intercellular penetration of fine hyphae and colonization of the cortical cells by swollen hyphae of the same fungus. These structures were formed by hymenomycetes and ascomycetes. Molecular phylogenetic analysis detected seven groups of mycorrhizal fungi belonging to the Sebacinales. This is the first study to obtain evidence of ectendomycorrhizas in the Vaccinioideae. The ascomycetous nucLSU sequences belonged to members of the Leotiomycetes. The ectendomycorrhiza of C. nobilis with Sebacinales is discussed as a specific, hitherto undescribed mycorrhizal subcategory of ectomycorrhizas. We propose the term 'cavendishioid mycorrhiza'. This subcategory is most likely specific for the Andean clade of Ericaceae.

Summary • One way to elucidate whether ammonium could act as a nitrogen (N) source delivered by the fungus in ectomycorrhizal symbiosis is to investigate plant ammonium importers. • Expression analysis of a high-affinity ammonium importer from Populus tremula× tremuloides (PttAMT1.2) and of known members of the AMT1 gene family from Populus trichocarpa was performed. In addition, PttAMT1.2 function was studied in detail by heterologous expression in yeast. • PttAMT1.2 expression proved to be root-specific, affected by N nutrition, and strongly increased in a N-independent manner upon ectomycorrhiza formation. The corresponding protein had a KM value for ammonium of c. 52 µm. From the seven members of the AMT1 gene family, one gene was exclusively expressed in roots while four genes were detectable in all poplar organs but with varying degrees of expression. Ectomycorrhiza formation resulted in a strong upregulation of three of these genes. • Our results indicate an increased ammonium uptake capacity of mycorrhized poplar roots and suggest, together with the expression of putative ammonium exporter genes in the ectomycorrhizal fungus Amanita muscaria, that ammonium could be a major N source delivered from the fungus towards the plant in symbiosis.

Lady’s slipper orchids ( Cypripedium spp.) are rare terrestrial plants that grow throughout the temperate Northern Hemisphere. Like all orchids, they require mycorrhizal fungi for germination and seedling nutrition. The nutritional relationships of adult Cypripedium mycorrhizae are unclear; however, Cypripedium distribution may be limited by mycorrhizal specificity, whether this specificity occurs only during the seedling stage or carries on into adulthood. We attempted to identify the primary mycorrhizal symbionts for 100 Cypripedium plants, and successfully did so with two Cypripedium calceolus , 10 Cypripedium californicum , six Cypripedium candidum , 16 Cypripedium fasciculatum , two Cypripedium guttatum , 12 Cypripedium montanum , and 11 Cypripedium parviflorum plants from a total of 44 populations in Europe and North America, yielding fungal nuclear large subunit and mitochondrial large subunit sequence and RFLP (restriction fragment length polymorphism) data for 59 plants. Because orchid mycorrhizal fungi are typically observed without fruiting structures, we assessed fungal identity through direct PCR (polymerase chain reaction) amplification of fungal genes from mycorrhizally colonized root tissue. Phylogenetic analysis revealed that the great majority of Cypripedium mycorrhizal fungi are members of narrow clades within the fungal family Tulasnellaceae. Rarely occurring root endophytes include members of the Sebacinaceae, Ceratobasidiaceae, and the ascomycetous genus, Phialophora . C. californicum was the only orchid species with apparently low specificity, as it associated with tulasnelloid, ceratobasidioid, and sebacinoid fungi in roughly equal proportion. Our results add support to the growing literature showing that high specificity is not limited to nonphotosynthetic plants, but also occurs in photosynthetic ones.

Neuroaktive Steroide vermitteln ihre Wirkungen hauptsachlich durch die Interaktion mit GABAA-Rezeptoren. Sie beeinflussen dadurch eine Reihe zentralnervoser Prozesse, die Auswirkungen auf unser Denken und Empfinden haben. Gleichzeitig stellen sie eine vielversprechende Arzneimittelgruppe fur wichtige Indikationen wie Epilepsie, Angststorungen und Dementien dar. Daruberhinaus beeinflussen sie das Sozial- und Sexualverhalten. Die Grundlagen fur diese vielfaltigen Wirkungen und die neuesten Erkenntnisse uber deren therapeutischen Einsatz werden zusammenfassend vorgestellt.

1 The binding kinetics of diclofenac to hepatocellular structures were evaluated in the perfused rat liver using the multiple indicator dilution technique and a stochastic model of organ transit time density. 2 The single-pass, in situ rat liver preparation was perfused with buffer solution (containing 2% albumin) at 30 ml min(-1) Diclofenac and [C-14]-sucrose (extracellular reference) were injected simultaneously as a bolus dose into the portal vein (six experiments in three rats). An analogous series of experiments was performed with [C-14]-diclofenac and [H-3]-sucrose. 3 The diclofenac outflow data were analysed using three models of intracellular distribution kinetics, assuming (1) instantaneous distribution and binding (well-mixed model), (2) 'slow' binding at specific intracellular sites after instantaneous distribution throughout the cytosol (slow binding model), and (3) 'slowing' of cytoplasmic diffusion due to instantaneous binding (slow diffusion model). 4 The slow binding model provided the best description of the data. The rate constants for cellular influx and sequestration were 0.126+/-0.026 and 0.013+/-0.009 s(-1), respectively. The estimated ratio of cellular initial distribution volume to extracellular volume of 2.82 indicates an almost instantaneous distribution in the cellular water space, while the corresponding ratio of 5.54 estimated for the apparent tissue distribution volume suggests a relatively high hepatocellular binding. The non-instantaneous intracellular equilibration process was characterized by time constants of the binding and unbinding process of 53.8 and 49.5 s, respectively. The single-pass availability of diclofenac was 86%. The results obtained with [C-14]-diclofenac and [H-3]-sucrose were not statistically different.

1. The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-situ rat liver preparation. 2. The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3. Pregenerated SA ([14C]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4. The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5. The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6. The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUC', MTT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7. The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. Methods A bolus of injectate containing [Cr-51] labelled red blood cells, [C-14]-sucrose and [H-3]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [Cr-51] or beta [C-14 and H-3] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). Results The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. Conclusions The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

SIMD computer systems offer tremendous potential speed-ups but aggressive compilation strategies are required to realize this potential. The paper presents the Compass SIMD compiler technology developed while working on a number of SIMD compilers. Although the various targets have much in common, our increased understanding of the SIMD compilation process on each successive project and the differences in the targets themselves has affected the shape of each compiler.

Giant cell (temporal, cranial) arteritis (GCA) is usually confirmed in patients presenting with classic features. Those who present with atypical features often undergo prolonged evaluations until a diagnosis is established. Severe anemia as an initial manifestation of GCA has rarely been described. We describe herein 2 patients with biopsy-proven GCA who presented with severe anemia and significant weight loss, which corrected after corticosteroid therapy.

(i) Synopsis. The discovery, around 1960, of the 'Kervaire Invariant' for almost framed manifolds of dimension 4k+ 2 (see [12]) was an important stimulant for the development of surgery theory; but it also led to the theory of the 'generalized Kervaire Invariant' of Browder and Brown [2, 3]. The present paper is an attempt at uniting these two theories, by constructing a non-simply-connected and in other respects updated version of the generalized Kervaire Invariant. The construction has three surprising aspects. Firstly, it is conceptually satisfying and, in the simply-connected case, clarifies Brown's original theory; for instance, the 'product formula problem' (see [4]) evaporates. Most of the new concepts are borrowed from the 'algebraic theory of surgery'; see [15]. Secondly, it is computationally satisfying. Thirdly, it has applications to classical surgery theory, especially to the calculation of the symmetric L-groups of [13] and [15]; and therefore to anything which involves product formulae for surgery obstructions. A black box description of the theory has been given in [22]; in this introduction I shall concentrate on the concepts inside the box.