Showing papers by "Radboud University Nijmegen published in 2002"

Voriconazole versus Amphotericin B for Primary Therapy of Invasive Aspergillosis

Abstract: Background Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. Methods In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. Results A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematop...

Corporate social responsibility in europe and the u.s.: insights from businesses self-presentations

Abstract: The paper compares the extent and content of businesses’ communications about corporate social responsibility (CSR) in France, the Netherlands, the U.K., and the U.S. In particular, the study investigates the nature of CSR principles, processes, and stakeholder issues discussed in web pages. The results show that businesses in the four countries do not display the same eagerness to appear as socially responsible and employ diverse means to convey social responsibility images.

The architecture of the bilingual word recognition system: From identification to decision

Abstract: The paper opens with an evaluation of the BIA model of bilingual word recognition in the light of recent empirical evidence. After pointing out problems and omissions, a new model, called the BIA+, is proposed. Structurally, this new model extends the old one by adding phonological and semantic lexical representations to the available orthographic ones, and assigns a different role to the so-called language nodes. Furthermore, it makes a distinction between the effects of non-linguistic context (such as instruction and stimulus list composition) and linguistic context (such as the semantic and syntactic effects of sentence context), based on a distinction between the word identification system itself and a task/decision system that regulates control. At the end of the paper, the generalizability of the BIA+ model to different tasks and modalities is discussed.

Biochemical diagnosis of pheochromocytoma: which test is best?

Abstract: ContextDiagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined.ObjectiveTo determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma.Design, Setting, and ParticipantsMulticenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor.Main Outcome MeasuresTest sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid.ResultsSensitivities of plasma free metanephrines (99% [95% confidence interval {CI}, 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines.ConclusionPlasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

Cortical Focus Drives Widespread Corticothalamic Networks during Spontaneous Absence Seizures in Rats

Abstract: Absence seizures are the most pure form of generalized epilepsy. They are characterized in the electroencephalogram by widespread bilaterally synchronous spike-wave discharges (SWDs), which are the reflections of highly synchronized oscillations in thalamocortical networks. To reveal network mechanisms responsible for the initiation and generalization of the discharges, we studied the interrelationships between multisite cortical and thalamic field potentials recorded during spontaneous SWDs in the freely moving WAG/Rij rat, a genetic model of absence epilepsy. Nonlinear association analysis revealed a consistent cortical "focus" within the peri-oral region of the somatosensory cortex. The SWDs recorded at other cortical sites consistently lagged this focal site, with time delays that increased with electrode distance (corresponding to a mean propagation velocity of 1.4 m/sec). Intra-thalamic relationships were more complex and could not account for the observed cortical propagation pattern. Cortical and thalamic sites interacted bi-directionally, whereas the direction of this coupling could vary throughout one seizure. However, during the first 500 msec, the cortical focus was consistently found to lead the thalamus. These findings argue against the existence of one common subcortical pacemaker for the generation of generalized spike-wave discharges characteristic for absence seizures in the rat. Instead, the results suggest that a cortical focus is the dominant factor in initiating the paroxysmal oscillation within the corticothalamic loops, and that the large-scale synchronization is mediated by ways of an extremely fast intracortical spread of seizure activity. Analogous mechanisms may underlie the pathophysiology of human absence epilepsy.

Hostile attribution of intent and aggressive behavior: a meta-analysis.

Abstract: A meta-analytic review was conducted to explain divergent findings on the relation between children's aggressive behavior and hostile attribution of intent to peers. Forty-one studies with 6,017 participants were included in the analysis. Ten studies concerned representative samples from the general population, 24 studies compared nonaggressive to extremely aggressive nonreferred samples, and 7 studies compared nonreferred samples with children referred for aggressive behavior problems. A robust significant association between hostile attribution of intent and aggressive behavior was found. Effect sizes differed considerably between studies. Larger effects were associated with more severe aggressive behavior, rejection by peers as one of the selection criteria, inclusion of 8- to-12-year-old participants, and absence of control for intelligence. Video and picture presentation of stimuli were associated with smaller effect sizes than was audio presentation. Staging of actual social interactions was associated with the largest effects. The importance of understanding moderators of effect size for theory development is stressed.

Melanopsin (Opn4) Requirement for Normal Light-Induced Circadian Phase Shifting

Abstract: The master circadian oscillator in the hypothalamic suprachiasmatic nucleus is entrained to the day/night cycle by retinal photoreceptors. Melanopsin (Opn4), an opsin-based photopigment, is a primary candidate for photoreceptor-mediated entrainment. To investigate the functional role of melanopsin in light resetting of the oscillator, we generated melanopsin-null mice (Opn4-/-). These mice entrain to a light/dark cycle and do not exhibit any overt defect in circadian activity rhythms under constant darkness. However, they display severely attenuated phase resetting in response to brief pulses of monochromatic light, highlighting the critical role of melanopsin in circadian photoentrainment in mammals.

Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner

Abstract: Bone is a complex highly structured mechanically active 3D tissue composed of cellular and matrix elements. The true biological environment of a bone cell is thus derived from a dynamic interaction between responsively active cells experiencing mechanical forces and a continuously changing 3D matrix architecture. To investigate this phenomenon in vitro, marrow stromal osteoblasts were cultured on 3D scaffolds under flow perfusion with different rates of flow for an extended period to permit osteoblast differentiation and significant matrix production and mineralization. With all flow conditions, mineralized matrix production was dramatically increased over statically cultured constructs with the total calcium content of the cultured scaffolds increasing with increasing flow rate. Flow perfusion induced de novo tissue modeling with the formation of pore-like structures in the scaffolds and enhanced the distribution of cells and matrix throughout the scaffolds. These results represent reporting of the long-term effects of fluid flow on primary differentiating osteoblasts and indicate that fluid flow has far-reaching effects on osteoblast differentiation and phenotypic expression in vitro. Flow perfusion culture permits the generation and study of a 3D, actively modeled, mineralized matrix and can therefore be a valuable tool for both bone biology and tissue engineering.

Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry

Abstract: The annotated genomes of organisms define a 'blueprint' of their possible gene products. Post-genome analyses attempt to confirm and modify the annotation and impose a sense of the spatial, temporal and developmental usage of genetic information by the organism. Here we describe a large-scale, high-accuracy (average deviation less than 0.02 Da at 1,000 Da) mass spectrometric proteome analysis of selected stages of the human malaria parasite Plasmodium falciparum. The analysis revealed 1,289 proteins of which 714 proteins were identified in asexual blood stages, 931 in gametocytes and 645 in gametes. The last two groups provide insights into the biology of the sexual stages of the parasite, and include conserved, stage-specific, secreted and membrane-associated proteins. A subset of these proteins contain domains that indicate a role in cell-cell interactions, and therefore can be evaluated as potential components of a malaria vaccine formulation. We also report a set of peptides with significant matches in the parasite genome but not in the protein set predicted by computational methods.

Extreme right-wing voting in Western Europe

Abstract: In this study we explain extreme right-wing voting behaviour in the countries of the European Union and Norway from a micro and macro perspective. Using a multidisciplinary multilevel approach, we take into account individual-level social background characteristics and public opinion alongside country characteristics and characteristics of extreme right-wing parties themselves. By making use of large-scale survey data (N = 49,801) together with country-level statistics and expert survey data, we are able to explain extreme right-wing voting behaviour from this multilevel perspective. Our results show that cross-national differences in support of extreme right-wing parties are particularly due to differences in public opinion on immigration and democracy, the number of non-Western residents in a country and, above all, to party characteristics of the extreme right-wing parties themselves.

Extreme right-wing voting in Western Europe

Abstract: In this study we explain extreme right-wing voting behaviour in the countries of the European Union and Norway from a micro and macro perspective. Using a multidisci- plinary multilevel approach, we take into account individual-level social background char- acteristics and public opinion alongside country characteristics and characteristics of extreme right-wing parties themselves. By making use of large-scale survey data (N = 49,801) together with country-level statistics and expert survey data, we are able to explain extreme right-wing voting behaviour from this multilevel perspective. Our results show that cross- national differences in support of extreme right-wing parties are particularly due to dif- ferences in public opinion on immigration and democracy, the number of non-Western residents in a country and, above all, to party characteristics of the extreme right-wing parties themselves.

Foreign language knowledge can influence native language performance in exclusively native contexts

Abstract: In three experiments, we studied the influence of foreign language knowledge on native language performance in an exclusively native language context. Trilinguals with Dutch as their native and dominant language (L1), English as their second language (L2), and French as their third language (L3) performed a word association task (Experiment 1) or a lexical decision task (Experiments 2 and 3) in L1. The L1 stimulus words were cognates with their translations in English, cognates with their translations in French, or were noncognates. In Experiments 1 and 2 with trilinguals who were highly proficient in English and relatively low in proficiency in French, we observed shorter word association and lexical decision times to the L1 words that were cognates with English than to the noncognates. In these relatively low-proficiency French speakers, response times (RTs) for the L1 words that were cognates with French did not differ from those for the noncognates. In Experiment 3, we tested Dutch-English- French trilinguals with a higher level of fluency in French (i.e., equally fluent in English and in French). We now observed faster responses on the L1 words that were cognates with French than on the noncognates. Lexical decision times to the cognates with English were also shorter than those to the noncognates. The results indicate that words presented in the dominant language, to naive participants, activate information in the nontarget, and weaker, language in parallel, implying that the multilinguals’ processing system is profoundly nonselective with respect to language. A minimal level of nontarget language fluency seems to be required, however, before any weaker language effects become noticeable in L1 processing.

A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors.

Abstract: Purpose: α-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients. Experimental Design: Patients with solid tumors received i.v. KRN7000 (50–4800 μg/m 2 ) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients. Results: Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50–4800 μg/m 2 ). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Vα24+Vβ11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor α and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls ( P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days. Conclusion: i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.

Equilibrium lithium transport between nanocrystalline phases in intercalated TiO2 anatase

Abstract: Microcrystalline TiO2 with an anatase crystal structure is used as an anode material for lithium rechargeable batteries1,2, and also as a material for electrochromic3,4,5,6 and solar-cell devices7,8. When intercalated with lithium, as required for battery applications, TiO2 anatase undergoes spontaneous phase separation into lithium-poor (Li0.01TiO2) and lithium-rich (Li0.6TiO2) domains on a scale of several tens of nanometres9. During discharge, batteries need to maintain a constant electrical potential between their electrodes over a range of lithium concentrations. The two-phase equilibrium system in the electrodes provides such a plateau in potential, as only the relative phase fractions vary on charging (or discharging) of the lithium. Just as the equilibrium between a liquid and a vapour is maintained by a continuous exchange of particles between the two phases, a similar exchange is required to maintain equilibrium in the solid state. But the time and length scales over which this exchange takes place are unclear. Here we report the direct observation by solid-state nuclear magnetic resonance of the continuous lithium-ion exchange between the intermixed crystallographic phases of lithium-intercalated TiO2. We find that, at room temperature, the continuous flux of lithium ions across the phase boundaries is as high as 1.2 × 1020 s-1 m-2.

Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus

Abstract: It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent functional impairment in its regulation, which may subserve a specific role for coping with challenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases.

Linearly concatenated cyclobutane lipids form a dense bacterial membrane

Abstract: Lipid membranes are essential to the functioning of cells, enabling the existence of concentration gradients of ions and metabolites. Microbial membrane lipids can contain three-, five-, six- and even seven-membered aliphatic rings, but four-membered aliphatic cyclobutane rings have never been observed. Here we report the discovery of cyclobutane rings in the dominant membrane lipids of two anaerobic ammonium-oxidizing (anammox) bacteria. These lipids contain up to five linearly fused cyclobutane moieties with cis ring junctions. Such 'ladderane' molecules are unprecedented in nature but are known as promising building blocks in optoelectronics. The ladderane lipids occur in the membrane of the anammoxosome, the dedicated intracytoplasmic compartment where anammox catabolism takes place. They give rise to an exceptionally dense membrane, a tight barrier against diffusion. We propose that such a membrane is required to maintain concentration gradients during the exceptionally slow anammox metabolism and to protect the remainder of the cell from the toxic anammox intermediates. Our results further illustrate that microbial membrane lipid structures are far more diverse than previously recognized.

The Importance of Drug Interactions in Epilepsy Therapy

Abstract: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

Ultrafast precessional magnetization reversal by picosecond magnetic field pulse shaping

Abstract: Since the invention of the first magnetic memory disk in 1954, much effort has been put into enhancing the speed, bit density and reliability of magnetic memory devices. In the case of magnetic random access memory (MRAM) devices, fast coherent magnetization rotation by precession of the entire memory cell is desired1,2,3,4,5,6, because reversal by domain-wall motion is much too slow. In principle, the fundamental limit of the switching speed via precession is given by half of the precession period. However, under-critically damped systems exhibit severe ringing7,8 and simulations show that, as a consequence, undesired back-switching of magnetic elements of an MRAM can easily be initiated by subsequent write pulses, threatening data integrity. We present a method to reverse the magnetization in under-critically damped systems by coherent rotation of the magnetization while avoiding any ringing. This is achieved by applying specifically shaped magnetic field pulses that match the intrinsic properties of the magnetic elements. We demonstrate, by probing all three magnetization components9,10, that reliable precessional reversal in lithographically structured micrometre-sized elliptical permalloy elements is possible at switching times of about 200 ps, which is ten times faster than the natural damping time constant.

The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements.

Abstract: HeLa cytoplasmic extracts contain both 3′–5′ and 5′–3′ exonuclease activities that may play important roles in mRNA decay. Using an in vitro RNA deadenylation/decay assay, mRNA decay intermediates were trapped using phosphothioate-modified RNAs. These data indicate that 3′–5′ exonucleolytic decay is the major pathway of RNA degradation following deadenylation in HeLa cytoplasmic extracts. Immunodepletion using antibodies specific for the exosomal protein PM-Scl75 demonstrated that the human exosome complex is required for efficient 3′–5′ exonucleolytic decay. Furthermore, 3′–5′ exonucleolytic decay was stimulated dramatically by AU-rich instability elements (AREs), implicating a role for the exosome in the regulation of mRNA turnover. Finally, PM-Scl75 protein was found to interact specifically with AREs. These data suggest that the interaction between the exosome and AREs plays a key role in regulating the efficiency of ARE-containing mRNA turnover.

Group model building effectiveness: a review of assessment studies †

Abstract: Over the last decades system dynamicists have experimented with approaches to achieve more involvement of their clients in the model building process. As a result the number of reports in the literature on the use of system dynamics as an organizational intervention tool has increased dramatically. From the literature we have identified 107 cases that provide details on the modeling process and the assessment of results. The cases show a wide variety in the way the interventions are reported and assessed. From a research point of view this is clearly an undesirable state of affairs. This article reports on a meta analysis of findings of these studies and tries to provide an overview of outcome studies on system dynamics interventions. It attempts to draw some preliminary conclusions on the effectiveness of system dynamics modeling interventions, to clarify differences in definitions of outcomes, and to provide guidelines for more standardized assessments and reports. Rather than remaining in the stage of single case descriptions, the latter will enable the accumulation of research results in the future, a prerequisite for institutional learning within the system dynamics community. Copyright © 2002 John Wiley & Sons, Ltd.

The Dialogical Self as a Society of Mind: Introduction

Abstract: The dialogical self works as a society with oppositions, conflicts, negotiations, cooperation and coalitions between positions. As society becomes more heterogeneous, more relatively autonomous spatial domains emerge in the self. Like a society, the self is based on two principles: intersubjective exchange and social domination. The article briefly discusses the different contributions in the light of the developing theory.

Intonation and Interpretation: Phonetics and Phonology

Abstract: Intonational meaning is located in two components of language, the phonetic implementation and the intonational grammar. The phonetic implementation is widely used for the expression of universal meanings that derive from ‘biological codes’, meaning dimensions based on aspects of the production process of pitch variation. Three codes are identified, Ohala’s Frequency Code, the Effort Code and the Production Code. In each case, ‘informational’ meanings (which relate to the message) are identified, while for the first two codes also ‘affective’ meanings (relating to the state of the speaker) are discussed. Speech communities will vary in the extent to which they employ those meanings, and in the choices they make when they conflict. What they will never do, however, is change the natural form-function relations that they embody. By contrast, grammaticalised meanings often mimic the natural meanings, but linguistic change may create quite arbitrary form-meaning relations when forms are phonologised, and the semantics is systematised. English grammaticalised intonational meaning concerns information status.

Caffeine Can Decrease Insulin Sensitivity in Humans

Abstract: OBJECTIVE —Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake. RESEARCH DESIGN AND METHODS —Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects. RESULTS —Caffeine decreased insulin sensitivity by 15% ( P P P P P P CONCLUSIONS —Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect.

Crystal structure prediction of small organic molecules: a second blind test

Abstract: The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

Local staging of prostate cancer using magnetic resonance imaging: a meta-analysis.

Abstract: Our objective was to determine the influence of patient-, study design-, and imaging protocol characteristics on staging performance of MR imaging in prostate cancer. In an electronic literature search and review of bibliographies (January 1984 to May 2000) the articles selected included data on sensitivity and specificity for local staging. Subgroup analyses examined the influence of age, prostate specific antigen, tumor grade, hormonal pre-treatment, stage distribution, publication year, department of origin, verification bias, time between biopsy and MR imaging; consensus reading, study design, consecutive patients, sample size, histology preparation, imaging planes, fast spin echo, fat suppression, endorectal coil, field strength, resolution, glucagon, contrast agents, MR spectroscopy, and dynamic contrast-enhanced MRI. Seventy-one articles and five abstracts were included, yielding 146 studies. Missing values were highly prevalent for patient characteristics and study design. Publication year, sample size, histologic gold standard, number of imaging planes, turbo spin echo, endorectal coil, and contrast agents influenced staging performance ( p=0.05). Due to poor reporting it was not possible to fully explain the heterogeneity of performance presented in the literature. Our results suggest that turbo spin echo, endorectal coil, and multiple imaging planes improve staging performance. Studies with small sample sizes may result in higher staging performance.

Laboratory Phonology 7

Abstract: This collection of recent papers in Laboratory Phonology approaches phonological theory from several different empirical directions. Psycholinguistic research into the perception and production of speech has produced results that challenge current conceptions about phonological structure. Field work studies provide fresh insights into the structure of phonological features, and the phonology-phonetics interface is investigated in phonetic research involving both segments and prosody, while the role of underspecification is put to the test in automatic speech recognition.