bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Initiation and Acute Withdrawal of Statins on the Neurovascular Coupling Mechanism in Healthy, Normocholesterolemic Humans
Authors: Rosengarten Bernhard , Auch Dieter , Kaps Manfred
Published: October 2007

Background and Purpose—

Recent clinical trials imply increased risk of vascular events after statin withdrawal. There is evidence that this observation relates to an impaired nitric oxide system. The present analysis investigates the effect of initiation and withdrawal of statin therapy on resting and functionally activated cerebral hemodynamics in healthy young volunteers.

Methods—

Sixteen healthy students (aged 23.7±3.3 years, 10 male) were subjected to a placebo-controlled, double-blind crossover study with a washout phase between blocks of 4 weeks. In the verum group, 20 mg pravastatin was taken for 2 weeks followed by 40 mg for 4 weeks. Withdrawal effects were investigated the day after discontinuation. Total cholesterol levels, blood pressure, resting and evoked hemodynamic responses due to a visual stimulation task in the posterior cerebral artery were obtained at baseline and then weekly and the day after discontinuation.

Results—

In the verum group, cholesterol levels significantly decreased after 2 weeks (from 183±30 to 150±28 mg/dL;
P
<0.001) and then remained nearly stable (147±21 mg/dL after 6 weeks). Blood pressure, resting and evoked hemodynamic responses remained constant throughout the study. The day after statin withdrawal, evoked flow velocity responses were significantly lower (11±4% versus 13±5% at baseline;
P
<0.01) indicating inappropriate blood supply of active neurons.

Conclusions—

Reduction in evoked flow velocity responses reflects reduced nitric oxide bioavailability and therefore supports molecular findings of acute statin withdrawal. Questions arise if the present data might give a link to reports of increased vascular events in patients at vascular risk after acute statin withdrawal.
Using Neuroimaging to Resolve the Psi Debate
Authors: Moulton Samuel T. , Kosslyn Stephen M.
Published: October 2007

Parapsychology is the scientific investigation of apparently paranormal mental phenomena (such as telepathy, i.e., “mind reading”), also known as psi. Despite widespread public belief in such phenomena and over 75 years of experimentation, there is no compelling evidence that psi exists. In the present study, functional magnetic resonance imaging (fMRI) was used in an effort to document the existence of psi. If psi exists, it occurs in the brain, and hence, assessing the brain directly should be more sensitive than using indirect behavioral methods (as have been used previously). To increase sensitivity, this experiment was designed to produce positive results if telepathy, clairvoyance (i.e., direct sensing of remote events), or precognition (i.e., knowing future events) exist. Moreover, the study included biologically or emotionally related participants (e.g., twins) and emotional stimuli in an effort to maximize experimental conditions that are purportedly conducive to psi. In spite of these characteristics of the study, psi stimuli and non-psi stimuli evoked indistinguishable neuronal responses—although differences in stimulus arousal values of the same stimuli had the expected effects on patterns of brain activation. These findings are the strongest evidence yet obtained against the existence of paranormal mental phenomena.
Electrophysiological Measures of Time Processing in Infant and Adult Brains: Weber's Law Holds
Authors: Brannon Elizabeth M. , Libertus Melissa E. , Meck Warren H. , Woldorff Marty G.
Published: October 2007

Behavioral studies have demonstrated that time perception in adults, children, and nonhuman animals is subject to Weber's Law. More specifically, as with discriminations of other features, it has been found that it is the ratio between two durations rather than their absolute difference that controls the ability of an animal to discriminate them. Here, we show that scalp-recorded event-related electrical brain potentials (ERPs) in both adults and 10-month-old human infants, in response to changes in interstimulus interval (ISI), appear to obey the scalar property found in time perception in adults, children, and nonhuman animals. Using a timing-interval oddball paradigm, we tested adults and infants in conditions where the ratio between the standard and deviant interval in a train of homogeneous auditory stimuli varied such that there was a 1:4 (only for the infants), 1:3, 1:2, and 2:3 ratio between the standard and deviant intervals. We found that the amplitude of the deviant-triggered mismatch negativity ERP component (deviant-ISI ERP minus standard-ISI ERP) varied as a function of the ratio of the standard to deviant interval. Moreover, when absolute values were varied and ratio was held constant, the mismatch negativity did not vary.
Different Brain Circuits Underlie Motor and Perceptual Representations of Temporal Intervals
Authors: Bueti Domenica , Walsh Vincent , Frith Chris , Rees Geraint
Published: October 2007

In everyday life, temporal information is used for both perception and action, but whether these two functions reflect the operation of similar or different neural circuits is unclear. We used functional magnetic resonance imaging to investigate the neural correlates of processing temporal information when either a motor or a perceptual representation is used. Participants viewed two identical sequences of visual stimuli and used the information differently to perform either a temporal reproduction or a temporal estimation task. By comparing brain activity evoked by these tasks and control conditions, we explored commonalities and differences in brain areas involved in reproduction and estimation of temporal intervals. The basal ganglia and the cerebellum were commonly active in both temporal tasks, consistent with suggestions that perception and production of time are subserved by the same mechanisms. However, only in the reproduction task was activity observed in a wider cortical network including the right pre-SMA, left middle frontal gyrus, left premotor cortex, with a more reliable activity in the right inferior parietal cortex, left fusiform gyrus, and the right extrastriate visual area V5/MT. Our findings point to a role for the parietal cortex as an interface between sensory and motor processes and suggest that it may be a key node in translation of temporal information into action. Furthermore, we discuss the potential importance of the extrastriate cortex in processing visual time in the context of recent findings.
The Electrophysiological Dynamics of Interference during the Stroop Task
Authors: Hanslmayr Simon , Pastötter Bernhard , Bäuml Karl-Heinz , Gruber Sieglinde , Wimber Maria , Klimesch Wolfgang
Published: October 2007

If subjects are required to name the color of the word red printed in blue ink, interference between word meaning and ink color occurs, which slows down reaction time. This effect is well known as the Stroop effect. It is still an unresolved issue how the brain deals with interference in this type of task. To explore this question, an electroencephalogram (EEG) study was carried out. By analyzing several measures of EEG activity, two main findings emerged. First, the event-related potential (ERP) showed increased fronto-central negativity in a time window around 400 msec for incongruent items in contrast to congruent and neutral items. Source localization analysis revealed that a source in the anterior cingulate cortex (ACC) contributed most to the difference. Second, time-frequency analysis showed that theta oscillations (4–7 Hz) in the ACC increased linearly with increasing interference and that phase coupling between the ACC and the left prefrontal cortex was longer persistent for incongruent items compared to congruent and neutral items. These effects occurred at a time window around 600 msec. We conclude that interference between color naming and word meaning in the Stroop task manifests itself at around 400 msec and mainly activates the ACC. Thereafter, sustained phase coupling between the ACC and the prefrontal cortex occurs, which most likely reflects the engagement of cognitive control mechanisms.
Neural Substrates for Action Understanding at Different Description Levels in the Human Brain
Authors: Lestou Vaia , Pollick Frank E. , Kourtzi Zoe
Published: October 2007

Understanding complex movements and abstract action goals is an important skill for our social interactions. Successful social interactions entail understanding of actions at different levels of action description, ranging from detailed movement trajectories that support learning of complex motor skills through imitation to distinct features of actions that allow us to discriminate between action goals and different action styles. Previous studies have implicated premotor, parietal, and superior temporal areas in action understanding. However, the role of these different cortical areas in action understanding at different levels of action description remains largely unknown. We addressed this question using advanced animation and stimulus generation techniques in combination with sensitive functional magnetic resonance imaging adaptation or repetition suppression methods. We tested the neural sensitivity of fronto-parietal and visual areas to differences in the kinematics and goals of actions using kinematic morphs of arm movements. Our findings provide novel evidence for differential involvement of ventral premotor, parietal, and temporal regions in action understanding. We show that the ventral premotor cortex encodes the physical similarity between movement trajectories and action goals that are important for exact copying of actions and the acquisition of complex motor skills. In contrast, whereas parietal regions and the superior temporal sulcus process the perceptual similarity between movements and may support the perception and imitation of abstract action goals and movement styles. Thus, our findings propose that fronto-parietal and visual areas involved in action understanding mediate a cascade of visual-motor processes at different levels of action description from exact movement copies to abstract action goals achieved with different movement styles.
Visuotactile Learning and Body Representation: An ERP Study with Rubber Hands and Rubber Objects
Authors: Press Clare , Heyes Cecilia , Haggard Patrick , Eimer Martin
Published: October 2007

We studied how the integration of seen and felt tactile stimulation modulates somatosensory processing, and investigated whether visuotactile integration depends on temporal contiguity of stimulation, and its coherence with a preexisting body representation. During training, participants viewed a rubber hand or a rubber object that was tapped either synchronously with stimulation of their own hand, or in an uncorrelated fashion. In a subsequent test phase, somatosensory event-related potentials (ERPs) were recorded to tactile stimulation of the left or right hand, to assess how tactile processing was affected by previous visuotactile experience during training. An enhanced somatosensory N140 component was elicited after synchronous, compared with uncorrelated, visuotactile training, irrespective of whether participants viewed a rubber hand or rubber object. This early effect of visuotactile integration on somatosensory processing is interpreted as a candidate electro-physiological correlate of the rubber hand illusion that is determined by temporal contiguity, but not by preexisting body representations. ERP modulations were observed beyond 200 msec poststimulus, suggesting an attentional bias induced by visuotactile training. These late modulations were absent when the stimulation of a rubber hand and the participant's own hand was uncorrelated during training, suggesting that preexisting body representations may affect later stages of tactile processing.
Rhetorical and Scientific Aspects of the Nicomachean Ethics
Authors: Natali Carlo
Published: October 2007

There are fields of research on NE which still need attention: the edition of the text the style and rhetorical and logical instruments employed by Aristotle in setting out his position. After indicating the situation of the research on the text of NE, I describe some rhetorical devices used by Aristotle in his work: the presence of a preamble, clues about how the argument will be developed, a tendency to introduce new arguments in an inconspicuous way and the articulation of general definitions through more specific analyses. At a deeper level NE seems to be organised on the model of investigating definitions described in the second Book of the Posterior Analytics, and not according the so-called 'dialectical method'. In conclusion I argue that NE is not an early or a confused work, as some scholars maintain, but rather a skilful construction, the fruit of a mature intelligence.
Are Patients Reliable When Self‐Reporting Medication Use? Validation of Structured Drug Interviews and Home Visits by Drug Analysis and Prescription Data in Acutely Hospitalized Patients1
Authors: Glintborg Bente , Hillestrøm Peter René , Olsen Lenette Holm , Dalhoff Kim Peder , Poulsen Henrik Enghusen
Published: October 2007

The medication history among hospitalized patients often relies on patients'self‐reports due to insufficient communication between health care professionals. The aim of the present study was to estimate the reliability of patients'self‐reported medication use. Five hundred patients admitted to an acute medical department at a Danish university hospital were interviewed on the day of admission about their recent medication use. Blood samples drawn immediately after admission were screened for contents of 5 drugs (digoxin, bendroflumethiazide, amlodipine, simvastatin, glimepiride), and the results were compared to the patients'self‐reported medication history. Information on prescribed drugs dispensed from any Danish pharmacy was collected from nationwide real‐time pharmacy records. The authors performed home visits in a subgroup of 115 patients 4 weeks after their discharge. Stored drugs were inspected, and patients were interviewed about their drug use. Additional blood samples were drawn for drug analysis. The median age of included patients was 72 years, and 298 patients (60%) were women. Patients reported use of 3 (median) prescription‐only medications (range, 0–14) during the structured interview. The congruence between self‐report and drug analysis was high for all 5 drugs measured (all kappa >0.8). However, 9 patients (2%) reported use of drugs that were not detected in their blood samples. In 29 patients (6%), the blood samples contained drugs not reported during the structured interview, but 14 of these drugs were registered in either hospital files or pharmacy records. Overall, the sensitivity of information from hospital files, structured interviews, and pharmacy records in identifying drug users was 87% to 93%, with no significant differences between methods. In conclusion, patients'self‐reports are reliable when estimating recent use of cardiovascular and antidiabetic drugs.
Pharmacokinetic and Pharmacodynamic Properties of Methoxy Polyethylene Glycol‐Epoetin Beta Are Unaffected by the Site of Subcutaneous Administration1
Authors: Fishbane Steven , Pannier Anne , Liogier Xavier , Jordan Paul , Dougherty Frank C. , Reigner Bruno
Published: October 2007

C.E.R.A. (methoxy polyethylene glycol‐epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis‐stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open‐label, single‐center, single‐dose, 3‐way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 μg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half‐life from 160 to 164 hours, area under the concentration–time curve from 4088 to 4323 ngṁh/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count–time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half‐life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.
Pharmacokinetics of Lamivudine, Zidovudine, and Nevirapine Administered as a Fixed‐Dose Combination Formulation Versus Coadministration of the Individual Products
Authors: Marier J. F. , DiMarco M. , Guilbaud R. , Dodard C. , Morelli G. , Tippabhotla S. K. , Singla A. K. , Thudi N. R. , Monif T.
Published: October 2007

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed‐dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open‐label, randomized, 2‐way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed‐dose combination to individual products) and 90% confidence intervals of AUC0‐t, AUC0‐∞, and Cmax for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed‐dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed‐dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug‐related adverse events. The current fixed‐dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.
Modeling and Simulation of Abatacept Exposure and Interleukin‐6 Response in Support of Recommended Doses for Rheumatoid Arthritis1
Authors: Roy Amit , Mould Diane R. , Wang Xiao‐Feng , Tay Lee , Raymond Ralph , Pfister Marc
Published: October 2007

Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight‐tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)–6 concentration. The abatacept exposure and exposure‐response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL‐6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2‐compartmental model, in which clearance was linearly related to body weight. The IL‐6 response was characterized by an indirect‐response model, in which the IL‐6 production rate increased with baseline C‐reactive protein levels. Model‐based simulations demonstrated that body weight‐tiered dosing was desirable to ensure consistent steady‐state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing <60, 60–100, and >100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses >10 mg/kg did not result in further increases in IL‐6 suppression. These modeling and simulation results indicate that the body weight‐tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL‐6 suppression.
Psychopharmacologic Strategies and Associated Challenges in the Long-Term Treatment of Schizophrenia
Authors: Phillips McEnany Geoffry
Published: October 2007

The comprehensive treatment of persons who have been diagnosed with schizophrenia requires the application of an effective and tolerable pharmacologic treatment regimen in conjunction with psychosocial interventions. The mainstay of pharmacologic treatment of persons diagnosed with schizophrenia is antipsychotic medication. The most commonly prescribed are the atypical or second-generation antipsychotic medications that have efficacy that matches, or in many cases is superior to that of conventional antipsychotics. In practice, however, medication adherence, as much as medication efficacy, is the key to improving patient outcomes.J Am Psychiatr Nurses Assoc, 2007; 13(S5), S6.-S15. DOI: 10.1177/1078390307304078
A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma
Authors: Hoster Eva , Dreyling Martin , Klapper Wolfram , Gisselbrecht Christian , van Hoof Achiel , Kluin-Nelemans Hanneke C. , Pfreundschuh Michael , Reiser Marcel , Metzner Bernd , Einsele Hermann , Peter Norma , Jung Wolfram , Wörmann Bernhard , Ludwig Wolf-Dieter , Dührsen Ulrich , Eimermacher Hartmut , Wandt Hannes , Hasford Joerg , Hiddemann Wolfgang , Unterhalt Michael
Published: October 2007

There is no generally established prognostic index for patients with mantle cell lymphoma (MCL), because the International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been developed for diffuse large cell and follicular lymphoma patients, respectively. Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international prognostic index, MIPI) of overall survival (OS). Statistical methods included Kaplan-Meier estimates and the log-rank test for evaluating IPI and FLIPI and multiple Cox regression for developing the MIPI. IPI and FLIPI showed poor separation of survival curves. According to the MIPI, patients were classified into low risk (44% of patients, median OS not reached), intermediate risk (35%, 51 months), and high risk groups (21%, 29 months), based on the 4 independent prognostic factors: age, performance status, lactate dehydrogenase (LDH), and leukocyte count. Cell proliferation (Ki-67) was exploratively analyzed as an important biologic marker and showed strong additional prognostic relevance. The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.
Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report
Authors: Doolittle Nancy D. , Abrey Lauren E. , Shenkier Tamara N. , Tali Siegal , Bromberg Jacoline E.C. , Neuwelt Edward A. , Soussain Carole , Jahnke Kristoph , Johnston Patrick , Illerhaus Gerald , Schiff David , Batchelor Tracy , Montoto Silvia , Kraemer Dale F. , Zucca Emanuele
Published: October 2007

Isolated central nervous system (CNS) relapse involving the brain parenchyma is a rare complication of systemic non-Hodgkin lymphoma. We retrospectively analyzed patient characteristics, management, and outcomes of this complication. After complete response to initial non-Hodgkin lymphoma treatment, patients with isolated CNS relapse with the brain parenchyma as initial relapse site were eligible. Patients with isolated CNS relapse involving only the cerebrospinal fluid were not eligible. Information on 113 patients was assembled from 13 investigators; 94 (83%) had diffuse large B-cell lymphoma. Median time to brain relapse was 1.8 years (range, 0.25-15.9 years). Brain relapse was identified by neuroimaging in all patients; in 54 (48%), diagnostic brain tumor specimen was obtained. Median overall survival from date of brain relapse was 1.6 years (95% confidence interval, 0.9-2.6 years); 26 (23%) have survived 3 years or more. Median time to progression was 1.0 year (95% confidence interval, 0.7-1.7 years). Age less than 60 years (P = .006) at relapse and methotrexate use (P = .008) as front-line treatment for brain relapse were significantly associated with longer survival in a multivariate model. Our results suggest systemic methotrexate is the optimal treatment for isolated CNS relapse involving the brain parenchyma. Long-term survival is possible in some patients.
Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially released
Authors: Italiano Joseph E. , Richardson Jennifer L. , Patel-Hett Sunita , Battinelli Elisabeth , Zaslavsky Alexander , Short Sarah , Ryeom Sandra , Folkman Judah , Klement Giannoula L.
Published: October 2007

Platelets, in addition to their function in hemostasis, play an important role in wound healing and tumor growth. Because platelets contain angiogenesis stimulators and inhibitors, the mechanisms by which platelets regulate angiogenesis remain unclear. As platelets adhere to activated endothelium, their action can enhance or inhibit local angiogenesis. We therefore suspected a higher organization of angiogenesis regulators in platelets. Using double immunofluorescence and immunoelectron microscopy, we show that pro- and antiangiogenic proteins are separated in distinct subpopulations of α-granules in platelets and megakaryocytes. Double immunofluorescence labeling of vascular endothelial growth factor (VEGF) (an angiogenesis stimulator) and endostatin (an angiogenesis inhibitor), or for thrombospondin-1 and basic fibroblast growth factor, confirms the segregation of stimulators and inhibitors into separate and distinct α-granules. These observations motivated the hypothesis that distinct populations of α-granules could undergo selective release. The treatment of human platelets with a selective PAR4 agonist (AYPGKF-NH2) resulted in release of endostatin-containing granules, but not VEGF-containing granules, whereas the selective PAR1 agonist (TFLLR-NH2) liberated VEGF, but not endostatin-containing granules. In conclusion, the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of α-granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
BMDExpress: a software tool for the benchmark dose analyses of genomic data
Authors: Yang Longlong , Allen Bruce C , Thomas Russell S
Published: October 2007

Background

Dose-dependent processes are common within biological systems and include phenotypic changes following exposures to both endogenous and xenobiotic molecules. The use of microarray technology to explore the molecular signals that underlie these dose-dependent processes has become increasingly common; however, the number of software tools for quantitatively analyzing and interpreting dose-response microarray data has been limited.

Results

We have developed BMDExpress, a Java application that combines traditional benchmark dose methods with gene ontology classification in the analysis of dose-response data from microarray experiments. The software application is designed to perform a stepwise analysis beginning with a one-way analysis of variance to identify the subset of genes that demonstrate significant dose-response behavior. The second step of the analysis involves fitting the gene expression data to a selection of standard statistical models (linear, 2° polynomial, 3° polynomial, and power models) and selecting the model that best describes the data with the least amount of complexity. The model is then used to estimate the benchmark dose at which the expression of the gene significantly deviates from that observed in control animals. Finally, the software application summarizes the statistical modeling results by matching each gene to its corresponding gene ontology categories and calculating summary values that characterize the dose-dependent behavior for each biological process and molecular function. As a result, the summary values represent the dose levels at which genes in the corresponding cellular process show transcriptional changes.

Conclusion

The application of microarray technology together with the BMDExpress software tool represents a useful combination in characterizing dose-dependent transcriptional changes in biological systems. The software allows users to efficiently analyze large dose-response microarray studies and identify reference doses at which particular cellular processes are altered. The software is freely available athttp://sourceforge.net/projects/bmdexpress/and is distributed under the MIT Public License.
EuCAP, a Eukaryotic Community Annotation Package, and its application to the rice genome
Authors: Thibaud-Nissen Françoise , Campbell Matthew , Hamilton John P , Zhu Wei , Buell C Robin
Published: October 2007

Background

Despite the improvements of tools for automated annotation of genome sequences, manual curation at the structural and functional level can provide an increased level of refinement to genome annotation. The Institute for Genomic Research Rice Genome Annotation (hereafter named the Osa1 Genome Annotation) is the product of an automated pipeline and, for this reason, will benefit from the input of biologists with expertise in rice and/or particular gene families. Leveraging knowledge from a dispersed community of scientists is a demonstrated way of improving a genome annotation. This requires tools that facilitate 1) the submission of gene annotation to an annotation project, 2) the review of the submitted models by project annotators, and 3) the incorporation of the submitted models in the ongoing annotation effort.

Results

We have developed the Eukaryotic Community Annotation Package (EuCAP), an annotation tool, and have applied it to the rice genome. The primary level of curation by community annotators (CA) has been the annotation of gene families. Annotation can be submitted by email or through the EuCAP Web Tool. The CA models are aligned to the rice pseudomolecules and the coordinates of these alignments, along with functional annotation, are stored in the MySQL EuCAP Gene Model database. Web pages displaying the alignments of the CA models to the Osa1 Genome models are automatically generated from the EuCAP Gene Model database. The alignments are reviewed by the project annotators (PAs) in the context of experimental evidence. Upon approval by the PAs, the CA models, along with the corresponding functional annotations, are integrated into the Osa1 Genome Annotation. The CA annotations, grouped by family, are displayed on the Community Annotation pages of the project website http://rice.tigr.org, as well as in the Community Annotation track of the Genome Browser.

Conclusion

We have applied EuCAP to rice. As of July 2007, the structural and/or functional annotation of 1,094 genes representing 57 families have been deposited and integrated into the current gene set. All of the EuCAP components are open-source, thereby allowing the implementation of EuCAP for the annotation of other genomes. EuCAP is available at http://sourceforge.net/projects/eucap/.
How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study
Authors: Houghton Lisa A , Sherwood Kelly L , O'Connor Deborah L
Published: October 2007

Background

In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate.

Methods

The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55).

Results

Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46,P< 0.001) and RBC (r = 0.36,P< 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2ndquartile of intake) did not differ from that of women consuming >410 μg/d (3rdand 4thquartile).

Conclusion

Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 μg.
Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre- versus postmenopausal women
Authors: Deibert Peter , König Daniel , Vitolins Mara Z , Landmann Ulrike , Frey Ingrid , Zahradnik Hans-Peter , Berg Aloys
Published: October 2007

Background

The present study examines changes in body weight, fat mass, metabolic and hormonal parameters in overweight and obese pre- and postmenopausal women who participated in a weight loss intervention.

Methods

Seventy-two subjects were included in the analysis of this single arm study (premenopausal: 22 women, age 43.7 ± 6.4 years, BMI 31.0 ± 2.4 kg/m2; postmenopausal: 50 women, age 58.2 ± 5.1 years, BMI 32.9 ± 3.7 kg/m2). Weight reduction was achieved by the use of a meal replacement and fat-reduced diet. In addition, from week 6 to 24 participants attended a guided exercise program. Body composition was analyzed with the Bod Pod®. Blood pressures were taken at every visit and blood was collected at baseline and closeout of the study to evaluate lipids, insulin, cortisol and leptin levels.

Results

BMI, fat mass, waist circumference, systolic blood pressure, triglycerides, glucose, leptin and cortisol were higher in the postmenopausal women at baseline.

Both groups achieved a substantial and comparable weight loss (pre- vs. postmenopausal: 6.7 ± 4.9 vs 6.7 ± 4.4 kg; n.s.). However, in contrast to premenopausal women, weight loss in postmenopausal women was exclusively due to a reduction of fat mass (-5.3 ± 5.1 vs -6.6 ± 4.1 kg; p < 0.01). In premenopausal women 21% of weight loss was attributed to a reduction in lean body mass.

Blood pressure, triglycerides, HDL-cholesterol, and glucose improved significantly only in postmenopausal women whereas total cholesterol and LDL-cholesterol were lowered significantly in both groups.

Conclusion

Both groups showed comparable weight loss and in postmenopausal women weight loss was associated with a pronounced improvement in metabolic risk factors thereby reducing the prevalence of metabolic syndrome.
Enhancing the anti-angiogenic action of histone deacetylase inhibitors
Authors: Kuljaca Selena , Liu Tao , Tee Andrew EL , Haber Michelle , Norris Murray D , Dwarte Tanya , Marshall Glenn M
Published: October 2007

Background

Histone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action.

Results

Trichostatin A (TSA) and α-interferon (IFNα) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21WAF1expression and response to TSA and IFNα treatment. Moreover, inhibition of p21WAF1expression in a p21WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFNα.In vitroassays of endothelial cell function showed that TSA and IFNα decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFNα co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1α and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFNα therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice.

Conclusion

Our results indicate that combination TSA and IFNα therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21WAF1expression appears to be acting as a resistance factor to the combination therapy.
Dopamine receptor repertoire of human granulosa cells
Authors: Rey-Ares Veronica , Lazarov Nikolai , Berg Dieter , Berg Ulrike , Kunz Lars , Mayerhofer Artur
Published: October 2007

Background

High levels of dopamine (DA) were described in human ovary and recently evidence for DA receptors in granulosa and luteal cells has been provided, as well. However, neither the full repertoire of ovarian receptors for DA, nor their specific role, is established. Human granulosa cells (GCs) derived from women undergoing in vitro fertilization (IVF) are an adequate model for endocrine cells of the follicle and the corpus luteum and were therefore employed in an attempt to decipher their DA receptor repertoire and functionality.

Methods

Cells were obtained from patients undergoing IVF and examined using cDNA-array, RT-PCR, Western blotting and immunocytochemistry. In addition, calcium measurements (with FLUO-4) were employed. Expression of two DA receptors was also examined by in-situ hybridization in rat ovary. Effects of DA on cell viability and cell volume were studied by using an ATP assay and an electronic cell counter system.

Results

We found members of the two DA receptor families (D1- and D2 -like) associated with different signaling pathways in human GCs, namely D1 (as expected) and D5 (both are Gs coupled and linked to cAMP increase) and D2, D4 (Gi/Gq coupled and linked to IP3/DAG). D3 was not found. The presence of the trophic hormone hCG (10 IU/ml) in the culture medium for several days did not alter mRNA (semiquantitative RT-PCR) or protein levels (immunocytochemistry/Western blotting) of D1,2,4,5 DA receptors. Expression of prototype receptors for the two families, D1 and D2, was furthermore shown in rat granulosa and luteal cells by in situ hybridization. Among the DA receptors found in human GCs, D2 expression was marked both at mRNA and protein levels and it was therefore further studied. Results of additional RT-PCR and Western blots showed two splice variants (D2L, D2S). Irrespective of these variants, D2 proved to be functional, as DA raised intracellular calcium levels. This calcium mobilizing effect of DA was observed in the absence of extracellular calcium and was abolished by a D2 blocker (L-741,626). DA treatment (48 h) of human GCs resulted in slightly, but significantly enlarged, viable cells.

Conclusion

A previous study showed D2 in human GCs, which are linked to cAMP, and the present study reveals the full spectrum of DA receptors present in these endocrine cells, which also includes D2-like receptors, linked to calcium. Ovarian DA can act thus via D1,2,4,5, which are co-expressed by endocrine cells of the follicle and the corpus luteum and are linked to different signaling pathways. This suggests a complex role of DA in the regulation of ovarian processes.
Roles of TRPV1and Neuropeptidergic Receptors in Dorsal Root Reflex-Mediated Neurogenic Inflammation Induced by Intradermal Injection of Capsaicin
Authors: Lin Qing , Li Dingge , Xu Xijin , Zou Xiaoju , Fang Li
Published: October 2007

Background:

Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV1) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV1receptors initiates neurogenic inflammation via triggering DRRs.

Results:

Here we used pharmacological manipulations to analyze the roles of TRPV1and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABAAreceptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV1receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30–150 μg. In contrast, pretreatment of the periphery with different doses of CGRP8–37(a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK1receptors were blocked by co-administration of CGRP8–37and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.

Conclusion:

Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.
Coronary artery surgery: cardiotomy suction or cell salvage?
Authors: Lau Kelvin , Shah Hetul , Kelleher Andrea , Moat Neil
Published: October 2007

Coronary artery bypass grafting (CABG) today results in what may be regarded as acceptable levels of blood loss with many institutions avoiding allogeneic red cell transfusion in over 60% of their patients. The majority of cardiac surgeons employ cardiotomy suction to preserve autologous blood during on-pump coronary artery bypass surgery; however the use of cardiotomy suction is associated with a more pronounced systemic inflammatory response and a resulting coagulopathy as well as exacerbating the microembolic load. This leads to a tendency to increased blood loss, transfusion requirement and organ dysfunction. Conversely, the avoidance of cardiotomy suction in coronary artery bypass surgery is not associated with an increased transfusion requirement. There is therefore no indication for the routine use of cardiotomy suction in on-pump coronary artery surgery.
Fas–670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia
Authors: Farre L , Bittencourt A L , Silva-Santos G , Almeida A , Silva A C , Decanine D , Soares G M , Alcantara L C , Van Dooren S , Galvão-Castro B , Vandamme A M , Van Weyenbergh J
Published: October 2007

Fas (TNFRSF6/Apo-1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the –670 FAS promoter A/G polymorphism (STAT1-binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty-one patients with ATL, 33 healthy, human T lymphotropic virus type 1-infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS –670 polymorphism by PCR-restriction fragment-length polymorphism. The AA genotype was significantly over-represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28–11.41)] and 4.58 [95% CI (1.13–20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60–44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN-γ-induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN-dependent functionality of the –670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.