bluuebunny/crossref_metadata_2025 huggingface dataset:
High-intensity inspiratory muscle training in COPD
Authors: Hill K. , Jenkins S. C. , Philippe D. L. , Cecins N. , Shepherd K. L. , Green D. J. , Hillman D. R. , Eastwood P. R.
Published: June 2006

The aim of the present study was to investigate the effects of an interval-based high-intensity inspiratory muscle training (H-IMT) programme on inspiratory muscle function, exercise capacity, dyspnoea and health-related quality of life (QoL) in subjects with chronic obstructive pulmonary disease.

A double-blind randomised controlled trial was performed. Sixteen subjects (11 males, mean forced expiratory volume in one second (FEV1) 37.4±12.5%) underwent H-IMT performed at the highest tolerable inspiratory threshold load (increasing to 101% of baseline maximum inspiratory pressure). Seventeen subjects (11 males, mean FEV136.5±11.5%) underwent sham inspiratory muscle training (S-IMT) at 10% of maximum inspiratory pressure. Training took place three times a week for 8 weeks and was fully supervised. Pre- and post-training measurements of lung function, maximum inspiratory pressure, maximum threshold pressure, exercise capacity, dyspnoea and QoL (Chronic Respiratory Disease Questionnaire; CRDQ) were obtained.

H-IMT increased maximum inspiratory pressure by 29%, maximum threshold pressure by 56%, 6-min walk distance by 27 m, and improved dyspnoea and fatigue (CRDQ) by 1.4 and 0.9 points per item, respectively. These changes were significantly greater than any seen following S-IMT.

In conclusion, high-intensity inspiratory muscle training improves inspiratory muscle function in subjects with moderate-to-severe chronic obstructive pulmonary disease, yielding meaningful reductions in dyspnoea and fatigue.
Accelerating the reconstruction of genome-scale metabolic networks
Authors: Notebaart Richard A , van Enckevort Frank HJ , Francke Christof , Siezen Roland J , Teusink Bas
Published: June 2006

Background

The genomic information of a species allows for the genome-scale reconstruction of its metabolic capacity. Such a metabolic reconstruction gives support to metabolic engineering, but also to integrative bioinformatics and visualization. Sequence-based automatic reconstructions require extensive manual curation, which can be very time-consuming. Therefore, we present a method to accelerate the time-consuming process of network reconstruction for a query species. The method exploits the availability of well-curated metabolic networks and uses high-resolution predictions of gene equivalency between species, allowing the transfer of gene-reaction associations from curated networks.

Results

We have evaluated the method using Lactococcus lactis IL1403, for which a genome-scale metabolic network was published recently. We recovered most of the gene-reaction associations (i.e. 74 – 85%) which are incorporated in the published network. Moreover, we predicted over 200 additional genes to be associated to reactions, including genes with unknown function, genes for transporters and genes with specific metabolic reactions, which are good candidates for an extension to the previously published network. In a comparison of our developed method with the well-established approach Pathologic, we predicted 186 additional genes to be associated to reactions. We also predicted a relatively high number of complete conserved protein complexes, which are derived from curated metabolic networks, illustrating the potential predictive power of our method for protein complexes.

Conclusion

We show that our methodology can be applied to accelerate the reconstruction of genome-scale metabolic networks by taking optimal advantage of existing, manually curated networks. As orthology detection is the first step in the method, only the translated open reading frames (ORFs) of a newly sequenced genome are necessary to reconstruct a metabolic network. When more manually curated metabolic networks will become available in the near future, the usefulness of our method in network prediction is likely to increase.
Impact of RNA structure on the prediction of donor and acceptor splice sites
Authors: Marashi Sayed-Amir , Eslahchi Changiz , Pezeshk Hamid , Sadeghi Mehdi
Published: June 2006

Background

gene identification in genomic DNA sequences by computational methods has become an important task in bioinformatics and computational gene prediction tools are now essential components of every genome sequencing project. Prediction of splice sites is a key step of all gene structural prediction algorithms.

Results

we sought the role of mRNA secondary structures and their information contents for five vertebrate and plant splice site datasets. We selected 900-nucleotide sequences centered at each (real or decoy) donor and acceptor sites, and predicted their corresponding RNA structures by Vienna software. Then, based on whether the nucleotide is in a stem or not, the conventional four-letter nucleotide alphabet was translated into an eight-letter alphabet. Zero-, first- and second-order Markov models were selected as the signal detection methods. It is shown that applying the eight-letter alphabet compared to the four-letter alphabet considerably increases the accuracy of both donor and acceptor site predictions in case of higher order Markov models.

Conclusion

Our results imply that RNA structure contains important data and future gene prediction programs can take advantage of such information.
An alternative method to amplify RNA without loss of signal conservation for expression analysis with a proteinase DNA microarray in the ArrayTube® format
Authors: Schüler Susann , Wenz Ingrid , Wiederanders B , Slickers P , Ehricht R
Published: June 2006

Background

Recent developments in DNA microarray technology led to a variety of open and closed devices and systems including high and low density microarrays for high-throughput screening applications as well as microarrays of lower density for specific diagnostic purposes. Beside predefined microarrays for specific applications manufacturers offer the production of custom-designed microarrays adapted to customers' wishes.

Array based assays demand complex procedures including several steps for sample preparation (RNA extraction, amplification and sample labelling), hybridization and detection, thus leading to a high variability between several approaches and resulting in the necessity of extensive standardization and normalization procedures.

Results

In the present work a custom designed human proteinase DNA microarray of lower density in ArrayTube® format was established. This highly economic open platform only requires standard laboratory equipment and allows the study of the molecular regulation of cell behaviour by proteinases. We established a procedure for sample preparation and hybridization and verified the array based gene expression profile by quantitative real-time PCR (QRT-PCR). Moreover, we compared the results with the well established Affymetrix microarray. By application of standard labelling procedures with e.g. Klenow fragment exo-, single primer amplification (SPA) or In Vitro Transcription (IVT) we noticed a loss of signal conservation for some genes. To overcome this problem we developed a protocol in accordance with the SPA protocol, in which we included target specific primers designed individually for each spotted oligomer. Here we present a complete array based assay in which only the specific transcripts of interest are amplified in parallel and in a linear manner. The array represents a proof of principle which can be adapted to other species as well.

Conclusion

As the designed protocol for amplifying mRNA starts from as little as 100 ng total RNA, it presents an alternative method for detecting even low expressed genes by microarray experiments in a highly reproducible and sensitive manner. Preservation of signal integrity is demonstrated out by QRT-PCR measurements. The little amounts of total RNA necessary for the analyses make this method applicable for investigations with limited material as in clinical samples from, for example, organ or tumour biopsies. Those are arguments in favour of the high potential of our assay compared to established procedures for amplification within the field of diagnostic expression profiling. Nevertheless, the screening character of microarray data must be mentioned, and independent methods should verify the results.
Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes
Authors: Korostynski Michal , Kaminska-Chowaniec Dorota , Piechota Marcin , Przewlocki Ryszard
Published: June 2006

Background

Mouse strains with a contrasting response to morphine provide a unique model for studying the genetically determined diversity of sensitivity to opioid reward, tolerance and dependence. Four inbred strains selected for this study exhibit the most distinct opioid-related phenotypes. C57BL/6J and DBA/2J mice show remarkable differences in morphine-induced antinociception, self-administration and locomotor activity. 129P3/J mice display low morphine tolerance and dependence in contrast to high sensitivity to precipitated withdrawal observed in SWR/J and C57BL/6J strains. In this study, we attempted to investigate the relationships between genetic background and basal gene expression profile in the striatum, a brain region involved in the mechanism of opioid action.

Results

Gene expression was studied by Affymetrix Mouse Genome 430v2.0 arrays with probes for over 39.000 transcripts. Analysis of variance with the control for false discovery rate (q < 0.01) revealed inter-strain variation in the expression of ~3% of the analyzed transcripts. A combination of three methods of array pre-processing was used to compile a list of ranked transcripts covered by 1528 probe-sets significantly different between the mouse strains under comparison. Using Gene Ontology analysis, over-represented patterns of genes associated with cytoskeleton and involved in synaptic transmission were identified. Differential expression of several genes with relevant neurobiological function (e.g. GABA-A receptor alpha subunits) was validated by quantitative RT-PCR. Analysis of correlations between gene expression and behavioural data revealed connection between the level of mRNA for K homology domain containing, RNA binding, signal transduction associated 1 (Khdrbs1) and ATPase Na+/K+ alpha2 subunit (Atp1a2) with morphine self-administration and analgesic effects, respectively. Finally, the examination of transcript structure demonstrated a possible inter-strain variability of expressed mRNA forms as for example the catechol-O-methyltransferase (Comt) gene.

Conclusion

The presented study led to the recognition of differences in the gene expression that may account for distinct phenotypes. Moreover, results indicate strong contribution of genetic background to differences in gene transcription in the mouse striatum. The genes identified in this work constitute promising candidates for further animal studies and for translational genetic studies in the field of addictive and analgesic properties of opioids.
Identification and analysis of DNA-binding transcription factors in Bacillus subtilis and other Firmicutes- a genomic approach
Authors: Moreno-Campuzano Samadhi , Janga Sarath Chandra , Pérez-Rueda Ernesto
Published: June 2006

Background

Bacillus subtilis is one of the best-characterized organisms in Gram-positive bacteria. It represents a paradigm of gene regulation in bacteria due its complex life style (which could involve a transition between stages as diverse as vegetative cell and spore formation). In order to gain insight into the organization and evolution of the B. subtilis regulatory network and to provide an alternative framework for further studies in bacteria, we identified and analyzed its repertoire of DNA-binding transcription factors in terms of their abundance, family distribution and regulated genes.

Results

A collection of 237 DNA-binding Transcription Factors (TFs) was identified in B. subtilis, half of them with experimental evidence. 59% of them were predicted to be repressors, 17% activators, 17% were putatively identified as dual regulatory proteins and the remaining 6.3% could not be associated with a regulatory role. From this collection 56 TFs were found to be autoregulated, most of them negatively, though a significant proportion of positive feedback circuits were also identified. TFs were clustered into 51 regulatory protein families and then traced on 58 genomes from Firmicutes to detect their presence. From this analysis three families were found conserved in all the Firmicutes; fifteen families were distributed in all Firmicutes except in the phyla Mollicutes; two were constrained to Bacillales and finally two families were found to be specific to B. subtilis, due to their specie specific distribution. Repression seems to be the most common regulatory mechanism in Firmicutes due to the high proportion of repressors in the detected collection in these genomes. In addition, six global regulators were defined in B. subtilis based on the number and function of their regulated genes.

Conclusion

In this work we identified and described the characteristics associated to the repertoire of DNA-binding TFs in B. subtilis. We also quantified their abundance, family distribution, and regulatory roles in the context of Firmicutes. This work should not only contribute to our understanding of the regulation of gene expression in bacteria from the perspective of B. subtilis but also provide us the basis for comprehensive modeling of transcriptional regulatory networks in Firmicutes.
Wheat EST resources for functional genomics of abiotic stress
Authors: Houde Mario , Belcaid Mahdi , Ouellet François , Danyluk Jean , Monroy Antonio F , Dryanova Ani , Gulick Patrick , Bergeron Anne , Laroche André , Links Matthew G , MacCarthy Luke , Crosby William L , Sarhan Fathey
Published: June 2006

Background

Wheat is an excellent species to study freezing tolerance and other abiotic stresses. However, the sequence of the wheat genome has not been completely characterized due to its complexity and large size. To circumvent this obstacle and identify genes involved in cold acclimation and associated stresses, a large scale EST sequencing approach was undertaken by the Functional Genomics of Abiotic Stress (FGAS) project.

Results

We generated 73,521 quality-filtered ESTs from eleven cDNA libraries constructed from wheat plants exposed to various abiotic stresses and at different developmental stages. In addition, 196,041 ESTs for which tracefiles were available from the National Science Foundation wheat EST sequencing program and DuPont were also quality-filtered and used in the analysis. Clustering of the combined ESTs with d2_cluster and TGICL yielded a few large clusters containing several thousand ESTs that were refractory to routine clustering techniques. To resolve this problem, the sequence proximity and "bridges" were identified by an e-value distance graph to manually break clusters into smaller groups. Assembly of the resolved ESTs generated a 75,488 unique sequence set (31,580 contigs and 43,908 singletons/singlets). Digital expression analyses indicated that the FGAS dataset is enriched in stress-regulated genes compared to the other public datasets. Over 43% of the unique sequence set was annotated and classified into functional categories according to Gene Ontology.

Conclusion

We have annotated 29,556 different sequences, an almost 5-fold increase in annotated sequences compared to the available wheat public databases. Digital expression analysis combined with gene annotation helped in the identification of several pathways associated with abiotic stress. The genomic resources and knowledge developed by this project will contribute to a better understanding of the different mechanisms that govern stress tolerance in wheat and other cereals.
The Yersinia pestis gcvB gene encodes two small regulatory RNA molecules
Authors: McArthur Sarah D , Pulvermacher Sarah C , Stauffer George V
Published: June 2006

Background

In recent years it has become clear that small non-coding RNAs function as regulatory elements in bacterial virulence and bacterial stress responses. We tested for the presence of the small non-coding GcvB RNAs in Y. pestis as possible regulators of gene expression in this organism.

Results

In this study, we report that the Yersinia pestis KIM6 gcvB gene encodes two small RNAs. Transcription of gcvB is activated by the GcvA protein and repressed by the GcvR protein. The gcvB-encoded RNAs are required for repression of the Y. pestis dppA gene, encoding the periplasmic-binding protein component of the dipeptide transport system, showing that the GcvB RNAs have regulatory activity. A deletion of the gcvB gene from the Y. pestis KIM6 chromosome results in a decrease in the generation time of the organism as well as a change in colony morphology.

Conclusion

The results of this study indicate that the Y. pestis gcvB gene encodes two small non-coding regulatory RNAs that repress dppA expression. A gcvB deletion is pleiotropic, suggesting that the sRNAs are likely involved in controlling genes in addition to dppA.
Homozygous mutation of focal adhesion kinase in embryonic stem cell derived neurons: normal electrophysiological and morphological properties in vitro
Authors: Charlesworth P , Komiyama NH , Grant SGN
Published: June 2006

Background

Genetically manipulated embryonic stem (ES) cell derived neurons (ESNs) provide a powerful system with which to study the consequences of gene manipulation in mature, synaptically connected neuronsin vitro. Here we report a study of focal adhesion kinase (FAK), which has been implicated in synapse formation and regulation of ion channels, using the ESN system to circumvent the embryonic lethality of homozygous FAK mutant mice.

Results

Mouse ES cells carrying homozygous null mutations (FAK-/-) were generated and differentiatedin vitrointo neurons. FAK-/-ESNs extended axons and dendrites and formed morphologically and electrophysiologically intact synapses. A detailed study of NMDA receptor gated currents and voltage sensitive calcium currents revealed no difference in their magnitude, or modulation by tyrosine kinases.

Conclusion

FAK does not have an obligatory role in neuronal differentiation, synapse formation or the expression of NMDA receptor or voltage-gated calcium currents under the conditions used in this study. The use of genetically modified ESNs has great potential for rapidly and effectively examining the consequences of neuronal gene manipulation and is complementary to mouse studies.
Motor function in Parkinson's disease and supranuclear palsy: simultaneous factor analysis of a clinical scale in several populations
Authors: Kroonenberg Pieter M , Oort Frans J , Stebbins Glenn T , Leurgans Sue E , Cubo Esther , Goetz Christopher G
Published: June 2006

Background

In order to better understand the similarities and differences in the motor behaviour of different groups of patients, their scores on the Motor Examination section of the Unified Parkinson's Disease Rating Scale (UPDRS) were analysed simultaneously. The three groups consisted, respectively, of patients with Parkinson's disease (PD) on medication, patients with Parkinson's disease withdrawn from anti-parkinsonian medication for at least 12 hours, and patients diagnosed with a specific Parkinsonism syndrome: Progressive Supranuclear Palsy (PSP).

Methods

A total of 669 consecutively sampled patients from three separate hospital-based clinics participated (294 PD on medication; 200 PD off medication: 175 PSP). The Motor Examination section of the UPDRS was administered by neurologists at the three participating clinics. The patient scores on each item were recorded. To assess similarities and differences among the components of the UPDRS in these samples, we performed simultaneous or multigroup factor analysis on the covariance matrices of the three groups. In addition, it was investigated whether a single model for the Motor Examination section of the UPDRS could be developed which would be valid for all three groups at the same time.

Results

A single six-dimensional factor solution was found that fitted all groups, although this was not straightforward due to differences between the tremor-at-rest variables. The factors were identified as Tremor-at-rest, Postural Tremor, Axial Dysfunctioning, Rigidity, Left Bradykinesia and Right Bradykinesia. The analysis also pointed to a somewhat lower lateralization in bradykinesia for PSP patients. The groups differed in intensity of motor impairment, especially with respect to Tremor-at-Rest, but the overall relationships between the variables were shared by the three groups. In addition, apart from the common factor structure evidence of differences in body part-specific and motor-specific variances was found.

Conclusion

From a clinical point of view, the analyses showed that using the Motor Examination section of the UPDRS is also appropriate for patients with PSP, because the correlational structure of the items is directly comparable to that of Parkinson's patients. Methodologically, the analysis of all groups together showed that it is possible to evaluate similarities and differences between factor structures in great detail.
Neonatal malaria in Nigeria -a 2 year review
Authors: Runsewe-Abiodun Iyabo T , Ogunfowora Olusoga B , Fetuga Bolanle M
Published: June 2006

Background

In view of the fact that a significant proportion of neonates with malaria may be missed on our wards on the assumption that the disease condition is rare, this study aims at documenting the prevalence of malaria in neonates admitted into our neonatal ward. Specifically, we hope to describe its clinical features and outcome of this illness. Knowledge of these may ensure early diagnosis and institution of prompt management.

Methods

Methods Hospital records of all patients (two hundred and thirty) admitted into the Neonatal ward of Olabisi Onabanjo University Teaching Hospital, Sagamu between 1st January 1998 and 31st December 1999 were reviewed. All neonates (fifty-seven) who had a positive blood smear for the malaria parasite were included in the study. Socio-demographic data as well as clinical correlates of each of the patients were reviewed. The Epi-Info 6 statistical software was used for data entry, validation and analysis. A frequency distribution was generated for categorical variables. To test for an association between categorical variables, the chi-square test was used. The level of significance was put at values less than 5%.

Results

Prevalence of neonatal malaria in this study was 24.8% and 17.4% for congenital malaria.

While the mean duration of illness was 3.60 days, it varied from 5.14 days in those that died and and 3.55 in those that survived respectively. The duration of illness significantly affected the outcome (p value = 0.03). Fever alone was the clinical presentation in 44 (77.4%) of the patients. Maturity of the baby, sex and age did not significantly affect infestation. However, history of malaria/febrile illness within the 2 weeks preceding the delivery was present in 61.2% of the mothers. Maternal age, concurrent infection and duration of illness all significantly affected the outcome of illness. Forty-two (73.7%) of the babies were discharged home in satisfactory condition.

Conclusion

It was concluded that taking a blood smear to check for the presence of the malaria parasite should be included as part of routine workup for all neonates with fever or those whose mothers have history of fever two weeks prior to delivery. In addition, health education of pregnant mothers in the antenatal clinic should include early care-seeking for newborns.
Correlates of condom use in a sample of MSM in Ecuador
Authors: Gutiérrez Juan-Pablo , Molina-Yepez Diana , Morrison Ken , Samuels Fiona , Bertozzi Stefano M
Published: June 2006

Background

In Ecuador, the prevalence of HIV in the general population is approximately 0.3%. However, up to 17% prevalence has been reported among specific groups of homosexual and bisexual men. The objective of this study is to explore correlates of condom use among men who have sex with men (MSM) across eight cities in Ecuador.

Methods

A cross-sectional survey design was used. A questionnaire including variables on sexual behaviour, demographics, and socio-economic characteristics was distributed to a sample of MSM in eight Ecuadorian cities.

Results

Information was obtained for 2,594 MSM across the eight cities. The largest subcategory of self-identification was active bisexuals (35%), followed by those who described themselves as "hombrados" (masculine gays, 22%). The mean age was 25 years, and the majority were unmarried (78%), with a median of 10 years of schooling (IQR 7 – 12). Regarding condom use, 55% of those interviewed had unprotected penetrative sex with each of their last three partners, and almost 25% had never used a condom. The most important correlates of condom use were single status, high life-skills rating, and high socio-economic status (RP 5.45, 95% CI 4.26 – 6.37; RP 1.84, 95% CI 1.79 – 1.86, and RP 1.20, 95% CI 1.01 – 1.31, respectively).

Conclusion

Our data illustrate the urgent need for targeted HIV-prevention programs for MSM populations in Ecuador. MSM have the highest HIV prevalence in the country, and condom use is extremely low. It is imperative that prevention strategies be re-evaluated and re-prioritized to more effectively respond to the Ecuadorian epidemic.
A cluster-randomized educational intervention to reduce inappropriate prescription patterns for elderly patients in general practice – The Prescription Peer Academic Detailing (Rx-PAD) study [NCT00281450]
Authors: Straand Jørund , Fetveit Arne , Rognstad Sture , Gjelstad Svein , Brekke Mette , Dalen Ingvild
Published: June 2006

Background

Age-related alterations in metabolism and excretion of medications increase the risk of adverse drug events in the elderly. Inappropriate polypharmacy and prescription practice entails increased burdens of impaired quality of life and drug related morbidity and mortality. The main objective of this trial is to evaluate effects of a tailored educational intervention towards general practitioners (GPs) aimed at supporting the implementation of a safer drug prescribing practice for elderly patients ≥ 70 years.

Methods/design

Approximately 80 peer continuing medical education (CME) groups (about 600 GPs) in southern Norway will be recruited to a cluster randomized trial. Participating groups will be randomized either to an intervention- or a control group. The control group will not receive any intervention towards prescription patterns in elderly, but will be the target of an educational intervention for prescription of antibiotics for respiratory tract infections. A multifaceted intervention has been tailored, where key components are educational outreach visits to the CME-groups, work-shops, audit and feedback. Prescription Peer Academic Detailers (Rx-PADs), who are trained GPs, will conduct the educational outreach visits. During these visits, a set of quality indicators (QIs), i.e. explicit recommendations for safer prescribing for elderly patients, will be presented and discussed. Software will be handed out for installation in participants' practice computers to enable extraction of pre-defined prescription data. These data will subsequently be linked to corresponding data from the Norwegian Prescription Database (NorPD). Individual feedback reports will be sent all participating GPs during and one year after the intervention. Feedback reports will include QI-scores on individual- and group levels, before and after the intervention. The main outcome of this trial is the change in proportions of inappropriate prescriptions (QIs) for elderly patients ≥ 70 years following intervention, compared to baseline levels.

Discussion

Improvement of prescription patterns in medical practice is a challenging task. Evidence suggests that a thorough evaluation of diagnostic indications for drug treatment in the elderly and/or a reduction of potentially inappropriate drugs may impose significant clinical benefits. Our hypothesis is that an educational intervention program will be effective in improving prescribing patterns for elderly patients in GP settings.
A QTL on rat chromosome 7 modulates prepulse inhibition, a neuro-behavioral trait of ADHD, in a Lewis x SHR intercross
Authors: Vendruscolo Leandro Franco , Terenina-Rigaldie Elena , Raba Frantz , Ramos André , Takahashi Reinaldo Naoto , Mormède Pierre
Published: June 2006

Background

Attention deficit hyperactivity disorder (ADHD) is a complex neuropsychiatric disorder with a substantial genetic component. The Spontaneously Hypertensive Rats (SHR), considered as a good animal model of ADHD, also show less anxiety-like behaviors than Lewis (LEW) rats. The use of these inbred rat strains led us to the mapping of two quantitative trait loci (QTL), named Ofil1 (on chromosome 4) and Ofil2 (on chromosome 7), related to locomotion in the central and aversive area of an open field. Herein, we examined whether LEW and SHR rats differ in the acoustic startle reflex, a test used to study the neurobiology of anxiety, and in the prepulse inhibition of the startle response, which is known to be impaired in ADHD patients. The effect of the two aforementioned loci on these behavioral responses was also studied.

Methods

For this latter purpose, rats deriving from an F2 intercross between the LEW and SHR strains were selected according to their genotype at markers flanking the QTLs and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating 4 genotypic combinations.

Results

The SHR rats displayed decreased startle and prepulse inhibition levels when compared to LEW rats. Ofil2 affected prepulse inhibition in female rats only.

Conclusion

The results suggest that the LEW and SHR strains are appropriate for studying mechanisms of sensorimotor gating and indicate that the locus Ofil2 on rat chromosome 7 contain genes controlling prepulse inhibition, a neuro-behavioral trait of ADHD.
The time-course of a scrapie outbreak
Authors: McIntyre K Marie , Gubbins Simon , Goldmann Wilfred , Stevenson Emily , Baylis Matthew
Published: June 2006

Background

Because the incubation period of scrapie has a strong host genetic component and a dose-response relationship, it is possible that changes will occur during an outbreak, especially in the genotypes of cases, age-at-onset of disease and, perhaps, the clinical signs displayed. We investigated these factors for a large outbreak of natural scrapie, which yielded sufficient data to detect temporal trends.

Results

Cases occurred mostly in two genotypes, VRQ/VRQ and VRQ/ARQ, with those early in the outbreak more likely to be of the VRQ/VRQ genotype. As the epidemic progressed, the age-at-onset of disease increased, which reflected changes in the genotypes of cases rather than changes in the age-at-onset within genotypes. Clinical signs of cases changed over the course of the outbreak. As the epidemic progressed VRQ/VRQ and VRQ/ARQ sheep were more likely to be reported with behavioural changes, while VRQ/VRQ sheep only were less likely to be reported with loss of condition.

Conclusion

This study of one of the largest scrapie outbreaks in the UK allowed investigation of the effect of PrP genotype on other epidemiological parameters. Our analysis indicated that, although age-at-onset and clinical signs changed over time, the observed changes were largely, but not exclusively, driven by the time course of the PrP genotypes of cases.
Pathological and physiological functions of presenilins
Authors: Vetrivel Kulandaivelu S , Zhang Yun-wu , Xu Huaxi , Thinakaran Gopal
Published: June 2006

Mutations in PSEN1 and PSEN2 genes account for the majority of cases of early-onset familial Alzheimer disease. Since the first prediction of a genetic link between PSEN1 and PSEN2 with Alzheimer's disease, many research groups from both academia and pharmaceutical industry have sought to unravel how pathogenic mutations in PSEN cause presenile dementia. PSEN genes encode polytopic membrane proteins termed presenilins (PS1 and PS2), which function as the catalytic subunit of γ-secretase, an intramembrane protease that has a wide spectrum of type I membrane protein substrates. Sequential cleavage of amyloid precursor protein by BACE and γ-secretase releases highly fibrillogenic β-amyloid peptides, which accumulate in the brains of aged individuals and patients with Alzheimer's disease. Familial Alzheimer's disease-associated presenilin variants are thought to exert their pathogenic function by selectively elevating the levels of highly amyloidogenic Aβ42 peptides. In addition to Alzheimer's disease, several recent studies have linked PSEN1 to familiar frontotemporal dementia. Here, we review the biology of PS1, its role in γ-secretase activity, and discuss recent developments in the cell biology of PS1 with respect to Alzheimer's disease pathogenesis.
Halofuginone inhibits NF-κB and p38 MAPK in activated T cells
Authors: Leiba M , Cahalon L , Shimoni A , Lider O , Zanin-Zhorov A , Hecht I , Sela U , Vlodavsky I , Nagler A
Published: June 2006

Halofuginone, a low molecular weight plant alkaloid, inhibits collagen α1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-β (TGF-β), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-κB activity, production of tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10–40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-κB activity (80% inhibition following incubation with 40 ng halofuginone, P=0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-α, IFN-γ, interleukin (IL)-4, IL-13, and TGF-β (P<0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P=0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-κB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.
IFN-α promotes definitive maturation of dendritic cells generated by short-term culture of monocytes with GM-CSF and IL-4
Authors: Dauer Marc , Schad Katharina , Junkmann Jana , Bauer Christian , Herten Jan , Kiefl Rosemarie , Schnurr Max , Endres Stefan , Eigler Andreas
Published: June 2006

Dendritic cells (DC) generated in vitro have to be viable and phenotypically mature to be capable of inducing T cell-mediated immunity after in vivo administration. To facilitate optimization of DC-based vaccination protocols, we investigated whether the cytokine environment and the mode of activation affect maturation and survival of DC derived from monocytes by a short-term protocol. Monocytes cultured for 24 h with granulocyte macrophage-colony stimulating factor and interleukin-4 were stimulated with proinflammatory mediators for another 36 h to generate mature DC. Additional activation with CD40 ligand and interferon (IFN)-γ increased viability of DC and promoted definitive maturation as defined by maintenance of a mature phenotype after withdrawal of cytokines. Addition of IFN-α to DC cultures prior to stimulation further enhanced definitive maturation: IFN-α-primed DC expressed high levels of costimulatory molecules and CC chemokine receptor 7 (CCR7) up to 5 days after cytokine withdrawal. Compared with unprimed DC, IFN-α-primed DC displayed equal capacity to migrate upon CCR7 ligation and to prime antigen-specific T helper cell as well as cytolytic T cell responses. In conclusion, we show that optimal maturation and survival of monocyte-derived DC require multiple activation signals. Furthermore, we identified a novel role for IFN-α in DC development: IFN-α priming of monocytes promotes definitive maturation of DC upon activation.
Evaluation of Holocene crustal movement in the Ako Plain, western Japan
Authors: Sato Hiroshi , Okuno Jun' ichi , Katoh Shigehiro
Published: June 2006

Holocene sea-level observations have been obtained from the Ako Plain in western Japan. In this coastal area, the Holocene crustal movements have been evaluated, except the crustal response due to the last deglaciation, by comparing observations and theoretical predictions of relative sea-level (RSL) variations. Analyses of diatom assemblages and sedimentary sulphur in core sediments were used along with radiocarbon dates to derive the RSL variations. A crustal movement rate between +0.2 mm and-0.2 mm per year, corrected for the prediction, fits well with the observed RSL index points. Owing to the constraint of the reconstructed palaeo-mean sea level (PMSL) at 7300 cal. BP, the coast of the Ako Plain may have the best estimate of a tectonic subsidence rate of 0-0.2 mm/yr. The tectonic uplift rates along the tectonically active coast of western Kobe were derived to be 0.3-0.7 mm/yr and 0.11-0.45 mm/yr for Tarumi and Tamatsu, respectively, relative to Ako over the period concerned. The relative uplift along the traverse from Ako to western Kobe is primarily the result of the crustal movement resulting from the active faulting of the Rokko-Awaji fault system (RFS).
Effects of volcanic activity on mire development: case studies from Hokkaido, northern Japan
Authors: Hotes Stefan , Poschlod Peter , Takahashi Hidenori
Published: June 2006

Field stratigraphy and macrofossil composition of four mires in Hokkaido, northern Japan, were investigated to test whether tephra deposition induces long-term vegetation shifts. Macroscopic tephras of known origin ranging from 0.5 to > 25 cm in thickness were found in two or more of the study sites, allowing correlation of the stratigraphic development of the mires. Major peat types and position of macroscopic mineral layers were determined in the field, and selected cores were analysed by quantitative macrofossil analysis. Some macrofossil groups and the content of unidentifiable organic matter showed changes in the vicinity of tephra layers, but they did not indicate a clear response pattern of the vegetation or the decomposition dynamics of plant material. Mosses were expected to be most strongly affected by tephra deposition, but even in cases where tephra fell on Sphagnum-dominated vegetation, no fundamental shifts to new plant communities were found. This suggests that disturbance by widespread tephras less than 10 cm thick did not alter site conditions sufficiently to induce shifts in the peat-forming plant communities, or short-term changes did not become manifest in the macrofossil record. A correlation between tephra deposition and vegetation change from nutrient-and mineral-poor bog communities to richer fen communities that had been postulated by some authors was not found at our study sites.
Protection by Ziziphora clinopoides of acetic acid-induced toxic bowel inflammation through reduction of cellular lipid peroxidation and myeloperoxidase activity
Authors: Ghafari H , Yasa N , Mohammadirad A , Dehghan G , Zamani M J , Nikfar S , Khorasani R , Minaie B , Abdollahi M
Published: June 2006

Inflammatory bowel disease (IBD) is a chronic condition of the intestine with unknown etiology involving multiple immune, genetic and environmental factors. We were interested in examining the effect of a total extract from Ziziphora clinopoides, an Iranian folk herbal medicine, in the prevention and control of experimental mouse IBD. Z. clinopoides was administered (75, 150, 300 mg/kg) through drinking water to mice, which dispensed a toxic dose of acetic acid intrarectally. Prednisolone was used as the standard drug for comparison. Biochemical, macroscopic and microscopic examinations of the colon were performed. Biochemical evaluation of the inflamed colon was carried out using assays of myeloperoxidase (MPO) activity and thiobarbituric acid reacting substances (TBARS) as indicators of free radical activity and cellular lipid peroxidation.

Results indicated that the activity of MPO and lipid peroxidation products (TBARS) increased in acetic acidtreated groups, while recovered by pretreatment of animals with Z. clinopoides (75-300 mg/kg) and prednisolone. All doses of Z. clinopoides and prednisolonetreated groups showed significant lower score values of macroscopic and microscopic characters when compared to the acetic acid-treated group. The beneficial effect of Z. clinopoides (300 mg/kg) was comparable to that of prednisolone.

It is concluded that Z. clinopoides inhibits acetic acid toxic reactions in the mouse bowel through inhibition of cellular oxidative stress. Proper clinical investigation should be carried out to confirm the same activity in human.
Lack of toxicity from pediatric beta-blocker exposures
Authors: Love J N , Howell J M , Klein-Schwartz W , Litovitz T L
Published: June 2006

The risk of toxicity in a child who is unintentionally exposed to a beta-blocking drug remains uncertain. The current study further defines this risk, particularly in the common scenario of ingestion of one or two tablets. A prospective cohort of 208 pediatric patients, 6 months to 6 years of age, reported to two regional poison centers serves as the study population. Data were collected with a standardized instrument during the care of each patient and for a minimum of 24 hours after exposure. No instances of serious toxicity typical of beta-blocker intoxication, such as ‘shock-like’ states, arrhythmias or seizures were observed in this series. Furthermore, there were no reported episodes of hypoglycemia, symptomatic bradycardia or bronchospasm. Nine instances of altered mental status or behavioral changes were reported. All appeared to be minor in nature. The most serious outcome was charcoal aspiration during gastrointestinal decontamination. This study adds to a growing body of evidence suggesting that exposure to one or two beta-blocker tablets places children at very little, if any, risk of toxicity.
Does Granulocyte Colony-Stimulating Factor Worsen Anemia in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide?
Authors: Papaldo Paola , Ferretti Gianluigi , Di Cosimo Serena , Giannarelli Diana , Marolla Paolo , Lopez Massimo , Cortesi Enrico , Antimi Mauro , Terzoli Edmondo , Carlini Paolo , Vici Patrizia , Botti Claudio , Di Lauro Luigi , Naso Giuseppe , Nisticò Cecilia , Mottolese Marcella , Di Filippo Franco , Ruggeri Enzo Maria , Ceribelli Anna , Cognetti Francesco
Published: June 2006

Purpose

We report on the effects of granulocyte colony-stimulating factor (G-CSF) on hemoglobin (Hb) value in early breast cancer patients receiving high-dose epirubicin and cyclophosphamide (EC) adjuvant treatment.

Methods

Five hundred and six stage I or stage II female breast cancer patients were treated with E 120 mg/m2 and C 600 mg/m2 with or without G-CSF and randomly assigned to receive in a factorial 2 × 2 design: EC; EC + lonidamine; EC + G-CSF; EC + lonidamine + G-CSF. Five consecutive G-CSF schedules tested 100 randomly assigned patients each: (1) 480 μg subcutaneously on days 8 to 14; (2) 480 μg on days 8, 10, 12, 14; (3) 300 μg on days 8 to 14; (4) 300 μg on days 8, 10, 12, and 14; and (5) 300 μg on days 8 and 12. The mean Hb level of 246 patients receiving EC plus G-CSF was compared with that of 240 patients receiving EC alone. The data presented are derived from an exploratory hypothesis-generating analysis.

Results

The EC dose intensity did not statistically differ between the G-CSF and the control arm. From the third cycle onward, the mean Hb value resulted significantly lower in G-CSF arm compared with control at each time point of each cycle (P < .0001). No statistically significant difference in the mean Hb level was observed between schedule 5 and control. Of interest, from the second course onward, the mean Hb level tended to be lower in patients receiving seven or four G-CSF injections compared with those patients who received only two injections.

Conclusion

Our data suggest that a G-CSF dose-related effect may play a role in worsening anemia in patients receiving adjuvant EC.
Predictive and Prognostic Value of Peripheral Blood Cytokeratin-19 mRNA-Positive Cells Detected by Real-Time Polymerase Chain Reaction in Node-Negative Breast Cancer Patients
Authors: Xenidis Nikos , Perraki Maria , Kafousi Maria , Apostolaki Stella , Bolonaki Irene , Stathopoulou Aliki , Kalbakis Kostas , Androulakis Nikos , Kouroussis Charalambos , Pallis Thanos , Christophylakis Charalambos , Argyraki Katerina , Lianidou Evi S. , Stathopoulos Stathis , Georgoulias Vassilis , Mavroudis Dimitris
Published: June 2006

Purpose

To evaluate the predictive and prognostic value of peripheral blood cytokeratin-19 (CK-19) mRNA-positive cells in axillary lymph node–negative breast cancer patients.

Patients and Methods

Peripheral blood was obtained from 167 node-negative breast cancer patients before the initiation of any systemic adjuvant therapy, and was analyzed for the presence of CK-19 mRNA-positive cells using a real time polymerase chain reaction assay. The association with known prognostic factors and the effect of CK-19 mRNA-positive cells on patients' prognosis was investigated.

Results

CK-19 mRNA-positive cells were detected in the blood of 36 (21.6%) of the 167 patients. There was no correlation between the detection of CK-19 mRNA-positive cells in the peripheral blood and the various known pathologic and clinical prognostic factors; only overexpression of HER2 receptor (score 2+/3+) on the primary tumor was associated with a higher incidence of CK-19 mRNA-positive cell detection (P = .033). Multivariate analysis revealed that detection of peripheral blood CK-19 mRNA-positive cells was associated with early clinical relapse (P < .00001) and disease-related death (P = .008).

Conclusion

Detection of peripheral-blood CK-19 mRNA-positive cells is an independent predictive and prognostic factor for reduced disease-free interval and overall survival, respectively, in node-negative breast cancer patients.