bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional differences in multinational clinical trials: anticipating chance variation
Authors: Marschner Ian C
Published: March 2010

Background Multinational clinical trials efficiently pool resources and provide treatment comparisons across diverse populations. However, they may be difficult to interpret when there are larger than expected differences in region-specific treatment effects, such as a positive study that includes regions favoring the control arm.

Purpose This article investigates the extent of chance variation that can be expected in regional treatment effects from multinational studies. It advocates studying this expected variation during the design stage, hence limiting the potential for surprises and misinterpretations at the end of the study.

Methods The theory of order statistics was used to quantify chance variation between regions, assuming a homogeneous treatment effect. The expected values of the smallest and largest treatment difference were used to calculate the expected range of regional effects. This range was supplemented by the probability of observing at least one regional effect favoring the control arm.

Results Chance variation led to a wide range of expected regional effects. For a study with five regions and 80% power, the expected regional treatment effects ranged from no difference to double the true difference, while the probability of observing a region favoring the control was approximately 50%. With 10 regions this probability exceeded 85% and the expected range of regional effects extended to values substantially favoring the control. Increasing the power of the study to 90% or more offered little protection against wide variation in regional effects.

Limitations The proposed approach does not replace heterogeneity testing at the end of the study, but provides useful supporting information for interpreting such tests.

Conclusions Large differences between regions should be anticipated in multinational studies. The expected range of treatment effects should be assessed during study design in order to inform stakeholders and calibrate expectations. Clinical Trials 2010; 7: 147—156. http://ctj.sagepub.com
Routine data from hospital information systems can support patient recruitment for clinical studies
Authors: Dugas Martin , Lange Matthias , Müller-Tidow Carsten , Kirchhof Paulus , Prokosch Hans-Ulrich
Published: March 2010

Background Delayed patient recruitment is a common problem in clinical studies. Hospital information systems (HIS) contain data items relevant for inclusion or exclusion criteria of these studies.

Purpose We developed and assessed a system to support patient recruitment using HIS data.

Methods We developed a workflow integrated in our HIS to notify study physicians about potential trial subjects. Automatic HIS database queries based on inclusion and exclusion criteria for each clinical study are performed regularly and generate e-mail notifications via a communication server. Study physicians can verify eligibility with a specific HIS study module. The system performance was assessed with a survey addressing utility, usability, stability, change in recruitment rate, and estimated time savings.

Results During 10 months of operation, 1328 notifications were generated and 329 enrollments (25%) were documented for seven studies. Precision of alerts depends on availability of appropriate HIS items. Utility and usability were assessed as good, and stability as excellent. Users reported an increased patient recruitment rate for three studies. Three studies reported an estimated time saving of 10 min per recruited patient. The main perceived benefit was systematic identification of potentially eligible patients without time-consuming patient screening procedures in the different parts of the hospital.

Limitations Notifications about potentially eligible patients depend on HIS data quality regarding inclusion/exclusion criteria, in particular, completeness, timeliness, and validity.

Conclusions Routine HIS data can support patient recruitment for clinical studies by means of an automated notification workflow and efficient access to clinical data. Clinical Trials 2010; 7: 183-189. http://ctj.sagepub.com
Collective Identity in the Virtual Islamic Public Sphere
Authors: el-Nawawy Mohammed , Khamis Sahar
Published: March 2010

/ This study utilizes a textual analysis of selected threads from the Arabic discussion forums of two of the most popular Islamic websites — Islamonline.net and Islamway.com — to explore the potential impact of the new Islamic virtual public sphere, and the reconfiguration of the ‘virtual umma’ (Islamic community) online, on the creation of collective identities. The study also assesses whether the discourses and deliberations taking place in these two sites’ discussion forums exemplify an ideal Habermasian public sphere, through shura (consultation), ijtihad (interpretation) and ijma (consensus), as defined within the Islamic context. Findings indicate that there is an uncritical, unquestioning type of emotional consensus among posters who did not exemplify a truly rational-critical debate, particularly when it came to issues of political salience. Discussions among the posters show that they consider being a ‘Muslim’ as the most important ‘identity signifier’ in their lives. However, in some cases, especially while discussing political issues of a ‘pan-Arab’ nature, a parallel ‘Arab’ identity also emerged, confirming the parallelism and interrelatedness of ‘Arab’ and ‘Muslim’ identities, and the overlap between mediated ‘Arab’ and ‘Islamic’ public spheres.
Through a Western Lens
Authors: Freeman Bradley C.
Published: March 2010

Countries of the Association of Southeast Asian Nations (ASEAN) have long since declared their political independence from western powers, yet arguably they still stand in the long shadow of western media and culture. Recently though, the group has been taking more assertive steps to make ASEAN more cohesive and relevant in global affairs. ASEAN has several important trading partners, including the US. How is the association portrayed in US newspapers? Does the group’s coverage differ from that of its individual member states? And what bearing can such international media portrayals have on the institution’s identity? This study explores the treatment of ASEAN and its individual member states in The New York Times. A content analysis methodology is utilized to examine the variables of visibility and valence. Across time comparisons are made between ASEAN and its member states in terms of the total number of stories, media frames used and news categories present. Relationships between news coverage, framing and foreign policy concerns are also examined as advised by current understanding of framing and agenda-setting research.
AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2
Authors: Wang Wei , Schwemmers Sven , Hexner Elizabeth O. , Pahl Heike L.
Published: March 2010

The transcription factor NF-E2 is overexpressed in the majority of patients with polycythemia vera (PV). Concomitantly, 95% of these patients carry the JAK2V617F mutation. Although NF-E2 levels correlate with JAK2V671F allele burden in some PV cohorts, the molecular mechanism causing aberrant NF-E2 expression has not been described. Here we show that NF-E2 expression is also increased in patients with essential thrombocythemia and primary myelofibrosis independent of the presence of the JAK2V617F mutation. Characterization of the NF-E2 promoter revealed multiple functional binding sites for AML1/RUNX-1. Chromatin immunoprecipitation demonstrated AML1 binding to the NF-E2 promoter in vivo. Moreover, AML1 binding to the NF-E2 promoter was significantly increased in granulocytes from PV patients compared with healthy controls. AML1 mRNA expression was elevated in patients with PV, essential thrombocythemia, and primary myelofibrosis both in the presence and absence of JAK2V617F. In addition, AML1 and NF-E2 expression were highly correlated. RNAi-mediated suppression of either AML1 or of its binding partner CBF-β significantly decreased NF-E2 expression. Moreover, expression of the leukemic fusion protein AML/ETO drastically decreased NF-E2 protein levels. Our data identify NF-E2 as a novel AML1 target gene and delineate a role for aberrant AML1 expression in mediating elevated NF-E2 expression in MPN patients.
Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study
Authors: Mitchell Lesley , Lambers Moritz , Flege Silke , Kenet Gili , Li-Thiao-Te Valerie , Holzhauer Susanne , Bidlingmaier Christoph , Frühwald Michael C. , Heller Christine , Schmidt Wolfgang , Pautard Brigitte , Nowak-Göttl Ulrike
Published: March 2010

Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval [CI], 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials.
Reduced representation of protein structure: implications on efficiency and scope of detection of structural similarity
Authors: Zhang Zong Hong , Lee Hwee Kuan , Mihalek Ivana
Published: March 2010

Background

Computational comparison of two protein structures is the starting point of many methods that build on existing knowledge, such as structure modeling (including modeling of protein complexes and conformational changes), molecular replacement, or annotation by structural similarity. In a commonly used strategy, significant effort is invested in matching two sets of atoms. In a complementary approach, a global descriptor is assigned to the overall structure, thus losing track of the substructures within.

Results

Using a small set of geometric features, we define a reduced representation of protein structure, together with an optimizing function for matching two representations, to provide a pre-filtering stage in a database search. We show that, in a straightforward implementation, the representation performs well in terms of resolution in the space of protein structures, and its ability to make new predictions.

Conclusions

Perhaps unexpectedly, a substantial discriminating power already exists at the level of main features of protein structure, such as directions of secondary structural elements, possibly constrained by their sequential order. This can be used toward efficient comparison of protein (sub)structures, allowing for various degrees of conformational flexibility within the compared pair, which in turn can be used for modeling by homology of protein structure and dynamics.
Moara: a Java library for extracting and normalizing gene and protein mentions
Authors: Neves Mariana L , Carazo José-María , Pascual-Montano Alberto
Published: March 2010

Background

Gene/protein recognition and normalization are important preliminary steps for many biological text mining tasks, such as information retrieval, protein-protein interactions, and extraction of semantic information, among others. Despite dedication to these problems and effective solutions being reported, easily integrated tools to perform these tasks are not readily available.

Results

This study proposes a versatile and trainable Java library that implements gene/protein tagger and normalization steps based on machine learning approaches. The system has been trained for several model organisms and corpora but can be expanded to support new organisms and documents.

Conclusions

Moara is a flexible, trainable and open-source system that is not specifically orientated to any organism and therefore does not requires specific tuning in the algorithms or dictionaries utilized. Moara can be used as a stand-alone application or can be incorporated in the workflow of a more general text mining system.
The function and regulation of the bHLH gene, cato, in Drosophila neurogenesis
Authors: zur Lage Petra I , Jarman Andrew P
Published: March 2010

Background

bHLH transcription factors play many roles in neural development. cousin of atonal (cato) encodes one such factor that is expressed widely in the developing sensory nervous system of Drosophila. However, nothing definitive was known of its function owing to the lack of specific mutations.

Results

We characterised the expression pattern of cato in detail using newly raised antibodies and GFP reporter gene constructs. Expression is predominantly in sensory lineages that depend on the atonal and amos proneural genes. In lineages that depend on the scute proneural gene, cato is expressed later and seems to be particularly associated with the type II neurons. Consistent with this, we find evidence that cato is a direct target gene of Atonal and Amos, but not of Scute. We generated two specific mutations of cato. Mutant embryos show several defects in chordotonal sensory lineages, most notably the duplication of the sensory neuron, which appears to be caused by an extra cell division. In addition, we show that cato is required to form the single chordotonal organ that persists in atonal mutant embryos.

Conclusions

We conclude that although widely expressed in the developing PNS, cato is expressed and regulated very differently in different sensory lineages. Mutant phenotypes correlate with cato's major expression in the chordotonal sensory lineage. In these cells, we propose that it plays roles in sense organ precursor maintenance and/or identity, and in controlling the number of cell divisions in the neuronal branch of the lineage arising from these precursors.
Population dynamic of the extinct European aurochs: genetic evidence of a north-south differentiation pattern and no evidence of post-glacial expansion
Authors: Mona Stefano , Catalano Giulio , Lari Martina , Larson Greger , Boscato Paolo , Casoli Antonella , Sineo Luca , Di Patti Carolina , Pecchioli Elena , Caramelli David , Bertorelle Giorgio
Published: March 2010

Background

The aurochs (Bos primigenius) was a large bovine that ranged over almost the entirety of the Eurasian continent and North Africa. It is the wild ancestor of the modern cattle (Bos taurus), and went extinct in 1627 probably as a consequence of human hunting and the progressive reduction of its habitat. To investigate in detail the genetic history of this species and to compare the population dynamics in different European areas, we analysedBos primigeniusremains from various sites across Italy.

Results

Fourteen samples provided ancient DNA fragments from the mitochondrial hypervariable region. Our data, jointly analysed with previously published sequences, support the view that Italian aurochsen were genetically similar to modern bovine breeds, but very different from northern/central European aurochsen. Bayesian analyses and coalescent simulations indicate that the genetic variation pattern in both Italian and northern/central European aurochsen is compatible with demographic stability after the last glaciation. We provide evidence that signatures of population expansion can erroneously arise in stable aurochsen populations when the different ages of the samples are not taken into account.

Conclusions

Distinct groups of aurochsen probably inhabited Italy and northern/central Europe after the last glaciation, respectively. On the contrary, Italian and Fertile Crescent aurochsen likely shared several mtDNA sequences, now common in modern breeds. We argue that a certain level of genetic homogeneity characterized aurochs populations in Southern Europe and the Middle East, and also that post-glacial recolonization of northern and central Europe advanced, without major demographic expansions, from eastern, and not southern, refugia.
The response to unfolded protein is involved in osmotolerance of Pichia pastoris
Authors: Dragosits Martin , Stadlmann Johannes , Graf Alexandra , Gasser Brigitte , Maurer Michael , Sauer Michael , Kreil David P , Altmann Friedrich , Mattanovich Diethard
Published: March 2010

Background

The effect of osmolarity on cellular physiology has been subject of investigation in many different species. High osmolarity is of importance for biotechnological production processes, where high cell densities and product titers are aspired. Several studies indicated that increased osmolarity of the growth medium can have a beneficial effect on recombinant protein production in different host organisms. Thus, the effect of osmolarity on the cellular physiology ofPichia pastoris, a prominent host for recombinant protein production, was studied in carbon limited chemostat cultures at different osmolarities. Transcriptome and proteome analyses were applied to assess differences upon growth at different osmolarities in both, a wild type strain and an antibody fragment expressing strain. While our main intention was to analyze the effect of different osmolarities onP. pastorisin general, this was complemented by studying it in context with recombinant protein production.

Results

In contrast to the model yeastSaccharomyces cerevisiae, the main osmolyte inP. pastoriswas arabitol rather than glycerol, demonstrating differences in osmotic stress response as well as energy metabolism. 2D Fluorescence Difference Gel electrophoresis and microarray analysis were applied and demonstrated that processes such as protein folding, ribosome biogenesis and cell wall organization were affected by increased osmolarity. These data indicated that upon increased osmolarity less adaptations on both the transcript and protein level occurred in aP. pastorisstrain, secreting the Fab fragment, compared with the wild type strain. No transcriptional activation of the high osmolarity glycerol (HOG) pathway was observed at steady state conditions. Furthermore, no change of the specific productivity of recombinant Fab was observed at increased osmolarity.

Conclusion

These data point out that the physiological response to increased osmolarity is different to S.cerevisiae. Increased osmolarity resulted in an unfolded protein response (UPR) like response inP. pastorisand lead to pre-conditioning of the recombinant Fab producing strain ofP. pastoristo growth at high osmolarity. The current data demonstrate a strong similarity of environmental stress response mechanisms and recombinant protein related stresses. Therefore, these results might be used in future strain and bioprocess engineering of this biotechnologically relevant yeast.
First insights into the genetic diversity of Mycobacterium tuberculosis isolates from HIV-infected Mexican patients and mutations causing multidrug resistance
Authors: Lopez-Alvarez Rocio , Badillo-Lopez Claudia , Cerna-Cortes Jorge F , Castillo-Ramirez Ivan , Rivera-Gutierrez Sandra , Helguera-Repetto Addy C , Aguilar Diana , Hernandez-Pando Rogelio , Samper Sofia , Gonzalez-y-Merchand Jorge A
Published: March 2010

Background

The prevalence of infections with Mycobacterium tuberculosis (MTb) and nontuberculous mycobacteria (NTM) species in HIV-infected patients in Mexico is unknown. The aims of this study were to determine the frequency of MTb and NTM species in HIV-infected patients from Mexico City, to evaluate the genotypic diversity of the Mycobacterium tuberculosis complex strains, to determine their drug resistance profiles by colorimetric microplate Alamar Blue assay (MABA), and finally, to detect mutations present in kat G, rpo B and inh A genes, resulting in isoniazid (INH) and rifampin (RIF) resistance.

Results

Of the 67 mycobacterial strains isolated, 48 were identified as MTb, 9 as M. bovis, 9 as M. avium and 1 as M. intracellulare. IS6110-RFLP of 48 MTb strains showed 27 profiles. Spoligotyping of the 48 MTb strains yielded 21 patterns, and 9 M. bovis strains produced 7 patterns. Eleven new spoligotypes patterns were found. A total of 40 patterns were produced from the 48 MTb strains when MIRU-VNTR was performed. Nineteen (39.6%) MTb strains were resistant to one or more drugs. One (2.1%) multidrug-resistant (MDR) strain was identified. A novel mutation was identified in a RIF-resistant strain, GAG → TCG (Glu → Ser) at codon 469 of rpo B gene.

Conclusions

This is the first molecular analysis of mycobacteria isolated from HIV-infected patients in Mexico, which describe the prevalence of different mycobacterial species in this population. A high genetic diversity of MTb strains was identified. New spoligotypes and MIRU-VNTR patterns as well as a novel mutation associated to RIF-resistance were found. This information will facilitate the tracking of different mycobacterial species in HIV-infected individuals, and monitoring the spread of these microorganisms, leading to more appropriate measures for tuberculosis control.
Sequence analysis of two alleles reveals that intra-and intergenic recombination played a role in the evolution of the radish fertility restorer (Rfo)
Authors: Hernandez Mora José R , Rivals Eric , Mireau Hakim , Budar Françoise
Published: March 2010

Background

Land plant genomes contain multiple members of a eukaryote-specific gene family encoding proteins with pentatricopeptide repeat (PPR) motifs. Some PPR proteins were shown to participate in post-transcriptional events involved in organellar gene expression, and this type of function is now thought to be their main biological role. Among PPR genes, restorers of fertility (Rf) of cytoplasmic male sterility systems constitute a peculiar subgroup that is thought to evolve in response to the presence of mitochondrial sterility-inducing genes. Rf genes encoding PPR proteins are associated with very close relatives on complex loci.

Results

We sequenced a non-restoring allele (L7rfo) of the Rfo radish locus whose restoring allele (D81Rfo) was previously described, and compared the two alleles and their PPR genes. We identified a ca 13 kb long fragment, likely originating from another part of the radish genome, inserted into the L7rfo sequence. The L7rfo allele carries two genes (PPR-1 and PPR-2) closely related to the three previously described PPR genes of the restorer D81Rfo allele (PPR-A, PPR-B, and PPR-C). Our results indicate that alleles of the Rfo locus have experienced complex evolutionary events, including recombination and insertion of extra-locus sequences, since they diverged. Our analyses strongly suggest that present coding sequences of Rfo PPR genes result from intragenic recombination. We found that the 10 C-terminal PPR repeats in Rfo PPR gene encoded proteins result from the tandem duplication of a 5 PPR repeat block.

Conclusions

The Rfo locus appears to experience more complex evolution than its flanking sequences. The Rfo locus and PPR genes therein are likely to evolve as a result of intergenic and intragenic recombination. It is therefore not possible to determine which genes on the two alleles are direct orthologs. Our observations recall some previously reported data on pathogen resistance complex loci.
Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population
Authors: Tabassum Rubina , Mahajan Anubha , Chauhan Ganesh , Dwivedi Om Prakash , Ghosh Saurabh , Tandon Nikhil , Bharadwaj Dwaipayan
Published: March 2010

Background

Type 2 diabetes is a complex metabolic disorder with obesity being a major contributing factor in its development. Susceptibility loci for type 2 diabetes and obesity have been localized on different chromosomal regions by various genome-wide linkage scans. Of these chromosomal regions, 20q13 is one of the strongest linked regions for type 2 diabetes as well as obesity. On 20q13 lies DOK5 that seems to be a strong functional and positional candidate for type 2 diabetes and obesity because of its involvement in insulin signaling and immune responses. Hence, for the first time, we explored DOK5 as a potential type 2 diabetes and obesity susceptibility gene.

Methods

We sequenced 43 subjects for polymorphisms in functionally relevant regions of DOK5. A total of 10 SNPs that included 5 that were identified by sequencing and 5 additional SNPs from NCBI Variation Database were genotyped in 2,115 participants comprising of 1,073 patients with type 2 diabetes and 1,042 controls of Indo-European ethnicity from North India.

Results

We identified a novel variant in intron 7 referred to as DK176673. We found nominal association of three SNPs-rs6064099 (OR = 0.75, P = 0.019), rs873079 (OR = 0.76, P = 0.036) and DK176673 (OR = 1.55, P = 0.037) with type 2 diabetes among normal-weight subjects [BMI < 23 kg/m2]. The haplotype GGC harboring rs6068916, rs6064099 and rs873079 showed strong association with type 2 diabetes among normal-weight subjects (OR = 1.37, P/P
perm = 5.8 × 10-3/0.037). Association analysis with obesity revealed that rs6064099 is associated with reduced susceptibility for obesity (OR = 0.48, P = 6.8 × 10-3). Also, haplotype GGC conferred increased susceptibility for obesity (OR = 1.27, P/P
perm = 9.0 × 10-3/0.039). Also, rs6064099 was significantly associated with reduced BMI [median(IQR) = 24.0(20.7-27.1) vs 23.9(20.2-26.8) vs 21.8(19.2-24.7) for GG vs GC vs CC, P = 7.0 × 10-3].

Conclusions

We identified DOK5 as a novel susceptibility gene for obesity and type 2 diabetes in North Indian subjects. Association of DOK5 variants both with obesity and type 2 diabetes suggests that these variants might modulate type 2 diabetes susceptibility through obesity.
Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker
Authors: Kang Un-Beom , Ahn Younghee , Lee Jong Won , Kim Yong-Hak , Kim Joon , Yu Myeong-Hee , Noh Dong-Young , Lee Cheolju
Published: March 2010

Background

Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood.

Methods

Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT) labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays.

Results

A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD), and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002). BTD levels were lowered in all cancer grades (I-IV) except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940) and progesterone receptor status (p = 0.440) were not associated with the plasma BTD levels.

Conclusions

Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer.
The Heavy Vehicle Study: a case-control study investigating risk factors for crash in long distance heavy vehicle drivers in Australia
Authors: Stevenson Mark , Sharwood Lisa N , Wong Keith , Elkington Jane , Meuleners Lynn , Ivers Rebecca Q , Grunstein Ron R , Williamson Ann , Haworth Narelle , Norton Robyn
Published: March 2010

Background

Heavy vehicle transportation continues to grow internationally; yet crash rates are high, and the risk of injury and death extends to all road users. The work environment for the heavy vehicle driver poses many challenges; conditions such as scheduling and payment are proposed risk factors for crash, yet the precise measure of these needs quantifying. Other risk factors such as sleep disorders including obstructive sleep apnoea have been shown to increase crash risk in motor vehicle drivers however the risk of heavy vehicle crash from this and related health conditions needs detailed investigation.

Methods and Design

The proposed case control study will recruit 1034 long distance heavy vehicle drivers: 517 who have crashed and 517 who have not. All participants will be interviewed at length, regarding their driving and crash history, typical workloads, scheduling and payment, trip history over several days, sleep patterns, health, and substance use. All participants will have administered a nasal flow monitor for the detection of obstructive sleep apnoea.

Discussion

Significant attention has been paid to the enforcement of legislation aiming to deter problems such as excess loading, speeding and substance use; however, there is inconclusive evidence as to the direction and strength of associations of many other postulated risk factors for heavy vehicle crashes. The influence of factors such as remuneration and scheduling on crash risk is unclear; so too the association between sleep apnoea and the risk of heavy vehicle driver crash. Contributory factors such as sleep quality and quantity, body mass and health status will be investigated. Quantifying the measure of effect of these factors on the heavy vehicle driver will inform policy development that aims toward safer driving practices and reduction in heavy vehicle crash; protecting the lives of many on the road network.
Molecular defects in the mannose binding lectin pathway in dermatological disease: Case report and literature review
Authors: Miller Christopher , Wilgenbusch Sara , Michael Mini , Chi David S , Youngberg George , Krishnaswamy Guha
Published: March 2010

Mannose-binding lectin (MBL) and the Mannose-binding lectin-associated serine proteases (MASPs) are an essential aspect of innate immune responses that probably play an important but understudied role in cutaneous function. The MBL-MASP pathway appears to exert its primary role by assisting in the clearance of apoptotic skin cells (thus preventing accumulation and a subsequent autoimmune response) and promoting opsonophagocytosis of invading pathogens, limiting their dissemination. Deficiencies of the pathway have been described and are associated with infectious, autoimmune and vascular complications. However, the role of this pathway in dermatological disease is essentially unexplored. We describe 6 patients presenting with recurrent inflammatory and/or infectious skin conditions who also demonstrated severely low MBL levels. One patient also had a defect in the MASP2 gene. Genotype analysis revealed specific point mutations in theMBL2promoter in all 6 patients and a variant MASP-2 gene in one patient. Five patients presented recurrent pustular skin infections (cellulitis, folliculitis and cutaneous abscess). A case of Grover's disease and one forme fruste of Behcet's syndrome (orogenital ulcers) were also observed. The patients responded to antimicrobial therapy, although in some, recurrence of infection was the rule. It appears that MBL deficiency may contribute to recurrent skin infections and to certain forms of inflammatory skin disease. The mechanisms may relate to the role of this pathway in innate immunity, removal of apoptotic cells and in immune complexes. Further study of MBL pathway defects in dermatological disease is required.
Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics
Authors: Hsieh Chen-Hsi , Hsieh Yen-Ju , Liu Chia-Yuan , Tai Hung-Chi , Huang Yu-Chuen , Shueng Pei-Wei , Wu Le-Jung , Wang Li-Ying , Tsai Tung-Hu , Chen Yu-Jen
Published: March 2010

Background

Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for treatment of abdominal malignancy. Nonetheless, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of abdominal irradiation on the pharmacokinetics of 5-FU in rats.

Methods

The radiation dose distributions of cholangiocarcinoma patients were determined for the low dose areas, which are generously deposited around the intrahepatic target volume. Then, corresponding single-fraction radiation was delivered to the whole abdomen of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Ultrafiltration was used to measure protein-unbound 5-FU.

Results

Radiation at 2 Gy, simulating the daily human treatment dose, reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU by 31.7% compared to non-irradiated controls. This was accompanied by a reduction in mean residence time and incremental total plasma clearance values, and volume of distribution at steady state. Intriguingly, low dose radiation at 0.5 Gy, representing a dose deposited in the generous, off-target area in clinical practice, resulted in a similar pharmacokinetic profile, with a 21.4% reduction in the AUC. This effect was independent of protein binding capacity.

Conclusions

Abdominal irradiation appears to significantly modulate the systemic pharmacokinetics of 5-FU at both the dose level for target treatment and off-target areas. This unexpected and unwanted influence is worthy of further investigation and might need to be considered in clinical practice.
Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma
Authors: Chen Jing , Hu Chun-Fang , Hou Jing-Hui , Shao Qiong , Yan Li-Xu , Zhu Xiao-Feng , Zeng Yi-Xin , Shao Jian-Yong
Published: March 2010

Background

The oncoprotein Epstain-Barr Virus (EBV)-encoded latent membrane protein1 (LMP1) modulates the pathological effects of the NF-κB, AP-1 and JAK/STAT pathways in nasopharyngeal carcinoma (NPC).

Methods

Microarray analysis was performed on the NPC cell line HONE1 stably transfected with a LMP1-expression plasmid or an empty vector. Based on assigned pathways analyzed using the KEGG database, the mTOR signaling pathway was selected for verification by quantitative RT-PCR. Western blot, RNA interference and immunofluorescence were used to determine the relationship between LMP1 and mTOR signing pathway genes, and their clinical significance to NPC.

Results

Our studies revealed that overexpression of LMP1 upregulated the mTOR signaling pathway, possibly through phosphorylation of AKT/mTOR/P70S6K/4EBP1 in the NPC cell lines HONE1 and 6-10B. Knockdown of LMP1 reduced expression of p-mTOR and p-4EBP1 in EBV-positive NPC cell line C666-1. In addition, LMP1 expression closely correlated with expression of p-mTOR, p-P70S6K and p-4EBP1 in NPC tumors. Expression of p-P70S6K, p-4EBP1 and LMP1, but not p-mTOR, significantly correlated with overall survival of NPC patients. However, only LMP1 was an independent prognostic factor.

Conclusions

These results suggest that the mTOR signaling pathway is regulated by LMP1 expression in NPC. LMP1 and the genes in the mTOR pathway such as p-P70S6K and p-4EBP1 may be potential prognostic biomarkers.
Multiple oncogenic viruses identified in Ocular surface squamous neoplasia in HIV-1 patients
Authors: Simbiri Kenneth O , Murakami Masanao , Feldman Michael , Steenhoff Andrew P , Nkomazana Oathokwa , Bisson Gregory , Robertson Erle S
Published: March 2010

Background

Ocular surface squamous neoplasia (OSSN) is a rare cancer that has increased in incidence with the HIV pandemic in Africa. The underlying cause of this cancer in HIV-infected patients from Botswana is not well defined.

Results

Tissues were obtained from 28 OSSN and 8 pterygia patients. The tissues analyzed from OSSN patients were 83% positive for EBV, 75% were HPV positive, 70% were KSHV positive, 75% were HSV-1/2 positive, and 61% were CMV positive by PCR. Tissues from pterygium patients were 88% positive for EBV, 75% were HPV positive, 50% were KSHV positive, and 60% were CMV positive. None of the patients were JC or BK positive.In situhybridization and immunohistochemistry analyses further identified HPV, EBV, and KSHV in a subset of the tissue samples.

Conclusion

We identified the known oncogenic viruses HPV, KSHV, and EBV in OSSN and pterygia tissues. The presence of these tumor viruses in OSSN suggests that they may contribute to the development of this malignancy in the HIV population. Further studies are necessary to characterize the molecular mechanisms associated with viral antigens and their potential role in the development of OSSN.
Stochastic and deterministic multiscale models for systems biology: an auxin-transport case study
Authors: Twycross Jamie , Band Leah R , Bennett Malcolm J , King John R , Krasnogor Natalio
Published: March 2010

Background

Stochastic and asymptotic methods are powerful tools in developing multiscale systems biology models; however, little has been done in this context to compare the efficacy of these methods. The majority of current systems biology modelling research, including that of auxin transport, uses numerical simulations to study the behaviour of large systems of deterministic ordinary differential equations, with little consideration of alternative modelling frameworks.

Results

In this case study, we solve an auxin-transport model using analytical methods, deterministic numerical simulations and stochastic numerical simulations. Although the three approaches in general predict the same behaviour, the approaches provide different information that we use to gain distinct insights into the modelled biological system. We show in particular that the analytical approach readily provides straightforward mathematical expressions for the concentrations and transport speeds, while the stochastic simulations naturally provide information on the variability of the system.

Conclusions

Our study provides a constructive comparison which highlights the advantages and disadvantages of each of the considered modelling approaches. This will prove helpful to researchers when weighing up which modelling approach to select. In addition, the paper goes some way to bridging the gap between these approaches, which in the future we hope will lead to integrative hybrid models.
Addison's disease presenting with idiopathic intracranial hypertension in 24-year-old woman: a case report
Authors: Sharma Dushyant , Mukherjee Rohini , Moore Peter , Cuthbertson Daniel J
Published: March 2010

Introduction

Idiopathic intracranial hypertension can rarely be associated with an underlying endocrine disorder such as Cushing's syndrome, hyperthyroidism, or with administration of thyroxine or growth hormone. Though cases of idiopathic intracranial hypertension associated with Addison's disease in children have been reported, there is only one documented case report of this association in adults. We describe a case of an acute adrenal insufficiency precipitated by idiopathic intracranial hypertension in a Caucasian female.

Case presentation

A 24-year-old Caucasian woman was acutely unwell with a background of several months of generalised fatigue and intermittent headaches. She had unremarkable neurological and systemic examination with a normal computerised tomography and magnetic resonance imaging of the brain. Normal cerebrospinal fluid but increased opening pressure at lumbar puncture suggested intracranial hypertension. A flat short synacthen test and raised level of adrenocorticotrophic hormone were consistent with primary adrenal failure.

Conclusion

Addison's disease can remain unrecognised until precipitated by acute stress. This case suggests that idiopathic intracranial hypertension can rarely be associated with Addison's disease and present as an acute illness. Idiopathic intracranial hypertension is possibly related to an increase in the levels of arginine vasopressin peptide in serum and cerebrospinal fluid secondary to a glucocorticoid deficient state.
Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature
Authors: Bautista Marnelli A , Stevens W Tait , Chen Chien-Shing , Curtis Brian R , Aster Richard H , Hsueh Chung-Tsen
Published: March 2010

Background

Oxaliplatin is a platinum compound used in the treatment of gastrointestinal malignancies, including colorectal cancer. The incidence of hypersensitivity reaction in patients receiving oxaliplatin is approximately 15%, with severe reaction (grade 3 and 4) occurring in 2% of patients.

Case presentation

We report two patients with metastatic colorectal cancer who developed de novo hypersensitivity reaction and acute thrombocytopenia after oxaliplatin infusion. Both patients had oxaliplatin treatment several years before and exhibited hypersensitivity on the third dose of oxaliplatin in recent treatment. Oxaliplatin was discontinued when clinical reaction was identified. Both patients were confirmed to have strong oxaliplatin-induced IgG platelet-reactive antibodies. Both patients' thrombocytopenia resolved within two weeks after discontinuation of oxaliplatin. One patient had disease stabilization lasting for three months without chemotherapy. Both patients subsequently received other chemotherapeutic agents without evidence of hypersensitivity reaction or immune-mediated thrombocytopenia.

Conclusion

We recommend vigilant monitoring of complete blood count and signs and symptoms of bleeding after the occurrence of oxaliplatin-induced hypersensitivity to avoid serious complications of immune-mediated thrombocytopenia.
Methylation of the SPARC gene promoter and its clinical implication in pancreatic cancer
Authors: Gao Jun , Song Jian , Huang Haojie , Li Zhaoshen , Du Yiqi , Cao Jia , Li Minghui , Lv Shunli , Lin Han , Gong Yanfang
Published: March 2010

Background

The secreted protein acidic and rich in cysteine (SPARC) plays a pivotal role in regulating cell-matrix interactions and tumor angiogenesis, proliferation, and migration. Detection of SPARC gene methylation may be useful as a tumorigenesis marker for early detection of pancreatic cancer.

Methods

Methylation of the SPARC gene transcriptional regulation region (TRR) was detected using bisulfite-specific (BSP) PCR-based sequencing analysis in 40 cases of pancreatic cancer and the adjacent normal tissues, 6 chronic pancreatitis tissues, and 6 normal pancreatic tissues. BSP cloning-based sequencing analysis was also performed in selected cases. Clinicopathological data from the cancer patients were collected and analyzed.

Results

Analysis of SPARC gene TRR methylation showed two hypermethylation wave peak regions: CpG Region 1 (CpG site 1-7) and CpG Region 2 (CpG site 8-12). Pancreatic tissues have shown methylation in both regions with gradual increases from normal, chronic pancreatitis, and adjacent normal tissues to cancerous tissues. However, Methylation of CpG Region 2 was more sensitive than CpG Region 1 in pancreatic tumorigenesis. Furthermore, the methylation level of CpG Region 2 was associated with increased tumor size and exposure to the risk factors (tobacco smoke and alcohol consumption) for developing pancreatic cancer.

Conclusion

Methylation of the SPARC gene, specifically CpG Region 2, may be an early event during pancreatic tumorigenesis and should be further evaluated as a tumorigenesis marker for early detection of pancreatic cancer.
Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway
Authors: Vaschetto Rosanna , Kuiper Jan W , Musters René JP , Eringa Etto C , Della Corte Francesco , Murthy Kanneganti , Groeneveld AB Johan , Plötz Frans B
Published: March 2010

Introduction

Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.

Methods

Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining.

Results

High tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes.

Conclusions

The peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.
Translation-Equivariant Matchings of Coin Flips on ℤd
Authors: Soo Terry
Published: March 2010

Consider independent fair coin flips at each site of the lattice ℤd. A translation-equivariant matching rule is a perfect matching of heads to tails that commutes with translations of ℤd and is given by a deterministic function of the coin flips. Let ZΦ be the distance from the origin to its partner, under the translation-equivariant matching rule Φ. Holroyd and Peres (2005) asked, what is the optimal tail behaviour of ZΦ for translation-equivariant perfect matching rules? We prove that, for every d ≥ 2, there exists a translation-equivariant perfect matching rule Φ such that EZΦ2/3-ε < ∞ for every ε > 0.