bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the integrity of a single stud assembly with externally corroded nuts
Authors: Sutherland Peter F , Galloway Alex M , Longhurst Gary
Published: May 2012

The aim of this study was to determine whether a single 7/8′′ nominal diameter stud bolt and nuts assembly would fail to perform its required function in a flange assembly when the nut was corroded. This work was undertaken to form a basis for further work in development of a fitness-for-service assessment for corroded nuts. No current quantitative assessments exist for this area. A failure criterion was defined as a minimum 206.8 MPa stress in the stud, based on the bolting requirements stated in ASME B16.5-2003 pipe flanges and flanges fittings. A simple test rig was manufactured for testing the compliance of the corroded nuts subjected to the 206.8 MPa stress level and the corrosion was simulated by removing uniform layers of material from the surface of the nut. Finite element analysis (ANSYS 12.0) was also performed to evaluate the test rig and to consider the interaction between the nut and stud at the thread roots. It was found that no failure occurred in the threading and that failure of the assembly only occurred when there was a >60% material loss from the nut. The failure mode experienced was deformation of the flange plate. This analysis proved that a nut can experience significant effective material loss without damaging the flange integrity.
A multicentre, randomized study of telmisartan versus carvedilol for prevention of atrial fibrillation recurrence in hypertensive patients
Authors: Galzerano Domenico , Di Michele Sara , Paolisso Giuseppe , Tuccillo Bernardino , Lama Diana , Carbotta Sabino , Cittadini Antonio , Tedesco Michele Adolfo , Gaudio Carlo
Published: May 2012

Introduction:

Atrial remodelling, leading to atrial fibrillation (AF), is mediated by the renin–angiotensin–aldosterone system.

Methods:

Mild hypertensive outpatients (systolic/diastolic blood pressure 140–159/90–99 mmHg) in sinus rhythm who had experienced ≥ 1 electrocardiogram (ECG)-documented AF episode in the previous six months received randomly telmisartan 80 mg/day or carvedilol 25 mg/day. Blood pressure and 24-hour ECG were monitored monthly for one year; patients were asked to report symptomatic AF episodes and to undergo an ECG as early as possible.

Results:

One hundred and thirty-two patients completed the study (telmisartan, n=70; carvedilol, n=62). Significantly fewer AF episodes were reported with telmisartan versus carvedilol (14.3% vs. 37.1%; p<0.003). Left atrial diameter, assessed by echocardiography, was similar with telmisartan and carvedilol (3.4±2.3 cm vs. 3.6±2.4 cm). At study end, both regimes significantly reduced mean left ventricular mass index, but the reduction obtained with telmisartan was significantly greater than with carvedilol (117.8±10.7 vs. 124.7±14.5; p<0.0001). Mean blood pressure values were not significantly different between the groups (telmisartan 154/97 to 123/75 mmHg; p<0.001; carvedilol 153/94 to 125/78 mmHg; p<0.001).

Conclusions:

Telmisartan was significantly more effective than carvedilol in preventing recurrent AF episodes in hypertensive AF patients, despite a similar lowering of blood pressure.
Management of allergic bronchopulmonary aspergillosis: a review and update
Authors: Mahdavinia Mahboobeh , Grammer Leslie C.
Published: May 2012

Since the first description of allergic bronchopulmonary aspergillosis (ABPA) in the 1950s there have been numerous studies that have shed light on the characteristics and immunopathogenesis of this disease. The increased knowledge and awareness have resulted in earlier diagnosis and treatment of patients with this condition. This article aims to provide a summary and updates on ABPA by reviewing the results of recent studies on this disease with a focus on articles published within the last 5 years. A systematic search of PubMed/Medline with keywords of ABPA or allergic bronchopulmonary aspergillosis was performed. All selected articles were reviewed with a focus on findings of articles published from December 2006 to December 2011. The relevant findings are summarized in this paper.
Therapeutic procedures for coronary vasospasm-induced polymorphic ventricular tachycardia
Authors: Dresen William F. , Wells Quinn S. , Maron David J. , McPherson John A.
Published: May 2012

Coronary vasospasm is an unusual cause of angina and myocardial ischemia, with the potential to provoke acute myocardial infarction, malignant cardiac arrhythmias, and sudden cardiac death. The diagnosis is largely clinical and requires a high index of suspicion. Provocation studies are rarely performed due to the risks of the procedure and the relatively low incidence of disease. A subset of patients does not respond to conventional medical therapy and a paucity of evidence exists to guide therapy. While generally believed a multifocal phenomenon, there have been reports of successful treatment of focal, refractory vasospasm with coronary stent implantation. Furthermore, consideration of an implantable cardioverter defibrillator is warranted when vasospasm is complicated by lethal ventricular arrhythmias.
Breastfeeding the Infant With Cleft Lip and Palate
Authors: Donovan Kathleen
Published: May 2012

This article describes the importance of the nutritional and nurturing effects of breastfeeding for the infant with cleft lip (CL) or cleft palate (CP). Organizations recognize the health benefits of breastfeeding to the mother and infant. Research indicates that use of breast milk decreases childhood disease, reduces infections, and promotes healing, which are especially important for infants with CL or CP. The degree of the defect of the CL and CP influences potential complications associated with feedings and the nutritional status of the infant. The multidisciplinary team should include the infant’s physician, the craniofacial team, dietitian, lactation consultant, and speech and oral pathologist.
Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer
Authors: Wang Jian-Guo , Geddings Julia E. , Aleman Maria M. , Cardenas Jessica C. , Chantrathammachart Pichika , Williams Julie C. , Kirchhofer Daniel , Bogdanov Vladimir Y. , Bach Ronald R. , Rak Janusz , Church Frank C. , Wolberg Alisa S. , Pawlinski Rafal , Key Nigel S. , Yeh Jen Jen , Mackman Nigel
Published: May 2012

Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti–human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.
Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer
Authors: Ramsay Alan G. , Clear Andrew J. , Fatah Rewas , Gribben John G.
Published: May 2012

Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand–induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell–inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer.
How I treat POEMS syndrome
Authors: Dispenzieri Angela
Published: May 2012

POEMS syndrome is a paraneoplastic syndrome whose acronym stands for less than half of the defining features of the disease, that is, polyradiculoneuropathy, organomegaly, potentially including coexisting Castleman disease, endocrinopathy, monoclonal plasma cell neoplasm, and skin changes. The other important features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, elevated VEGF, and abnormal pulmonary function. The diagnosis is based on having both the polyradiculoneuropathy and the monoclonal plasma cell disorder, and at least 1 of the other 3 major criteria (Castleman disease, sclerotic bone lesions, or elevated VEGF) and at least one minor criterion. The diagnosis is often delayed with intervening incorrect diagnoses of chronic inflammatory demyelinating polyradiculoneuropathy, myeloproliferative disorder, and monoclonal gammopathy of undetermined significance. Prompt treatment directed at the underlying plasma cell clone produces dramatic responses in the majority of patients. Although there are no randomized clinical trial data to direct best therapy, for patients with disseminated disease, high-dose chemotherapy with peripheral blood transplantation has yielded durable benefit, whereas radiation therapy is typically effective for patients with a more localized presentation. More universal recognition of and more scientific inquiry into the underpinnings of the disease will provide direction toward the best treatment strategies in the future.
Mayday - integrative analytics for expression data
Authors: Battke Florian , Symons Stephan , Nieselt Kay
Published: May 2012

Background

DNA Microarrays have become the standard method for large scale analyses of gene expression and epigenomics. The increasing complexity and inherent noisiness of the generated data makes visual data exploration ever more important. Fast deployment of new methods as well as a combination of predefined, easy to apply methods with programmer's access to the data are important requirements for any analysis framework. Mayday is an open source platform with emphasis on visual data exploration and analysis. Many built-in methods for clustering, machine learning and classification are provided for dissecting complex datasets. Plugins can easily be written to extend Mayday's functionality in a large number of ways. As Java program, Mayday is platform-independent and can be used as Java WebStart application without any installation. Mayday can import data from several file formats, database connectivity is included for efficient data organization. Numerous interactive visualization tools, including box plots, profile plots, principal component plots and a heatmap are available, can be enhanced with metadata and exported as publication quality vector files.

Results

We have rewritten large parts of Mayday's core to make it more efficient and ready for future developments. Among the large number of new plugins are an automated processing framework, dynamic filtering, new and efficient clustering methods, a machine learning module and database connectivity. Extensive manual data analysis can be done using an inbuilt R terminal and an integrated SQL querying interface. Our visualization framework has become more powerful, new plot types have been added and existing plots improved.

Conclusions

We present a major extension of Mayday, a very versatile open-source framework for efficient micro array data analysis designed for biologists and bioinformaticians. Most everyday tasks are already covered. The large number of available plugins as well as the extension possibilities using compiled plugins and ad-hoc scripting allow for the rapid adaption of Mayday also to very specialized data exploration. Mayday is available at http://microarray-analysis.org.
Computational prediction and experimental validation of evolutionarily conserved microRNA target genes in bilaterian animals
Authors: Takane Kahori , Fujishima Kosuke , Watanabe Yuka , Sato Asako , Saito Nobuto , Tomita Masaru , Kanai Akio
Published: May 2012

Background

In many eukaryotes, microRNAs (miRNAs) bind to complementary sites in the 3'-untranslated regions (3'-UTRs) of target messenger RNAs (mRNAs) and regulate their expression at the stage of translation. Recent studies have revealed that many miRNAs are evolutionarily conserved; however, the evolution of their target genes has yet to be systematically characterized. We sought to elucidate a set of conserved miRNA/target-gene pairs and to analyse the mechanism underlying miRNA-mediated gene regulation in the early stage of bilaterian evolution.

Results

Initially, we extracted five evolutionarily conserved miRNAs (let-7, miR-1, miR-124, miR-125/lin-4, and miR-34) among five diverse bilaterian animals. Subsequently, we designed a procedure to predict evolutionarily conserved miRNA/target-gene pairs by introducing orthologous gene information. As a result, we extracted 31 orthologous miRNA/target-gene pairs that were conserved among at least four diverse bilaterian animals; the prediction set showed prominent enrichment of orthologous miRNA/target-gene pairs that were verified experimentally. Approximately 84% of the target genes were regulated by three miRNAs (let-7, miR-1, and miR-124) and their function was classified mainly into the following categories: development, muscle formation, cell adhesion, and gene regulation. We used a reporter gene assay to experimentally verify the downregulation of six candidate pairs (out of six tested pairs) in HeLa cells.

Conclusions

The application of our new method enables the identification of 31 miRNA/target-gene pairs that were expected to have been regulated from the era of the common bilaterian ancestor. The downregulation of all six candidate pairs suggests that orthologous information contributed to the elucidation of the primordial set of genes that has been regulated by miRNAs; it was also an efficient tool for the elimination of false positives from the predicted candidates. In conclusion, our study identified potentially important miRNA-target pairs that were evolutionarily conserved throughout diverse bilaterian animals and that may provide new insights into early-stage miRNA functions.
Functional and evolutionary correlates of gene constellations in the Drosophila melanogaster genome that deviate from the stereotypical gene architecture
Authors: Li Shuwei , Shih Ching-Hua , Kohn Michael H
Published: May 2012

Background

The biological dimensions of genes are manifold. These include genomic properties, (e.g., X/autosomal linkage, recombination) and functional properties (e.g., expression level, tissue specificity). Multiple properties, each generally of subtle influence individually, may affect the evolution of genes or merely be (auto-)correlates. Results of multidimensional analyses may reveal the relative importance of these properties on the evolution of genes, and therefore help evaluate whether these properties should be considered during analyses. While numerous properties are now considered during studies, most work still assumes the stereotypical solitary gene as commonly depicted in textbooks. Here, we investigate the Drosophila melanogaster genome to determine whether deviations from the stereotypical gene architecture correlate with other properties of genes.

Results

Deviations from the stereotypical gene architecture were classified as the following gene constellations: Overlapping genes were defined as those that overlap in the 5-prime, exonic, or intronic regions. Chromatin co-clustering genes were defined as genes that co-clustered within 20 kb of transcriptional territories. If this scheme is applied the stereotypical gene emerges as a rare occurrence (7.5%), slightly varied schemes yielded between ~1%-50%. Moreover, when following our scheme, paired-overlapping genes and chromatin co-clustering genes accounted for 50.1 and 42.4% of the genes analyzed, respectively. Gene constellation was a correlate of a number of functional and evolutionary properties of genes, but its statistical effect was ~1-2 orders of magnitude lower than the effects of recombination, chromosome linkage and protein function. Analysis of datasets on male reproductive proteins showed these were biased in their representation of gene constellations and evolutionary rate Ka/Ks estimates, but these biases did not overwhelm the biologically meaningful observation of high evolutionary rates of male reproductive genes.

Conclusion

Given the rarity of the solitary stereotypical gene, and the abundance of gene constellations that deviate from it, the presence of gene constellations, while once thought to be exceptional in large Eukaryote genomes, might have broader relevance to the understanding and study of the genome. However, according to our definition, while gene constellations can be significant correlates of functional properties of genes, they generally are weak correlates of the evolution of genes. Thus, the need for their consideration would depend on the context of studies.
Gene expression profile of the skin in the 'hairpoor' (HrHp) mice by microarray analysis
Authors: Kim Bong-Kyu , Baek In-Cheol , Lee Hwa-Young , Kim Jeong-Ki , Song Hae-Hiang , Yoon Sungjoo K
Published: May 2012

Background

The transcriptional cofactor, Hairless (HR), acts as one of the key regulators of hair follicle cycling; the loss of function mutations is the cause of the expression of the hairless phenotype in humans and mice. Recently, we reported a new Hr mutant mouse called 'Hairpoor' (Hr

Hp
). These mutants harbor a gain of the function mutation, T403A, in the Hr gene. This confers the overexpression of HR and Hr

Hp
is an animal model of Marie Unna hereditary hypotrichosis in humans. In the present study, the expression profile of Hr

Hp

/Hr

Hp
skin was investigated using microarray analysis to identify genes whose expression was affected by the overexpression of HR.

Results

From 45,282 mouse probes, differential expressions in 43 (>2-fold), 306 (>1.5-fold), and 1861 genes (>1.2-fold) in skin from Hr

Hp

/Hr

Hp
mice were discovered and compared with skin from wild-type mice. Among the 1861 genes with a > 1.2-fold increase in expression, further analysis showed that the expression of eight genes known to have a close relationship with hair follicle development, ascertained by conducting real-time PCR on skin RNA produced during hair follicle morphogenesis (P0-P14), indicated that four genes, Wif1, Casp14, Krt71, and Sfrp1, showed a consistent expression pattern with respect to HR overexpression in vivo.

Conclusion

Wif1 and Casp14 were found to be upregulated, whereas Krt71 and Sfrp1 were downregulated in cells overexpressing HR in transient transfection experiments on keratinocytes, suggesting that HR may transcriptionally regulate these genes. Further studies are required to understand the mechanism of this regulation by the HR cofactor.
Fibronectin-binding protein B variation in Staphylococcus aureus
Authors: Burke Fiona M , McCormack Niamh , Rindi Simonetta , Speziale Pietro , Foster Timothy J
Published: May 2012

Background

Fibronectin binding proteins A and B (FnBPA and FnBPB) mediate adhesion of S. aureus to fibrinogen, elastin and fibronectin. We previously identified seven different isotypes of FnBPA based on divergence in the fibrinogen- and elastin-binding A domains. The variation created differences in antigenicity while ligand binding functions were retained. Here, FnBPB variation was examined in both human and bovine isolates and compared to that of FnBPA.

Results

Seven different fnbB allelic variants were identified. Some strains that cluster by phylogenetic analysis contain different fnbB variants, whereas more divergent strains contain the same fnb B variant. The phylogeny of fnb B alleles does not match the phylogeny of fnbA alleles. Some FnBPA and FnBPB isotypes that are specified by human S. aureus strains are also found in bovine strains. The seven fnb B allelic variants encode seven distinct isotypes of the FnBPB A domain that are 61 to 85% identical in amino acid sequence. Variant amino acid residues were mapped on a three-dimensional model of the FnBPB A domain and were predicted to be surface-exposed. They are responsible for the antigenic diversity detected with polyclonal antibody and a monoclonal antibody raised against isotype I. Ligand binding by recombinant FnBPB N23 isotypes was compared by ELISA-based solid phase assays and surface plasmon resonance. Each bound to immobilized fibrinogen, elastin and fibronectin dose-dependently and saturably with similar affinities. Binding to fibronectin was surprising because the A domains do not contain any known motifs that mediate binding to fibronectin. This raises the possibility that the A domain of FnBPB contains a novel fibronectin binding motif that binds fibronectin by a novel mechanism.

Conclusions

Seven different isoforms of FnBPB A domain retain ligand-binding functions but are antigenically distinct. The variation in FnBPA and FnBPB occurs in human and bovine S. aureus strains and may act as an immune evasion mechanism. All seven isotypes of FnBPB are capable of binding fibronectin though none contain any known fibronectin-binding motifs. These results have implications for the development of vaccines or immunotherapeutics that target FnBPB
Comparison of BCG, MPL and cationic liposome adjuvant systems in leishmanial antigen vaccine formulations against murine visceral leishmaniasis
Authors: Ravindran Rajesh , Bhowmick Sudipta , Das Amrita , Ali Nahid
Published: May 2012

Background

The development of an effective vaccine against visceral leishmaniasis (VL) caused byLeishmania donovaniis an essential aim for controlling the disease. Use of the right adjuvant is of fundamental importance in vaccine formulations for generation of effective cell-mediated immune response. Earlier we reported the protective efficacy of cationic liposome-associatedL. donovanipromastigote antigens (LAg) against experimental VL. The aim of the present study was to compare the effectiveness of two very promising adjuvants, Bacille Calmette-Guerin (BCG) and Monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) with cationic liposomes, in combination with LAg, to confer protection against murine VL.

Results

All the three formulations afforded significant protection againstL. donovaniin both the visceral organs, liver and spleen. Although comparable level of protection was observed in BCG+LAg and MPL-TDM+LAg immunized mice, highest level of protection was exhibited by the liposomal LAg immunized group. Significant increase in anti-LAg IgG levels were detected in both MPL-TDM+LAg and liposomal LAg immunized animals with higher levels of IgG2a than IgG1. But BCG+LAg failed to induce any antibody response. As an index of cell-mediated immunity DTH responses were measured and significant response was observed in mice vaccinated with all the three different formulations. However, highest responses were observed with liposomal vaccine immunization. Comparative evaluation of IFN-γ and IL-4 responses in immunized mice revealed that MPL-TDM+LAg group produced the highest level of IFN-γ but lowest IL-4 level, while BCG+LAg demonstrated generation of suboptimum levels of both IFN-γ and IL-4 response. Elicitation of moderate levels of prechallenge IFN-γ along with optimum IL-4 corresponds with successful vaccination with liposomal LAg.

Conclusion

This comparative study reveals greater effectiveness of the liposomal vaccine for protection against progressive VL in BALB/c. Again, evaluation of the immune responses by vaccination emphasizes the need of stimulation of potent cellular immunity based on both Th1 and Th2 cell responses to confer protection against VL.
Apolipoprotein-E forms dimers in human frontal cortex and hippocampus
Authors: Elliott David A , Halliday Glenda M , Garner Brett
Published: May 2012

Background

Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions.

Results

In apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts.

Conclusion

The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.
Study protocol: population screening for colorectal cancer by colonoscopy or CT colonography: a randomized controlled trial
Authors: de Wijkerslooth Thomas R , de Haan Margriet C , Stoop Esther M , Deutekom Marije , Fockens Paul , Bossuyt Patrick MM , Thomeer Maarten , van Ballegooijen Marjolein , Essink-Bot Marie-Louise , van Leerdam Monique E , Kuipers Ernst J , Dekker Evelien , Stoker Jaap
Published: May 2012

Background

Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives.

Methods and design

7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods.

Discussion

This study will provide further evidence to enable decision making in population screening for colorectal cancer.

Trial registration

Dutch trial register: NTR1829
The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of China
Authors: Wang Shizhuo , Wei Heng , Wang Ning , Zhang Shulan , Zhang Yao , Ruan Qiang , Jiang Weiguo , Xiao Qian , Luan Xiaomei , Qian Xiuyan , Zhang Lili , Gao Xiang , Sun Xiaowei
Published: May 2012

Background

Studies have shown that type-specific persistence of high-risk human papillomavirus (HPV) infection contributed significantly to cervical carcinogenesis.

Methods

In this population-based study (on 24041 women), we report on the prevalent genotypes of HPVs and the prevalent genotypes of HPV persistent infection in the northeast of China.

Results

Our results showed that in HPV infected women (45.6% in total), (95% CI, 44.97%–46.23%), 17.35% (95%CI, 16.87%–17.83%) suffered persistent infection. The most common high-risk HPV types in persistent positivity were HPV-16 (18.21%; 95%CI, 17.04%–19.38%), HPV-58 (13.2%; 95%CI, 12.17%–14.23%), HPV-18 (8.66%; 95%CI, 7.81%–9.51%), HPV-52 (7.06%; 95% CI, 6.28%–7.84%) and HPV-33 (6.78%; 95% CI, 6.02%–7.54%). The prevalence of persistent infections with HPV-16,–58, −18, −52 and 33 in cervicitis were lower compared to those in CIN (all P < 0.05). HPV-58, −33 and multiple HPV persistent positivity were significantly associated with older age (all P < 0.05). HPV-18 persistent positivity was significantly associated with adenocarcinoma and lymphatic metastasis (all P < 0.05). HPV-18 persistent positivity was associated with cervical cancer prognosis (P <0.0001). Multivariate analyses showed that HPV-18 persistent positivity, (RR = 1.704, 95%CI = 1.095–2.654, p = 0.028) and lymphatic metastasis (RR = 2.304, 95%CI = 1.354–3.254, P = 0.015) were independent predictors for 3-year survival in cervical cancer.

Conclusions

we provided extensive results of HPV genotype prevalence and distribution in the northeast of China. HPV genotyping is worthwhile to perform because of its independent prognostic value in cervical cancer
Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene
Authors: Trdan Lušin Tina , Stieger Bruno , Marc Janja , Mrhar Aleš , Trontelj Jurij , Zavratnik Andrej , Ostanek Barbara
Published: May 2012

Background

Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene.

Methods

To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene.

Results

Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c. 388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene.

Conclusions

These findings indicate that SLCO1B1 c. 388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene.
Molecular target based combinational therapeutic approaches in thyroid cancer
Authors: Rajoria Shilpi , Suriano Robert , George Andrea L , Kamat Ameet , Schantz Stimson P , Geliebter Jan , Tiwari Raj K
Published: May 2012

Background

Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer.

Methods

In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3′-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations.

Results

Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3′-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs.

Conclusion

Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3′-diindolylmethane is a promising naturally occurring anti-estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer.
Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behçet’s disease
Authors: Sugita Sunao , Kawazoe Yuko , Imai Ayano , Yamada Yukiko , Horie Shintaro , Mochizuki Manabu
Published: May 2012

Introduction

The purpose of this study was to determine whether anti-tumour necrosis factor alpha (anti-TNF-α) antibody, infliximab, can inhibit T helper 17 (Th17) differentiation in uveitis patients who have Behçet's disease (BD).

Methods

To measure inflammatory cytokines, ocular fluid samples from BD patients being treated with infliximab were collected. Cluster of differentiation 4 (CD4)+ T cells from BD patients with active uveitis were co-cultured with anti-cluster of differentiation 3/cluster of differentiation 28 (CD3/CD28) antibodies in the presence of infliximab. For the induction of Th17 cells, CD4+ T cells from BD patients were co-cultured with anti-CD3/CD28, anti-interferon-gamma (anti-IFN-γ), anti-interleukin-4 (anti-IL-4), and recombinant proteins such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-23 (IL-23), and TNF-α. The BD T cells were co-cultured with infliximab, and the production of interleukin-17 (IL-17) was evaluated by ELISA and flow cytometry, and the expression of retinoid-acid receptor-related orphan receptor gamma t (RORγt) was also evaluated by flow cytometry. In addition, intraocular cells collected from mice with experimental autoimmune uveitis (EAU) were used for the assay with anti-TNF-α blocking antibody.

Results

Ocular fluids from active uveitis patients who have BD contained significant amounts of inflammatory cytokines such as IFN-γ, IL-2, TNF-α, IL-6, and IL-17, while ocular fluids from infliximab patients did not contain any inflammatory cytokines. Activated CD4+ T cells from BD patients produced large amounts of TNF-α and IL-17, whereas T cells in the presence of infliximab failed to produce these cytokines. Polarized Th17 cell lines from BD patients produced large amounts of IL-17, and Th17 cells exposed to infliximab had significantly reduced IL-17 production. Polarized BD Th17 cells expressed large amounts of transcription factor RORγt. In contrast, in vitro-treated infliximab Th17 cells expressed less RORγt. Moreover, intraocular T cells from EAU mice had a high population of IL-17+ cells, and retinal antigen-specific T cells from EAU mice produced large amounts of IL-17 in the presence of retinal peptide. However, the EAU T cells produced less IL-17 if the T cells were treated with anti-TNF-α antibody.

Conclusions

These results indicate that anti-TNF-α therapy suppresses effector T-cell differentiation in BD patients with uveitis. Thus, suppression of effector T-cell differentiation by anti-TNF-α therapy may provide protection from severe ocular inflammation in BD.
Sensory and sympathetic nerve fibers undergo sprouting and neuroma formation in the painful arthritic joint of geriatric mice
Authors: Jimenez-Andrade Juan M , Mantyh Patrick W
Published: May 2012

Introduction

Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice.

Methods

Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting).

Results

At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum.

Conclusions

Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain.
Gene regulatory network inference: evaluation and application to ovarian cancer allows the prioritization of drug targets
Authors: Madhamshettiwar Piyush B , Maetschke Stefan R , Davis Melissa J , Reverter Antonio , Ragan Mark A
Published: May 2012

Background

Altered networks of gene regulation underlie many complex conditions, including cancer. Inferring gene regulatory networks from high-throughput microarray expression data is a fundamental but challenging task in computational systems biology and its translation to genomic medicine. Although diverse computational and statistical approaches have been brought to bear on the gene regulatory network inference problem, their relative strengths and disadvantages remain poorly understood, largely because comparative analyses usually consider only small subsets of methods, use only synthetic data, and/or fail to adopt a common measure of inference quality.

Methods

We report a comprehensive comparative evaluation of nine state-of-the art gene regulatory network inference methods encompassing the main algorithmic approaches (mutual information, correlation, partial correlation, random forests, support vector machines) using 38 simulated datasets and empirical serous papillary ovarian adenocarcinoma expression-microarray data. We then apply the best-performing method to infer normal and cancer networks. We assess the druggability of the proteins encoded by our predicted target genes using the CancerResource and PharmGKB webtools and databases.

Results

We observe large differences in the accuracy with which these methods predict the underlying gene regulatory network depending on features of the data, network size, topology, experiment type, and parameter settings. Applying the best-performing method (the supervised method SIRENE) to the serous papillary ovarian adenocarcinoma dataset, we infer and rank regulatory interactions, some previously reported and others novel. For selected novel interactions we propose testable mechanistic models linking gene regulation to cancer. Using network analysis and visualization, we uncover cross-regulation of angiogenesis-specific genes through three key transcription factors in normal and cancer conditions. Druggabilty analysis of proteins encoded by the 10 highest-confidence target genes, and by 15 genes with differential regulation in normal and cancer conditions, reveals 75% to be potential drug targets.

Conclusions

Our study represents a concrete application of gene regulatory network inference to ovarian cancer, demonstrating the complete cycle of computational systems biology research, from genome-scale data analysis via network inference, evaluation of methods, to the generation of novel testable hypotheses, their prioritization for experimental validation, and discovery of potential drug targets.
Let's get physical: improving the medical care of people with severe mental illness
Authors: Mitchell Alex J. , Delaffon Vijay , Lord Oliver
Published: May 2012

There is clear evidence of increased medical comorbidity and related mortality in people with severe mental illness, despite numerous guidelines for managing medical conditions in this population. This article assesses inequalities in medical treatment and preventive healthcare received by psychiatric patients compared with the general population. It considers whether the medical care provided is adequate and whether published guidelines improve it. Mental health specialists, general practitioners and hospital specialists appear to deliver poorer than average medical care for this vulnerable population. Implementation of physical healthcare guidelines is incomplete and the guidelines must be matched with resources to address this deficit.
Expert evidence on trial
Authors: Rix Keith J. B.
Published: May 2012

The complex nature and consequences of fraud are illustrated by the case of ‘Dr’ Barian Baluchi, who held himself out to be a consultant neuropsychiatrist before being convicted of deception, actual bodily harm and procuring registration by making false declarations. Under the proposed UK Criminal Evidence (Experts) Bill, psychiatric experts in fraud cases are likely to find the admissibility of their evidence tested against statutory criteria. Where they rely on test results, they will need to know the validity of the methods and show that they have taken proper account of the degree of precision or margin of uncertainty affecting the accuracy or reliability of their results. Proposals to reform the law on unfitness also have implications for psychiatric assessment in fraud cases. It will now be even more important for psychiatric opinion evidence to be demonstrably sound and of such evident strength that there is no issue as to its admissibility and the judge can presume evidentiary reliability.
Behavioural activation: history, evidence and
promise
Authors: Kanter Jonathan W. , Puspitasari Ajeng J. , Santos Maria M. , Nagy Gabriela A.
Published: May 2012

Behavioural activation holds promise to reduce the global burden of
depression as a treatment approach that is effective, easy to teach,
scalable and acceptable to providers and patients across settings and
cultures. This editorial reviews the history of behavioural activation, what
it is, current evidence for its use and future directions.
Self-harm in older people: a clear need for specialist assessment and care
Authors: Dennis Michael S. , Owens David W.
Published: May 2012

Suicide rates are generally elevated after episodes of non-fatal self-harm, especially among older adults. Evidence suggests that non-fatal and fatal self-harm are more closely related in older than in younger adults. Older people who have self-harmed need specialist assessment followed by good short-term and long-term evidence-based care.
Adult attention-deficit hyperactivity disorder and child protection: review of evidence and child safeguarding guidelines
Authors: Jeffs James , Cubbin Sally , Xenitidis Kiriakos
Published: May 2012

This paper takes a broad view of the challenges to parenting faced by adults with attention-deficit hyperactivity disorder (ADHD). Issues in risk assessment are discussed. We place these in the context of the published UK national guidelines on child safeguarding for professionals working with parents who have mental disorders, and consider how this may inform practice in this field.
Futurology and mental health services: are we ready for the demographic transition?
Authors: Connolly Moira
Published: May 2012

Planning for the future development of mental health services requires an understanding of the changing demographics of local populations. It is argued that the demographic transition faced by the UK requires mental health services to adopt an approach more typical of public health in responding to the needs of an increasingly ageing population.