bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-state Markov models in cancer screening evaluation: a brief review and case study
Authors: Uhry Z. , Hédelin G. , Colonna M. , Asselain B. , Arveux P. , Rogel A. , Exbrayat C. , Guldenfels C. , Courtial I. , Soler-Michel P. , Molinié F. , Eilstein D. , Duffy SW
Published: March 2010

This work presents a brief overview of Markov models in cancer screening evaluation and focuses on two specific models. A three-state model was first proposed to estimate jointly the sensitivity of the screening procedure and the average duration in the preclinical phase, i.e. the period when the cancer is asymptomatic but detectable by screening. A five-state model, incorporating lymph node involvement as a prognostic factor, was later proposed combined with a survival analysis to predict the mortality reduction associated with screening. The strengths and limitations of these two models are illustrated using data from French breast cancer service screening programmes. The three-state model is a useful frame but parameter estimates should be interpreted with caution. They are highly correlated and depend heavily on the parametric assumptions of the model. Our results pointed out a serious limitation to the five-state model, due to implicit assumptions which are not always verified. Although it may still be useful, there is a need for more flexible models. Over-diagnosis is an important issue for both models and induces bias in parameter estimates. It can be addressed by adding a non-progressive state, but this may provide an uncertain estimation of over-diagnosis. When the primary goal is to avoid bias, rather than to estimate over-diagnosis, it may be more appropriate to correct for over-diagnosis assuming different levels in a sensitivity analysis. This would be particularly relevant in a perspective of mortality reduction estimation.
An action research approach to the inclusion of immigrants in work life and local community life
Authors: Ataöv Anli , Brøgger Benedicte , Hildrum Jarle Moss
Published: March 2010

Recent increases in the immigrant population in Norway have raised the issue of immigrant inclusion in the Norwegian society. The political emphasis has been on welfare, education and health for many decades. However, today the increasing shortage of labor in the market has raised the issue of inclusion of the immigrant population in work life. This article documents a 3-year-long action research process that laid the groundwork for collaboration among public, private, and nongovernmental organizations in order to find solutions to this newly emergent need in work life. The purpose was to complement existing top-down policy initiatives in this area with a novel bottom-up strategy, aiming to facilitate action-oriented dialogues about the inclusion of immigrants in working life. Initially an international project targeting the cities of Oslo and Drammen was narrowed to a group of large firms in The Grorud Valley in Oslo, where a substantial proportion of the country’s immigrants live and work. The project demonstrates several valuable aspects of this action-research strategy — such as creating a broad-based dialogue platform on which novel policies and practices might be generated — but also a number of challenges, such as mobilizing private firms to participate in dialogues and keeping initiated dialogues active.
Developing human capital through a pragmatic oriented action research project
Authors: Cappelletti Laurent G. , Baker Charles Richard
Published: March 2010

The action research methodology used in this article is referred to as ‘intervention research’. In specific terms, it is called the Socio-Economic Approach to Management (SEAM). The SEAM approach is both participatory and collaborative. It is a pragmatic oriented action research methodology and it belongs to the French action research tradition with roots in the UK and the work of Tavistock Institute. The action research project described in this study was carried out in a company in the security sector in France. The findings of the study indicate that a pragmatic oriented action research methodology such as SEAM may enhance the quality of human resource management and capabilities, and thus increase the value of human capital. The article also discusses the measurement of human capital and the factors which contribute to the sustainable development of human capital through time.
Action research as a sustainable endeavor for teachers
Authors: Volk Kenneth S.
Published: March 2010

Action research has been recognized as a necessary part of teacher preparation programs. It is assumed that with sufficient training in action research methodology, teachers will continue as action researchers to improve the quality of instruction in their classrooms. Expecting this benefit and outcome, a college in the Middle East requires students to complete one total semester of action research in the final year of their Bachelor of Education program, with students’ research conducted in schools during their assigned teaching practice. To examine whether graduates from the program continue to practice action research once they become teachers, telephone interviews were conducted. The findings were less than convincing that action research was later being utilized or applied by teachers, leading to recommendations for improvement.
Homeodomain-interacting protein kinase 2 plays an important role in normal terminal erythroid differentiation
Authors: Hattangadi Shilpa M. , Burke Karly A. , Lodish Harvey F.
Published: March 2010

Gene-targeting experiments report that the homeodomain-interacting protein kinases 1 and 2, Hipk1 and Hipk2, are essential but redundant in hematopoietic development because Hipk1/Hipk2 double-deficient animals exhibit severe defects in hematopoiesis and vasculogenesis, whereas the single knockouts do not. These serine-threonine kinases phosphorylate and consequently modify the functions of several important hematopoietic transcription factors and cofactors. Here we show that Hipk2 knockdown alone plays a significant role in terminal fetal liver erythroid differentiation. Hipk1 and Hipk2 are highly induced during primary mouse fetal liver erythropoiesis. Specific knockdown of Hipk2 inhibits terminal erythroid cell proliferation (explained in part by impaired cell-cycle progression as well as increased apoptosis) and terminal enucleation as well as the accumulation of hemoglobin. Hipk2 knockdown also reduces the transcription of many genes involved in proliferation and apoptosis as well as important, erythroid-specific genes involved in hemoglobin biosynthesis, such as α-globin and mitoferrin 1, demonstrating that Hipk2 plays an important role in some but not all aspects of normal terminal erythroid differentiation.
Complement receptor 2/CD21− human naive B cells contain mostly autoreactive unresponsive clones
Authors: Isnardi Isabelle , Ng Yen-Shing , Menard Laurence , Meyers Greta , Saadoun David , Srdanovic Iva , Samuels Jonathan , Berman Jessica , Buckner Jane H. , Cunningham-Rundles Charlotte , Meffre Eric
Published: March 2010

Complement receptor 2–negative (CR2/CD21−) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21−/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21−/lo B cells in their blood. A majority of CD21−/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21−/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21−/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.
Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk
Authors: Hosking Fay J. , Papaemmanuil Elli , Sheridan Eammon , Kinsey Sally E. , Lightfoot Tracy , Roman Eve , Irving Julie A. E. , Allan James M. , Taylor Malcolm , Tomlinson Ian P. , Greaves Mel , Houlston Richard S.
Published: March 2010

Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations.
High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease
Authors: Palacios Florencia , Moreno Pilar , Morande Pablo , Abreu Cecilia , Correa Agustín , Porro Valentina , Landoni Ana Ines , Gabus Raul , Giordano Mirta , Dighiero Guillermo , Pritsch Otto , Oppezzo Pablo
Published: March 2010

Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment.
Quantitative evaluation of motor function before and after engraftment of dopaminergic neurons in a rat model of Parkinson's disease
Authors: Chuang Chieh-Sen , Su Hong-Lin , Cheng Fu-Chou , Hsu Shan-hui , Chuang Chi-Fen , Liu Chin-San
Published: March 2010

Although gait change is considered a useful indicator of severity in animal models of Parkinson's disease, systematic and extensive gait analysis in animal models of neurological deficits is not well established. The CatWalk-assisted automated gait analysis system provides a comprehensive way to assess a number of dynamic and static gait parameters simultaneously. In this study, we used the Catwalk system to investigate changes in gait parameters in adult rats with unilateral 6-OHDA-induced lesions and the rescue effect of dopaminergic neuron transplantation on gait function. Four weeks after 6-OHDA injection, the intensity and maximal area of contact were significantly decreased in the affected paws and the swing speed significantly decreased in all four paws. The relative distance between the hind paws also increased, suggesting that animals with unilateral 6-OHDA-induced lesions required all four paws to compensate for loss of balance function. At 8 weeks post-transplantation, engrafted dopaminergic neurons expressed tyrosine hydroxylase. In addition, the intensity, contact area, and swing speed of the four limbs increased and the distance between the hind paws decreased. Partial recovery of methamphetamine-induced rotational response was also noted.
A novel link between Sus1 and the cytoplasmic mRNA decay machinery suggests a broad role in mRNA metabolism
Authors: Cuenca-Bono Bernardo , García-Molinero Varinia , Pascual-García Pau , García-Oliver Encar , Llopis Ana , Rodríguez-Navarro Susana
Published: March 2010

Background

Gene expression is achieved by the coordinated action of multiple factors to ensure a perfect synchrony from chromatin epigenetic regulation through to mRNA export. Sus1 is a conserved mRNA export/transcription factor and is a key player in coupling transcription initiation, elongation and mRNA export. In the nucleus, Sus1 is associated to the transcriptional co-activator SAGA and to the NPC associated complex termed TREX2/THSC. Through these associations, Sus1 mediates the nuclear dynamics of different gene loci and facilitate the export of the new transcripts.

Results

In this study, we have investigated whether the yeast Sus1 protein is linked to factors involved in mRNA degradation pathways. We provide evidence for genetic interactions between SUS1 and genes coding for components of P-bodies such as PAT1, LSM1, LSM6 and DHH1. We demonstrate that SUS1 deletion is synthetic lethal with 5'→3' decay machinery components LSM1 and PAT1 and has a strong genetic interaction with LSM6 and DHH1. Interestingly, Sus1 overexpression led to an accumulation of Sus1 in cytoplasmic granules, which can co-localise with components of P-bodies and stress granules. In addition, we have identified novel physical interactions between Sus1 and factors associated to P-bodies/stress granules. Finally, absence of LSM1 and PAT1 slightly promotes the Sus1-TREX2 association.

Conclusions

In this study, we found genetic and biochemical association between Sus1 and components responsible for cytoplasmic mRNA metabolism. Moreover, Sus1 accumulates in discrete cytoplasmic granules, which partially co-localise with P-bodies and stress granules under specific conditions. These interactions suggest a role for Sus1 in gene expression during cytoplasmic mRNA metabolism in addition to its nuclear function.
Systematic analysis of off-target effects in an RNAi screen reveals microRNAs affecting sensitivity to TRAIL-induced apoptosis
Authors: Sudbery Ian , Enright Anton J , Fraser Andrew G , Dunham Ian
Published: March 2010

Background

RNA inhibition by siRNAs is a frequently used approach to identify genes required for specific biological processes. However RNAi screening using siRNAs is hampered by non-specific or off target effects of the siRNAs, making it difficult to separate genuine hits from false positives. It is thought that many of the off-target effects seen in RNAi experiments are due to siRNAs acting as microRNAs (miRNAs), causing a reduction in gene expression of unintended targets via matches to the 6 or 7 nt 'seed' sequence. We have conducted a careful examination of off-target effects during an siRNA screen for novel regulators of the TRAIL apoptosis induction pathway(s).

Results

We identified 3 hexamers and 3 heptamer seed sequences that appeared multiple times in the top twenty siRNAs in the TRAIL apoptosis screen. Using a novel statistical enrichment approach, we systematically identified a further 17 hexamer and 13 heptamer seed sequences enriched in high scoring siRNAs. The presence of one of these seeds sequences (which could explain 6 of 8 confirmed off-target effects) is sufficient to elicit a phenotype. Three of these seed sequences appear in the human miRNAs miR-26a, miR-145 and miR-384. Transfection of mimics of these miRNAs protects several cell types from TRAIL-induced cell death.

Conclusions

We have demonstrated a role for miR-26a, miR-145 and miR-26a in TRAIL-induced apoptosis. Further these results show that RNAi screening enriches for siRNAs with relevant off-target effects. Some of these effects can be identified by the over-representation of certain seed sequences in high-scoring siRNAs and we demonstrate the usefulness of such systematic analysis of enriched seed sequences.
Co-expression of neighbouring genes in Arabidopsis: separating chromatin effects from direct interactions
Authors: Chen Wei-Hua , de Meaux Juliette , Lercher Martin J
Published: March 2010

Background

In all eukaryotic species examined, genes that are chromosomal neighbours are more similar in their expression than random gene pairs. Currently, it is still unclear how much of this local co-expression is caused by direct transcriptional interactions, and how much is due to shared chromatin environments.

Results

We analysed neighbouring genes in Arabidopsis thaliana. At large intergenic distances (>400 bp), divergently and convergently transcribed gene pairs show very similar levels of co-expression, mediated most likely by shared chromatin environments. At gene distances below 400 bp, co-expression is strongly enhanced only for divergently transcribed gene pairs, indicating bi-directional transcription from a single promoter. Conversely, co-expression is suppressed for short convergently or uni-directionally transcribed pairs. This suppression points to transcriptional interference concentrated at the 3' end, e.g., in the context of transcription termination.

Conclusions

Classifying linked gene pairs by their orientation, we are able to partially tease apart the different levels of regional expression modulation. (i) Regional chromatin characteristics modulate the accessibility for regulation and transcription, regardless of gene orientation; the strength of this chromatin effect can be assessed from divergently or convergently transcribed distant neighbours. (ii) Shared promoter regions up to 400 bp in length enhance the co-expression of close bi-directional neighbours. (iii) Transcriptional interference of close neighbours is concentrated at the 3' ends of genes, and reduces co-expression on average by 40%.
Inter-country and ethnic variation in colorectal cancer survival: Comparisons between a Philippine population, Filipino-Americans and Caucasians
Authors: Redaniel Maria Theresa , Laudico Adriano , Mirasol-Lumague Maria Rica , Gondos Adam , Uy Gemma , Brenner Hermann
Published: March 2010

Background

Previous population-based studies showed differences in international and within country colorectal cancer survival estimates, but few investigated the role of prognostic factors. Using a "high resolution approach", we aimed to determine the effect of ethnicity and health care by comparing Filipino-Americans with Philippine residents, who have the same ethnicity, and with Caucasians living in the US, who have the same health care system.

Methods

Using databases from the Manila and Rizal Cancer Registries and the United States Surveillance, Epidemiology and End Results, age-adjusted five-year absolute and relative survival estimates were computed and compared between Filipino-American colorectal cancer patients, cancer patients from the Philippines and Caucasian patients. Cox proportional hazards modelling was used to determine factors affecting survival differences.

Results

Much lower 5-year relative survival estimates were obtained for Philippine residents (37%) as compared to those in Filipino-Americans (60.3%) and Caucasians (62.4%). Differences in age, stage and receipt of surgery explained a large proportion of the survival differences between Philippine residents and Filipino-Americans. However, strong excess risk of death for Philippine residents remained after controlling for these and other variables (relative risk, RR, 2.03, 95% confidence interval, 95% CI, 1.83-2.25).

Conclusions

Strong survival disadvantages of Philippine residents compared to Filipino-American patients were disclosed, which most likely reflect differences in access to and utilization of health care. Health education and advocacy, for both patients and health practitioners, should likewise be given priority.
A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes
Authors: Fumagalli Debora , Gavin Patrick G , Taniyama Yusuke , Kim Seung-Il , Choi Hyun-Joo , Paik Soonmyung , Pogue-Geile Katherine L
Published: March 2010

Background

An increasing number of studies show that genetic markers can aid in refining prognostic information and predicting the benefit from systemic therapy. Our goal was to develop a high throughput, cost-effective and simple methodology for the detection of clinically relevant hot spot mutations in colon cancer.

Methods

The Maldi-Tof mass spectrometry platform and OncoCarta panel from Sequenom were used to profile 239 colon cancers and 39 metastatic lymph nodes from NSABP clinical trial C-07 utilizing routinely processed FFPET (formalin-fixed paraffin-embedded tissue).

Results

Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples. Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta. Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible. Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database. The frequencies were 43.5% for KRAS, 20.1% for PIK3CA, and 12.1% for BRAF. In addition, infrequent mutations in NRAS, AKT1, ABL1, and MET were detected. Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant. All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only.

Conclusions

This study describes a high throughput technology that can be used to interrogate DNAs isolated from routinely processed FFPET and identifies the specific mutations that are common to colon cancer. The development of this technology and the ColoCarta panel may provide a mechanism for rapid screening of mutations in clinically relevant genes like KRAS, PIK3CA, and BRAF.

Trial Registration

ClinicalTrials.gov: NSABP C-07: NCT00004931
Genetic and epigenetic silencing of the beclin 1gene in sporadic breast tumors
Authors: Li Zidong , Chen Bo , Wu Yiqing , Jin Feng , Xia Yongjing , Liu Xiangjun
Published: March 2010

Background

Beclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Beclin 1 mapped to human chromosome 17q21. It is widely expressed in normal mammary epithelial cells. Although down-regulated expression with mono-allelic deletions of beclin 1 gene was frequently observed in breast tumors, whether there was other regulatory mechanism of beclin 1 was to be investigated. We studied the expression of beclin 1 and explored the possible regulatory mechanisms on its expression in breast tumors.

Methods

20 pairs of tumors and adjacent normal tissues from patients with sporadic breast invasive ductal cancer (IDCs) were collected. The mRNA expression of beclin 1 was detected by real-time quantitative RT-PCR. Loss of heterozygosity (LOH) was determined by real-time quantitative PCR and microsatellite methods. The protein expression of beclin 1, p53, BRCA1 and BRCA2 was assessed by immunohistochemistry. CpG islands in 5' genomic region of beclin 1 gene were identified using MethylPrimer Program. Sodium bisulfite sequencing was used in examining the methylation status of each CpG island.

Results

Decreased beclin 1 mRNA expression was detected in 70% of the breast tumors, and the protein levels were co-related to the mRNA levels. Expression of beclin 1 mRNA was demonstrated to be much higher in the BRCA1 positive tumors than that in the BRCA1 negative ones. Loss of heterozygosity was detected in more than 45% of the breast tumors, and a dense cluster of CpG islands was found from the 5' end to the intron 2 of the beclin 1 gene. Methylation analysis showed that the promoter and the intron 2 of beclin 1 were aberrantly methylated in the tumors with decreased expression.

Conclusions

These data indicated that LOH and aberrant DNA methylation might be the possible reasons of the decreased expression of beclin 1 in the breast tumors. The findings here shed some new light on the regulatory mechanisms of beclin 1 in breast cancer.
Socio-economic differences in life expectancy among persons with diabetes mellitus or myocardial infarction: results from the German MONICA/KORA study
Authors: Perna Laura , Thien-Seitz Uta , Ladwig Karl-Heinz , Meisinger Christa , Mielck Andreas
Published: March 2010

Background

Differences in life expectancy (LE) between social groups in a specific country are a fundamental measure of health inequalities within that country. Constant monitoring of these differences provides important information on the population's general health. The purpose of the present study is to explore and quantify the socio-economic differences in LE in Germany, focussing on a topic rarely assessed in other studies, the dependency of these LE differences on the presence of myocardial infarction or diabetes mellitus.

Methods

The dataset consists of 13,427 participants (6,725 men, 6,702 women) aged 25-74 years, recruited in the region of Augsburg in Germany through three independent cross-sectional representative surveys conducted in 1984/85, 1989/90, 1994/95, with a mortality follow up in 1998 and 2002. We use a parametric model for the survival function based on the Weibull distribution, in which the hazard function is described in terms of two parameters. We estimate these parameters with a maximum likelihood method that takes into account censoring and data truncation.

Results

The difference in LE between the lowest and the highest socio-economic group is estimated to be 3.79 years for men and 4.10 years for women. Diabetes mellitus reduces LE of men from the upper three income quartiles by 4.88 years, and LE of men belonging to the lowest income quartile by 7.97 years. For women, the corresponding figures are 5.79 and 5.72 years. Myocardial infarction reduces LE of men and women from the upper three income quartiles by 3.65 and 3.75 years, respectively, and LE of men and women belonging to the lowest income quartile by 5.11 and 10.95 years, respectively.

Conclusions

This study shows that in Germany the differences in LE by socio-economic status are comparable to those found in other European countries, and that these differences seem to increase when diabetes mellitus or myocardial infarction is present. The statistical method used allows estimates of LE with relatively small datasets.
Pilot case-control investigation of risk factors for hip fractures in the urban Indian population
Authors: Jha Ruchira M , Mithal Ambrish , Malhotra Nidhi , Brown Edward M
Published: March 2010

Background

Despite the reported high prevalence of osteoporosis in India, there have been no previous studies examining the risk factors for hip fracture in the Indian population.

Methods

We carried out a case control investigation comprising 100 case subjects (57 women and 43 men) admitted with a first hip fracture into one of three hospitals across New Delhi. The 100 controls were age and sex matched subjects who were either healthy visitors not related to the case patients or hospital staff. Information from all subjects was obtained through a questionnaire based interview.

Results

There was a significant increase in the number of cases of hip fracture with increasing age. There were significantly more women (57%) than men (43%). Univariate analysis identified protective effects for increased activity, exercise, calcium and vitamin supplements, almonds, fish, paneer (cottage cheese), curd (plain yogurt), and milk. However, tea and other caffeinated beverages were significant risk factors. In women, hormone/estrogen therapy appeared to have a marginal protective effect. For all cases, decreased agility, visual impairment, long term medications, chronic illnesses increased the risk of hip fracture. The multivariate analysis confirmed a protective effect of increased activity and also showed a decrease in hip fracture risk with increasing body mass index (odds ratio (OR) 0.024, 95% confidence interval (CI) 0.006-0.10 & OR 0.81, 95% CI 0.68-0.97 respectively). Individuals who take calcium supplements have a decreased risk of hip fracture (OR 0.076; CI 0.017-0.340), as do individuals who eat fish (OR 0.094; CI 0.020-0.431), and those who eat paneer (OR 0.152; 0.031-0.741). Tea drinkers have a higher risk of hip fracture (OR 22.8; 95% CI 3.73-139.43). Difficulty in getting up from a chair also appears to be an important risk factor for hip fractures (OR 14.53; 95% CI 3.86-54.23).

Conclusions

In the urban Indian population, dietary calcium, vitamin D, increased body mass index, and higher activity levels have a significant protective effect on hip fracture. On the other hand, caffeine intake and decreased agility increase the risk of hip fracture. Future studies should be done in order to direct primary preventive programs for hip fracture in India.
Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis
Authors: Ong Zhi Yi , Gibson Rachel J , Bowen Joanne M , Stringer Andrea M , Darby Jocelyn M , Logan Richard M , Yeoh Ann SJ , Keefe Dorothy M
Published: March 2010

Background

Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity.

Methods

Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry.

Results

Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy.

Conclusions

Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.
RNA isolation method for single embryo transcriptome analysis in zebrafish
Authors: de Jong Mark , Rauwerda Han , Bruning Oskar , Verkooijen Jurgo , Spaink Herman P , Breit Timo M
Published: March 2010

Background

Transcriptome analysis during embryogenesis usually requires pooling of embryos to obtain sufficient RNA. Hence, the measured levels of gene-expression represent the average mRNA levels of pooled samples and the biological variation among individuals is confounded. This can irreversibly reduce the robustness, resolution, or expressiveness of the experiment. Therefore, we developed a robust method to isolate abundant high-quality RNA from individual embryos to perform single embryo transcriptome analyses using zebrafish as a model organism. Available methods for embryonic zebrafish RNA isolation minimally utilize ten embryos. Further downscaling of these methods to one embryo is practically not feasible.

Findings

We developed a single embryo RNA extraction method based on sample homogenization in liquid nitrogen, RNA extraction with phenol and column purification. Evaluation of this method showed that: the quality of the RNA was very good with an average RIN value of 8.3-8.9; the yield was always ≥ 200 ng RNA per embryo; the method was applicable to all stages of zebrafish embryogenesis; the success rate was almost 100%; and the extracted RNA performed excellent in microarray experiments in that the technical variation was much lower than the biological variation.

Conclusions

Presented is a high-quality, robust RNA isolation method. Obtaining sufficient RNA from single embryos eliminates the necessity of sample pooling and its associated drawbacks. Although our RNA isolation method has been setup for transcriptome analysis in zebrafish, it can also be used for other model systems and other applications like (q)PCR and transcriptome sequencing.
Scenario based outdoor simulation in pre-hospital trauma care using a simple mannequin model
Authors: Bredmose Per P , Habig Karel , Davies Gareth , Grier Gareth , Lockey David J
Published: March 2010

Introduction

We describe a system of scenario-based training using simple mannequins under realistic circumstances for the training of pre-hospital care providers.

Methods

A simple intubatable mannequin or student volunteers are used together with a training version of the equipment used on a routine basis by the pre-hospital care team (doctor + paramedic).

Training is conducted outdoors at the base location all year round. The scenarios are led by scenario facilitators who are predominantly senior physicians. Their role is to brief the training team and guide the scenario, results of patient assessment and the simulated responses to interventions and treatment. Pilots, fire-fighters and medical students are utilised in scenarios to enhance realism by taking up roles as bystanders, additional ambulance staff and police. These scenario participants are briefed and introduced to the scene in a realistic manner. After completion of the scenario, the training team would usually be invited to prepare and deliver a hospital handover as they would in a real mission. A formal structured debrief then takes place.

Results

This training method technique has been used for the training of all London Helicopter Emergency Medical Service (London HEMS) doctors and paramedics over the last 24 months. Informal participant feedback suggests that this is a very useful teaching method, both for improving motor skills, critical decision-making, scene management and team interaction. Although formal assessment of this technique has not yet taken place we describe how this type of training is conducted in a busy operational pre-hospital trauma service.

Discussion

The teaching and maintenance of pre-hospital care skills is essential to an effective pre-hospital trauma care system. Simple mannequin based scenario training is feasible on a day-to-day basis and has the advantages of low cost, rapid set up and turn around. The scope of scenarios is limited only by the imagination of the trainers. Significant effort is made to put the participants into "the Zone" - the psychological mindset, where they believe they are in a realistic setting and treating a real patient, so that they gain the most from each teaching session. The method can be used for learning new skills, communication and leadership as well as maintaining existing skills.

Conclusion

The method described is a low technology, low cost alternative to high technology simulation which may provide a useful adjunct to delivering effective training when properly prepared and delivered. We find this useful for both induction and regular training of pre-hospital trauma care providers.
Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis
Authors: Rudwaleit Martin , Claudepierre Pascal , Kron Martina , Kary Sonja , Wong Robert , Kupper Hartmut
Published: March 2010

Introduction

The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS).

Methods

Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20).

Results

Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both.

Conclusions

Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS.

Trial registration

ClinicalTrials.gov NCT00478660.
Switching of mesodermal and endodermal properties in hTERT-modified and expanded fetal human pancreatic progenitor cells
Authors: Cheng Kang , Follenzi Antonia , Surana Manju , Fleischer Norman , Gupta Sanjeev
Published: March 2010

Introduction

The ability to expand organ-specific stem/progenitor cells is critical for translational applications, although uncertainties often arise in identifying the lineage of expanded cells. Therefore, superior insights into lineage maintenance mechanisms will be helpful for cell/gene therapy.

Methods

We studied epithelial cells isolated from fetal human pancreas to assess their proliferation potential, changes in lineage markers during culture, and capacity for generating insulin-expressing beta cells. Cells were isolated by immunomagnetic sorting for epithelial cell adhesion molecule (EpCAM), and characterized for islet-associated transcription factors, hormones, and ductal markers. Further studies were performed after modification of cells with the catalytic subunit of human telomerase reverse transcriptase (hTERT).

Results

Fetal pancreatic progenitor cells efficiently formed primary cultures, although their replication capacity was limited. This was overcome by introduction and expression of hTERT with a retroviral vector, which greatly enhanced cellular replication in vitro. However, we found that during culture hTERT-modified pancreatic progenitor cells switched their phenotype with gain of additional mesodermal properties. This phenotypic switching was inhibited when a pancreas-duodenal homeobox (Pdx)-1 transgene was expressed in hTERT-modified cells with a lentiviral vector, along with inductive signaling through activin A and serum deprivation. This restored endocrine properties of hTERT-modified cells in vitro. Moreover, transplantation studies in immunodeficient mice verified the capacity of these cells for expressing insulin in vivo.

Conclusions

Limited replication capacity of pancreatic endocrine progenitor cells was overcome by the hTERT mechanism, which should facilitate further studies of such cells, although mechanisms regulating switches between meso-endodermal fates of expanded cells will need to be controlled for developing specific applications. The availability of hTERT-expanded fetal pancreatic endocrine progenitor cells will be helpful for studying and recapitulating stage-specific beta lineage advancement in pluripotent stem cells.
Gene Expression–Based Classification As an Independent Predictor of Clinical Outcome in Juvenile Myelomonocytic Leukemia
Authors: Bresolin Silvia , Zecca Marco , Flotho Christian , Trentin Luca , Zangrando Andrea , Sainati Laura , Stary Jan , de Moerloose Barbara , Hasle Henrik , Niemeyer Charlotte M. , te Kronnie Geertruy , Locatelli Franco , Basso Giuseppe
Published: March 2010

Purpose

Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far. We applied gene expression–based classification to JMML samples in order to identify prognostic categories related to clinical outcome.

Patients and Methods

Samples of 44 patients with JMML were available for microarray gene expression analysis. A diagnostic classification (DC) model developed for leukemia and myelodysplastic syndrome classification was used to classify the specimens and identify prognostically relevant categories. Statistical analysis was performed to determine the prognostic value of the classification and the genes identifying prognostic categories were further analyzed through R software.

Results

The samples could be divided into two major groups: 20 specimens were classified as acute myeloid leukemia (AML) –like and 20 samples as nonAML-like. Four patients could not be assigned to a unique class. The 10-year probability of survival after diagnosis of AML-like and nonAML-like patients was significantly different (7% v 74%; P = .0005). Similarly, the 10-year event-free survival after HSCT was 6% for AML-like and 63% for nonAML-like patients (P = .0010).

Conclusion

Gene expression–based classification identifies two groups of patients with JMML with distinct prognosis outperforming all known clinical parameters in terms of prognostic relevance. Gene expression–based classification could thus be prospectively used to guide clinical/therapeutic decisions.
Prognostic Factors in Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract Experiencing Treatment Failure With Platinum-Containing Regimens
Authors: Bellmunt Joaquim , Choueiri Toni K. , Fougeray Ronan , Schutz Fabio A.B. , Salhi Yacine , Winquist Eric , Culine Stéphane , von der Maase Hans , Vaughn David J. , Rosenberg Jonathan E.
Published: March 2010

Purpose

The present study sought to identify pretreatment prognostic factors for overall survival (OS) in patients with metastatic transitional cell carcinoma of the urothelial tract (TCCU) who experienced treatment failure with the first-line, platinum-based regimen included in the phase III vinflunine trial.

Patients and Methods

In total, 370 patients with platinum-refractory TCCU were included in this analysis. Potential prognostic factors were recorded prospectively. Univariate analysis was used to identify clinical and laboratory factors that significantly impact survival. Multivariate analysis was used to identify independent prognostic factors, and bootstrap analysis was performed for internal validation, forming a prognostic model. External validation was performed on the phase II vinflunine study CA183001.

Results

Multivariate analysis and the internal validation identified Eastern Cooperative Oncology Group performance status (PS) more than 0, hemoglobin level less than 10 g/dL, and the presence of liver metastasis as the main adverse prognostic factors for OS. External validation confirmed these prognostic factors. Four subgroups were formed based on the presence of zero, one, two, or three prognostic factors; the median OS times for these groups were 14.2, 7.3, 3.8, and 1.7 months (P < .001), respectively.

Conclusion

We identified and both internally and externally validated three adverse risk factors (PS, hemoglobin level, and liver metastasis) that predict for OS and developed a scoring system that classifies patients with platinum-refractory disease on second-line chemotherapy into four risk groups with different outcome. Similar to the first-line setting, the presence of visceral metastases and poor PS predict a worse prognosis. These factors, together with low hemoglobin, can be used for prognostication and future patient stratification in clinical trials.
Iran, in Search of a Nonsecular and Nontheocratic Politics
Authors: Hurd Elizabeth Shakman
Published: March 2010

The Iranian oppositional movement led by Mir Hussein Moussavi offers a glimpse of a third path that departs from a rigid dichotomy between secularism and political Islam and leads toward alternative religiopolitical possibilities not only for Iran but for other countries as well. How the West responds to this crisis, specifically to the democratic potential of nonsecular and nontheocratic forms of politics, is crucial.
The Reckless Will: Prison Chaplaincy and the Problem of Mara Salvatrucha
Authors: O'Neill Kevin Lewis
Published: March 2010

Mara Salvatrucha, or MS-13, is a transnational criminal network that originated among Central American immigrants in Los Angeles during the gang wars of the 1980s. Since then U.S. deportation policies have transported MS-13 back to (and helped it expand in) Central America, with the strongest networks forming in the postwar countries of Guatemala, Honduras, and El Salvador. Today a range of security officials train their efforts on a curious loophole in gang membership—Christian conversion as a way out—and by doing so open up new streams of funding and prompt a specialized cadre of ministers to apply their therapeutic skills to gangs. Relying on the promise of self-esteem, these ministers have placed the problem of MS-13 in the soul rather than on the streets, training an increasing number of eyes on atrophied wills that only the saving grace of Jesus Christ can strengthen. Gang ministry, as the effort is known, makes MS-13 the perfect problem through which to see the politics of American security anew, linking relatively mundane ministerial efforts to contemporary threads of religion and globalization, the politics of frontiers, borders and boundaries, and deportation and democratization as embodied practice.
The Mortality Effect: Counting the Dead in the Cancer Trial
Authors: Jain S. Lochlann
Published: March 2010

This essay analyzes the subject positioning demanded by randomized control trials (RCT). Taking seriously the fact that people in late-stage cancer treatments will die, even if one arm of the study receives a “successful” treatment, Jain argues that the RCT framework carries a politics belied by its status as an objective research method.