bluuebunny/crossref_metadata_2025_split huggingface dataset:
A flexible futility monitoring method with time-varying conditional power boundary
Authors: Ying Zhang  , Clarke William R 
Published: April 2010

Background In an ongoing multi-center randomized control clinical trial, the Carotid Occlusion Surgery Study (COSS), the study protocol specifies multiple interim analyses whose results will be reviewed by an independent DSMB to determine if the trial needs to be stopped early due to either efficacy or futility. Conditional power is used as the decision rule for the DSMB to recommend stopping the trial for futility. An aggressive rule for futility stopping sets a relatively high threshold for the conditional power which may result in significant loss of overall power of the study. A conservative rule using a lower threshold may not be able to stop the trial early when there is indeed no treatment efficacy. Purpose The goal of this article is to develop a flexible futility monitoring plan with a time-varying conditional power boundary that maintains the overall power of the study well, but has a better chance to stop the trial earlier for futility compared to a futility stopping rule with a fixed value for the minimum conditional power to continue. Methods The conditional power boundary for futility is developed using the β-spending function method for sequential test statistics and assuming no interim analysis for efficacy. It is then modified to account for the repeated interim analyses for efficacy. Results Simulation studies that mirror the design of the COSS trial show that the proposed method with sample size calculated without considering interim analyses will maintain the designed size and power well when the designed effect size holds, but will have a better chance to exit the trial earlier if the true effect size is smaller than the designed size such that it is not clinically meaningful to conduct the trial. Limitations The method is valid for sequential test statistics that constitute of a stochastic process which approximates the Brownian motion. It is not applicable to the monitored process that behaves quire differently from the Brownian motion. Conclusions The proposed conditional power method facilitates a flexible futility monitoring plan that can be easily implemented in long-term clinical trials where multiple interim analyses are required. It provides the DSMB an objective guideline to use in considering early stopping for futility. Clinical Trials 2010; 7: 209. http:// ctj.sagepub.com
Macrophage-specific gene functions in Spi1-directed innate immunity
Authors: Zakrzewska Anna , Cui Chao , Stockhammer Oliver W. , Benard Erica L. , Spaink Herman P. , Meijer Annemarie H. 
Published: April 2010

AbstractThe Spi1/Pu.1 transcription factor plays a crucial role in myeloid cell development in vertebrates. Despite extensive studies of Spi1, the controlled gene group remains largely unknown. To identify genes dependent on Spi1, we used a microarray strategy using a knockdown approach in zebrafish embryos combined with fluorescence-activated cell sorting of myeloid cells from transgenic embryos. This approach of using knockdowns with specific green fluorescent protein-marked cell types was highly successful in identifying macrophage-specific genes in Spi1-directed innate immunity. We found a gene group down-regulated on spi1 knockdown, which is also enriched in fluorescence-activated cell-sorted embryonic myeloid cells of a spi1:GFP transgenic line. This gene group, representing putative myeloid-specific Spi1 target genes, contained all 5 previously identified Spi1-dependent zebrafish genes as well as a large set of novel immune-related genes. Colocalization studies with neutrophil and macrophage markers revealed that genes cxcr3.2, mpeg1, ptpn6, and mfap4 were expressed specifically in early embryonic macrophages. In a functional approach, we demonstrated that gene cxcr3.2, coding for chemokine receptor 3.2, is involved in macrophage migration to the site of bacterial infection. Therefore, based on our combined transcriptome analyses, we discovered novel early macrophage-specific marker genes, including a signal transducer pivotal for macrophage migration in the innate immune response.
Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis
Authors: Kourtzelis Ioannis , Markiewski Maciej M. , Doumas Michael , Rafail Stavros , Kambas Konstantinos , Mitroulis Ioannis , Panagoutsos Stelios , Passadakis Ploumis , Vargemezis Vasilios , Magotti Paola , Qu Hongchang , Mollnes Tom Eirik , Ritis Konstantinos , Lambris John D. 
Published: April 2010

AbstractThrombosis is a common complication of end-stage renal disease, particularly in patients on hemodialysis. Although substantial progress has been made in preventing thrombotic complications in various other groups of patients, the mechanisms of thrombosis during hemodialysis require clarification. In this report, we demonstrate that complement activation triggered by hemodialysis biomaterials, and the subsequent generation of the complement anaphylatoxin C5a, results in the expression of functionally active tissue factor (TF) in peripheral blood neutrophils. Because TF is a key initiator of coagulation in vivo, we postulate that the recurring complement activation that occurs during long-term hemodialysis contributes to thrombosis in dialyzed end-stage renal disease patients. Furthermore, we found that complement contributed to the induction of granulocyte colony-stimulating factor, which has been implicated in the pathogenesis of thrombosis in patients treated with the recombinant form of this molecule. Importantly, the inhibition of complement activation attenuated the TF expression and granulocyte colony-stimulating factor induction in blood passing through a hemodialysis circuit, suggesting that the complement system could become a new therapeutic target for preventing thrombosis in patients with chronic renal failure who are maintained on hemodialysis.
Different effects of the probe summarization algorithms PLIER and RMA on high-level analysis of Affymetrix exon arrays
Authors: Qu Yi , He Fei , Chen Yuchen 
Published: April 2010

Abstract

Background
Alternative splicing is an important mechanism that increases protein diversity and functionality in higher eukaryotes. Affymetrix exon arrays are a commercialized platform used to detect alternative splicing on a genome-wide scale. Two probe summarization algorithms, PLIER (Probe Logarithmic Intensity Error) and RMA (Robust Multichip Average), are commonly used to compute gene-level and exon-level expression values. However, a systematic comparison of these two algorithms on their effects on high-level analysis of the arrays has not yet been reported.

Results
In this study, we showed that PLIER summarization led to over-estimation of gene-level expression changes, relative to exon-level expression changes, in two-group comparisons. Consequently, it led to detection of substantially more skipped exons on up-regulated genes, as well as substantially more included (i.e., non-skipped) exons on down-regulated genes. In contrast, this bias was not observed for RMA-summarized data. By using a published human tissue dataset, we compared the tissue-specific expression and splicing detected by Affymetrix exon arrays with those detected based on expressed sequence databases. We found the tendency of PLIER was not supported by the expressed sequence data.

Conclusion
We showed that the tendency of PLIER in detection of alternative splicing is likely caused by a technical bias in the approach, rather than a biological bias. Moreover, we observed abnormal summarization results when using the PLIER algorithm, indicating that mathematical problems, such as numerical instability, may affect PLIER performance.
EST analysis reveals putative genes involved in glycyrrhizin biosynthesis
Authors: Li Ying , Luo Hong-Mei , Sun Chao , Song Jing-Yuan , Sun Yong-Zhen , Wu Qiong , Wang Ning , Yao Hui , Steinmetz André , Chen Shi-Lin 
Published: April 2010

Abstract

Background

Glycyrrhiza uralensis is one of the most popular medicinal plants in the world and is also widely used in the flavoring of food and tobacco. Due to limited genomic and transcriptomic data, the biosynthetic pathway of glycyrrhizin, the major bioactive compound in G. uralensis, is currently unclear. Identification of candidate genes involved in the glycyrrhizin biosynthetic pathway will significantly contribute to the understanding of the biosynthetic and medicinal chemistry of this compound.

Results
We used the 454 GS FLX platform and Titanium regents to produce a substantial expressed sequence tag (EST) dataset from the vegetative organs of G. uralensis. A total of 59,219 ESTs with an average read length of 409 bp were generated. 454 ESTs were combined with the 50,666 G. uralensis ESTs in GenBank. The combined ESTs were assembled into 27,229 unique sequences (11,694 contigs and 15,535 singletons). A total of 20,437 unique gene elements representing approximately 10,000 independent transcripts were annotated using BLAST searches (e-value ≤ 1e-5) against the SwissProt, KEGG, TAIR, Nr and Nt databases. The assembled sequences were annotated with gene names and Gene Ontology (GO) terms. With respect to the genes related to glycyrrhizin metabolism, genes encoding 16 enzymes of the 18 total steps of the glycyrrhizin skeleton synthesis pathway were found. To identify novel genes that encode cytochrome P450 enzymes and glycosyltransferases, which are related to glycyrrhizin metabolism, a total of 125 and 172 unigenes were found to be homologous to cytochrome P450s and glycosyltransferases, respectively. The cytochrome P450 candidate genes were classified into 32 CYP families, while the glycosyltransferase candidate genes were classified into 45 categories by GO analysis. Finally, 3 cytochrome P450 enzymes and 6 glycosyltransferases were selected as the candidates most likely to be involved in glycyrrhizin biosynthesis through an organ-specific expression pattern analysis based on real-time PCR.

Conclusions
Using the 454 GS FLX platform and Titanium reagents, our study provides a high-quality EST database for G. uralensis. Based on the EST analysis, novel candidate genes related to the secondary metabolite pathway of glycyrrhizin, including novel genes encoding cytochrome P450s and glycosyltransferases, were found. With the assistance of organ-specific expression pattern analysis, 3 unigenes encoding cytochrome P450s and 6 unigenes encoding glycosyltransferases were selected as the candidates most likely to be involved in glycyrrhizin biosynthesis.
Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance
Authors: Harper Lisa J , Costea Daniela Elena , Gammon Luke , Fazil Bilal , Biddle Adrian , Mackenzie Ian C 
Published: April 2010

Abstract

Background
Subsets of cells with stem-like properties have been previously isolated from human epithelial cancers and their resistance to apoptosis-inducing stimuli has been related to carcinoma recurrence and treatment failure. The aim of this study was to investigate the mechanisms of resistance to apoptosis-inducing agents of cells with stem-like properties in both normal and malignant human epithelia.

Methods
Cells isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5), were exposed to various apoptosis-inducing stimuli (UV, Tumour Necrosis Factor, Cisplatin, Etoposide, and Neocarzinostatin). Flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays were used to identify the subset of cells with stem-like properties. Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed (Western Blot, qPCR). The role of G2-checkpoint regulators Chk1 and Chk2 was investigated by use of debromohymenialdisine (DBH) and siRNA.

Results
In both cancer biopsies and carcinoma cell lines a subset of CD44high cells showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the percentage of cells in G2-phase and the rate of apoptosis was found. Pulse-chase with iododeoxyuridine (IdU) demonstrated that CD44high carcinoma cells spent longer time in G2, even in un-treated controls. These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis. Low passage cultures of normal keratinocytes were also found to contain a subset of CD44high cells showing increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance.

Conclusions
These data indicate that both normal and malignant human epithelial cells with stem-like properties show greater resistance to apoptosis associated with extended G2 cell cycle phase, and that this property is not a consequence of neoplastic transformation. Targeting G2 checkpoint proteins releases these cells from the G2-block and makes them more prone to apoptosis, implying an opportunity for improved therapeutic approaches.
The association between problematic cellular phone use and risky behaviors and low self-esteem among Taiwanese adolescents
Authors: Yang Yuan-Sheng , Yen Ju-Yu , Ko Chih-Hung , Cheng Chung-Ping , Yen Cheng-Fang 
Published: April 2010

Abstract

Background
Cellular phone use (CPU) is an important part of life for many adolescents. However, problematic CPU may complicate physiological and psychological problems. The aim of our study was to examine the associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents.

Methods
A total of 11,111 adolescent students in Southern Taiwan were randomly selected into this study. We used the Problematic Cellular Phone Use Questionnaire to identify the adolescents with problematic CPU. Meanwhile, a series of risky behaviors and self-esteem were evaluated. Multilevel logistic regression analyses were employed to examine the associations between problematic CPU and risky behaviors and low self-esteem regarding gender and age.

Results
The results indicated that positive associations were found between problematic CPU and aggression, insomnia, smoking cigarettes, suicidal tendencies, and low self-esteem in all groups with different sexes and ages. However, gender and age differences existed in the associations between problematic CPU and suspension from school, criminal records, tattooing, short nocturnal sleep duration, unprotected sex, illicit drugs use, drinking alcohol and chewing betel nuts.

Conclusions
There were positive associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents. It is worthy for parents and mental health professionals to pay attention to adolescents' problematic CPU.
A rare case of low-grade myofibroblastic sarcoma of the femur in a 38-year-old woman: a case report
Authors: Arora Raman , Gupta Ruchika , Sharma Alok , Dinda Amit K 
Published: April 2010

Abstract

Introduction
Primary myofibroblastic sarcoma of the bone is a rare spindle cell tumour with, to the best of our knowledge, only eight cases reported in the available English language literature. The disease's rarity and its low-grade features make an accurate diagnosis difficult in most cases. The differential diagnoses of this unusual tumour include various benign entities as well as other sarcomas. Due to the difference in prognosis, a precise pathologic diagnosis is essential, which requires a combination of thorough morphologic examination, immunohistochemistry and electron microscopy wherever available.

Case presentation
We report the case of a 38-year-old Indian woman with a lytic lesion in her left femur. The tumour was associated with cortical destruction and soft tissue extension. A biopsy from the soft tissue component showed features suggestive of a low-grade malignant mesenchymal tumour. Excision of the tumour was performed and histopathological examination showed a low-grade spindle cell sarcoma with collagenous stroma. Expressions of vimentin and smooth muscle actin were also noted. Ultrastructural examination confirmed its myofibroblastic nature. A final diagnosis of low-grade myofibroblastic sarcoma of the left femur was thus rendered.

Conclusion
Low-grade myofibroblastic sarcoma is one of the rarer osseous spindle cell sarcomas depicting a favourable prognosis in the cases reported so far. Its diagnosis requires ancillary techniques like immunohistochemistry and electron microscopy. To the best of our knowledge, we report the ninth case in the literature and the first case from our subcontinent.
Dihydrotachysterol intoxication treated with pamidronate: a case report
Authors: Jensterle Mojca , Pfeifer Marija , Sever Matjaz , Kocjan Tomaz 
Published: April 2010

Abstract

Introduction
Hypoparathyroidism is a chronic condition which requires a lifelong substitution with vitamin D analogues and careful monitoring. This is especially true for older patients and older compounds as dihydrotachysterol with longer half-life that might lead to long-lasting hypercalcemic episodes.

Case presentation
A 74-year old male patient with postsurgical hypoparathyroidism who has been successfully supplemented with dihydrotachysterol (1.7 ml/day) for over 50 years presented with neuropsychiatric disturbances, constipation, renal insufficiency and polyuria. Laboratory investigation demonstrated serum calcium 3.7 mmol/L, serum creatinine 180 micromol/L, urine calcium excretion 1.1 mmol/mmol of the creatinine, normal 25 OH vitamin D3 and low parathormone and 1,25 di OH vitamin D3. Careful history revealed that he has been erroneously taking 2.5 ml of dihydrotachysterol per day for at least 6 to 8 weeks that caused vitamin D intoxication and symptomatic hypercalcemia. He was treated with intravenous saline infusion, prednisolone and 60 mg of intravenous sodium pamidronate. On the fourth day after admission serum calcium dropped rapidly within the reference range. The treatment for hypoparathyroidism had to be reinstituted 10 days after dihydrotachysterol had been discontinued when the patient was switched to shorter acting calcitriol.

Conclusions
Here we reported that the immediate use of pamidronate in addition to classic treatment of dihydrotachysterol intoxication with intravenous saline, diuretics and glucocorticoids is an effective treatment choice that leads to rapid resolution of hypercalcemia.
Insulin like growth factor-I in acute subarachnoid hemorrhage: a prospective cohort study
Authors: Bendel Stepani , Koivisto Timo , Ryynänen Olli-Pekka , Ruokonen Esko , Romppanen Jarkko , Kiviniemi Vesa , Uusaro Ari 
Published: April 2010

Abstract
Introduction
Neuroendocrine deficiencies may affect recovery after aneurysmal subarachnoid hemorrhage (aSAH). Insulin like growth factor-I (IGF-I) regulates neuronal growth and apoptosis in ischemic stroke. Our study was designed to a) characterize the behavior of serum IGF-I and growth hormone (GH) in the acute and late phases after aSAH reflecting possible pituitary gland function and b) evaluate the association between IGF-I and morbidity assessed by Glasgow outcome scale (GOS) and health related quality of life (HRQoL) in patients with aSAH.

Methods
In this prospective cohort study, patients with aSAH (n = 30) were compared to patients who underwent elective aneurysm surgery (n = 16). Serum GH and IGF-I concentrations were measured daily for five (controls) or seven (aSAH) days and at three months. GOS and 15d HRQoL was measured at three months. A mixed models method was used for testing between the groups. For factors possibly affecting HRQoL in aSAH patients, we constructed a Bayesian predicting model using a P-course Bayesian classifier.

Results
The mean IGF-I concentrations for days one to five were 8.1 ± 3.5 nmol/l in patients with aSAH and 11.2 ± 3.1 in the control group (P = 0.01). No corresponding difference was found at three months. Serum GH concentrations were similar in both patient groups. Severity of the aSAH did not affect serum IGF-I concentrations. Patients with GOS ≤ 4 had lower IGF-I concentrations and lower HRQoL than patients with GOS 5 (P = 0.02 and 0.003 respectively). The 15d HRQoL was 0.81 ± 0.16 in patients with aSAH and 0.86 ± 0.09 in control patients (P = 0.24). In the Bayesian model, the use of statins prior to aSAH, hyponatremia, high maximal sequential organ specific score (SOFAmax), and low cumulative IGF-I concentrations on days one to seven were associated with poor HRQoL (accuracy 89%, sensitivity 86%, and specificity 93%).

Conclusions
IGF-I concentrations are low during acute aSAH, which may have an impact on morbidity.

Trial registration
ClinicalTrials.gov Identifier NCT00614887
Tilting Trains: Benefits and Motion Sickness
Authors: Persson R 
Published: April 2010

Carbody tilting is today a mature and inexpensive technology that allows higher speeds on curves, thus shortening travel time. The technology has been accepted by many train operators, but some issues are still holding back the full potential of tilting trains. This paper focuses on improving the benefits and limiting the drawbacks of tilting trains. This is done by quantifying the possible running time benefits compared with today's tilting trains, identifying what motion components have an influence on motion sickness, and finally quantifying the influence from the increased speed on these motion components. A running time analysis was made to show what potential there is to further improve running times by optimizing tracks and trains. Relations between cant deficiency, top speed, tractive performance, and running times are shown for a tilting train. About 9 per cent running time may be gained on the Stockholm-Gothenburg (457 km) main line in Sweden if cant deficiency, top speed, and tractive performance are improved compared with existing tilting trains. Introduction of non-tilting high-speed trains is not an option on this line due to the large number of 1000 m curves. However, tilting trains run a greater risk of causing motion sickness than non-tilting trains. Roll velocity and vertical acceleration are the two motion components that show the largest increase, but the amplitudes are lower than those used in laboratory tests that caused motion sickness. Higher curve speeds will increase carbody motions still further, but there are some possibilities to trade between vertical and lateral carbody acceleration by increasing or decreasing roll.
‘School's a big part of your life …’: Adolescent Perspectives of Their School Participation Following Traumatic Brain Injury
Authors: Mealings Margaret , Douglas Jacinta 
Published: April 2010

AbstractSustaining a traumatic brain injury (TBI) as an adolescent has a significant impact on life roles and most notably on that of school participation. In the literature there is a wide range of studies that provide clinicians with information regarding recommendations for assisting students in their return to school. However this information has predominantly been provided from the perspectives of educators and rehabilitation staff. The aim of this preliminary project was to hear the stories of three male adolescent students as they reflected on their own experiences of what it was like to go back to school after sustaining a severe TBI. Using a qualitative research design and in-depth interviews, the students' stories were transcribed and coded using grounded theory principles. Despite persisting communication difficulties, the students were able to provide rich stories indicative of their personal experiences. Three key themes emerged from the interviews: theadolescent student's sense of self, changesthe students noted; andsupportsthe students identified. A tentative model illustrating the relationship between these areas was developed. It is anticipated that this model will assist clinicians and educators to develop a holistic picture of a student's school participation from transition to ongoing school life.