bluuebunny/crossref_metadata_2025 huggingface dataset:
Joint latent class models for longitudinal and time-to-event data: A review
Authors: Proust-Lima Cécile , Séne Mbéry , Taylor Jeremy MG , Jacqmin-Gadda Hélène
Published: April 2012

Most statistical developments in the joint modelling area have focused on the shared random-effect models that include characteristics of the longitudinal marker as predictors in the model for the time-to-event. A less well-known approach is the joint latent class model which consists in assuming that a latent class structure entirely captures the correlation between the longitudinal marker trajectory and the risk of the event. Owing to its flexibility in modelling the dependency between the longitudinal marker and the event time, as well as its ability to include covariates, the joint latent class model may be particularly suited for prediction problems. This article aims at giving an overview of joint latent class modelling, especially in the prediction context. The authors introduce the model, discuss estimation and goodness-of-fit, and compare it with the shared random-effect model. Then, dynamic predictive tools derived from joint latent class models, as well as measures to evaluate their dynamic predictive accuracy, are presented. A detailed illustration of the methods is given in the context of the prediction of prostate cancer recurrence after radiation therapy based on repeated measures of Prostate Specific Antigen.
Statistical approaches for farm and parasitic risk profiling in geographical veterinary epidemiology
Authors: Catelan Dolores , Rinaldi Laura , Musella Vincenzo , Cringoli Giuseppe , Biggeri Annibale
Published: April 2012

We address the problem of farm and parasitic risk profiling in the context of Veterinary Epidemiology. We take advantage of a cross-sectional study carried out in the Campania Region in order to study the spatial distribution of 16 parasites in 121 ovine farms. We propose a tri-level hierarchical Bayesian model, which account for multivariate spatially structured overdispersion, to obtain estimate of posterior classification probabilities, that is for each parasite and farm the probability to belong to the set of the null hypothesis. We explore four decision rules based on either posterior probabilities or posterior means and compare the results in terms of the number of false discoveries/non-discoveries or the rate of false discovery/non-discovery. Our approach proved useful for parasitological risk profiling and we show that decision rules can be easily handled.
Commercialization versus open science: Making sense of the message(s) in the bottle
Authors: Harmon Shawn HE , Caulfield Timothy , Joly Yann
Published: April 2012

Efforts to improve research outcomes have resulted in genomic researchers being confronted with complex and seemingly contradictory instructions about how to perform their tasks. For example, increasing pressure to commercialise (academic) research is paralleled by pressure to collaborate, share data, and disseminate knowledge quickly so as to encourage scientific progress, maximise research impact, and meet humanitarian goals. This article briefly explores some of the relevant instructions in Canada and the United Kingdom and concludes that commercialisation and more open collaborative practices are not necessarily irreconcilable. They should be viewed as complementary elements of an innovation framework for which more evidence must be gathered with respect to the impact of this coexistence.
Putting Fun into Video Games for Older Adults
Authors: McLaughlin Anne , Gandy Maribeth , Allaire Jason , Whitlock Laura
Published: April 2012

Our observations of players older than 65 suggested that they weighed costs and benefits when deciding whether or not to play video games. Current games can be higher in cost for seniors because of the perceptual and cognitive changes that tend to occur with age. When seniors choose to invest effort in overcoming those costs, it is often because they perceive a high benefit. Creating successful games for seniors will likely require designers to increase the perceived benefits of games, such as engagement, even more than lowering costs such as frustration, time, and money.
Internalization of External Costs of Energy Generation in Central and Eastern European Countries
Authors: Máca Vojtěch , Melichar Jan , Ščasný Milan
Published: April 2012

In this article a bottom-up approach to quantification of air pollution externalities from electricity generation is used to show that market-based instruments are not very effective in internalizing these external costs in six CEE countries. Although governments in CEE countries have regulated air emissions by imposing strict command-and-control measures, most of them have also introduced air emission charges and more recently taxes on electricity. We find however that the level of internalization by these two economic instruments is fairly low for existing fossil-fired power plants ranging from 3% for coal- and lignite-fuelled plants to 31% for gas-fuelled plants. The picture improves if cross-subsidies for renewable electricity are accounted for but the internalization level is still below air pollution–related external costs, between 9% and 55% for coal- and oil-fired power plants. A substantial overinternalization by these three instruments is however encountered in the case of gas-fired power plants.
Measurement Differences From Rating Posttraumatic Stress Disorder Symptoms in Response to Differentially Distressing Traumatic Events
Authors: Elhai Jon D. , Fine Thomas H.
Published: April 2012

The authors explored differences in posttraumatic stress disorder (PTSD) symptoms as a result of rating symptoms from two separate, differentially distressing traumatic events. In an initial sample of 400 nonclinical participants, the authors inquired through a web survey about previous psychological trauma, instructing participants to nominate their most distressing and second most distressing traumatic events experienced. Using the PTSD Checklist, participants rated their PTSD symptoms separately from these worst and second worst events. Using the four-factor emotional numbing PTSD model in confirmatory factor analysis, results demonstrated evidence supporting separation of PTSD symptom rating sets from two differentially distressing traumas—specifically, the worst and second worst events. Measurement invariance tests revealed that factor loadings did not vary between the worst and second worst event PTSD ratings; item thresholds (indexing symptom severity) differed. Results generally support the recommended PTSD assessment protocol instructing participants to rate PTSD symptoms from a single, worst index event.
Who Chose this Restaurant Anyway? The Effect of Responsibility for Choice, Guarantees, and Failure Stability on Customer Complaining
Authors: McQuilken Lisa , Robertson Nichola
Published: April 2012

Customers often behave in the context of a group, with different behavior occurring in this context to that which transpires in an individual context. However, customer complaining behavior (CCB), including voice, negative word of mouth, in addition to that transmitted electronically, and exit, in a group setting has not been studied previously. A service failure during a group celebration at a restaurant and the pattern of CCB that ensues is examined. This is based on customers’ level of responsibility in restaurant selection on behalf of the group, the presence of an unconditional service guarantee, and the perceived stability of the failure. Findings suggest that customers are more inclined to exit when they have participated to a greater degree in choice and that the presence of an unconditional guarantee interacts with participation to influence negative word of mouth intentions. Perceived failure stability had the greatest influence on CCB.
Clothing Color and Tipping
Authors: Guéguen Nicolas , Jacob Céline
Published: April 2012

Recent research conducted with humans demonstrated that red, relative to other achromatic or chromatic colors, led men to view women presented on a photograph as more attractive. The effect of color on behavior was tested in a tipping context. Eleven waitresses in five restaurants were instructed to wear the same tee shirt with different colors (black, white, red, blue, green, or yellow). The effect of color on tipping according to patron’s gender was measured. It was found that waitresses wearing red received more tips but only with male patrons. Waitresses color had no effect on female patrons’ tipping behavior. The relation between red and sexual attractiveness are used to explain the results. Managerial interests related with clothing appearance were discussed.
Signifying Security
Authors: Haggerty Kevin D. , Tokar Camille
Published: April 2012

ID scanning systems have become a fixture at the entrances of private bars and nightclubs in many North American jurisdictions. This article draws from an ongoing ethnographic study to interrogate the diverse appeals of such devices to institutional audiences. The authors situate these devices within the occupational culture and routines of door staff, and accentuate how the real world operation of these tools can at times circumvent any promised security gains. They then consider why the devices are nonetheless appealing to nightclub representatives because of their potential sign value that allows bar staff to advance preferred sets of communications with influential audiences.
Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features
Authors: Absoud Michael , Lim Ming J , Chong Wui K , De Goede Christian G , Foster Katharine , Gunny Roxana , Hemingway Cheryl , Jardine Philip E , Kneen Rachel , Likeman Marcus , Nischal Ken K , Pike Michael G , Sibtain Naomi A , Whitehouse William P , Cummins Carole , Wassmer Evangeline ,   The UK and Ireland Childhood CNS Inflammatory Demyelination Working Group
Published: April 2012

Objective:

Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time.

Methods:

We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review.

Results:

Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years ( n = 63) was 1.52:1 ( p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria.

Conclusions:

We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.
Are you sitting too comfortably? Using the praxis of positioning to move between the activities of therapy-supervision and the identities of therapist-supervisor
Authors: Burnham John
Published: April 2012

Practitioners extending their repertoire to include supervising the practice of others may see it as an additional professional activity which may be accommodated within their current identities. For some, it may also become a turning point that requires/promotes a second order development across personal and professional identities. Positioning theory (Harre and Langhove 1999) offers a framework which practitioners can use in making the intellectual and linguistic distinctions between different activities/identities, including the supervisory relationship. This paper further explores how a reflexive awareness of physical position, and an ability/willingness to move and re-position can facilitate the elaboration of both the activity of supervision and the identity of supervisor at the levels of approach, method and technique (Burnham 1992, 1993)
Mental health conditions, individual and job characteristics and sleep disturbances among firefighters
Authors: Vargas de Barros Víviam , Martins Leonardo Fernandes , Saitz Richard , Bastos Ronaldo Rocha , Ronzani Telmo Mota
Published: April 2012

This study aimed to assess the associations between mental health conditions, individual and job characteristics and sleep disturbances among firefighters. Of 303 participants, 51.2% reported sleep disturbances. Psychological distress and psychosomatic disturbances were significantly associated with sleep disturbances. Suicidal ideation, unhealthy alcohol use and time as a firefighter were also associated with sleep disturbances but at a borderline level of significance (0.05 < p < .085). These findings may be related to the psychological and physical hazards of firefighting and indicate the importance of research on associated professions.
Individuals’ experiences of, and responses to, a negative genetic test result for familial hypercholesterolaemia
Authors: Hilgart Jennifer , Mercer Jenny , Thirlaway Kathryn
Published: April 2012

This study aimed to explore the responses of individuals who have undergone genetic testing for familial hypercholesterolaemia (FH) where no genetic mutation has been identified. Semi-structured interviews were conducted with 11 patients and interpretative phenomenological analysis (IPA) was employed. This article describes three inter-related themes: ‘feeling in limbo’, ‘exploring causes of raised cholesterol’ and ‘contradictions in talk about diet’. Although participants generally adhered to medication and engaged in healthy lifestyles, the findings have clinical implications for how genetic test results are communicated.
How people with Alzheimer’s disease express their sense of self: Analysis using Rom Harré’s theory of selfhood
Authors: Hedman Ragnhild , Hansebo Görel , Ternestedt Britt-Marie , Hellström Ingrid , Norberg Astrid
Published: April 2012

The aim of this study was to use Harré’s social constructionist theory of selfhood to describe how people with mild and moderate Alzheimer’s disease (AD) express their sense of self. The findings show that Self 1, the embodied sense of being a person, was expressed fluently by participants through the use of first-person indexicals. Self 2, the experienced personal attributes and life narrative, had undergone changes. Those changes were not entirely for the worse; participants had also developed new skills in managing life with AD. In a lifetime perspective, those changes were minor and participants perceived themselves to be basically the same people that they were before having AD. When constructing Self 3, the social personae, participants usually described being supported by others, but sometimes described being exposed to malignant positioning. They also feared that they might become more exposed to negative attitudes as their AD progressed. However, participants were understanding towards the offensive behaviours of others.
The experience of people with dementia in a social care group: Case study
Authors: Hochgraeber Iris , Riesner Christine , Schoppmann Susanne
Published: April 2012

In Germany hourly care for people with dementia and relief for family caregivers are often delivered through social care groups. The existing literature describes these groups from the perspective of professionals or family caregivers, with little involvement of people with dementia. This qualitative study is the first step in exploring the experiences of people with dementia in social care groups. Five persons suffering from dementia in one group were interviewed and additionally observed with DCM in three group sessions. The interview transcripts were coded open and axial according to Grounded Theory. The DCM data was analysed descriptive. The main phenomena in the interviews are ‘familiar community’ and ‘personal meaning’. The DCM results show that people with lower cognitive function are excluded from most activities, whereas more staff attention causes better well-being. To create a ‘familiar community’ in a social care group, staff skills and knowledge are required.
The Los Angeles Urban Rangers: actualizing geographic thought
Authors: Bauch Nicholas , Scott Emily Eliza
Published: April 2012

The Los Angeles Urban Rangers (LAUR) is one of a growing number of collectives associated with the art world that offer new methods for expressing and performing insights rooted in geographical thought. Borrowing the US National Park Service ranger ‘persona,’ the LAUR demonstrate a number of ways to untangle nature-society issues in cities. The ranger persona is successful in part because of its ability to spatially relocate the affect associated with (supposed) pristine nature to urban places. The article contains a toolkit of programs that the LAUR have employed to re-activate urban space.
Enhancing student research through a virtual participatory action research project: Student benefits and administrative challenges
Authors: Gordon Sue Marquis , Edwards Jennifer Lynne
Published: April 2012

Can graduate students in a distance learning environment gain meaningful research experience through a virtual participatory action research project? The answer is an emphatic ‘yes.’ The purpose of this article is twofold: to demonstrate how and to what extent graduate students can gain research experience through participation with alumni and faculty in an action research project, and to examine administrative issues arising from adhering to the democratic participatory action research process under virtual constraints. Project success is determined through documents produced by participants in the Faculty-Student Mentoring Project and from two focus group evaluations held via conference calls. The data demonstrated that the students and alumni increased their research skills, used their skills and knowledge in other courses and their dissertations, presented, and published. The university gained valuable information. The democratic participatory aspect of action research and the virtual environment created administrative challenges such as scheduling and workload issues. Recommendations include: screening volunteers to determine their levels of expertise and commitment; providing time for participants to get to know each other and the technology at the outset of the project; setting expectations for participation; sharing the project management; and anticipating more time for virtual than face-to-face research.
Individualized Behavior Management Program for Alzheimer’s/Dementia Residents Using Behavior-Based Ergonomic Therapies
Authors: Bharwani Govind , Parikh Pratik J. , Lawhorne Larry W. , VanVlymen Eric , Bharwani Meena
Published: April 2012

Person-centered, nonpharmacological interventions for managing Alzheimer’s/dementia-related behavioral disturbances have received significant attention. However, such interventions are quite often of a single type limiting their benefits. We develop a comprehensive nonpharmacological intervention, the Behavior-Based Ergonomic Therapy (BBET), which consists of multiple therapies. This low-cost, 24/7 program uses learning, personality, and behavioral profiles and cognitive function of each resident to develop a set of individualized therapies. These therapies are made available through an accessible resource library of music and video items, games and puzzles, and memory props to provide comfort or stimulation depending on an individual resident’s assessment. The quantitative and qualitative benefits of the BBET were evaluated at the dementia care unit in a not-for-profit continuing care retirement community in west central Ohio. The 6-month pilot study reduced falls by 32.5% and markedly reduced agitation through increased resident engagement.
Are Podcasts Effective at Educating African American Men About Diabetes?
Authors: Johnson Jarrett , Ross Levi , Iwanenko Walter , Schiffert Judith , Sen Arup
Published: April 2012

Education is a critical component of the National Blueprint to eliminate racial disparities in diabetes. Research indicates that traditional methods of diabetes education has had limited effectiveness with minority populations and suggests that different educational approaches be explored. The purpose of the research was to explore the effectiveness of an emergent technology (podcast) for use in educating inner-city, African American men about diabetes prevention. Thirty African American men participated in self-administered, pretest–posttest surveys in August 2009. Surveys collected information on demographic characteristics, perceptions of diabetes, and diabetes knowledge. Paired samples t test was computed to evaluate pretest–posttest changes in overall knowledge. McNemar or binomial tests were computed to evaluate pretest–posttest knowledge changes on each of the 15 individual knowledge items. Diabetes knowledge scores for the sample increased from 8.27 at pretest to 10.47 at posttest ( p = .001). Posttest knowledge scores increased for 77% of men, stayed the same for 13%, and decreased for 10%. Men who listened to the podcast correctly answered 40% more knowledge questions on their posttest assessments. Results from this exploratory study suggest that podcasts are useful for helping inner-city, African American men recall diabetes prevention information. Additional research is recommended with larger randomly selected samples using more rigorous research designs.
The impact of perceived social support and sense of coherence on health-related quality of life in multimorbid primary care patients
Authors: Vogel Ines , Miksch Antje , Goetz Katja , Ose Dominik , Szecsenyi Joachim , Freund Tobias
Published: April 2012

This study explores the impact of perceived social support and sense of coherence as positive resources for health-related quality of life in multimorbid primary care patients. We analysed cross-sectional survey data on health-related quality of life (EQ-5D), perceived social support (FSozU-K22), sense of coherence (SOC-L9), social demographics and self reported morbidity of 103 multimorbid patients from 10 general practices in Germany. A multiple linear regression model was used to determine the impact of social support and sense of coherence on the health-related quality of life while controlling for age, sex, educational level, marital status and number of chronic conditions. In the final regression model, higher sense of coherence scores were associated with higher health-related quality of life scores (standardized ß 0.34, p < 0.001) whereas a higher number of chronic conditions was associated with lower health-related quality of life scores (standardized ß −0.41, p < 0.001). In the bivariate model, higher perceived social support was associated with higher health-related quality of life scores (standardized ß 0.35, p < 0.001), whereas the model failed to show a significant association after controlling for sense of coherence which is a potential resource for improving health-related quality of life in multimorbid primary care patients. It emerged as a significant element contributing to the prediction of health-related quality of life. This issue may indicate the importance of internal resources for multimorbid patients.
Premium or Discount in Hotel Room Rates? The Dual Effects of a Central Downtown Location
Authors: Lee Seul Ki , Jang SooCheong (Shawn)
Published: April 2012

The hotel industry generally recognizes the advantages of a central business district location, resulting in higher demand, pricing ability, and profitability. What research has not done is to consider the negative effects of agglomeration and competition among centrally located hotels. Reasoning that hotels engage in price competition through revenue management, the authors developed a theoretical framework of bounded price competition. The authors theorize that rate-based competition would intensify among contiguous hotels, but they also propose that such rate-based competition is contingent on demand levels. When demand is strong, one would not expect rate-based competition. A test of this hypothesis using data from the downtown Chicago hotel market supported that a central location has a dual effect on hotel room rates. Hotels see higher premiums in the peak season, due to strong demand, and steeper discounts in shoulder seasons, as a result of competition with nearby hotels. The findings also suggest that existing models, which do not consider hotel spacing, may have overestimated the central location premium.
SOCS1 cooperates with FLT3-ITD in the development of myeloproliferative disease by promoting the escape from external cytokine control
Authors: Reddy Pavankumar N. G. , Sargin Bülent , Choudhary Chunaram , Stein Stefan , Grez Manuel , Müller-Tidow Carsten , Berdel Wolfgang E. , Serve Hubert , Brandts Christian H.
Published: April 2012

Activating mutations in the receptor tyrosine kinase FLT3 are frequently found in acute myelogenous leukemia patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control that regulates normal hematopoiesis. We have recently demonstrated that FLT3-internal tandem duplication (ITD), when localized to the biosynthetic compartment, aberrantly activates STAT5. Here, we show that one of the target genes induced by STAT5 is suppressor of cytokine signaling (SOCS)1—a surprising finding for a known tumor suppressor. Although SOCS1 expression in murine bone marrow severely impaired cytokine-induced colony growth, it failed to inhibit FLT3-ITD–supported colony growth, indicating resistance of FLT3-ITD to SOCS1. In addition, SOCS1 coexpression did not affect FLT3-ITD–mediated signaling or proliferation. Importantly, SOCS1 coexpression inhibited interferon-α and interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-mediated growth inhibitory effects. In a murine bone marrow transplantation model, the coexpression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared with FLT3-ITD alone (P < .01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting leukemogenesis. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention.
Agrin is required for survival and function of monocytic cells
Authors: Mazzon Cristina , Anselmo Achille , Soldani Cristiana , Cibella Javier , Ploia Cristina , Moalli Federica , Burden Steven J. , Dustin Michael L. , Sarukhan Adelaida , Viola Antonella
Published: April 2012

Agrin, an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), is expressed by cells of the hematopoietic system but its role in leukocyte biology is not yet clear. Here we demonstrate that agrin has a crucial, nonredundant role in myeloid cell development and functions. We have identified lineage-specific alterations that affect maturation, survival and properties of agrin-deficient monocytic cells, and occur at stages later than stem cell precursors. Our data indicate that the cell-autonomous signals delivered by agrin are sensed by macrophages through the α-DC (DG) receptor and lead to the activation of signaling pathways resulting in rearrangements of the actin cytoskeleton during the phagocytic synapse formation and phosphorylation of extracellular signal-regulated kinases (Erk 1/2). Altogether, these data identify agrin as a novel player of innate immunity.
Multiscale prediction of patient-specific platelet function under flow
Authors: Flamm Matthew H. , Colace Thomas V. , Chatterjee Manash S. , Jing Huiyan , Zhou Songtao , Jaeger Daniel , Brass Lawrence F. , Sinno Talid , Diamond Scott L.
Published: April 2012

During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A2, recruiting additional platelets to a growing deposit that distorts the flow field. Prediction of clotting function under hemodynamic conditions for a patient's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using pairwise agonist scanning, in which calcium dye–loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate the P2Y1/P2Y12, TP, and GPVI receptors, respectively, with and without the prostacyclin receptor agonist iloprost. A neural network model was trained on each donor's pairwise agonist scanning experiment and then embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were compared directly with microfluidic experiments of whole blood flowing over collagen at 200 and 1000/s wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (a P2Y1 inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots and another presented with indomethacin resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of a subject's platelet phenotype allowed prediction of blood function under flow, essential for identifying patient-specific risks, drug responses, and novel genotypes.
RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia
Authors: Aimiuwu Josephine , Wang Hongyan , Chen Ping , Xie Zhiliang , Wang Jiang , Liu Shujun , Klisovic Rebecca , Mims Alice , Blum William , Marcucci Guido , Chan Kenneth K.
Published: April 2012

5-Azacytidine (5-azaC) is an azanucleoside approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2, that provides the deoxyribonucleotides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC–induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5-azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination.
The interferon-dependent orchestration of innate and adaptive immunity after transplantation
Authors: Robb Renee J. , Hill Geoffrey R.
Published: April 2012

The therapeutic GVL effect after allogeneic stem cell transplantation is limited by the development of GVHD. The ultimate aim of current research is to separate the 2 processes in a meaningful fashion. The IFNs are a pleiotropic group of cytokines that were originally recognized because of their ability to interfere with viral replication. However, it is now established that these cytokines play an important role in orchestrating both innate and adaptive immunity. Multiple studies have investigated the effects of both types I and II IFN on GVHD and GVL in preclinical transplant models. The results indicate variable effects that are dependent on the period of activity within the developing immune response, the presence and type of pretransplant conditioning and the differential mechanisms, and IFN sensitivity of immune pathology within individual target organs during GVHD. This Perspective discusses the current literature on the IFNs and their potential modulation within clinical transplantation, focusing particularly on enhancing the therapeutic GVL effects.
Characterization of C-strain “Riems” TAV-epitope escape variants obtained through selective antibody pressure in cell culture
Authors: Leifer Immanuel , Blome Sandra , Blohm Ulrike , König Patricia , Küster Heike , Lange Bodo , Beer Martin
Published: April 2012

Classical swine fever virus (CSFV) C-strain “Riems” escape variants generated under selective antibody pressure with monoclonal antibodies and a peptide-specific antiserum in cell culture were investigated. Candidates with up to three amino acid exchanges in the immunodominant and highly conserved linear TAV-epitope of the E2-glycoprotein, and additional mutations in the envelope proteins ERNS and E1, were characterized both in vitro and in vivo.

It was further demonstrated, that intramuscular immunization of weaner pigs with variants selected after a series of passages elicited full protection against lethal CSFV challenge infection. These novel CSFV C-strain variants with exchanges in the TAV-epitope present potential marker vaccine candidates. The DIVA (differentiating infected from vaccinated animals) principle was tested for those variants using commercially available E2 antibody detection ELISA. Moreover, direct virus differentiation is possible using a real-time RT-PCR system specific for the new C-strain virus escape variants or using differential immunofluorescence staining.
Characterization of a novel chaperone/usher fimbrial operon present on KpGI-5, a methionine tRNA gene-associated genomic island in Klebsiella pneumoniae
Authors: van Aartsen Jon J , Stahlhut Steen G , Harrison Ewan M , Crosatti Marialuisa , Ou Hong-Yu , Krogfelt Karen A , Struve Carsten , Rajakumar Kumar
Published: April 2012

Background

Several strain-specific Klebsiella pneumoniae virulence determinants have been described, though these have almost exclusively been linked with hypervirulent liver abscess-associated strains. Through PCR interrogation of integration hotspots, chromosome walking, island-tagging and fosmid-based marker rescue we captured and sequenced KpGI-5, a novel genomic island integrated into the met56 tRNA gene of K. pneumoniae KR116, a bloodstream isolate from a patient with pneumonia and neutropenic sepsis.

Results

The 14.0 kb KpGI-5 island exhibited a genome-anomalous G + C content, possessed near-perfect 46 bp direct repeats, encoded a γ1-chaperone/usher fimbrial cluster (fim2) and harboured seven other predicted genes of unknown function. Transcriptional analysis demonstrated expression of three fim2 genes, and suggested that the fim2A-fim2K cluster comprised an operon. As fimbrial systems are frequently implicated in pathogenesis, we examined the role of fim2 by analysing KR2107, a streptomycin-resistant derivative of KR116, and three isogenic mutants (Δfim, Δfim2 and ΔfimΔfim2) using biofilm assays, human cell adhesion assays and pair-wise competition-based murine models of intestinal colonization, lung infection and ascending urinary tract infection. Although no statistically significant role for fim2 was demonstrable, liver and kidney CFU counts for lung and urinary tract infection models, respectively, hinted at an ordered gradation of virulence: KR2107 (most virulent), KR2107∆fim2, KR2107∆fim and KR2107∆fim∆fim2 (least virulent). Thus, despite lack of statistical evidence there was a suggestion that fim and fim2 contribute additively to virulence in these murine infection models. However, further studies would be necessary to substantiate this hypothesis.

Conclusion

Although fim2 was present in 13% of Klebsiella spp. strains investigated, no obvious in vitro or in vivo role for the locus was identified, although there were subtle hints of involvement in urovirulence and bacterial dissemination from the respiratory tract. Based on our findings and on parallels with other fimbrial systems, we propose that fim2 has the potential to contribute beneficially to pathogenesis and/or environmental persistence of Klebsiella strains, at least under specific yet-to-be identified conditions.
The family of Deg/HtrA proteases in plants
Authors: Schuhmann Holger , Huesgen Pitter F , Adamska Iwona
Published: April 2012

Background

The Deg/HtrA family of ATP-independent serine endopeptidases is present in nearly all organisms from bacteria to human and vascular plants. In recent years, multiple deg/htrA protease genes were identified in various plant genomes. During genome annotations most proteases were named according to the order of discovery, hence the same names were sometimes given to different types of Deg/HtrA enzymes in different plant species. This can easily lead to false inference of individual protease functions based solely on a shared name. Therefore, the existing names and classification of these proteolytic enzymes does not meet our current needs and a phylogeny-based standardized nomenclature is required.

Results

Using phylogenetic and domain arrangement analysis, we improved the nomenclature of the Deg/HtrA protease family, standardized protease names based on their well-established nomenclature in Arabidopsis thaliana, and clarified the evolutionary relationship between orthologous enzymes from various photosynthetic organisms across several divergent systematic groups, including dicots, a monocot, a moss and a green alga. Furthermore, we identified a “core set” of eight proteases shared by all organisms examined here that might provide all the proteolytic potential of Deg/HtrA proteases necessary for a hypothetical plant cell.

Conclusions

In our proposed nomenclature, the evolutionarily closest orthologs have the same protease name, simplifying scientific communication when comparing different plant species and allowing for more reliable inference of protease functions. Further, we proposed that the high number of Deg/HtrA proteases in plants is mainly due to gene duplications unique to the respective organism.
Evaluation of the clinical value of ELISA based on MPT64 antibody aptamer for serological diagnosis of pulmonary tuberculosis
Authors: Zhu Changtai , Liu Jinming , Ling Yang , Yang Hua , Liu Zhonghua , Zheng Ruijuan , Qin Lianhua , Hu Zhongyi
Published: April 2012

Background

Presently, tuberculosis (TB) poses a global threat to human health. The development of reliable laboratory tools is vital to the diagnosis and treatment of TB. MPT64, a protein secreted by Mycobacterium tuberculosis complex, is highly specific for TB, making antibody to MPT64 a reagent specific for the diagnosis of TB.

Method

Antibody to MPT64 was obtained by a combination of genetic engineering and immunization by the system evolution of ligands by exponential enrichment. A high-affinity aptamer of antibody to MPT64 was selected from a random single-stranded DNA library, and a sandwich ELISA method based on this aptamer was developed. This ELISA method was used to detect TB in 328 serum samples, 160 from patients with pulmonary TB (PTB) and 168 from non-tuberculous controls.

Results

The minimum limit of detection of the ELISA method was 2.5 mg/L, and its linear range varied from 10 mg/L to 800 mg/L. Its sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and area under the curve, with 95 % confidence intervals, were 64.4 % (56.7 %–71.4 %), 99.4 % (96.7 %–99.9 %), 108.2 (15.3–765.9), 0.350 (0.291–0.442) and 0.819 (0.770–0.868), respectively. No significant difference in sensitivity was observed between sputum smear positive (73/112, 65.2 %) and negative (30/48, 62.5 %) individuals.

Conclusions

This sandwich ELISA based on an MPT64 antibody aptamer may be useful for the serological diagnosis of PTB, both in sputum smear positive and negative patients.
Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"
Authors: Galatola Martina , Paparo Lorella , Duraturo Francesca , Turano Mimmo , Rossi Giovanni Battista , Izzo Paola , De Rosa Marina
Published: April 2012

Background

The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues.

The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration.

Methods

We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques.

Results

Our data provide the first evidence of β-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1β) was found to be overexpressed.

Conclusion

In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as β-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers.
Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic Cleft in Ireland
Authors: Minguzzi Stefano , Molloy Anne M , Peadar Kirke , Mills James , Scott John M , Troendle James , Pangilinan Faith , Brody Lawrence , Parle-McDermott Anne
Published: April 2012

Background

Polymorphisms within the MTHFD1L gene were previously associated with risk of neural tube defects in Ireland. We sought to test the most significant MTHFD1L polymorphisms for an association with risk of cleft in an Irish cohort. This required the development of a new melting curve assay to genotype the technically challenging MTHFD1L triallelic deletion/insertion polymorphism (rs3832406).

Methods

Melting curve analysis was used to genotype the MTHFD1L triallelic deletion/insertion polymorphism (rs3832406) and a Single Nucleotide Polymorphism rs17080476 in an Irish cohort consisting of 981 Irish case-parent trios and 1,008 controls. Tests for association with nonsyndromic cleft lip with or without cleft palate and cleft palate included case/control analysis, mother/control analysis and Transmission Disequilibrium Tests of case-parent trios.

Results

A successful melting curve genotyping assay was developed for the deletion/insertion polymorphism (rs3832406). The TDT analysis initially showed that the rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate. However, corrected p-values indicated that this association was not significant.

Conclusions

Melting Curve Analysis can be employed to successfully genotype challenging polymorphisms such as the MTHFD1L triallelic deletion/insertion polymorphism (DIP) reported here (rs3832406) and is a viable alternative to capillary electrophoresis. Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort.
Association analysis between HOXD9 genes and the development of developmental dysplasia of the hip in Chinese female Han population
Authors: Tian Wei , Zhao Lixi , Wang Jing , Suo Peisu , Wang Jianmin , Cheng Longfei , Cheng Zhi , Jia Jian , Kan Shilian , Wang Binbin , Ma Xu
Published: April 2012

Background

Developmental dysplasia of the hip (DDH) is a congenital or acquired deformation or misalignment of the hip joint which affects mainly females. We hypothesized thatHOXD9gene could be regulated in acetabular size or shape and related in DDH developing.

Methods

Two hundred and nine Chinese Han female DDH patients and 173 ethnic, age matched healthy female controls were genotyped forHOXD9two tag SNPs using sequenom method.

Results

One of the two tag SNPs, rs711822, was not shown significantly differences in genotypic or allelic distribution between case and control group. Comparing the genotypic distribution of rs711819, there was significant differences between DDH patients group and control group (χ2 = 7.54, df =2,P=0.023), and the association to DDH developing reached significance (P=0.045, OR =1.79, 95 % CI: 1.01-3.17 by dominant mode).

Conclusion

In conclusion, the association between one tag SNP ofHOXD9gene and the development of DDH reach significant in our study population, this result indicate the positive correlation betweenHOXD9gene and DDH developing. Further study in larger sample size and different population as well as functional studies will help to understand the pathogenesis of DDH.
Assessment of leukemia inhibitory factor and glycoprotein 130 expression in endometrium and uterine flushing: a possible diagnostic tool for impaired fertility
Authors: Tawfeek Manal A , Eid Manal A , Hasan Azza M , Mostafa Manal , El-Serogy Hesham A
Published: April 2012

Background

Uterine receptivity and implantation are complex processes requiring coordinated expression of molecules by zygote and uterus. Our objective was to evaluate the role of the endometrial expression of leukemia inhibitory factor (LIF) and its glycoprotein 130 (gp130) receptor molecules and their secretion in uterine flushing during the window of implantation in cases of primary unexplained infertility

Case presentation

The study was conducted on 25 infertile women with unexplained infertility for at least two years and 10 normal fertile women as a control group . Endometrial tissue and uterine flushing were obtained. Each tissue specimen was divided into two pieces; one piece was used for histological dating of the endometrium and for immunostaining of progesterone receptors, and the second was used for RNA extraction and PCR assay of LIF and gp130 mRNA expression. Serum estrogen and progesterone were measured for all subjects. LIF mRNA was expressed in the endometrium of all normal fertile women but significantly decreased in infertile women. LIF was not detectable in 88% of infertile women while it was fairly detectable in 12% of them. Gp130 mRNA was hardly detectable in both fertile and infertile women with no difference between them. Infertile women secreted significantly less LIF and gp130 molecules in the uterine flushing compared with normal fertile women.

Conclusions

Expression of LIF mRNA in endometrium could be used as a molecular marker of unexplained infertility. Assessment of secreted LIF and gp130 molecules in uterine flushing could be another useful and safe method for predicting successful implantation as well as for diagnosing and eventually treating women with impaired fertility using recombinant human LIF.