bluuebunny/crossref_metadata_2025 huggingface dataset:
Listening Walks and Singing Maps
Authors: Cardany Audrey Berger
Published: January 2011

The Listening Walk by Paul Showers and illustrated by Aliki, and It’s My City: A Singing Map by April Pulley Sayre with pictures by Denis Roche, provide two examples of texts that aid in building children’s phonological awareness for reading and music. The author describes each narrative and discusses its function as a springboard to composition lessons in a primary and an upper-elementary general music classroom. Visual aids and examples of student work are presented.
Appalachian Residents’ Experiences With and Management of Multiple Morbidity
Authors: Schoenberg Nancy E. , Bardach Shoshana H. , Manchikanti Kavita N. , Goodenow Anne C.
Published: January 2011

Approximately three fourths of middle-aged and older adults have at least two simultaneously occurring chronic conditions (“multiple morbidity,” or MM), a trend expected to increase dramatically throughout the world. Rural residents, who tend to have fewer personal and health resources, are more likely to experience MM. To improve our understanding of the ways in which vulnerable, rural residents in the United States experience and manage MM, we interviewed 20 rural Appalachian residents with MM. We identified the following themes: (a) MM has multifaceted challenges and is viewed as more than the sum of its parts; (b) numerous challenges exist to optimal MM self-management, particularly in a rural, underresourced context; however, (c) participants described strategic methods of managing MM, including prioritizing certain conditions and management strategies and drawing heavily on assistance from informal and formal sources.
Implementing a Problem-Solving Intervention With Students With Mild to Moderate Disabilities
Authors: Cote Debra L.
Published: January 2011

Students with mild and moderate disabilities need to be skillful at problem solving. This article provides an overview of a problem-solving intervention designed to teach students with mild and moderate disabilities the skills of problem solving. An explanation of the assessments, materials, instructional outline, and methods is presented.
Animals in War
Authors: Johnston Steven
Published: January 2011

Patriotism poses a threat, not just to democracy but also to life itself. It finds expression in a new species of civic memorial dedicated to animals. In wartime, the animal world, including dogs, horses, elephants, and mules, is forced to serve. It is treated as militarily indispensable but also utterly disposable. Millions of animals have been killed in the name of country—not despite the patriotic love professed for them, but precisely because of it. The treatment of animals mimics the treatment of citizens and vice versa, where no sacrifice ultimately lies beyond justification. Thus, patriotism’s dependence on and even addiction to death acquires added intensity and depth.
Tourist perceived value in a community-based homestay visit: An investigation into the functional and experiential aspect of value
Authors: Jamal Salamiah A. , Othman Nor'Ain , Nik Maheran Nik Muhammad
Published: January 2011

This study analyses the dimensionality of tourist perceived value in a context that is rarely studied, community-based homestay tourism. A survey of 353 tourists to homestay villages was used to examine both functional and experiential aspects of perceived value, and structural equation models were used to verify the validity and reliability of the scales. Tourist perceived value was tested and illustrated through a parsimonious construct with five dimensions: (i) functional value (establishment); (ii) functional value (price); (iii) experiential value (host-guest interaction); (iv) experiential value (activity, culture and knowledge); and (v) emotional value. These dimensions were measured by 20 significant items. The results indicate that functional, emotional and experiential factors are important determinants of the perceived value of community-based homestay tourism. It is therefore recommended that host providers, marketers and governments should pay attention to the order of importance of these value dimensions to increase overall tourist value as well as to better develop the positioning strategies and promotion of this tourism niche.
Group treatment of obesity in primary care practice: A qualitative study of patients’ perspectives
Authors: Östberg A.L. , Wikstrand I. , Bengtsson Boström K.
Published: January 2011

Aims: To explore patients’ experiences of very low calorie diet (VLCD) and subsequent corset treatment of obesity in a primary care setting, and to explore their perceptions of factors influencing weight control. Methods: In western Sweden, five focus group sessions were carried out. The main themes for the discussions were the informants’ perceptions of the treatment they had received and their experiences of living with obesity. The analysis was based on the Grounded Theory methodology. Results: The outcomes reflect obese individuals’ struggle to handle the demands of their life situation and to recognize their own resources. The core category generated was labelled ‘‘Achieving a balance in life and adjusting one’s identity’’. Three categories related to the process of weight reduction were identified: living with obesity, reducing weight and developing self-management. The group treatment with VLCD was positively perceived by the participants, but the corset treatment was considered to be of less value. Conclusions: Maintenance after weight reduction was demanding and the findings indicate a need for extended support. For some individuals the corset treatment could be a psychological support. Follow-up after weight reduction programmes should focus on long-term self-help strategies.
Vacations to sunny destinations, sunburn, and intention to tan: A cross-sectional study in Denmark, 2007-2009
Authors: Køster Brian , Thorgaard Camilla , Philip Anja , Clemmensen Inge Haunstrup
Published: January 2011

Background: Denmark has experienced an increase in melanoma incidence since the 1960s. Exposure to ultraviolet radiation is the main preventable cause of this cancer. We examined current travel to, and sun-related behaviour of Danes at, sunny destinations in relation to their risk for sunburn. Method: A population-based sample of 11,158 respondents aged 15—59 years completed three questionnaires in 2007—2009 that included items on exposure to ultraviolet radiation. Using logistic regression analysis we examined the relations between sunny vacations, sun-related behaviour, demographic factors and risk for sunburn. Results: During 2007—2009, 44.8—45.8% of the respondents travelled to a sunny destination at least once a year; 24% became sunburnt, and 69% tanned intentionally. The odds ratio for sunburn in general for people who went on a sunny vacation as compared with those who did not was 1.6 (1.5—1.7). Sunscreen use (1.9; 1.4—2.6) and intentional tanning (3.4; 2.8—4.1) were positively associated with sunburn on vacation. Conclusions: Taking a vacation in a sunny place is a risk factor for sunburn, especially for young people. The recommendation for sunscreen use should be re-evaluated, as intention to tan is the most important factor in sunburn on vacation and should be targeted more strategically.
How physicians have learned to handle sickness-certification cases
Authors: Löfgren Anna , Silén Charlotte , Alexanderson Kristina
Published: January 2011

Background: Sickness absence is a common ‘‘prescription’’ in health care in many Western countries. Despite the significance of sick-listing for the life situation of patients, physicians have limited training in how to handle sickness-certification cases and the research about sickness-certification practices is scarce. Aim: gain knowledge on physicians’ learning regarding management of sickness certification of patients in formal, informal, and non-formal learning situations, respectively, and possible changes in this from 2004 to 2008. Methods: Data from two comprehensive questionnaires to physicians in Sweden about their sickness-certification practice in 2004 (n = 7665) and 2008 (n = 36898); response rates: 71% and 61%, respectively. Answers from all the physicians ≤64 years old and who had sickness certification tasks (n = 4019 and n = 14210) were analysed. Outcome measures: ratings of importance of different types of learning situations for their sickness-certification competence. Results: Few physicians stated that formal learning situations had contributed to a large or fairly large extent to their competence in sickness certification, e.g. undergraduate studies had done that for 17%, internship for 37%, and resident training for 46%, respectively. Contacts with colleagues had been helpful for 65%. One-third was helped by training arranged by social insurance offices. There was a significant increase between 2004 and 2008 in all items related to formal and non-formal learning situations, while there were no changes regarding informal learning situations. Conclusions: This study of all physicians in Sweden shows that physicians primarily attain competence in sickness certification in their daily clinical practice; through contacts with colleagues and patients.
Adversarial moments: A study of short-form interviews in the news
Authors: Eriksson Göran
Published: January 2011

Through an analysis of news journalism in Sweden, the development of a more adversarial, critical or interpretive news journalism is discussed in this article. A frequent form of politicians’ appearances in the news is in short-form interviews in news stories. Such interviews are often reduced to single turns or answers. The aim of this study is to identify the more communicative techniques used, when politicians’ answers are cut and incorporated into news stories, and how these techniques are related to the roles set up for politicians and reporters. What potential relationships are set up between politicians, reporters and the viewers? Swedish television data from 1978, 1993 and 2003 have been analysed. The analysis shows that in the early period, news journalism appears as a mediator or interrogator. In the latter periods, news journalism appears in an adversarial role. It becomes more of an interpreter or a critical interrogator of politician’s actions.
The role of the Director of Public Health in England
Authors: Pittam Gail , Wright Jenny
Published: January 2011

Gail Pittam and Jenny Wright from Solutions for Public Health, a not-for-profit NHS public health organization, look to the future while highlighting the lessons of the past
RSPH Training Solutions: Developing health improvement in the wider public health workforce
Authors: Davison Heather
Published: January 2011

Dr Heather Davison, Development Director at the RSPH, discusses the importance of updating skills and broadening knowledge in the public health sector
Building capacity across the frontline nutrition workforce
Authors: Radford Stefanie , Hall Amy
Published: January 2011

Project Manager Stefanie Radford from the Association for Nutrition, and her colleague Amy Hall, offer an insight into the development of a unique quality assurance framework in nutrition and the rapid progress being made.
An emerging model for publishing and using open educational resources in public health
Authors: Hemingway A. , Angell C. , Hartwell H. , Heller Richard F
Published: January 2011

Introduction: The open source revolution has enabled the development of open educational resources (OER) and the potential for sharing lessons learned. We present a potential model for publishing OER in public health to inform workforce development.

Methods: As part of the PHORUS (Public Health Open Resources for the University Sector) Project, a review of the literature relating to the development of OER was followed by an online search for OER resources relating specifically to public health. Furthermore, a Delphi study was conducted to identify and prioritize barriers and enablers to the production and use of public health OER.

Results: A wide array of OER literature was identified, although there were a limited Number of public health-related papers. The key concepts influencing public health OER release found in the literature were identified as quality, ethics and values, rewards, risks and practical aspects, such as technological developments. These concepts were then further developed through the PHORUS project research findings to produce the basis of a potential model for OER development in public health.

Discussion/Conclusion: The synthesis of a literature review and Delphi study has produced a potential model to guide the development of OER in public health. The model provides a matrix where the questions about whether and how an academic can produce and publish OER are answered, according to various risks and benefits to them and their institution. We hope that this will provide practical assistance and encouragement for the academic public health community to create and share OER.
In Practice
Authors: Cronin Eugenia , Endersby Fiona
Published: January 2011

Dr Eugenia Cronin, a consultant in public health and Fiona Endersby, a change management consultant and coach, discuss the best way to cope with the changes facing the public health workforce
FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo
Authors: Sato Takashi , Yang Xiaochuan , Knapper Steven , White Paul , Smith B. Douglas , Galkin Steven , Small Donald , Burnett Alan , Levis Mark
Published: January 2011

We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.
Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome–positive acute lymphoblastic leukemia
Authors: Boulos Nidal , Mulder Heather L. , Calabrese Christopher R. , Morrison Jeffrey B. , Rehg Jerold E. , Relling Mary V. , Sherr Charles J. , Williams Richard T.
Published: January 2011

The introduction of cultured p185BCR-ABL-expressing (p185+) Arf−/− pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome–positive (Ph+) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph+ ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I “gatekeeper” mutations resistant to all 3 Food and Drug Administration–approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non–tumor-cell–autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of “conventional” chemotherapeutic agents with alternate antileukemic mechanisms of action.
How I treat relapsed and refractory Hodgkin lymphoma
Authors: Kuruvilla John , Keating Armand , Crump Michael
Published: January 2011

Relapsed or refractory Hodgkin lymphoma is a challenging problem for clinicians who treat hematologic malignancies. The standard management of these patients should include the use of salvage chemotherapy followed by autologous stem cell transplant (ASCT) in patients who are chemotherapy sensitive. Open issues in this area include the role of functional imaging, the specific chemotherapy regimen to be used before ASCT, and the role of consolidative radiotherapy. Some patients will not be eligible for ASCT, and alternative approaches with conventional chemotherapy alone or with salvage radiotherapy should be considered. Prognostic factors for relapsed/refractory disease have been identified but generally are not used as a part of risk-adapted therapy. Allogeneic transplantation may offer the potential of a graft-versus-lymphoma effect, but this therapy has significant toxicity and results in few long-term disease-free survivors; hence, it should only be offered in the context of disease-specific clinical trials. An expanding list of novel drugs has exhibited promising single-agent activity. Patients have effective options beyond primary therapy, and continued progress through controlled trials remains a tangible goal in the treatment of relapsed and refractory disease.
Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA
Authors: Tsui Nancy B. Y. , Kadir Rezan A. , Chan K. C. Allen , Chi Claudia , Mellars Gillian , Tuddenham Edward G. , Leung Tak Y. , Lau Tze K. , Chiu Rossa W. K. , Lo Y. M. Dennis
Published: January 2011

Hemophilia is a bleeding disorder with X-linked inheritance. Current prenatal diagnostic methods for hemophilia are invasive and pose a risk to the fetus. Cell-free fetal DNA analysis in maternal plasma provides a noninvasive mean of assessing fetal sex in such pregnancies. However, the disease status of male fetuses remains unknown if mutation-specific confirmatory analysis is not performed. Here we have developed a noninvasive test to diagnose whether the fetus has inherited a causative mutation for hemophilia from its mother. The strategy is based on a relative mutation dosage approach, which we have previously established for determining the mutational status of fetuses for autosomal disease mutations. In this study, the relative mutation dosage method is used to deduce whether a fetus has inherited a hemophilia mutation on chromosome X by detecting whether the concentration of the mutant or wild-type allele is overrepresented in the plasma of heterozygous women carrying male fetuses. We correctly detected fetal genotypes for hemophilia mutations in all of the 12 studied maternal plasma samples obtained from at-risk pregnancies from as early as the 11th week of gestation. This development would make the decision to undertake prenatal testing less traumatic and safer for at-risk families.
Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo
Authors: Isern Joan , He Zhiyong , Fraser Stuart T. , Nowotschin Sonja , Ferrer-Vaquer Anna , Moore Rebecca , Hadjantonakis Anna-Katerina , Schulz Vincent , Tuck David , Gallagher Patrick G. , Baron Margaret H.
Published: January 2011

Primitive erythroid (EryP) progenitors are the first cell type specified from the mesoderm late in gastrulation. We used a transgenic reporter to image and purify the earliest blood progenitors and their descendants from developing mouse embryos. EryP progenitors exhibited remarkable proliferative capacity in the yolk sac immediately before the onset of circulation, when these cells comprise nearly half of all cells of the embryo. Global expression profiles generated at 24-hour intervals from embryonic day 7.5 through 2.5 revealed 2 abrupt changes in transcript diversity that coincided with the entry of EryPs into the circulation and with their late maturation and enucleation, respectively. These changes were paralleled by the expression of critical regulatory factors. Experiments designed to test predictions from these data demonstrated that the Wnt-signaling pathway is active in EryP progenitors, which display an aerobic glycolytic profile and the numbers of which are regulated by transforming growth factor-β1 and hypoxia. This is the first transcriptome assembled for a single hematopoietic lineage of the embryo over the course of its differentiation.
Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly
Authors: Fabbro Shay , Kahr Walter H. A. , Hinckley Jesse , Wang Kai , Moseley Jack , Ryu Gi-Yung , Nixon Brie , White James G. , Bair Thomas , Schutte Brian , Di Paola Jorge
Published: January 2011

Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by thrombocytopenia and the absence of α-granules in platelets. Patients with GPS present with mild to moderate bleeding and many develop myelofibrosis. The genetic cause of GPS is unknown. We present 2 Native American families with a total of 5 affected persons and a single affected patient of Pakistani origin in which GPS appears to be inherited in an autosomal recessive manner. Homozygosity mapping using the Affymetrix 6.0 chips demonstrates that all 6 GPS-affected persons studied are homozygous for a 1.7-Mb region in 3p21. Linkage analysis confirmed the region with a logarithm of the odds score of 2.7. Data from our families enabled us to significantly decrease the size of the critical region for GPS from the previously reported 9.4-Mb region at 3p21.
Identification of novel DNA methylation inhibitors via a two-component reporter gene system
Authors: Lin Yi-Shiuan , Shaw Arthur Y , Wang Shi-Gang , Hsu Chia-Chen , Teng I-Wen , Tseng Min-Jen , Huang Tim HM , Chen Ching-Shih , Leu Yu-Wei , Hsiao Shu-Huei
Published: January 2011

Background

Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation. While procainamide is much safer than 5-aza-2'-deoxycytidine, it requires high concentrations to be effective in DNA demethylation in suppressing cancer cell growth. Thus, our laboratories have embarked on the pharmacological exploitation of procainamide to develop potent DNA methylation inhibitors through lead optimization.

Methods

We report the use of a DNA methylation two-component enhanced green fluorescent protein reporter system as a screening platform to identify novel DNA methylation inhibitors from a compound library containing procainamide derivatives.

Results

A lead agent IM25, which exhibits substantially higher potency in GSTp1 DNA demethylation with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2'-deoxycytidine, was identified by the screening platform.

Conclusions

Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to develop novel DNA methylation inhibitors, of which the translational potential in cancer therapy/prevention is currently under investigation.
Worm Phenotype Ontology: Integrating phenotype data within and beyond the C. elegans community
Authors: Schindelman Gary , Fernandes Jolene S , Bastiani Carol A , Yook Karen , Sternberg Paul W
Published: January 2011

Background

Caenorhabditis elegans gene-based phenotype information dates back to the 1970's, beginning with Sydney Brenner and the characterization of behavioral and morphological mutant alleles via classical genetics in order to understand nervous system function. Since then C. elegans has become an important genetic model system for the study of basic biological and biomedical principles, largely through the use of phenotype analysis. Because of the growth of C. elegans as a genetically tractable model organism and the development of large-scale analyses, there has been a significant increase of phenotype data that needs to be managed and made accessible to the research community. To do so, a standardized vocabulary is necessary to integrate phenotype data from diverse sources, permit integration with other data types and render the data in a computable form.

Results

We describe a hierarchically structured, controlled vocabulary of terms that can be used to standardize phenotype descriptions in C. elegans, namely the Worm Phenotype Ontology (WPO). The WPO is currently comprised of 1,880 phenotype terms, 74% of which have been used in the annotation of phenotypes associated with greater than 18,000 C. elegans genes. The scope of the WPO is not exclusively limited to C. elegans biology, rather it is devised to also incorporate phenotypes observed in related nematode species. We have enriched the value of the WPO by integrating it with other ontologies, thereby increasing the accessibility of worm phenotypes to non-nematode biologists. We are actively developing the WPO to continue to fulfill the evolving needs of the scientific community and hope to engage researchers in this crucial endeavor.

Conclusions

We provide a phenotype ontology (WPO) that will help to facilitate data retrieval, and cross-species comparisons within the nematode community. In the larger scientific community, the WPO will permit data integration, and interoperability across the different Model Organism Databases (MODs) and other biological databases. This standardized phenotype ontology will therefore allow for more complex data queries and enhance bioinformatic analyses.
ZINC-INDUCED FACILITATOR-LIKE family in plants: lineage-specific expansion in monocotyledons and conserved genomic and expression features among rice (Oryza sativa) paralogs
Authors: Ricachenevsky Felipe K , Sperotto Raul A , Menguer Paloma K , Sperb Edilena R , Lopes Karina L , Fett Janette P
Published: January 2011

Background

Duplications are very common in the evolution of plant genomes, explaining the high number of members in plant gene families. New genes born after duplication can undergo pseudogenization, neofunctionalization or subfunctionalization. Rice is a model for functional genomics research, an important crop for human nutrition and a target for biofortification. Increased zinc and iron content in the rice grain could be achieved by manipulation of metal transporters. Here, we describe the ZINC-INDUCED FACILITATOR-LIKE (ZIFL) gene family in plants, and characterize the genomic structure and expression of rice paralogs, which are highly affected by segmental duplication.

Results

Sequences of sixty-eight ZIFL genes, from nine plant species, were comparatively analyzed. Although related to MSF_1 proteins, ZIFL protein sequences consistently grouped separately. Specific ZIFL sequence signatures were identified. Monocots harbor a larger number of ZIFL genes in their genomes than dicots, probably a result of a lineage-specific expansion. The rice ZIFL paralogs were named OsZIFL1 to OsZIFL13 and characterized. The genomic organization of the rice ZIFL genes seems to be highly influenced by segmental and tandem duplications and concerted evolution, as rice genome contains five highly similar ZIFL gene pairs. Most rice ZIFL promoters are enriched for the core sequence of the Fe-deficiency-related box IDE1. Gene expression analyses of different plant organs, growth stages and treatments, both from our qPCR data and from microarray databases, revealed that the duplicated ZIFL gene pairs are mostly co-expressed. Transcripts of OsZIFL4, OsZIFL5, OsZIFL7, and OsZIFL12 accumulate in response to Zn-excess and Fe-deficiency in roots, two stresses with partially overlapping responses.

Conclusions

We suggest that ZIFL genes have different evolutionary histories in monocot and dicot lineages. In rice, concerted evolution affected ZIFL duplicated genes, possibly maintaining similar expression patterns between pairs. The enrichment for IDE1 boxes in rice ZIFL gene promoters suggests a role in Zn-excess and Fe-deficiency up-regulation of ZIFL transcripts. Moreover, this is the first description of the ZIFL gene family in plants and the basis for functional studies on this family, which may play important roles in Zn and Fe homeostasis in plants.
Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US
Authors: Been Latonya F , Ralhan Sarju , Wander Gurpreet S , Mehra Narinder K , Singh JaiRup , Mulvihill John J , Aston Christopher E , Sanghera Dharambir K
Published: January 2011

Background

Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.

Methods

We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.

Results

Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).

Conclusions

Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.
Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations
Authors: Li Xin-Hua , Lu Yi , Ling Yun , Fu Qing-Chun , Xu Jie , Zang Guo-Qing , Zhou Feng , De-Min Yu , Han Yue , Zhang Dong-Hua , Gong Qi-Ming , Lu Zhi-Meng , Kong Xiao-Fei , Wang Jian-She , Zhang Xin-Xin
Published: January 2011

Background

Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.

Methods

The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).

Results

Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).

Conclusions

We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.
SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis
Authors: Rousseau Guillaume , Noguchi Tetsuro , Bourdon Violaine , Sobol Hagay , Olschwang Sylviane
Published: January 2011

Background

Schwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic NF2 mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the SMARCB1 (INI1) tumor suppressor gene were described in familial and sporadic schwannomatosis patients.

Methods

To delineate the SMARCB1 gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas.

Results

Nine variants scattered along the sequence of SMARCB1 were identified. Five of them were classified as deleterious. All five patients carrying a SMARCB1 mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age.

Conclusions

These results suggest that patients with schwannomas have a significant probability of carrying a SMARCB1 mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the SMARCB1 gene.
Incidence of bone metastases and skeletal-related events in breast cancer patients: A population-based cohort study in Denmark
Authors: Jensen Annette Ø , Jacobsen Jacob B , Nørgaard Mette , Yong Mellissa , Fryzek Jon P , Sørensen Henrik T
Published: January 2011

Background

Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, and orthopaedic surgery. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. Few epidemiological data exist on SREs after primary diagnosis of BrCa and subsequent bone metastasis. We therefore estimated the incidence of bone metastases and SREs in newly-diagnosed BrCa patients in Denmark from 1999 through 2007.

Methods

We estimated the overall and annual incidence of bone metastases and SREs in newly-diagnosed breast cancer patients in Denmark from January 1, 1999 to December 31, 2007 using the Danish National Patient Registry (DNPR), which covers all Danish hospitals. We estimated the cumulative incidence of bone metastases and SREs and associated 95% confidence intervals (CI) using the Kaplan-Meier method.

Results

Of the 35,912 BrCa patients, 178 (0.5%) presented with bone metastases at the time of primary breast cancer diagnosis, and of these, 77 (43.2%) developed an SRE during follow up. A total of 1,272 of 35,690 (3.6%) BrCa patients without bone metastases at diagnosis developed bone metastases during a median follow-up time of 3.4 years. Among these patients, 590 (46.4%) subsequently developed an SRE during a median follow-up time of 0.7 years. Incidence rates of bone metastases were highest the first year after the primary BrCa diagnosis, particularly among patients with advanced BrCa at diagnosis. Similarly, incidence rates of a first SRE was highest the first year after first diagnosis of a bone metastasis.

Conclusions

The high incidence of SREs following the first year after first diagnosis of a bone metastasis underscores the need for early BrCa detection and research on effective treatments to delay the onset of SREs.
A human ribonuclease induces apoptosis associated with p21WAF1/CIP1induction and JNK inactivation
Authors: Castro Jessica , Ribó Marc , Navarro Susanna , Nogués Maria Victòria , Vilanova Maria , Benito Antoni
Published: January 2011

Background

Ribonucleases are promising agents for use in anticancer therapy. Among the different ribonucleases described to be cytotoxic, a paradigmatic example is onconase which manifests cytotoxic and cytostatic effects, presents synergism with several kinds of anticancer drugs and is currently in phase II/III of its clinical trial as an anticancer drug against different types of cancer. The mechanism of cytotoxicity of PE5, a variant of human pancreatic ribonuclease carrying a nuclear localization signal, has been investigated and compared to that of onconase.

Methods

Cytotoxicity was measured by the MTT method and by the tripan blue exclusion assay. Apoptosis was assessed by flow cytometry, caspase enzymatic detection and confocal microscopy. Cell cycle phase analysis was performed by flow cytometry. The expression of different proteins was analyzed by western blot.

Results

We show that the cytotoxicity of PE5 is produced through apoptosis, that it does not require the proapoptotic activity of p53 and is not prevented by the multiple drug resistance phenotype. We also show that PE5 and onconase induce cell death at the same extent although the latter is also able to arrest the cell growth. We have compared the cytotoxic effects of both ribonucleases in the NCI/ADR-RES cell line by measuring their effects on the cell cycle, on the activation of different caspases and on the expression of different apoptosis- and cell cycle-related proteins. PE5 increases the number of cells in S and G2/M cell cycle phases, which is accompanied by the increased expression of cyclin E and p21WAF1/CIP1 together with the underphosphorylation of p46 forms of JNK. Citotoxicity of onconase in this cell line does not alter the cell cycle phase distribution and it is accompanied by a decreased expression of XIAP

Conclusions

We conclude that PE5 kills the cells through apoptosis associated with the p21WAF1/CIP1 induction and the inactivation of JNK. This mechanism is significantly different from that found for onconase.
Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial
Authors: Dekkers Johanna C , van Wier Marieke F , Ariëns Geertje AM , Hendriksen Ingrid JM , Pronk Nico P , Smid Tjabe , van Mechelen Willem
Published: January 2011

Background

Overweight (Body Mass Index [BMI] ≥ 25 kg/m2) and obesity (BMI≥ 30 kg/m2) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.

Methods

Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m2 [SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.

Results

At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.

Conclusions

The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.

Trial registration

ISRCTN04265725
Evaluation of a pilot cooperative medical scheme in rural China: impact on gender patterns of health care utilization and prescription practices
Authors: Jiang Qicheng , Jiang Zhen , Zhao Ming , Tao Jie , Ling Chunsun , Cherry Nicola
Published: January 2011

Background

In 2003 the Chinese government introduced voluntary cooperative medical schemes (CMS), soon to be in place throughout rural China. Families who chose to enroll do so as a single unit and nothing is known about any differential effect of these new schemes on family members. This study evaluates the impact of one pilot CMS in Anhui Province on health care use by girls aged less than 5 years and women 65 years or older, and on the pattern and cost of prescriptions.

Methods

Health care records were extracted covering a 10 year period, before, during and after the pilot CMS in 4 townships, one with the intervention and 3 comparison townships without. The impact of the intervention on the age and gender distribution of patients presenting for health care and on the prescription of certain drugs was assessed by logistic regression. The cost of prescriptions before, during and after the intervention period was also assessed.

Results

203,058 registration and 643,588 prescription records were identified. During the intervention there was a reduced likelihood overall that a patient was female (OR = 0.92: 95%CI 0.87 - 0.97) at the intervention site. Girls aged < 5 years had an increased likelihood of health care (OR = 1.41: 95%CI 1.23 - 1.59) during the CMS, but women ≥ 65 years were relatively disadvantaged (OR = 0.84: 95%CI 0.75 - 0.95). The use of antibiotics and systemic steroids increased disproportionately at the intervention site for patients ≥ 5 years. Prescription costs at the township hospital also increased at the intervention site, particularly for older men.

Conclusions

This evaluation suggests that all family members did not benefit equally from the pilot CMS and that women ≥ 65 years may be disadvantaged by the newly available reimbursements of health care costs through the CMS. It points to the need, in future evaluations, to use individuals rather than families as the unit of analysis, in order to determine whether such health care inequalities are wide-spread and persistent or are reduced in the longer term. The results also support earlier concerns about the influence of new funding resources on prescription practices and the need for regulation of for-profit prescribing.
IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics
Authors: Motokawa Satoru , Torigoshi Takafumi , Maeda Yumi , Maeda Kazushige , Jiuchi Yuka , Yamaguchi Takayuki , Someya Shinsuke , Shindo Hiroyuki , Migita Kiyoshi
Published: January 2011

Background

Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).

Methods

A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation.

Results

In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT.

Conclusion

Our findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).
A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication
Authors: Huelsmann Peter M , Hofmann Andreas D , Knoepfel Stefanie A , Popp Jasmin , Rauch Pia , Di Giallonardo Francesca , Danke Christina , Gueckel Eva , Schambach Axel , Wolff Horst , Metzner Karin J , Berens Christian
Published: January 2011

Background

Regulated expression of suicide genes is a powerful tool to eliminate specific subsets of cells and will find widespread usage in both basic and applied science. A promising example is the specific elimination of human immunodeficiency virus type 1 (HIV-1) infected cells by LTR-driven suicide genes. The success of this approach, however, depends on a fast and effective suicide gene, which is expressed exclusively in HIV-1 infected cells. These preconditions have not yet been completely fulfilled and, thus, success of suicide approaches has been limited so far. We tested truncated Bid (tBid), a human pro-apoptotic protein that induces apoptosis very rapidly and efficiently, as suicide gene for gene therapy against HIV-1 infection.

Results

When tBid was introduced into the HIV-1 LTR-based, Tat- and Rev-dependent transgene expression vector pLRed(INS)2R, very efficient induction of apoptosis was observed within 24 hours, but only in the presence of both HIV-1 regulatory proteins Tat and Rev. Induction of apoptosis was not observed in their absence. Cells containing this vector rapidly died when transfected with plasmids containing full-length viral genomic DNA, completely eliminating the chance for HIV-1 replication. Viral replication was also strongly reduced when cells were infected with HIV-1 particles.

Conclusions

This suicide vector has the potential to establish a safe and effective gene therapy approach to exclusively eliminate HIV-1 infected cells before infectious virus particles are released.