bluuebunny/crossref_metadata_2025 huggingface dataset:
Building capacity and capability in patient safety, innovation and service improvement: an English case study
Authors: Butterworth Tony , Jones Kate , Jordan Simone
Published: May 2011

It is clear that for at least the next decade, funding for many health systems across the world will be challenged by serious uncertainties in country economies.

In facing these challenges nurses have to respond positively to innovations in the delivery of care, increases in productivity and the eradication of errors that result in harm to patients.

In committing to supporting this necessary change, quality improvement and innovation programmes are now available from national, not-for-profit organisations, such as the Health Foundation (UK) and the Institute for Health Improvement (USA) and the National Health Service Institute for Innovation an Improvement (UK) that specifically address these important issues. Although the targets for these programmes are often health care systems at the macro level, the role of nurses in understanding and delivering innovative practices at a more micro level is vital. Evidence is now available that demonstrates the outputs of such programmes and the impact from making consequent changes to nursing practice. Education programmes and research activity by nurses can also take advantage of this activity and begin to ask questions that focus on those subject areas, as well as adding positive value to people who use health care services.

This paper briefly describes background developments during the last decade, offers one example of innovation programme content, describes the results of introducing patient safety, quality improvement and innovation into education curricula and suggests potential areas for future research by clinical academic nurse researchers.
Controlling risk in the built environment — evaluation of a risk assessment algorithm
Authors: Knox Alison , Pollock Kevin GJ , Ritchie Lisa M
Published: May 2011

This study describes a small-scale evaluation of an environmental risk assessment algorithm. The risk assessment algorithm was developed in response to a local need to adapt the Healthcare Associated Infection System for Controlling Risk in the Built Environment (HAI-SCRIBE) guidance (Health Facilities Scotland, 2007a) for use with routine maintenance and repair works in order to ensure measures were put in place to protect patients from environmental contamination during such work.

The suitability and acceptability of the risk assessment algorithm was evaluated by Estates and Maintenance staff using a two-stage staff questionnaire. We present the results of the evaluation and describe the advantages of implementing this model of environmental assessment. Limitations and possible further work are considered, including the use of the risk assessment algorithm to confirm its suitability within a larger study group.
Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms
Authors: Anand Shubha , Stedham Frances , Beer Philip , Gudgin Emma , Ortmann Christina A. , Bench Anthony , Erber Wendy , Green Anthony R. , Huntly Brian J. P.
Published: May 2011

The JAK2 V617F mutation is present in the majority of patients with a myeloproliferative neoplasm (MPN) and is sufficient to recapitulate an MPN in murine models. However, the consequences of JAK2 mutations for myeloid differentiation are poorly understood. After systematic analyses of a large cohort of JAK2-mutated MPN patients, we demonstrate in vivo that JAK2 mutations do not alter hematopoietic stem and progenitor cell com-partment size or in vitro behavior but generate expansion of later myeloid differentiation compartments, where homozygous expression of the mutation confers an added proliferative advantage at the single-cell level. In addition, we demonstrate that these findings may be partially explained by the expression pattern of JAK2, which markedly increases on myeloid differentiation. Our findings have potential clinical relevance, as they predict that JAK2 inhibitors may control myeloproliferation, but may have limited efficacy in eradicating the leukemic stem cells that sustain the human MPN.
Divergence in cis-regulatory sequences surrounding the opsin gene arrays of African cichlid fishes
Authors: O'Quin Kelly E , Smith Daniel , Naseer Zan , Schulte Jane , Engel Samuel D , Loh Yong-Hwee E , Streelman J Todd , Boore Jeffrey L , Carleton Karen L
Published: May 2011

Background

Divergence within cis-regulatory sequences may contribute to the adaptive evolution of gene expression, but functional alleles in these regions are difficult to identify without abundant genomic resources. Among African cichlid fishes, the differential expression of seven opsin genes has produced adaptive differences in visual sensitivity. Quantitative genetic analysis suggests that cis-regulatory alleles near the SWS2-LWS opsins may contribute to this variation. Here, we sequence BACs containing the opsin genes of two cichlids, Oreochromis niloticus and Metriaclima zebra. We use phylogenetic footprinting and shadowing to examine divergence in conserved non-coding elements, promoter sequences, and 3'-UTRs surrounding each opsin in search of candidate cis-regulatory sequences that influence cichlid opsin expression.

Results

We identified 20 conserved non-coding elements surrounding the opsins of cichlids and other teleosts, including one known enhancer and a retinal microRNA. Most conserved elements contained computationally-predicted binding sites that correspond to transcription factors that function in vertebrate opsin expression; O. niloticus and M. zebra were significantly divergent in two of these. Similarly, we found a large number of relevant transcription factor binding sites within each opsin's proximal promoter, and identified five opsins that were considerably divergent in both expression and the number of transcription factor binding sites shared between O. niloticus and M. zebra. We also found several microRNA target sites within the 3'-UTR of each opsin, including two 3'-UTRs that differ significantly between O. niloticus and M. zebra. Finally, we examined interspecific divergence among 18 phenotypically diverse cichlids from Lake Malawi for one conserved non-coding element, two 3'-UTRs, and five opsin proximal promoters. We found that all regions were highly conserved with some evidence of CRX transcription factor binding site turnover. We also found three SNPs within two opsin promoters and one non-coding element that had weak association with cichlid opsin expression.

Conclusions

This study is the first to systematically search the opsins of cichlids for putative cis-regulatory sequences. Although many putative regulatory regions are highly conserved across a large number of phenotypically diverse cichlids, we found at least nine divergent sequences that could contribute to opsin expression differences in cis and stand out as candidates for future functional analyses.
Fusidic acid resistance among clinical isolates of methicillin-resistant Staphylococcus aureus in a Taiwanese hospital
Authors: Chen Chih-Ming , Huang Mei , Chen Huei-Fen , Ke Se-Chin , Li Chia-Ru , Wang Jen-Hsien , Wu Lii-Tzu
Published: May 2011

Background

The prevalence of resistance to fusidic acid of methicillin-resistant Staphylococcus aureus (MRSA) was increased each year in a Taiwan hospital. Thirty-four MRSA clinical isolates collected in 2007 and 2008 with reduced susceptibility to FA were selected for further evaluation the presence of resistance determinants.

Results

The most common resistance determinant was fusC, found in 25 of the 34 MRSA isolates. One of the 25 fusidic acid-resistant MRSA harboured both fusB and fusC, which is the first time this has been identified. Mutations in fusA were found in 10 strains, a total of 3 amino-acid substitutions in EF-G (fusA gene) were detected. Two substitutions with G556S and R659L were identified for the first time. Low-level resistance to fusidic acid (MICs, ≤ 32 μg/ml) was found in most our collection. All collected isolates carried type III SCCmec elements. MLST showed the isolates were MRSA ST239. PFGE revealed nine different pulsotypes in one cluster.

Conclusions

Our results indicate that the increase in the number of fusidic acid resistant among the MRSA isolates in this hospital is due mainly to the distribution of fusC determinants. Moreover, more than one fusidic acid-resistance mechanism was first detected in a same stain in our collection.
Identification of a novel temperature sensitive promoter in cho cells
Authors: Thaisuchat Haruthai , Baumann Martina , Pontiller Jens , Hesse Friedemann , Ernst Wolfgang
Published: May 2011

Background

The Chinese hamster ovary (CHO) expression system is the leading production platform for manufacturing biopharmaceuticals for the treatment of numerous human diseases. Efforts to optimize the production process also include the genetic construct encoding the therapeutic gene. Here we report about the successful identification of an endogenous highly active gene promoter obtained from CHO cells which shows conditionally inducible gene expression at reduced temperature.

Results

Based on CHO microarray expression data abundantly transcribed genes were selected as potential promoter candidates. The S100a6 (calcyclin) and its flanking regions were identified from a genomic CHO-K1 lambda-phage library. Computational analyses showed a predicted TSS, a TATA-box and several TFBSs within the 1.5 kb region upstream the ATG start signal. Various constructs were investigated for promoter activity at 37°C and 33°C in transient luciferase reporter gene assays. Most constructs showed expression levels even higher than the SV40 control and on average a more than two-fold increase at lower temperature. We identified the core promoter sequence (222 bp) comprising two SP1 sites and could show a further increase in activity by duplication of this minimal sequence.

Conclusions

This novel CHO promoter permits conditionally high-level gene expression. Upon a shift to 33°C, a two to three-fold increase of basal productivity (already higher than SV40 promoter) is achieved. This property is of particular advantage for a process with reduced expression during initial cell growth followed by the production phase at low temperature with a boost in expression. Additionally, production of toxic proteins becomes feasible, since cell metabolism and gene expression do not directly interfere. The CHO S100a6 promoter can be characterized as cold-shock responsive with the potential for improving process performance of mammalian expression systems.
Cost effectiveness of pediatric pneumococcal conjugate vaccines: a comparative assessment of decision-making tools
Authors: Chaiyakunapruk Nathorn , Somkrua Ratchadaporn , Hutubessy Raymond , Henao Ana Maria , Hombach Joachim , Melegaro Alessia , Edmunds John W , Beutels Philippe
Published: May 2011

Background

Several decision support tools have been developed to aid policymaking regarding the adoption of pneumococcal conjugate vaccine (PCV) into national pediatric immunization programs. The lack of critical appraisal of these tools makes it difficult for decision makers to understand and choose between them. With the aim to guide policymakers on their optimal use, we compared publicly available decision-making tools in relation to their methods, influential parameters and results.

Methods

The World Health Organization (WHO) requested access to several publicly available cost-effectiveness (CE) tools for PCV from both public and private provenance. All tools were critically assessed according to the WHO's guide for economic evaluations of immunization programs. Key attributes and characteristics were compared and a series of sensitivity analyses was performed to determine the main drivers of the results. The results were compared based on a standardized set of input parameters and assumptions.

Results

Three cost-effectiveness modeling tools were provided, including two cohort-based (Pan-American Health Organization (PAHO) ProVac Initiative TriVac, and PneumoADIP) and one population-based model (GlaxoSmithKline's SUPREMES). They all compared the introduction of PCV into national pediatric immunization program with no PCV use. The models were different in terms of model attributes, structure, and data requirement, but captured a similar range of diseases. Herd effects were estimated using different approaches in each model. The main driving parameters were vaccine efficacy against pneumococcal pneumonia, vaccine price, vaccine coverage, serotype coverage and disease burden. With a standardized set of input parameters developed for cohort modeling, TriVac and PneumoADIP produced similar incremental costs and health outcomes, and incremental cost-effectiveness ratios.

Conclusions

Vaccine cost (dose price and number of doses), vaccine efficacy and epidemiology of critical endpoint (for example, incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models we compared. Understanding the differences and similarities of such CE tools through regular comparisons could render decision-making processes in different countries more efficient, as well as providing guiding information for further clinical and epidemiological research. A tool comparison exercise using standardized data sets can help model developers to be more transparent about their model structure and assumptions and provide analysts and decision makers with a more in-depth view behind the disease dynamics. Adherence to the WHO guide of economic evaluations of immunization programs may also facilitate this process.

Please see related article: http://www.biomedcentral.com/1741-7007/9/55
Results from evaluations of models and cost-effectiveness tools to support introduction decisions for new vaccines need critical appraisal
Authors: Hutubessy Raymond , Henao Ana Maria , Namgyal Pem , Moorthy Vasee , Hombach Joachim
Published: May 2011

The World Health Organization (WHO) recommends that the cost-effectiveness (CE) of introducing new vaccines be considered before such a programme is implemented. However, in low- and middle-income countries (LMICs), it is often challenging to perform and interpret the results of model-based economic appraisals of vaccines that benefit from locally relevant data. As a result, WHO embarked on a series of consultations to assess economic analytical tools to support vaccine introduction decisions for pneumococcal, rotavirus and human papillomavirus vaccines. The objectives of these assessments are to provide decision makers with a menu of existing CE tools for vaccines and their characteristics rather than to endorse the use of a single tool. The outcome will provide policy makers in LMICs with information about the feasibility of applying these models to inform their own decision making. We argue that if models and CE analyses are used to inform decisions, they ought to be critically appraised beforehand, including a transparent evaluation of their structure, assumptions and data sources (in isolation or in comparison to similar tools), so that decision makers can use them while being fully aware of their robustness and limitations.
A Functional Role for ADAM10 in Human Immunodeficiency Virus Type-1 Replication
Authors: Friedrich Brian M , Murray James L , Li Guangyu , Sheng Jinsong , Hodge Thomas W , Rubin Donald H , O'Brien William A , Ferguson Monique R
Published: May 2011

Background

Gene trap insertional mutagenesis was used as a high-throughput approach to discover cellular genes participating in viral infection by screening libraries of cells selected for survival from lytic infection with a variety of viruses. Cells harboring a disruptedADAM10(A Disintegrin and Metalloprotease 10) allele survived reovirus infection, and subsequently ADAM10 was shown by RNA interference to be important for replication of HIV-1.

Results

Silencing ADAM10 expression with small interfering RNA (siRNA) 48 hours before infection significantly inhibited HIV-1 replication in primary human monocyte-derived macrophages and in CD4+cell lines. In agreement, ADAM10 over-expression significantly increased HIV-1 replication. ADAM10 down-regulation did not inhibit viral reverse transcription, indicating that viral entry and uncoating are also independent of ADAM10 expression. Integration of HIV-1 cDNA was reduced in ADAM10 down-regulated cells; however, concomitant 2-LTR circle formation was not detected, suggesting that HIV-1 does not enter the nucleus. Further, ADAM10 silencing inhibited downstream reporter gene expression and viral protein translation. Interestingly, we found that while the metalloprotease domain of ADAM10 is not required for HIV-1 replication, ADAM15 and γ-secretase (which proteolytically release the extracellular and intracellular domains of ADAM10 from the plasma membrane, respectively) do support productive infection.

Conclusions

We propose that ADAM10 facilitates replication at the level of nuclear trafficking. Collectively, our data support a model whereby ADAM10 is cleaved by ADAM15 and γ-secretase and that the ADAM10 intracellular domain directly facilitates HIV-1 nuclear trafficking. Thus, ADAM10 represents a novel cellular target class for development of antiretroviral drugs.
Selected amino acid mutations in HIV-1 B subtype gp41 are Associated with Specific gp120V3signatures in the regulation of Co-Receptor usage
Authors: Dimonte Salvatore , Mercurio Fabio , Svicher Valentina , D'Arrigo Roberta , Perno Carlo-Federico , Ceccherini-Silberstein Francesca
Published: May 2011

Background

The third variable loop (V3) of the HIV-1 gp120 surface protein is a major determinant of cellular co-receptor binding. However, HIV-1 can also modulate its tropism through other regions in gp120, such as V1, V2 and C4 regions, as well as in the gp41 protein. Moreover, specific changes in gp41 are likely to be responsible for of damage in gp120-CCR5 interactions, resulting in potential resistance to CCR5 inhibitors.

In order to genetically characterize the two envelope viral proteins in terms of co-receptor usage, we have analyzed 526 full-length env sequences derived from HIV-1 subtype-B infected individuals, from our and public (Los Alamos) databases. The co-receptor usage was predicted by the analysis of V3 sequences using Geno2Pheno (G2P) algorithm. The binomial correlation phi coefficient was used to assess covariation among gp120V3 and gp41 mutations; subsequently the average linkage hierarchical agglomerative clustering was performed.

Results

According to G2P false positive rate (FPR) values, among 526 env-sequences analyzed, we further characterized 196 sequences: 105 with FPR <5% and 91 with FPR >70%, for X4-using and R5-using viruses, respectively.

Beyond the classical signatures at 11/25 V3 positions (S11S and E25D, R5-tropic viruses; S11KR and E25KRQ, X4-tropic viruses), other specific V3 and gp41 mutations were found statistically associated with the co-receptor usage. Almost all of these specific gp41 positions are exposed on the surface of the glycoprotein. By the covariation analysis, we found several statistically significant associations between V3 and gp41 mutations, especially in the context of CXCR4 viruses. The topology of the dendrogram showed the existence of a cluster associated with R5-usage involving E25DV3, S11SV3, T22AV3, S129DQgp41 and A96Ngp41 signatures (bootstrap = 0.88). Conversely, a large cluster was found associated with X4-usage involving T8IV3, S11KRV3, F20IVYV3, G24EKRV3, E25KRV3, Q32KRV3, A30Tgp41, A189Sgp41, N195Kgp41 and L210Pgp41 mutations (bootstrap = 0.84).

Conclusions

Our results show that gp120V3 and several specific amino acid changes in gp41 are associated together with CXCR4 and/or CCR5 usage. These findings implement previous observations that determinants of tropism may reside outside the V3-loop, even in the gp41. Further studies will be needed to confirm the degree to which these gp41 mutations contribute directly to co-receptor use.
Dynamic variations in the peripheral blood lymphocyte subgroups of patients with 2009 pandemic H1N1 swine-origin influenza A virus infection
Authors: Guo Xichao , Chen Yu , Li Xuefen , Kong Haishen , Yang Shigui , Ye Bo , Cui Dawei , Wu Wei , Li Lanjuan
Published: May 2011

Background

Novel Influenza A (H1N1) is an acute respiratory infectious disease. Animal experiments indicated that when H1N1 virus infected early hosts, it showed strong CD4+, CD8+, and CD4+CD25+ T cell reactions. The aim of this study was to investigate the dynamic fluctuations of the peripheral blood lymphocyte subgroups in patients infected with H1N1 swine-origin influenza A virus (S-OIV).

Methods

The frequency of T cells, B cells, natural killer (NK) cells, and regulatory T cells (Treg) in 36 severe H1N1 and 40 moderate H1N1 patients were detected at different periods by flow cytometry. In parallel, serum cytokines were detected by enzyme-linked immunosorbent assay and C-reactive protein (CRP) was analyzed through an image-type automatic biochemical analyzer. In addition, 20 healthy volunteers, who were not infected with 2009 H1N1 virus, were selected as controls.

Results

The frequency of NK cells were decreased in all cases and CD19+ B cells were increased in severe cases than those of the controls. At 1-2d from onset, the frequency of CD4+ and CD4+CD25+ T cells in moderate cases was higher than in the severe cases. Serum cytokines, specifically IL-2, IL-4, IL-6, IL-10, and IFN-γ exhibited no significant change both in the moderate and the severe cases during the whole monitoring process. In the early stage of the disease, serum CRP levels in the severe and moderate groups were significantly higher than that in the control group.

Conclusions

Patients showed different lymphocyte subgroup distributions between mild and severe cases, which might affect the incidence and development of 2009 H1N1.
Seroprevalence of cytomegalovirus and rubella among pregnant women in western Sudan
Authors: Hamdan Hamdan Z , Abdelbagi Ismail E , Nasser Nasser M , Adam Ishag
Published: May 2011

Background

Maternal cytomegalovirus (CMV) and rubella infections have adverse neonatal outcomes. Basic epidemiological data concerning CMV and rubella is necessary for health planners and care providers.

Methods

A cross sectional study was conducted at El-Rahad hospital, Sudan to investigate seroprevalence of CMV and rubella infections and associated possible risk factors among pregnant women. Structured questionnaires were used to gather socio-demographic data and ELISA was used to detect CMV and rubella infections using IgG and IgM.

Results

Out of 231 pregnant women, 167 (72.2%) and 151 (65.3%) were CMV-IgG and rubella-IgG positive, respectively. Only 6 (2.5%) and 8 women (3.4%) were CMV-IgM and rubella-IgM positive, respectively. While, high parity (OR = 14.7, 95%CI = 1.7 - 123.6;P= 0.01] and illiteracy (OR = 3.0, CI = 1.4 - 6.5;P= 0.004) were significantly associated with seropostive CMV-IgG in multivariate analysis, none of the other obstetrical and medical characteristics were significantly associated with CMV or rubella infections.

Conclusion

CMV prevalence was 72.2% and rubella susceptibility among pregnant women was 34.6%. Rubella vaccine and routine screening for rubella and CMV should be introduced for pregnant women in this setting. Further research is needed.
A comparison of machine learning techniques for survival prediction in breast cancer
Authors: Vanneschi Leonardo , Farinaccio Antonella , Mauri Giancarlo , Antoniotti Marco , Provero Paolo , Giacobini Mario
Published: May 2011

Background

The ability to accurately classify cancer patients into risk classes, i.e. to predict the outcome of the pathology on an individual basis, is a key ingredient in making therapeutic decisions. In recent years gene expression data have been successfully used to complement the clinical and histological criteria traditionally used in such prediction. Many "gene expression signatures" have been developed, i.e. sets of genes whose expression values in a tumor can be used to predict the outcome of the pathology. Here we investigate the use of several machine learning techniques to classify breast cancer patients using one of such signatures, the well established 70-gene signature.

Results

We show that Genetic Programming performs significantly better than Support Vector Machines, Multilayered Perceptrons and Random Forests in classifying patients from the NKI breast cancer dataset, and comparably to the scoring-based method originally proposed by the authors of the 70-gene signature. Furthermore, Genetic Programming is able to perform an automatic feature selection.

Conclusions

Since the performance of Genetic Programming is likely to be improvable compared to the out-of-the-box approach used here, and given the biological insight potentially provided by the Genetic Programming solutions, we conclude that Genetic Programming methods are worth further investigation as a tool for cancer patient classification based on gene expression data.
Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses' Health Study II
Authors: Eliassen A Heather , Spiegelman Donna , Hollis Bruce W , Horst Ronald L , Willett Walter C , Hankinson Susan E
Published: May 2011

Introduction

Experimental evidence indicates vitamin D may play an important role in breast cancer etiology but epidemiologic evidence to date is inconsistent. Vitamin D comes from dietary intake and sun exposure and plasma levels of 25-hydroxyvitamin D (25(OH)D) are considered the best measure of vitamin D status.

Methods

We conducted a prospective nested case-control study within the Nurses' Health Study II (NHSII). Plasma samples collected in 1996 to 1999 were assayed for 25(OH)D in 613 cases, diagnosed after blood collection and before 1 June 2007, and in 1,218 matched controls. Multivariate relative risks (RR) and 95% confidence intervals (CI) were calculated by conditional logistic regression, adjusting for several breast cancer risk factors.

Results

No significant association was observed between plasma 25(OH)D levels and breast cancer risk (top vs. bottom quartile multivariate RR = 1.20, 95% CI (0.88 to 1.63), P-value, test for trend = 0.32). Results were similar when season-specific quartile cut points were used. Results did not change when restricted to women who were premenopausal at blood collection or premenopausal at diagnosis. Results were similar between estrogen receptor (ER)+/progesterone receptor (PR)+ and ER-/PR- tumors (P-value, test for heterogeneity = 0.51). The association did not vary by age at blood collection or season of blood collection, but did vary when stratified by body mass index (P-value, test for heterogeneity = 0.01).

Conclusions

Circulating 25(OH)D levels were not significantly associated with breast cancer risk in this predominantly premenopausal population.
Dynamic reprogramming of chromatin accessibility during Drosophilaembryo development
Authors: Thomas Sean , Li Xiao-Yong , Sabo Peter J , Sandstrom Richard , Thurman Robert E , Canfield Theresa K , Giste Erika , Fisher William , Hammonds Ann , Celniker Susan E , Biggin Mark D , Stamatoyannopoulos John A
Published: May 2011

Background

The development of complex organisms is believed to involve progressive restrictions in cellular fate. Understanding the scope and features of chromatin dynamics during embryogenesis, and identifying regulatory elements important for directing developmental processes remain key goals of developmental biology.

Results

We used in vivo DNaseI sensitivity to map the locations of regulatory elements, and explore the changing chromatin landscape during the first 11 hours of Drosophila embryonic development. We identified thousands of conserved, developmentally dynamic, distal DNaseI hypersensitive sites associated with spatial and temporal expression patterning of linked genes and with large regions of chromatin plasticity. We observed a nearly uniform balance between developmentally up- and down-regulated DNaseI hypersensitive sites. Analysis of promoter chromatin architecture revealed a novel role for classical core promoter sequence elements in directing temporally regulated chromatin remodeling. Another unexpected feature of the chromatin landscape was the presence of localized accessibility over many protein-coding regions, subsets of which were developmentally regulated or associated with the transcription of genes with prominent maternal RNA contributions in the blastoderm.

Conclusions

Our results provide a global view of the rich and dynamic chromatin landscape of early animal development, as well as novel insights into the organization of developmentally regulated chromatin features.
The innate immune system and the clearance of apoptotic cells
Authors: Devitt Andrew , Marshall Lindsay J
Published: May 2011

Removal of unwanted, effete, or damaged cells through apoptosis, an active cell death culminating in phagocytic removal of cell corpses, is an important process throughout the immune system in development, control, and homeostasis. For example, neutrophil apoptosis is central to the resolution of acute inflammation, whereas autoreactive and virus-infected cells are similarly deleted. The AC removal process functions not only to remove cell corpses but further, to control inappropriate immune responses so that ACs are removed in an anti-inflammatory manner. Such ″silent″ clearance is mediated by the innate immune system via polarized monocyte/macrophage populations that use a range of PRRs and soluble molecules to promote binding and phagocytosis of ACs. Additionally, attractive signals are released from dying cells to recruit phagocytes to sites of death. Here, we review the molecular mechanisms associated with innate immune removal of and responses to ACs and outline how these may impact on tissue homeostasis and age-associated pathology (e.g., cardiovascular disease). Furthermore, we discuss how an aging innate immune system may contribute to the inflammatory consequences of aging and why the study of an aging immune system may be a useful path to advance characterization of mechanisms mediating effective AC clearance.
MAPK Phosphatase-1 (MKP-1) Expression Is Up-Regulated by hCG/cAMP and Modulates Steroidogenesis in MA-10 Leydig Cells
Authors: Brion Laura , Maloberti Paula M. , Gomez Natalia V. , Poderoso Cecilia , Gorostizaga Alejandra B. , Mori Sequeiros Garcia Maria M. , Acquier Andrea B. , Cooke Mariana , Mendez Carlos F. , Podesta Ernesto J. , Paz Cristina
Published: May 2011

MAP kinases (MAPKs), such as ERK1/2, exert profound effects on a variety of physiological processes. In steroidogenic cells, ERK1/2 are involved in the expression and activation of steroidogenic acute regulatory protein, which plays a central role in the regulation of steroidogenesis. In MA-10 Leydig cells, LH and chorionic gonadotropin (CG) trigger transient ERK1/2 activation via protein kinase A, although the events that lead to ERK1/2 inactivation are not fully described. Here, we describe the hormonal regulation of MAPK phosphatase-1 (MKP-1), an enzyme that inactivates MAPKs, in MA-10 cells. In our experiments, human CG (hCG)/cAMP stimulation rapidly and transiently increased MKP-1 mRNA levels by a transcriptional action. This effect was accompanied by an increase in protein levels in both nuclear and mitochondrial compartments. In cells transiently expressing flag-MKP-1 protein, hCG/cAMP promoted the accumulation of the recombinant protein in a time-dependent manner (10-fold at 1 h). Moreover, hCG/cAMP triggered ERK1/2-dependent MKP-1 phosphorylation. The blockade of cAMP-induced MAPK kinase/ERK activation abated MKP-1 phosphorylation but only partially reduced flag-MKP-1 protein accumulation. Together, these results suggest that hCG regulates MKP-1 at transcriptional and posttranslational level, protein phosphorylation being one of the mechanisms involved in this regulation. Our study also demonstrates that MKP-1 overexpression reduces the effects of cAMP on ERK1/2 phosphorylation, steroidogenic acute regulatory gene promoter activity, mRNA levels, and steroidogenesis, whereas MKP-1 down-regulation by small interfering RNA produces opposite effects. In summary, our data demonstrate that hCG regulates MKP-1 expression at multiple stages as a negative feedback regulatory mechanism to modulate the hormonal action on ERK1/2 activity and steroidogenesis.
Characterization of Differential Gene Expression in Adrenocortical Tumors Harboring β-Catenin (CTNNB1) Mutations
Authors: Durand Julien , Lampron Antoine , Mazzuco Tania L. , Chapman Audrey , Bourdeau Isabelle
Published: May 2011

Background:

Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors.

Objective:

Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin.

Methods:

Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells.

Results:

RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654.

Conclusion:

This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.
IGF binding protein 3 exerts its ligand-independent action by antagonizing BMP in zebrafish embryos
Authors: Zhong Yingbin , Lu Ling , Zhou Jianfeng , Li Yun , Liu Yunzhang , Clemmons David R. , Duan Cunming
Published: May 2011

IGFBP3 is a multi-functional protein that has IGF-dependent and IGF-independent actions in cultured cells. Here we show that the IGF binding domain (IBD), nuclear localization signal (NLS) and transactivation domain (TA) are conserved and functional in zebrafish Igfbp3. The in vivo roles of these domains were investigated by expression of Igfbp3 and its mutants in zebrafish embryos. Igfbp3, and its NLS and TA mutants had equally strong dorsalizing effects. Human IGFBP3 had similar dorsalizing effects in zebrafish embryos. The activities of IBD and IBD+NLS mutants were lower, but they still caused dorsalization. Thus, the IGF-independent action of Igfbp3 is not related to NLS or TA in this in vivo model. We next tested the hypothesis that Igfbp3 exerts its IGF-independent action by affecting Bmp signaling. Co-expression of Igfbp3 with Bmp2b abolished Bmp2b-induced gene expression and inhibited its ventralizing activity. Biochemical assays and in vitro experiments revealed that IGFBP3 bound BMP2 and inhibited BMP2-induced Smad signaling in cultured human cells. In vivo expression of Igfbp3 increased chordin expression in zebrafish embryos by alleviating the negative regulation of Bmp2. The elevated level of Chordin acted together with Igfbp3 to inhibit the actions of Bmp2. Knockdown of Igfbp3 enhanced the ventralized phenotype caused by chordin knockdown. These results suggest that Igfbp3 exerts its IGF-independent actions by antagonizing Bmp signaling and that this mechanism is conserved.
Differential muscular myosin heavy chain expression of the pectoral and pelvic girdles during early growth in the king penguin (Aptenodytes patagonicus) chick
Authors: Erbrech Aude , Robin Jean-Patrice , Guérin Nathalie , Groscolas René , Gilbert Caroline , Martrette Jean-Marc
Published: May 2011

Continuous growth, associated with a steady parental food supply, is a general pattern in offspring development. So that young chicks can acquire their locomotor independence, this period is usually marked by a fast maturation of muscles, during which different myosin heavy chain (MyHC) isoforms are expressed. However, parental food provisioning may fluctuate seasonally, and offspring therefore face a challenge to ensure the necessary maturation of their tissues when energy is limited. To address this trade-off we investigated muscle maturation in both the pectoral and pelvic girdles of king penguin chicks. This species has an exceptionally long rearing period (1 year), which is prolonged when parental food provisioning is drastically reduced during the sub-Antarctic winter. Approximately 1 month post hatching, chicks acquire a functional pedestrian locomotion, which uses pelvic muscles, whereas swimming, which uses the pectoral muscles, only occurs 1 year later. We therefore tested the hypothesis that the MyHC content of the leg muscles reaches a mature state before those of the pectoral muscles. We found that leg muscle MyHC composition changed with the progressive acquisition of pedestrian locomotion, whereas pectoral muscle fibres reached their mature MyHC profile as early as hatching. Contrary to our predictions, the acquisition of the adult profile in pectoral muscles could be related to an early maturation of the contractile muscular proteins, presumably associated with early thermoregulatory capacities of chicks, necessary for survival in their cold environment. This differential maturation appears to reconcile both the locomotor and environmental constraints of king penguin chicks during growth.
A numerical study of the effects of bell pulsation dynamics and oral arms on the exchange currents generated by the upside-down jellyfish Cassiopea xamachana
Authors: Hamlet Christina , Santhanakrishnan Arvind , Miller Laura A.
Published: May 2011

Mathematical and experimental studies of the flows generated by jellyfish have focused primarily on mechanisms of swimming. More recent work has also considered the fluid dynamics of feeding from currents generated during swimming. Here we capitalize on the benthic lifestyle of the upside-down jellyfish (Cassiopea xamachana) to explore the fluid dynamics of feeding uncoupled from swimming. A two-dimensional mathematical model is developed to capture the fundamental characteristics of the motion of the unique concave bell shape. Given the prominence of the oral arms, this structure is included and modeled as a porous layer that perturbs the flow generated by bell contractions. The immersed boundary method is used to solve the fluid–structure interaction problem. Velocity fields obtained from live organisms using digital particle image velocimetry were used to validate the numerical simulations. Parameter sweeps were used to numerically explore the effects of changes in pulse dynamics and the properties of the oral arms independently. Numerical experiments allow the opportunity to examine physical effects and limits within and beyond the biologically relevant range to develop a better understanding of the system. The presence of the prominent oral arm structures in the field of flow increased the flux of new fluid from along the substrate to the bell. The numerical simulations also showed that the presence of pauses between bell expansion and the next contraction alters the flow of the fluid over the bell and through the oral arms.
Coordination of cytochrome c oxidase gene expression in the remodelling of skeletal muscle
Authors: Duggan Ana T. , Kocha Katrinka M. , Monk Christopher T. , Bremer Katharina , Moyes Christopher D.
Published: May 2011

Many fish species respond to low temperature by inducing mitochondrial biogenesis, reflected in an increase in activity of the mitochondrial enzyme cytochrome c oxidase (COX). COX is composed of 13 subunits, three encoded by mitochondrial (mt)DNA and 10 encoded by nuclear genes. We used real-time PCR to measure mRNA levels for the 10 nuclear-encoded genes that are highly expressed in muscle. We measured mRNA levels in white muscle of three minnow species, each at two temperatures: zebrafish (Danio rerio) acclimated to 11 and 30°C, goldfish (Carassius auratus) acclimated to 4 and 35°C, and northern redbelly dace (Chrosomus eos) collected in winter and summer. We hypothesized that temperature-induced changes in COX activity would be paralleled by COX nuclear-encoded subunit transcript abundance. However, we found mRNA for COX subunits showed pronounced differences in thermal responses. Though zebrafish COX activity did not change in the cold, the transcript levels of four subunits decreased significantly (COX5A1, 60% decrease; COX6A2, 70% decrease; COX6C, 50% decrease; COX7B, 55% decrease). Treatments induced changes in COX activity in both dace (2.9 times in winter fish) and goldfish (2.5 times in cold fish), but the response in transcript levels was highly variable. Some subunits failed to increase in one (goldfish COX7A2, dace COX6A2) or both (COX7B, COX6B2) species. Other transcripts increased 1.7–100 times. The most cold-responsive subunits were COX4-1 (7 and 21.3 times higher in dace and goldfish, respectively), COX5A1 (13.9 and 5 times higher), COX6B1 (6 and 10 times higher), COX6C (11 and 4 times higher) and COX7C (13.3 and 100 times higher). The subunits that most closely paralleled COX increases in the cold were COX5B2 (dace 2.5 times, goldfish 1.7 times) and COX6A2 (dace 4.1 times, goldfish 1.7 times). Collectively, these studies suggest that COX gene expression is not tightly coordinated during cold-induced mitochondrial remodelling in fish muscle. Further, they caution against arguments about the importance of transcriptional regulation based on measurement of mRNA levels of select subunits of multimeric proteins.
Hydrodynamic discrimination of wakes caused by objects of different size or shape in a harbour seal (Phoca vitulina)
Authors: Wieskotten Sven , Mauck Björn , Miersch Lars , Dehnhardt Guido , Hanke Wolf
Published: May 2011

Harbour seals can use their mystacial vibrissae to detect and track hydrodynamic wakes. We investigated the ability of a harbour seal to discriminate objects of different size or shape by their hydrodynamic signature and used particle image velocimetry to identify the hydrodynamic parameters that a seal may be using to do so. Hydrodynamic trails were generated by different sized or shaped paddles that were moved in the calm water of an experimental box to produce a characteristic signal. In a two-alternative forced-choice procedure the blindfolded subject was able to discriminate size differences of down to 3.6 cm (Weber fraction 0.6) when paddles were moved at the same speed. Furthermore the subject distinguished hydrodynamic signals generated by flat, cylindrical, triangular or undulated paddles of the same width. Particle image velocimetry measurements demonstrated that the seal could have used the highest velocities and the steepness of the gradients within the wake to discriminate object size, beside the size of counter-rotating vortices and the spatial extension of a wake. For shape discrimination the subject could have used the spatial extension of the whole wake, in addition to the arrangement of the vortices. We tested whether the seal used highest velocities, the steepness of the gradients and the spatial extension of the wake in a second set of experiments by varying moving speed and paddle size, respectively. The subject was still able to discriminate between the respective object sizes, but the minimum detectable size difference increased to 4.4 cm (Weber fraction 3.6). For the shape discrimination task, the seal was only able to distinguish flat from triangular paddles. Our results indicate that the seal's discrimination abilities depend on more than one hydrodynamic parameter.
Synthesis and Stereochemical Behavior of (E)-Cyclononene Derivatives
Authors: Tomooka Katsuhiko , Inoue Hiroko , Igawa Kazunobu
Published: May 2011

A versatile synthetic approach to planar chiral molecules from (E)-5-cyclononen-1-one (1) has been developed; these molecules have multifunctionalities with (E)-cyclononene skeleton. The newly synthesized keto-ester 3 having central chirality shows labile planar chirality. In contrast, enol derivative 4 and enyne 5 show robust planar chirality.
Photoisomerization and Fluorescence Characteristics of Tetramethoxystilbene in Ionic Liquid
Authors: Tamura Hiroyasu , Arai Tatsuo
Published: May 2011

Photochemical behavior of 3,3′,5,5′-tetramethoxystilbene (TMST) has been explored in ionic liquid. Two fluorescence components with the lifetime of 4.3 and 23.0 ns were observed for trans-TMST in ionic liquid solution. From this experimental evidence one could propose that ionic liquid may provide two different environments with highly different polarity, nonpolar and highly polar environments.
Prevalence of HIV in the Mthatha area of South Africa, as estimated from the testing of rape victims
Authors: Meel Banwari , Kwizera Enoch
Published: May 2011

Background

Tremendous challenges remain in the field of HIV education, prevention and care in South Africa. There is conflicting data on the prevalence of HIV in South Africa from two major studies. Antenatal surveillance showed 29.5% prevalence whereas a household HIV survey showed a prevalence nearly half of that, at 16.2%. There is therefore a need for a third estimate in this situation.

Objective

To estimate HIV prevalence in the Mthatha area of South Africa.

Methods

Retrospective review of HIV testing results among victims of sexual assault who presented for the first time to the Sinawe Referral Centre, Mthatha General Hospital, for the period 2001–2005 (inclusive).

Results

Between 2001 and 2005, 1691 victims of sexual assault presented to the Sinawe Referral Centre. Of these 1435 (84.8%) were tested for HIV at the time of first consultation. One hundred and ninety-seven were found to be HIV positive on the screening test. In a space of five years (2001–2005), there was an increase in HIV prevalence from 0.9% to 6.4%. The highest HIV positive rate (3.7%) was found in the 16–20 year age group.

Conclusion

The HIV prevalence rate is 13.7% in the Mthatha area, and just over a half (7%) of HIV-positive rape survivors were aged 16–25 years.
Vascular malformation in the uterus: a case report and literature review
Authors: Vohra Suman , Papadopoulou Anthie , Economides Demetrios L
Published: May 2011

Uterine vascular malformations are rare, potentially life-threatening lesions that originate from dysfunctional venous and arterial communications. They present with heavy vaginal bleeding which does not respond to conventional treatment. They can be congenital or acquired. Acquired arterio-venous malformations (AVMs) may be preceded by uterine curettage, caesarean section, gestational trophoblastic neoplasia or endometrial carcinoma. Ultrasound with colour Doppler is the most common initial investigation, with magnetic resonance imaging being used for detailed evaluation. However, angiography remains the gold standard. Embolization is becoming increasingly the first choice of treatment with excellent results. We present a case of uterine AVM successfully treated with embolization, along with a review of the literature.