bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-derived vesicles exposing coagulant tissue factor in saliva
Authors: Berckmans René J. , Sturk Auguste , van Tienen Laurens M. , Schaap Marianne C. L. , Nieuwland Rienk
Published: January 2011

On vascular damage, coagulation is initiated by extravascular tissue factor (TF). Intravascular TF, which is present on circulating cell-derived vesicles, is noncoagulant under physiologic conditions but prothrombotic under pathologic conditions. Human saliva triggers coagulation, but the mechanism and physiologic relevance are unknown. Because saliva is known to contain TF, we hypothesized that this TF may also be associated with cell-derived vesicles to facilitate coagulation when saliva directly contacts blood. The saliva-induced shortening of the clotting time of autologous plasma and whole blood from healthy subjects (n = 10) proved TF-dependent. This TF was associated with various types of cell-derived vesicles, including microparticles and exosomes. The physiologic function was shown by adding saliva to human pericardial wound blood collected from patients undergoing cardiac surgery. Addition of saliva shortened the clotting time from 300 ± 96 to 186 ± 24 seconds (P = .03). Our results show that saliva triggers coagulation, thereby reducing blood loss and the risk of pathogens entering the blood. We postulate that our reflex to lick a wound may be a mechanism to enable TF-exposing vesicles, present in saliva, to aid in the coagulation process and thus protect the organism from entering pathogens. This unique compartmentalization may be highly conserved because also animals lick their wounds.
Polyclonal fluctuation of lentiviral vector–transduced and expanded murine hematopoietic stem cells
Authors: Maetzig Tobias , Brugman Martijn H. , Bartels Stefan , Heinz Niels , Kustikova Olga S. , Modlich Ute , Li Zhixiong , Galla Melanie , Schiedlmeier Bernhard , Schambach Axel , Baum Christopher
Published: January 2011

Gene therapy has proven its potential to cure diseases of the hematopoietic system. However, severe adverse events observed in clinical trials have demanded improved gene-transfer conditions. Whereas progress has been made to reduce the genotoxicity of integrating gene vectors, the role of pretransplantation cultivation is less well investigated. We observed that the STIF (stem cell factor [SCF], thrombopoietin [TPO], insulin-like growth factor-2 [IGF-2], and fibroblast growth factor-1 [FGF-1]) cytokine cocktail developed to effectively expand murine hematopoietic stem cells (HSCs) also supports the expansion of leukemia-initiating insertional mutants caused by gammaretroviral gene transfer. We compared 4 protocols to examine the impact of prestimulation and posttransduction culture in STIF in the context of lentiviral gene transfer. Observing 56 transplanted mice for up to 9.5 months, we found consistent engraftment and gene-marking rates after prolonged ex vivo expansion. Although a lentiviral vector with a validated insertional-mutagenic potential was used, longitudinal analysis identifying > 7000 integration sites revealed polyclonal fluctuations, especially in “expanded” groups, with de novo detection of clones even at late time points. Posttransduction expansion in STIF did not enrich clones with insertions in proto-oncogenes but rather increased clonal diversity. Our data indicate that lentiviral transduction in optimized media mediates intact polyclonal hematopoiesis without selection for growth-promoting hits by posttransduction expansion.
Regulation and expression of sexual differentiation factors in embryonic and extragonadal tissues of Atlantic salmon
Authors: von Schalburg Kristian R , Yasuike Motoshige , Yazawa Ryosuke , de Boer Johan G , Reid Linda , So Stacy , Robb Adrienne , Rondeau Eric B , Phillips Ruth B , Davidson William S , Koop Ben F
Published: January 2011

Background

The products of cyp19, dax, foxl2, mis, sf1 and sox9 have each been associated with sex-determining processes among vertebrates. We provide evidence for expression of these regulators very early in salmonid development and in tissues outside of the hypothalamic-pituitary-adrenal/gonadal (HPAG) axis. Although the function of these factors in sexual differentiation have been defined, their roles in early development before sexual fate decisions and in tissues beyond the brain or gonad are essentially unknown.

Results

Bacterial artificial chromosomes containing salmon dax1 and dax2, foxl2b and mis were isolated and the regulatory regions that control their expression were characterized. Transposon integrations are implicated in the shaping of the dax and foxl2 loci. Splice variants for cyp19b1 and mis in both embryonic and adult tissues were detected and characterized. We found that cyp19b1 transcripts are generated that contain 5'-untranslated regions of different lengths due to cryptic splicing of the 3'-end of intron 1. We also demonstrate that salmon mis transcripts can encode prodomain products that present different C-termini and terminate before translation of the MIS hormone. Regulatory differences in the expression of two distinct aromatases cyp19a and cyp19b1 are exerted, despite transcription of their transactivators (ie; dax1, foxl2, sf1) occurring much earlier during embryonic development.

Conclusions

We report the embryonic and extragonadal expression of dax, foxl2, mis and other differentiation factors that indicate that they have functions that are more general and not restricted to steroidogenesis and gonadogenesis. Spliced cyp19b1 and mis transcripts are generated that may provide regulatory controls for tissue- or development-specific activities. Selection of cyp19b1 transcripts may be regulated by DAX-1, FOXL2 and SF-1 complexes that bind motifs in intron 1, or by signals within exon 2 that recruit splicing factors, or both. The potential translation of proteins bearing only the N-terminal MIS prodomain may modulate the functions of other TGF β family members in different tissues. The expression patterns of dax1 early in salmon embryogenesis implicate its role as a lineage determination factor. Other roles for these factors during embryogenesis and outside the HPAG axis are discussed.
Transcriptome profiling of the rice blast fungus during invasive plant infection and in vitro stresses
Authors: Mathioni Sandra M , Beló André , Rizzo Christopher J , Dean Ralph A , Donofrio Nicole M
Published: January 2011

Background

Rice blast is the most threatening disease to cultivated rice. Magnaporthe oryzae, its causal agent, is likely to encounter environmental challenges during invasive growth in its host plants that require shifts in gene expression to establish a compatible interaction. Here, we tested the hypothesis that gene expression patterns during in planta invasive growth are similar to in vitro stress conditions, such as nutrient limitation, temperature up shift and oxidative stress, and determined which condition most closely mimicked that of in planta invasive growth. Gene expression data were collected from these in vitro experiments and compared to fungal gene expression during the invasive growth phase at 72 hours post-inoculation in compatible interactions on two grass hosts, rice and barley.

Results

We identified 4,973 genes that were differentially expressed in at least one of the in planta and in vitro stress conditions when compared to fungal mycelia grown in complete medium, which was used as reference. From those genes, 1,909 showed similar expression patterns between at least one of the in vitro stresses and rice and/or barley. Hierarchical clustering of these 1,909 genes showed three major clusters in which in planta conditions closely grouped with the nutrient starvation conditions. Out of these 1,909 genes, 55 genes and 129 genes were induced and repressed in all treatments, respectively. Functional categorization of the 55 induced genes revealed that most were either related to carbon metabolism, membrane proteins, or were involved in oxidoreduction reactions. The 129 repressed genes showed putative roles in vesicle trafficking, signal transduction, nitrogen metabolism, or molecular transport.

Conclusions

These findings suggest that M. oryzae is likely primarily coping with nutrient-limited environments at the invasive growth stage 72 hours post-inoculation, and not with oxidative or temperature stresses.
Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection
Authors: Stewart Barbara S , Demarest Valerie L , Wong Susan J , Green Sharone , Bernard Kristen A
Published: January 2011

Background

West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.

Results

Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19+B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4+and CD8+T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8+T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.

Conclusions

Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.
Identification of differentially expressed genes induced by Bamboo mosaic virus infection in Nicotiana benthamianaby cDNA-amplified fragment length polymorphism
Authors: Cheng Shun-Fang , Huang Ying-Ping , Wu Zi-Rong , Hu Chung-Chi , Hsu Yau-Heiu , Tsai Ching-Hsiu
Published: January 2011

Background

The genes of plants can be up- or down-regulated during viral infection to influence the replication of viruses. Identification of these differentially expressed genes could shed light on the defense systems employed by plants and the mechanisms involved in the adaption of viruses to plant cells. Differential gene expression in Nicotiana benthamiana plants in response to infection with Bamboo mosaic virus (BaMV) was revealed using cDNA-amplified fragment length polymorphism (AFLP).

Results

Following inoculation with BaMV, N. benthamiana displayed differential gene expression in response to the infection. Isolation, cloning, and sequencing analysis using cDNA-AFLP furnished 90 cDNA fragments with eight pairs of selective primers. Fifteen randomly selected genes were used for a combined virus-induced gene silencing (VIGS) knockdown experiment, using BaMV infection to investigate the roles played by these genes during viral infection, specifically addressing the means by which these genes influence the accumulation of BaMV protein. Nine of the 15 genes showed either a positive or a negative influence on the accumulation of BaMV protein. Six knockdown plants showed an increase in the accumulation of BaMV, suggesting that they played a role in the resistance to viral infection, while three plants showed a reduction in coat protein, indicating a positive influence on the accumulation of BaMV in plants. An interesting observation was that eight of the nine plants showing an increase in BaMV coat protein were associated with cell rescue, defense, death, aging, signal transduction, and energy production.

Conclusions

This study reports an efficient and straightforward method for the identification of host genes involved in viral infection. We succeeded in establishing a cDNA-AFLP system to help track changes in gene expression patterns in N. benthamiana plants when infected with BaMV. The combination of both DNA-AFLP and VIGS methodologies made it possible to screen a large number of genes and identify those associated with infections of plant viruses. In this report, 9 of the 15 analyzed genes exhibited either a positive or a negative influence on the accumulation of BaMV in N. benthamiana plants.
Deletion of the thrombin cleavage domain of osteopontin mediates breast cancer cell adhesion, proteolytic activity, tumorgenicity, and metastasis
Authors: Beausoleil Michel S , Schulze Erika B , Goodale David , Postenka Carl O , Allan Alison L
Published: January 2011

Background

Osteopontin (OPN) is a secreted phosphoprotein often overexpressed at high levels in the blood and primary tumors of breast cancer patients. OPN contains two integrin-binding sites and a thrombin cleavage domain located in close proximity to each other.

Methods

To study the role of the thrombin cleavage site of OPN, MDA-MB-468 human breast cancer cells were stably transfected with either wildtype OPN (468-OPN), mutant OPN lacking the thrombin cleavage domain (468-ΔTC) or an empty vector (468-CON) and assessed for in vitro and in vivo functional differences in malignant/metastatic behavior.

Results

All three cell lines were found to equivalently express thrombin, tissue factor, CD44, αvβ5 integrin and β1 integrin. Relative to 468-OPN and 468-CON cells, 468-ΔTC cells expressing OPN with a deleted thrombin cleavage domain demonstrated decreased cell adhesion (p < 0.001), decreased mRNA expression of MCAM, maspin and TRAIL (p < 0.01), and increased uPA expression and activity (p < 0.01) in vitro. Furthermore, injection of 468-ΔTC cells into the mammary fat pad of nude mice resulted in decreased primary tumor latency time (p < 0.01) and increased primary tumor growth and lymph node metastatic burden (p < 0.001) compared to 468-OPN and 468-CON cells.

Conclusions

The results presented here suggest that expression of thrombin-uncleavable OPN imparts an early tumor formation advantage as well as a metastatic advantage for breast cancer cells, possibly due to increased proteolytic activity and decreased adhesion and apoptosis. Clarification of the mechanisms responsible for these observations and the translation of this knowledge into the clinic could ultimately provide new therapeutic opportunities for combating breast cancer.
Fish consumption and the risk of gastric cancer: systematic review and meta-analysis
Authors: Wu Shengjun , Liang Jie , Zhang Lei , Zhu Xia , Liu Xufeng , Miao Danmin
Published: January 2011

Background

Gastric cancer is the fourth most frequently occurring malignancy after lung, breast, and colorectal cancer, and the second most common cause of death from cancer worldwide. Epidemiologic studies have examined the possible association between fish consumption and gastric cancer, but the results were inconclusive. We conducted a systematic review and meta-analysis to examine the association between fish intake and the risk of gastric cancer.

Methods

PubMed was searched for studies published in English-language journals from 1991 through 2009. We identified 17 epidemiologic studies (15 case-control and 2 cohort studies) that included relative risks (RRs) or odds ratios (ORs) estimates with 95% confidence intervals (CIs) of the relationship between gastric cancer and fish consumption. Data were extracted using standardized data forms. Summary RRs or ORs for the highest versus non/lowest fish consumption levels were calculated using random-effects model. Heterogeneity among studies was examined using Q and I2 statistics.

Results

In this study, 5,323 cases of gastric cancer and over 130,000 non-cases were included. The combined results from all studies indicated that the association between high fish consumption and reduced gastric cancer risk was not statistically insignificant (RR = 0.87, 95% CI = 0.71-1.07).

Conclusions

Current evidence indicated that the association between fish consumption and risk of gastric cancer remains unclear.
Potent α-amylase inhibitory activity of Indian Ayurvedic medicinal plants
Authors: P Sudha , Zinjarde Smita S , Bhargava Shobha Y , Kumar Ameeta R
Published: January 2011

Background

Indian medicinal plants used in the Ayurvedic traditional system to treat diabetes are a valuable source of novel anti-diabetic agents. Pancreatic α-amylase inhibitors offer an effective strategy to lower the levels of post-prandial hyperglycemia via control of starch breakdown. In this study, seventeen Indian medicinal plants with known hypoglycemic properties were subjected to sequential solvent extraction and tested for α-amylase inhibition, in order to assess and evaluate their inhibitory potential on PPA (porcine pancreatic α-amylase). Preliminary phytochemical analysis of the lead extracts was performed in order to determine the probable constituents.

Methods

Analysis of the 126 extracts, obtained from 17 plants (Aloe vera (L.) Burm.f., Adansonia digitata L., Allium sativum L., Casia fistula L., Catharanthus roseus (L.) G. Don., Cinnamomum verum Persl., Coccinia grandis (L.) Voigt., Linum usitatisumum L., Mangifera indica L., Morus alba L., Nerium oleander L., Ocimum tenuiflorum L., Piper nigrum L., Terminalia chebula Retz., Tinospora cordifolia (Willd.) Miers., Trigonella foenum-graceum L., Zingiber officinale Rosc.) for PPA inhibition was initially performed qualitatively by starch-iodine colour assay. The lead extracts were further quantified with respect to PPA inhibition using the chromogenic DNSA (3, 5-dinitrosalicylic acid) method. Phytochemical constituents of the extracts exhibiting≥ 50% inhibition were analysed qualitatively as well as by GC-MS (Gas chromatography-Mass spectrometry).

Results

Of the 126 extracts obtained from 17 plants, 17 extracts exhibited PPA inhibitory potential to varying degrees (10%-60.5%) while 4 extracts showed low inhibition (< 10%). However, strong porcine pancreatic amylase inhibitory activity (> 50%) was obtained with 3 isopropanol extracts. All these 3 extracts exhibited concentration dependent inhibition with IC50 values, viz., seeds of Linum usitatisumum (540 μgml-1), leaves of Morus alba (1440 μgml-1) and Ocimum tenuiflorum (8.9 μgml-1). Acarbose as the standard inhibitor exhibited an IC50 (half maximal inhibitory concentration)value of 10.2 μgml-1. Phytochemical analysis revealed the presence of alkaloids, tannins, cardiac glycosides, flavonoids, saponins and steroids with the major phytoconstituents being identified by GC-MS.

Conclusions

This study endorses the use of these plants for further studies to determine their potential for type 2 diabetes management. Results suggests that extracts of Linum usitatisumum, Morus alba and Ocimum tenuiflorum act effectively as PPA inhibitors leading to a reduction in starch hydrolysis and hence eventually to lowered glucose levels.
Intraplaque hemorrhage is associated with higher structural stresses in human atherosclerotic plaques: an in vivo MRI-based 3d fluid-structure interaction study
Authors: Huang Xueying , Teng Zhongzhao , Canton Gador , Ferguson Marina , Yuan Chun , Tang Dalin
Published: January 2011

Background

Studies using medical images have shown that intraplaque hemorrhage may accelerate plaque progression and may produce a stimulus for atherosclerosis development by increasing lipid core and plaque volume and creating new destabilizing factors. Image-based 3D computational models with fluid-structure interactions (FSI) will be used to perform plaque mechanical analysis and investigate possible associations between intraplaque hemorrhage and both plaque wall stress (PWS) and flow shear stress (FSS).

Methods

In vivo MRI data of carotid plaques from 5 patients with intraplaque hemorrhage confirmed by histology were acquired. 3D multi-component FSI models were constructed for each plaque to obtain mechanical stresses. Plaque Wall Stress (PWS) and Flow Shear Stress (FSS) were extracted from all nodal points on the lumen surface of each plaque for analysis.

Results

The mean PWS value from all hemorrhage nodes of the 5 plaques combined was higher than that from non-hemorrhage nodes (75.6 versus 68.1 kPa, P = 0.0003). The mean PWS values from hemorrhage nodes for each of the 5 plaques were all significantly higher (5 out of 5) than those from non-hemorrhage nodes (P < 0.05). The mean FSS value from all hemorrhage nodes of the 5 plaques combined was 30.4% higher than that from all non-hemorrhage nodes (15.0 versus 11.5 dyn/cm2, P = 0.0002). However, the mean flow shear stress values from individual cases showed mixed results: only one out of five plaques showed mean FSS value from hemorrhage nodes was higher than that from non-hemorrhage nodes; three out of five plaques showed that their mean FSS values from hemorrhage nodes were lower than those from non-hemorrhage nodes; and one plaque showed that the difference had no statistical significance.

Conclusion

The results of this study suggested that intraplaque hemorrhage nodes were associated with higher plaque wall stresses. Compared to flow shear stress, plaque wall stress has a better correlation with plaque component feature (hemorrhage) linked to plaque progression and vulnerability. With further validation, plaque stress analysis may provide additional stress indicators for image-based vulnerability assessment.
A probabilistic sampling method (PSM) for estimating geographic distance to health services when only the region of residence is known
Authors: Beyer Kirsten MM , Saftlas Audrey F , Wallis Anne B , Peek-Asa Corinne , Rushton Gerard
Published: January 2011

Background

The need to estimate the distance from an individual to a service provider is common in public health research. However, estimated distances are often imprecise and, we suspect, biased due to a lack of specific residential location data. In many cases, to protect subject confidentiality, data sets contain only a ZIP Code or a county.

Results

This paper describes an algorithm, known as "the probabilistic sampling method" (PSM), which was used to create a distribution of estimated distances to a health facility for a person whose region of residence was known, but for which demographic details and centroids were known for smaller areas within the region. From this distribution, the median distance is the most likely distance to the facility. The algorithm, using Monte Carlo sampling methods, drew a probabilistic sample of all the smaller areas (Census blocks) within each participant's reported region (ZIP Code), weighting these areas by the number of residents in the same age group as the participant. To test the PSM, we used data from a large cross-sectional study that screened women at a clinic for intimate partner violence (IPV). We had data on each woman's age and ZIP Code, but no precise residential address. We used the PSM to select a sample of census blocks, then calculated network distances from each census block's centroid to the closest IPV facility, resulting in a distribution of distances from these locations to the geocoded locations of known IPV services. We selected the median distance as the most likely distance traveled and computed confidence intervals that describe the shortest and longest distance within which any given percent of the distance estimates lie. We compared our results to those obtained using two other geocoding approaches. We show that one method overestimated the most likely distance and the other underestimated it. Neither of the alternative methods produced confidence intervals for the distance estimates. The algorithm was implemented in R code.

Conclusions

The PSM has a number of benefits over traditional geocoding approaches. This methodology improves the precision of estimates of geographic access to services when complete residential address information is unavailable and, by computing the expected distribution of possible distances for any respondent and associated distance confidence limits, sensitivity analyses on distance access measures are possible. Faulty or imprecise distance measures may compromise decisions about service location and misdirect scarce resources.
Association of basal serum testosterone levels with ovarian response and in vitro fertilization outcome
Authors: Qin Yingying , Zhao Zhiyi , Sun Mei , Geng Ling , Che Li , Chen Zi-Jiang
Published: January 2011

Background

To evaluate basal testosterone (T) levels during follicular phase of the menstrual cycle as a predictor for ovarian response and in vitro fertilization (IVF) outcome.

Method

We analyzed data retrospectively from hospital-based IVF center including one thousand two hundred and sixty Chinese Han women under their first IVF cycle reached the ovum pick-up stage, without polycystic ovary syndrome (PCOS) or endometriosis undergoing long IVF protocol. Patients were divided into 2 groups. Group 1: patients with diminished ovarian reserve (basal FSH >10 IU/L) (n = 187); Group 2: patients with normal ovarian reserve (basal FSH < = 10 IU/L) (n = 1073). We studied the association of basal T levels with ovarian response and IVF outcome in the two groups. Long luteal down-regulation protocol was used in all patients, that is, the gonadotropin releasing hormone agonist was administered in the midluteal phase of the previous cycle and use of recombinant FSH was started when satisfactory pituitary desensitization was achieved.

Results

Basal T levels were markly different between pregnant and non-pregnant women in Group 1; whereas not in Group 2. A testosterone level of 47.85 ng/dl was shown to predict pregnancy outcome with a sensitivity of 52.8% and specificity of 65.3%; and the basal T was correlated with the numbers of large follicles (> 14 mm) on HCG day in Group 1. Significantly negative correlations were observed between basal T, days of stimulation and total dose of gonadotropins after adjusting for confounding factors in both groups.

Conclusion

In women with diminished ovarian reserve, basal T level was a predictor for the number of large follicles on HCG day and pregnancy outcome; but could not in those with normal serum FSH. Basal T levels were associated with both days of stimulation and total dose of gonadotropins, indicating that lower level of T might relate with potential ovarian poor response.
A system dynamics analysis determining willingness to wait and pay for the implementation of data standards in clinical research
Authors: Cofiel Luciana , Zammar Guilherme R , Zaveri Amrapali J , Shah Jatin Y , Carvalho Elias , Nahm Meredith , Kesselring Gustavo , Pietrobon Ricardo
Published: January 2011

Background

Industry standards provide rigorous descriptions of required data presentation, with the aim of ensuring compatibility across different clinical studies. However despite their crucial importance, these standards are often not used as expected in the development of clinical research. The reasons for this lack of compliance could be related to the high cost and time-intensive nature of the process of data standards implementation. The objective of this study was to evaluate the value of the extra time and cost required for different levels of data standardisation and the likelihood of researchers to comply with these levels. Since we believe that the cost and time necessary for the implementation of data standards can change over time, System Dynamics (SD) analysis was used to investigate how these variables interact and influence the adoption of data standards by clinical researchers.

Methods

Three levels of data standards implementation were defined through focus group discussion involving four clinical research investigators. Ten Brazilian and eighteen American investigators responded to an online questionnaire which presented possible standards implementation scenarios, with respondents asked to choose one of two options available in each scenario. A random effects ordered probit model was used to estimate the effect of cost and time on investigators' willingness to adhere to data standards. The SD model was used to demonstrate the relationship between degrees of data standardisation and subsequent variation in cost and time required to start the associated study.

Results

A preference for low cost and rapid implementation times was observed, with investigators more likely to incur costs than to accept a time delay in project start-up. SD analysis indicated that although initially extra time and cost are necessary for clinical study standardisation, there is a decrease in both over time.

Conclusions

Future studies should explore ways of creating mechanisms which decrease the time and cost associated with standardisation processes. In addition, the fact that the costs and time necessary for data standards implementation decrease with time should be made known to the wider research community. Policy makers should attempt to match their data standardisation policies better with the expectations of researchers.
Conceptualising population health: from mechanistic thinking to complexity science
Authors: Jayasinghe Saroj
Published: January 2011

The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections.
Quality of data collection in a large HIV observational clinic database in sub‐Saharan Africa: implications for clinical research and audit of care
Authors: Kiragga Agnes N , Castelnuovo Barbara , Schaefer Petra , Muwonge Timothy , Easterbrook Philippa J
Published: January 2011

Background

Observational HIV clinic databases are now widely used to answer key questions related to HIV care and treatment, but there has been no systematic evaluation of their quality of data. Our objective was to evaluate the completeness and accuracy of recording of key data HIV items in a large routine observational HIV clinic database.

Methods

We looked at the number and rate of opportunistic infections (OIs) per 100 person years at risk in the 24 months following antiretroviral therapy (ART) initiation in 559 patients who initiated ART in 2004‐2005 and enrolled into a research cohort. We compared this with data in a routine clinic database for the same 559 patients, and a further 1233 patients who initiated ART in the same period. The Research Cohort database was considered as the reference “gold standard” for the assessment of data accuracy. A crude percentage of underreporting of OIs in the clinic database was calculated based on the difference between the OI rates reported in both databases.

We reviewed 100 clinic patient medical records to assess the accuracy of recording of key data items of OIs, ART toxicities and ART regimen changes.

Results

The overall incidence rate per 100 person years at risk for the initial OI in the 559 patients in the research cohort and clinic databases was 24.1 (95% CI: 20.5‐28.2) and 13.2 (95% CI: 10.8‐16.2) respectively, and 10.4 (95% CI: 9.1‐11.9) for the 1233 clinic patients. This represents a 1.8‐ and 2.3‐fold higher rate of events in the research cohort database compared with the same 599 patients and 1233 patients in the routine clinic database, or a 45.1% and 56.8% rate of underreporting, respectively. The combined error rate of missing and incorrect items from the medical records' review was 67% for OIs, 52% for ART‐related toxicities, and 83% and 58% for ART discontinuation and modification, respectively.

Conclusions

There is a high rate of underreporting of OIs in a routine HIV clinic database. This has important implications for the use and interpretation of routine observational databases for research and audit, and highlights the need for regular data validation of these databases.
Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors
Authors: Mao Jun J , Su H Irene , Feng Rui , Donelson Michelle L , Aplenc Richard , Rebbeck Timothy R , Stanczyk Frank , DeMichele Angela
Published: January 2011

Introduction

Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synthesis, may be associated with the occurrence of AIAA.

Methods

We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor (AI) therapy. Patient-reported AIAA was the primary outcome. DNA was genotyped for candidate CYP19A1 polymorphisms. Serum estrogen levels were evaluated by radioimmunoassay. Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders.

Results

Among 390 Caucasian participants, 50.8% reported AIAA. Women carrying at least one 8-repeat allele had lower odds of AIAA (adjusted odds ratio (AOR) 0.41, 95% confidence interval (CI) 0.21 to 0.79, P = 0.008) after adjusting for demographic and clinical covariates. Estradiol and estrone were detectable in 47% and 86% of subjects on AIs, respectively. Although these post-AI levels were associated with multiple genotypes, they were not associated with AIAA. In multivariate analyses, women with more recent transition into menopause (less than five years) were significantly more likely to report AIAA than those greater than ten years post-menopause (AOR 3.31, 95% CI 1.72 to 6.39, P < 0.001).

Conclusions

Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA, supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA. Prospective investigation is needed to further delineate relationships between host genetics, changing estrogen levels and AIAA.
Obstacles and opportunities for understanding macrophage polarization
Authors: Murray Peter J , Wynn Thomas A
Published: January 2011

Macrophages are now routinely categorized into phenotypic subtypes based on gene expression induced in response to cytokine and pathogen-derived stimulation. In the broadest division, macrophages are described as being CAMs (M1 macrophages) or AAMs (M2 macrophages) based on their exposure to TLR and IFN signals or Th2 cytokines, respectively. Despite the prolific use of this simple classification scheme, little is known about the precise functions of effector molecules produced by AAMs, especially how representative the CAM and AAM subtypes are of tissue macrophages in homeostasis, infection, or tissue repair and how plasticity in gene expression regulates macrophage function in vivo. Furthermore, correlations between mouse and human tissue macrophages and their representative subtypes are lacking and are a major barrier to understanding human immunity. Here, we briefly summarize current features of macrophage polarization and discuss the roles of various macrophage subpopulations and macrophage-associated genes in health and disease.
SerpinB1 protects the mature neutrophil reserve in the bone marrow
Authors: Benarafa Charaf , LeCuyer Tessa E , Baumann Mathias , Stolley James Michael , Cremona Tiziana P , Remold-O′Donnell Eileen
Published: January 2011

SerpinB1 is among the most efficient inhibitors of neutrophil serine proteases—NE, CG, and PR-3—and we investigated here its role in neutrophil development and homeostasis. We found that serpinB1 is expressed in all human bone marrow leukocytes, including stem and progenitor cells. Expression levels were highest in the neutrophil lineage and peaked at the promyelocyte stage, coincident with the production and packaging of the target proteases. Neutrophil numbers were decreased substantially in the bone marrow of serpinB1−/− mice. This cellular deficit was associated with an increase in serum G-CSF levels. On induction of acute pulmonary injury, neutrophils were recruited to the lungs, causing the bone marrow reserve pool to be completely exhausted in serpinB1−/− mice. Numbers of myeloid progenitors were normal in serpinB1−/− bone marrow, coincident with the absence of target protease expression at these developmental stages. Maturation arrest of serpinB1−/− neutrophils was excluded by the normal CFU-G growth in vitro and the normal expression in mature neutrophils of early and late differentiation markers. Normal absolute numbers of proliferating neutrophils and pulse-chase kinetic studies in vivo showed that the bone marrow deficit in serpinB1−/− mice was largely restricted to mature, postmitotic neutrophils. Finally, upon overnight culture, apoptosis and necrosis were greater in purified bone marrow neutrophils from serpinB1−/− compared with WT mice. Collectively, these findings demonstrate that serpinB1 sustains a healthy neutrophil reserve that is required in acute immune responses.
Sox3 Functions in a Cell-Autonomous Manner to Regulate Spermatogonial Differentiation in Mice
Authors: Laronda Monica M. , Jameson J. Larry
Published: January 2011

The X-linked Sox3 gene encodes a member of the Sry high-mobility group box proteins, which play a role in many developmental processes including neurogenesis and testis development. This study further examined the role of Sox3 in spermatogenesis. Males without Sox3 expression exhibited a similar number of germ cell nuclear antigen-positive germ cells at 1, 5, and 10 d postpartum (dpp) compared to their wild-type littermates, but there was significant germ cell depletion by 20 dpp. However, spermatogenesis later resumed and postmeiotic germ cells were observed by 56 dpp. The VasaCre transgene was used to generate a germ cell-specific deletion of Sox3. The phenotype of the germ cell-specific Sox3 knockout was similar to the ubiquitous knockout, indicating an intrinsic role for Sox3 in germ cells. The residual germ cells in 20 dpp Sox3−/Y males were spermatogonia as indicated by their expression of neurogenin3 but not synaptonemal complex protein 3, which is expressed within cells undergoing meiosis. RNA expression analyses corroborated the histological analyses and revealed a gradual transition from relatively increased expression of spermatogonia genes at 20 dpp to near normal expression of genes characteristic of undifferentiated and meiotic germ cells by 84 dpp. Fluorescent-activated cell sorting of undifferentiated (ret tyrosine kinase receptor positive) and differentiated (kit receptor tyrosine kinase-positive) spermatogonia revealed depletion of differentiated spermatogonia in Sox3−/Y tubules. These results indicate that Sox3 functions in an intrinsic manner to promote differentiation of spermatogonia in prepubertal mice but it is not required for ongoing spermatogenesis in adults. The Sox3−/Y males provide a unique model for studying the mechanism of germ cell differentiation in prepubertal testes.
Lack of the ventral anterior homeodomain transcription factor VAX1 leads to induction of a second pituitary
Authors: Bharti Kapil , Gasper Melanie , Bertuzzi Stefano , Arnheiter Heinz
Published: January 2011

The pituitary gland is an endocrine organ that is developmentally derived from a fold in the oral ectoderm and a juxtaposed fold in the neural ectoderm. Here, we show that the absence of Vax1, a homeodomain transcription factor known for its role in eye and optic chiasm development, causes the rostral oral ectoderm to form an ectopic fold that eventually develops into a separate second pituitary with all the pituitary cell types and neuronal fibers characteristic of the normal pituitary. The induction of the second pituitary is associated with a localized ectopic expression of Fgf10, a gene encoding a growth factor known to recruit oral ectodermal cells into the pituitary. Interestingly, there are rare cases of pituitary duplications in humans that are also associated with optic nerve dysplasia, suggesting that VAX1 might be involved in the pathogenesis of this disorder.
Two-Year Outcome Following Traumatic Brain Injury and Rehabilitation: A Comparison of Patients From Metropolitan Melbourne and Those Residing in Regional Victoria
Authors: Ponsford Jennie , Olver John , Ponsford Michael , Schönberger Michael
Published: January 2011

Background and Objective:Victoria's trauma management system provides acute care and rehabilitation following traumatic brain injury (TBI), with care of more complex injuries generally provided in specialist centres in metropolitan Melbourne. Little is known about how the outcomes of TBI survivors living in metropolitan Melbourne compare to those who reside in regional Victoria once they return to their community, where support services may be less available. The aim of the present study was to compare, in TBI individuals who have been treated at an inner-city rehabilitation centre in Melbourne, the long-term outcomes of those who live in metropolitan Melbourne (termed ‘Metro’) with those who reside in regional Victoria, termed ‘Regional.’Design and participants:Comparative study with quantitative outcome measures. A total of 959 patients, of whom 645 were designated ‘metro’ and 314 ‘regional’, were followed-up routinely at 2 years post-injury.Outcome measures:Structured Outcome Questionnaire, Glasgow Outcome Scale — Extended, Sickness Impact Profile, Craig Handicap Assessment and Reporting Technique, Hospital Anxiety and Depression Scale, Alcohol Use Disorders Identification Test and Drug Abuse Screening Test.Results:Few differences in outcomes were found between groups. However, after controlling for group differences in age and injury severity, some non-significant trends were suggestive of better outcomes in terms of less social isolation and anxiety and fewer dysexecutive behaviours in regional dwellers.Conclusions:These findings suggest that outcomes in patients from regional areas are at least as good as those from metropolitan Melbourne.
Comparison of People With ABI Living in Two Accommodation Settings: Shared Supported Accommodation and Residential Aged Care
Authors: Winkler Dianne , Farnworth Louise , Sloan Sue , Brown Ted , Callaway Libby
Published: January 2011

Background:People with severe acquired brain injury (ABI) often require high and ongoing levels of paid support, which is sometimes provided within a shared supported accommodation service (SSA). In Victoria there are more than 140 people with severe ABI living in shared supported accommodation services who have a similar level of disability as young people with ABI in residential aged care (RAC).Objectives:The aims of this article are twofold: (1) to describe the characteristics, support needs and level of community inclusion of people with an ABI living in shared SSA in Victoria and (2) to compare the characteristics, support needs, social contact, community integration and leisure participation of this group with a group of people with ABI under 50 years old living in RAC reported in a previous study.Participants:Information was obtained from SSA managers on 128 residents with an ABI, aged under 60 years, who were living in shared supported accommodation.Measures:Questionnaires were used to obtain information about the characteristics, support needs and occupational participation of participants. Support needs were measured utilising the Care and Needs Scale (CANS).Method:Questionnaires were sent to and completed by SSA managers.Results:Of the 39 SSA managers contacted, 32 provided information about the characteristics of 128 residents with ABI living in their facilities. While 72% of SSA residents accessed the community almost everyday or more often, 40% of this sample received a visit from a friend less often than once per year. Results of the CANS indicated that the SSA group required a similar level of support to the comparison group of people with ABI living in RAC, but went outside, participated in community based leisure activities, and visited friends significantly more often. There was no significant difference between the two groups in the frequency of visits to the facility from relatives or friends.Conclusion:Although the relationship between client outcomes and accommodation is a complex one, this study suggests that the type of accommodation and support has a significant impact on the frequency of community participation experienced people with ABI and high care needs.
Under siege by commercial interests? BBC and DR Online between the national and European policy frameworks
Authors: Brevini Benedetta
Published: January 2011

The increasing competition in media markets, the economic downturn and the cyclical decline in advertising revenues have put the private media sector under increasing strain around the world. As a result, commercial operators have boosted their lobbying activities to increase their
influence on media policy-making. They are demanding that national authorities reduce regulatory control on private enterprises while raising oversight on public initiatives and cutting new public sector initiatives. This article examines how two European public service broadcasters (PSBs)
have expanded in the online world: the BBC in the United Kingdom and Danmarks Radio (DR) in Denmark. It analyses the main policies adopted by the governments of the two nations to regulate the evolution of PSBs on the Internet as well as the policies and practices adopted by the BBC and DR.
Furthermore, it reveals how the commercial pressure that has clearly influenced the more recent national policies on public service broadcasting in the United Kingdom and that has spread its influence in Brussels is impacting on the expansion online of PSBs. The article eventually questions
the possibility of developing a public service broadcasting philosophy across the Internet (PSB 2.0).
The promotion of public interest through new policy initiatives for public television: the cases of France and Spain
Authors: Ibarra Karen Arriaza
Published: January 2011

Public television in France and Spain differs from those in other European countries in the historical socio-political changes it has gone through in the last century. Coincidentally, today both media are working towards a new, similar model of public service television, and the implementation of some radical changes, such as the progressive suppression of advertising until its complete elimination in 2011, strengthens the assumption that new policy initiatives are being taken in order to finance and re-structure public television in both countries.

The economic answer to the elimination of advertising has been the creation of new taxes to telecommunications' operators and private television companies in order to help support public media, but with these, controversy came: the European Commission has already accepted complaints from both countries' companies stating that these new taxes are illegal. The economic future of public television in France and Spain, then, is yet to be determined.