bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic burden of near-roadway traffic pollution in 10 European cities (APHEKOM network)
Authors: Perez Laura , Declercq Christophe , Iñiguez Carmen , Aguilera Inmaculada , Badaloni Chiara , Ballester Ferran , Bouland Catherine , Chanel Olivier , Cirarda Francisco B. , Forastiere Francesco , Forsberg Bertil , Haluza Daniela , Hedlund Britta , Cambra Koldo , Lacasaña Marina , Moshammer Hanns , Otorepec Peter , Rodríguez-Barranco Miguel , Medina Sylvia , Künzli Nino
Published: March 2013

Recent epidemiological research suggests that near road traffic-related pollution may cause chronic disease, as well as exacerbation of related pathologies, implying that the entire “chronic disease progression” should be attributed to air pollution, no matter what the proximate cause was. We estimated the burden of childhood asthma attributable to air pollution in 10 European cities by calculating the number of cases of 1) asthma caused by near road traffic-related pollution, and 2) acute asthma events related to urban air pollution levels. We then expanded our approach to include coronary heart diseases in adults.

Derivation of attributable cases required combining concentration–response function between exposures and the respective health outcome of interest (obtained from published literature), an estimate of the distribution of selected exposures in the target population, and information about the frequency of the assessed morbidities.

Exposure to roads with high vehicle traffic, a proxy for near road traffic-related pollution, accounted for 14% of all asthma cases. When a causal relationship between near road traffic-related pollution and asthma is assumed, 15% of all episodes of asthma symptoms were attributable to air pollution. Without this assumption, only 2% of asthma symptoms were attributable to air pollution. Similar patterns were found for coronary heart diseases in older adults.

Pollutants along busy roads are responsible for a large and preventable share of chronic disease and related acute exacerbations in European urban areas.
Early intervention studies in infants and preschool children with cystic fibrosis: are we ready?
Authors: Stick Stephen , Tiddens Harm , Aurora Paul , Gustafsson Per , Ranganathan Sarath , Robinson Paul , Rosenfeld Margaret , Sly Peter , Ratjen Felix
Published: March 2013

Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed; both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review; chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.
Ciliary dyskinesia is an early feature of respiratory syncytial virus infection
Authors: Smith Claire M. , Kulkarni Hemant , Radhakrishnan Priya , Rutman Andrew , Bankart Michael J. , Williams Gwyneth , Hirst Robert A. , Easton Andrew J. , Andrew Peter W. , O’Callaghan Chris
Published: March 2013

Respiratory syncytial virus is a major cause of respiratory disease. There are conflicting accounts of the response of human epithelial cells to respiratory syncytial virus and a lack of data on its effect on ciliary function. Our aim was to study the early stages of respiratory syncytial virus infection of primary human basal and ciliated cultures.

Using high speed videomicroscopy, we found that ciliary beat frequency was unaffected by respiratory syncytial virus infection over 72 h; however, ciliary dyskinesia significantly increased within 24 h of infection (p<0.05). Transmission electron microscopy revealed that ultrastructural abnormalities were confined to ciliated cells, including increased cilia loss and mitochondrial damage. Confocal immunofluorescence microscopy showed that respiratory syncytial virus antigen gradually spread from the cell surface to the ciliary tip of infected cells over 3 days. Interestingly, ciliated cultures secreted fewer viruses than basal (progenitor) cell cultures and produced a chemokine response focused on recruitment of neutrophils.

This study highlights differences in infection models and underscores the need to explore further the role of ciliated cells in the establishment of respiratory syncytial virus infection.

Increased ciliary dyskinesia combined with ciliary loss and epithelial damage is likely to result in reduced mucociliary clearance early in the infective process.
Intron retention and transcript chimerism conserved across mammals: Ly6g5b and Csnk2b-Ly6g5b as examples
Authors: Hernández-Torres Francisco , Rastrojo Alberto , Aguado Begoña
Published: March 2013

Background

Alternative splicing (AS) is a major mechanism for modulating gene expression of an organism, allowing the synthesis of several structurally and functionally distinct mRNAs and protein isoforms from a unique gene. Related to AS is the Transcription Induced Chimerism (TIC) or Tandem Chimerism, by which chimeric RNAs between adjacent genes can be found, increasing combinatorial complexity of the proteome. The Ly6g5b gene presents particular behaviours in its expression, involving an intron retention event and being capable to form RNA chimera transcripts with the upstream gene Csnk2b. We wanted to characterise these events more deeply in four tissues in six different mammals and analyse their protein products.

Results

While canonical Csnk2b isoform was widely expressed, Ly6g5b canonical isoform was less ubiquitous, although the Ly6g5b first intron retained transcript was present in all the tissues and species analysed. Csnk2b-Ly6g5b chimeras were present in all the samples analysed, but with restricted expression patterns. Some of these chimeric transcripts maintained correct structural domains from Csnk2b and Ly6g5b. Moreover, we found Csnk2b, Ly6g5b, and Csnk2b-Ly6g5b transcripts that present exon skipping, alternative 5' and 3' splice site and intron retention events. These would generate truncated or aberrant proteins whose role remains unknown. Some chimeric transcripts would encode CSNK2B proteins with an altered C-terminus, which could affect its biological function broadening its substrate specificity. Over-expression of human CSNK2B, LY6G5B, and CSNK2B-LY6G5B proteins, show different patterns of post-translational modifications and cell distribution.

Conclusions

Ly6g5b intron retention and Csnk2b-Ly6g5b transcript chimerism are broadly distributed in tissues of different mammals.
Xylem transcription profiles indicate potential metabolic responses for economically relevant characteristics of Eucalyptusspecies
Authors: Salazar Marcela Mendes , Nascimento Leandro Costa , Camargo Eduardo Leal Oliveira , Gonçalves Danieli Cristina , Neto Jorge Lepikson , Marques Wesley Leoricy , Teixeira Paulo José Pereira Lima , Mieczkowski Piotr , Mondego Jorge Maurício Costa , Carazzolle Marcelo Falsarella , Deckmann Ana Carolina , Pereira Gonçalo Amarante Guimarães
Published: March 2013

Background

Eucalyptus is one of the most important sources of industrial cellulose. Three species of this botanical group are intensively used in breeding programs: E. globulus, E. grandis and E. urophylla. E. globulus is adapted to subtropical/temperate areas and is considered a source of high-quality cellulose; E. grandis grows rapidly and is adapted to tropical/subtropical climates; and E. urophylla, though less productive, is considered a source of genes related to robustness. Wood, or secondary xylem, results from cambium vascular differentiation and is mostly composed of cellulose, lignin and hemicelluloses. In this study, the xylem transcriptomes of the three Eucalyptus species were investigated in order to provide insights on the particularities presented by each of these species.

Results

Data analysis showed that (1) most Eucalyptus genes are expressed in xylem; (2) most genes expressed in species-specific way constitutes genes with unknown functions and are interesting targets for future studies; (3) relevant differences were observed in the phenylpropanoid pathway: E. grandis xylem presents higher expression of genes involved in lignin formation whereas E. urophylla seems to deviates the pathway towards flavonoid formation; (4) stress-related genes are considerably more expressed in E. urophylla, suggesting that these genes may contribute to its robustness.

Conclusions

The comparison of these three transcriptomes indicates the molecular signatures underlying some of their distinct wood characteristics. This information may contribute to the understanding of xylogenesis, thus increasing the potential of genetic engineering approaches aiming at the improvement of Eucalyptus forest plantations productivity.
CbCTB2, an O-methyltransferase is essential for biosynthesis of the phytotoxin cercosporin and infection of sugar beet by Cercospora beticola
Authors: Staerkel Cornelia , Boenisch Marike J , Kröger Cathrin , Bormann Jörg , Schäfer Wilhelm , Stahl Dietmar
Published: March 2013

Background

Cercospora leaf spot disease, caused by the fungus Cercospora beticola, is the most destructive foliar disease of sugar beets (Beta vulgaris) worldwide. Cercosporin, a light-inducible toxin, is essential for necrosis of the leaf tissue and development of the typical leaf spots on sugar beet leaves.

Results

In this study we show that the O-methyltransferase gene CTB2 is essential for cercosporin production and pathogenicity in two C. beticola isolates. We established a transformation system for C. beticola protoplasts, disrupted CTB2, and transformed the Δctb2 strains as well as a wild type strain with the DsRed reporter gene. The Δctb2 strains had lost their pigmentation and toxin measurements demonstrated that the Δctb2 strains were defective in cercosporin production. Infection of sugar beets with the wild type and Δctb2 DsRed strains showed that the deletion strain was severely impaired in plant infection. Histological analysis revealed that the CTB2-deficient isolate cannot enter the leaf tissue through stomata like the wild type.

Conclusions

Taken together, these observations indicate that cercosporin has a dual function in sugar beet infection: in addition to the well-known role in tissue necrosis, the toxin is required for the early phase of sugar beet infection.
The combination of ANT2 shRNA and hNIS radioiodine gene therapy increases CTL cytotoxic activity through the phenotypic modulation of cancer cells: combination treatment with ANT2 shRNA and I-131
Authors: Choi Yun , Lee Ho Won , Lee Jaetae , Jeon Yong Hyun
Published: March 2013

Background

It is important to simultaneously induce strong cell death and antitumor immunity in cancer patients for successful cancer treatment. Here, we investigated the cytotoxic and phenotypic modulation effects of the combination of ANT2 shRNA and human sodium iodide symporter (hNIS) radioiodine gene therapy in vitro and in vivo and visualized the antitumor effects in an immunocompromised mouse colon cancer model.

Methods

A mouse colon cancer cell line co-expressing hNIS and the luciferase gene (CT26/hNIS-Fluc, named CT26/NF) was established. CT26/NF cells and tumor-bearing mice were treated with HBSS, scramble, ANT2 shRNA, I-131, and ANT2 shRNA + I-131. The apoptotic rates (%) and MHC class I and Fas gene expression levels were determined in treated CT26/NF cells using flow cytometry. Concurrently, the level of caspase-3 activation was determined in treated cells in vitro. For in vivo therapy, tumor-bearing mice were treated with scramble, ANT2 shRNA, I-131, and the combination therapy, and the anti-tumor effects were monitored using bioluminescence. The killing activity of cytotoxic T cells (CTLs) was measured with a lactate dehydrogenase (LDH) assay.

Results

For the in vitro experiments, the combination of ANT2 shRNA and I-131 resulted in a higher apoptotic cell death rate compared with ANT2 shRNA or I-131 alone, and the levels of MHC class I and Fas-expressing cancer cells were highest in the cells receiving combination treatment, while single treatment modestly increased the level of MHC class I and Fas gene expression. The combination of ANT2 shRNA and I-131 resulted in a higher caspase-3 activation than single treatments. Interestingly, in vivo combination treatment led to increased gene expression of MHC class I and Fas than the respective mono-therapies; furthermore, bioluminescence showed increased antitumor effects after combination treatment than monotherapies. The LDH assay revealed that the CTL killing activity against CT26/NF cells was most effective after combination therapy.

Conclusions

Increased cell death and phenotypic modulation of cancer cells in vitro and in vivo were achieved simultaneously after combination therapy with ANT2 shRNA and I-131, and this combination therapy induced remarkable antitumor outcomes through improvements in CTL immunity against CT26/NF. Our results suggest that combination therapy can be used as a new therapeutic strategy for cancer patients who show resistance to single therapy such as radiation or immunotherapy.
Derepression of Cancer/Testis Antigens in cancer is associated with distinct patterns of DNA Hypomethylation
Authors: Kim Robert , Kulkarni Prakash , Hannenhalli Sridhar
Published: March 2013

Background

The Cancer/Testis Antigens (CTAs) are a heterogeneous group of proteins whose expression is typically restricted to the testis. However, they are aberrantly expressed in most cancers that have been examined to date. Broadly speaking, the CTAs can be divided into two groups: the CTX antigens that are encoded by the X-linked genes and the non-X CT antigens that are encoded by the autosomes. Unlike the non-X CTAs, the CTX antigens form clusters of closely related gene families and their expression is frequently associated with advanced disease with poorer prognosis. Regardless however, the mechanism(s) underlying their selective derepression and stage-specific expression in cancer remain poorly understood, although promoter DNA demethylation is believed to be the major driver.

Methods

Here, we report a systematic analysis of DNA methylation profiling data from various tissue types to elucidate the mechanism underlying the derepression of the CTAs in cancer. We analyzed the methylation profiles of 501 samples including sperm, several cancer types, and their corresponding normal somatic tissue types.

Results

We found strong evidence for specific DNA hypomethylation of CTA promoters in the testis and cancer cells but not in their normal somatic counterparts. We also found that hypomethylation was clustered on the genome into domains that coincided with nuclear lamina-associated domains (LADs) and that these regions appeared to be insulated by CTCF sites. Interestingly, we did not observe any significant differences in the hypomethylation pattern between the CTAs without CpG islands and the CTAs with CpG islands in the proximal promoter.

Conclusion

Our results corroborate that widespread DNA hypomethylation appears to be the driver in the derepression of CTA expression in cancer and furthermore, demonstrate that these hypomethylated domains are associated with the nuclear lamina-associated domains (LADS). Taken together, our results suggest that wide-spread methylation changes in cancer are linked to derepression of germ-line-specific genes that is orchestrated by the three dimensional organization of the cancer genome.
Psychometric behaviour of the strengths and difficulties questionnaire (SDQ) in the Spanish national health survey 2006
Authors: Gómez-Beneyto Manuel , Nolasco Andreu , Moncho Joaquín , Pereyra-Zamora Pamela , Tamayo-Fonseca Nayara , Munarriz Mikel , Salazar José , Tabarés-Seisdedos Rafael , Girón Manuel
Published: March 2013

Background

The Strengths and Difficulties Questionnaire (SDQ) is a tool to measure the risk for mental disorders in children. The aim of this study is to describe the diagnostic efficiency and internal structure of the SDQ in the sample of children studied in the Spanish National Health Survey 2006.

Methods

A representative sample of 6,773 children aged 4 to 15 years was studied. The data were obtained using the Minors Questionnaire in the Spanish National Health Survey 2006. The ROC curve was constructed and calculations made of the area under the curve, sensitivity, specificity and the Youden J indices. The factorial structure was studied using models of exploratory factorial analysis (EFA) and confirmatory factorial analysis (CFA).

Results

The prevalence of behavioural disorders varied between 0.47% and 1.18% according to the requisites of the diagnostic definition. The area under the ROC curve varied from 0.84 to 0.91 according to the diagnosis. Factor models were cross-validated by means of two different random subsamples for EFA and CFA. An EFA suggested a three correlated factor model. CFA confirmed this model. A five-factor model according to EFA and the theoretical five-factor model described in the bibliography were also confirmed. The reliabilities of the factors of the different models were acceptable (>0.70, except for one factor with reliability 0.62).

Conclusions

The diagnostic behaviour of the SDQ in the Spanish population is within the working limits described in other countries. According to the results obtained in this study, the diagnostic efficiency of the questionnaire is adequate to identify probable cases of psychiatric disorders in low prevalence populations. Regarding the factorial structure we found that both the five and the three factor models fit the data with acceptable goodness of fit indexes, the latter including an externalization and internalization dimension and perhaps a meaningful positive social dimension.

Accordingly, we recommend studying whether these differences depend on sociocultural factors or are, in fact, due to methodological questions.
Compliance, persistence, costs and quality of life in young patients treated with antipsychotic drugs: results from the COMETA study
Authors: Cortesi Paolo A , Mencacci Claudio , Luigi Ferrannini , Pirfo Elvezio , Berto Patrizia , Sturkenboom Miriam CJM , Lopes Fabiana L , Giustra Maria G , Mantovani Lorenzo G , Scalone Luciana
Published: March 2013

Background

Little data is available on the real-world socio-economic burden and outcomes in schizophrenia. This study aimed to assess persistence, compliance, costs and Health-Related Quality-of-Life (HRQoL) in young patients undergoing antipsychotic treatment according to clinical practice.

Methods

A naturalistic, longitudinal, multicentre cohort study was conducted: we involved 637 patients aged 18–40 years, with schizophrenia or schizophreniform disorder diagnosed ≤10 years before, enrolled in 86 Italian Mental Health Centres and followed-up for 1 year. Comparisons were conducted between naïve (i.e., patients visiting the centre for the first time and starting a new treatment regimen) and non naïve patients.

Results

At enrolment, 84% of patients were taking atypical drugs, 3.7% typical, 10% a combination of the two classes, and 2% were untreated. During follow-up, 23% of patients switched at least once to a different class of treatment, a combination or no treatment. The mean Drug-Attitude-Inventory score was 43.4, with 94.3% of the patients considered compliant by the clinicians. On average, medical costs at baseline were 390.93€/patient-month, mostly for drug treatment (29.5%), psychotherapy (29.2%), and hospitalizations (27.1%). Patients and caregivers lost 3.5 days/patient-month of productivity. During follow-up, attitude toward treatment remained fairly similar, medical costs were generally stable, while productivity, clinical statusand HRQoL significantly improved. While no significantly different overall direct costs trends were found between naïve and non naïve patients, naïve patients showed generally a significant mean higher improvement of clinical outcomes, HRQoL and indirect costs, compared to the others.

Conclusions

Our results suggest how tailoring the treatment strategy according to the complex and specific patient needs make it possible to achieve benefits and to allocate more efficiently resources. This study can also provide information on the most relevant items to be considered when conducting cost-effectiveness studies comparing specific alternatives for the treatment of target patients.
The role of nicotine replacement therapy for temporary abstinence in the home to protect children from environmental tobacco smoke exposure: a qualitative study with disadvantaged smokers
Authors: Atkinson Olesya , Coleman Tim , McNeill Ann , Lewis Sarah , Jones Laura L
Published: March 2013

Background

Nicotine replacement therapy (NRT) has recently been licensed to help smokers to abstain from smoking for short time periods and recent studies have shown that 8-14% of smokers are regularly using NRT to cope when they cannot or are not allowed to smoke. These data suggest that, potentially, NRT for temporary abstinence might be an acceptable method to help smoking caregivers, who are not able to stop smoking completely, to avoid smoking whilst inside their home in order to protect their children from the harms of environmental tobacco smoke (ETS). The aim of this study was therefore to explore the concept of using NRT for temporary abstinence in the home, to protect children from exposure to ETS.

Methods

Qualitative in-depth interviews were conducted with thirty six disadvantaged smoking parents who were currently, or had recently stopped smoking in the home with at least one child under the age of five. Parents were recruited from Children’s Centres and Health Visitor Clinics in Nottingham, UK. Interviews were audio recorded and transcribed verbatim. Data were coded and analysed thematically to identify emergent main and subthemes.

Results

Overall, participants responded negatively to the concept of attempting temporary abstinence in the home in general and more specifically to the use of NRT whilst at home to reduce children’s exposure to ETS. Many parents would prefer to either attempt cutting down or quitting completely to make a substantial effort to change their smoking behaviour. There was limited interest in the use of NRT for temporary abstinence in the home as a first step to quitting, although some parents did express a willingness to use NRT to cut down as a first step to quitting.

Conclusion

Disadvantaged smoking parents were reluctant to initiate and maintain temporary abstinence with or without NRT as a way of making their homes smoke free to protect their children’s health. More education about the specific risks of ETS to their children and the utility of NRT for use in the home might be needed to have a public health impact on children’s health.
Gaps in detailed knowledge of human papillomavirus (HPV) and the HPV vaccine among medical students in Scotland
Authors: McCusker Sarah M , Macqueen Ishbel , Lough Graham , MacDonald Alasdair I , Campbell Christine , Graham Sheila V
Published: March 2013

Background

A vaccination programme targeted against human papillomavirus (HPV) types16 and 18 was introduced in the UK in 2008, with the aim of decreasing incidence of cervical disease. Vaccine roll out to 12–13 year old girls with a catch-up programme for girls aged up to 17 years and 364 days was accompanied by a very comprehensive public health information (PHI) campaign which described the role of HPV in the development of cervical cancer.

Methods

A brief questionnaire, designed to assess acquisition of knowledge of HPV infection and its association to cervical cancer, was administered to two different cohorts of male and female 1st year medical students (school leavers: 83% in age range 17–20) at a UK university. The study was timed so that the first survey in 2008 immediately followed a summer's intensive PHI campaign and very shortly after vaccine roll-out (150 students). The second survey was exactly one year later over which time there was a sustained PHI campaign (213 students).

Results

We addressed three research questions: knowledge about three specific details of HPV infection that could be acquired from PHI, whether length of the PHI campaign and/or vaccination of females had any bearing on HPV knowledge, and knowledge differences between men and women regarding HPV. No female student in the 2008 cohort had completed the three-dose vaccine schedule compared to 58.4% of female students in 2009. Overall, participants’ knowledge regarding the sexually transmitted nature of HPV and its association with cervical cancer was high in both year groups. However, in both years, less than 50% of students correctly identified that HPV causes over 90% of cases of cervical cancer. Males gave fewer correct answers for these two details in 2009. In 2008 only around 50% of students recognised that the current vaccine protects against a limited subset of cervical cancer-causing HPV sub-types, although there was a significant increase in correct response among female students in the 2009 cohort compared to the 2008 cohort.

Conclusions

This study highlights a lack of understanding regarding the extent of protection against cervical cancer conferred by the HPV vaccine, even among an educated population in the UK who could have a vested interest in acquiring such knowledge. The intensive PHI campaign accompanying the first year of HPV vaccination seemed to have little effect on knowledge over time. This is one of the first studies to assess detailed knowledge of HPV in both males and females. There is scope for continued improvements to PHI regarding the link between HPV infection and cervical cancer.
Treatment for sleep apnea by continuous positive airway pressure improves levels of inflammatory markers - a meta-analysis
Authors: Baessler Aaron , Nadeem Rashid , Harvey Michael , Madbouly Essam , Younus Amna , Sajid Hassan , Naseem Jawed , Asif Asma , Bawaadam Hasnain
Published: March 2013

Background

Obstructive sleep apnea (OSA) is associated with coronary artery disease (CAD). Intermittent hypoxia associated with OSA increases sympathetic activity and may cause systemic inflammation, which may contribute to CAD in patients with OSA. Treatment with continuous positive airway pressure (CPAP) has been shown to change levels of inflammatory markers. We analyzed data from published studies by a systematic meta-analysis.

Objective

To asses if treatment for sleep apnea by CPAP will affect levels of inflammatory markers.

Data resources

PubMed, Embase and Cochrane library.

Methods

Study eligibility criteria full text English studies of adult, human subjects, addressing values of at least one of the inflammatory markers before and after CPAP treatment. We used the definition of OSA as an apnea-hypopnea index (AHI) of ≥ 5/h, reported values in mean and standard deviation or median with range.

Participants

Adult, human.

Interventions

CPAP treatment for OSA.

Study appraisal and synthesis method

A total of 3835 studies were reviewed for inclusion, while 23 studies pooled for analysis. A total of 14 studies with 771 patients were pooled for C-reactive protein (CRP); 9 studies with 209 patients were pooled for tumor necrosis factor-alpha (TNF-α); and 8 studies with 165 patients were pooled for interleukin-6 (IL-6).

Endpoint definitions

The following inflammatory markers were chosen: CRP, TNF-α, and IL-6.

Results

C-reactive protein: Study level means ranged from 0.18 to 0.85 mg/dl before CPAP treatment and 0.10 to 0.72 mg/dl after CPAP treatment. Mean differences, at a study level, ranged from −0.05 to 0.50. The pooled mean difference was 0.14 [95% confidence interval 0.08 to 0.20, p < 0.00001]. There was heterogeneity in this endpoint (df = 13, p < 0.00001, I2 = 95%).

Tumor necrosis factor-α: Study level means ranged from 1.40 to 50.24 pg/ml before CPAP treatment and 1.80 to 28.63 pg/ml after CPAP treatment. Mean differences, at a study level, ranged from −1.23 to 21.61. The pooled mean difference was 1.14 [95% confidence interval 0.12 to 2.15, p = 0.03]. There was heterogeneity in this endpoint (df = 8, p < 0.00001, I2 = 89%).

Interleukin-6: Study level means ranged from 1.2 to 131.66 pg/ml before CPAP treatment and 0.45 to 66.04 pg/ml after CPAP treatment. Mean differences, at a study level, ranged from −0.40 to 65.62. The pooled mean difference was 1.01 [95% confidence interval −0.00 to 2.03, p = 0.05]. There was heterogeneity in this endpoint (df = 7, p < 0.00001, I2 = 95%).

Limitations

Only published data. Studies pooled were mainly small, non-randomized trials.

Conclusion

Sleep apnea treatment with CPAP improves levels of inflammatory markers.
Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism
Authors: Valles Soraya L , Benlloch María , Rodriguez María L , Mena Salvador , Pellicer José A , Asensi Miguel , Obrador Elena , Estrela José M
Published: March 2013

Background

Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms.

Methods

Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-κB, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student’s t test.

Results

Plasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-κB, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a β-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in metastatic cells with low GSH content.

Conclusions

Our results describe an interorgan system where stress-related hormones, IL-6, and GSH coordinately regulate metastases growth.
A three-gene signature as potential predictive biomarker for irinotecan sensitivity in gastric cancer
Authors: Shen Jie , Wei Jia , Wang Hao , Yue Guofeng , Yu Lixia , Yang Yang , Xie Li , Zou Zhengyun , Qian Xiaoping , Ding Yitao , Guan Wenxian , Liu Baorui
Published: March 2013

Objective

Personalized chemotherapy based on molecular biomarkers can maximize anticancer efficiency. We aim to investigate predictive biomarkers capable of predicting response to irinotecan-based treatment in gastric cancer.

Methods

We examined gene expression of APTX, BRCA1, ERCC1, ISG15, Topo1 and methylation of SULF2 in formalin-fixed paraffin-embedded gastric cancer tissues from 175 patients and evaluated the association between gene expression levels or methylation status and in vitro sensitivity to irinotecan. We used multiple linear regression analysis to develop a gene-expression model to predict irinotecan sensitivity in gastric cancer and validated this model in vitro and vivo.

Results

Gene expression levels of APTX, BRCA1 and ERCC1 were significantly lower in irinotecan-sensitive gastric cancer samples than those irinotecan-resistant samples (P < 0.001 for all genes), while ISG15 (P = 0.047) and Topo1 (P = 0.002) were significantly higher. Based on those genes, a three-gene signature were established, which was calculated as follows: Index =0.488 - 0.020× expression level of APTX + 0.015× expression level of Topo1 - 0.011 × expression level of BRCA1. The three-gene signature was significantly associated with irinotecan sensitivity (rho = 0.71, P < 0.001). The sensitivity and specificity for the prediction of irinotecan sensitivity based on the three-gene signature reached 73% and 86%, respectively. In another independent testing set, the irinotecan inhibition rates in gastric samples with sensitive-signature were much higher than those with resistant-signature (65% vs. 22%, P < 0.001). Irinotecan therapy with 20 mg/kg per week to immunodeficient mice carrying xenografts with sensitive-signature dramatically arrested the growth of tumors (P < 0.001), but had no effect on mice carrying xenografts with resistant-signature.

Conclusions

The three-gene signature established herein is a potential predictive biomarker for irinotecan sensitivity in gastric cancer.
In silico approaches for designing highly effective cell penetrating peptides
Authors: Gautam Ankur , Chaudhary Kumardeep , Kumar Rahul , Sharma Arun , Kapoor Pallavi , Tyagi Atul ,   Open source drug discovery consortium, Raghava Gajendra P S
Published: March 2013

Background

Cell penetrating peptides have gained much recognition as a versatile transport vehicle for the intracellular delivery of wide range of cargoes (i.e. oligonucelotides, small molecules, proteins, etc.), that otherwise lack bioavailability, thus offering great potential as future therapeutics. Keeping in mind the therapeutic importance of these peptides, we have developed in silico methods for the prediction of cell penetrating peptides, which can be used for rapid screening of such peptides prior to their synthesis.

Methods

In the present study, support vector machine (SVM)-based models have been developed for predicting and designing highly effective cell penetrating peptides. Various features like amino acid composition, dipeptide composition, binary profile of patterns, and physicochemical properties have been used as input features. The main dataset used in this study consists of 708 peptides. In addition, we have identified various motifs in cell penetrating peptides, and used these motifs for developing a hybrid prediction model. Performance of our method was evaluated on an independent dataset and also compared with that of the existing methods.

Results

In cell penetrating peptides, certain residues (e.g. Arg, Lys, Pro, Trp, Leu, and Ala) are preferred at specific locations. Thus, it was possible to discriminate cell-penetrating peptides from non-cell penetrating peptides based on amino acid composition. All models were evaluated using five-fold cross-validation technique. We have achieved a maximum accuracy of 97.40% using the hybrid model that combines motif information and binary profile of the peptides. On independent dataset, we achieved maximum accuracy of 81.31% with MCC of 0.63.

Conclusion

The present study demonstrates that features like amino acid composition, binary profile of patterns and motifs, can be used to train an SVM classifier that can predict cell penetrating peptides with higher accuracy. The hybrid model described in this study achieved more accuracy than the previous methods and thus may complement the existing methods. Based on the above study, a user- friendly web server CellPPD has been developed to help the biologists, where a user can predict and design CPPs with much ease. CellPPD web server is freely accessible at http://crdd.osdd.net/raghava/cellppd/.
Strong plasmon-exciton coupling in a hybrid system of gold nanostars and J-aggregates
Authors: Melnikau Dzmitry , Savateeva Diana , Susha Andrey , Rogach Andrey L , Rakovich Yury P
Published: March 2013

Hybrid materials formed by plasmonic nanostructures and J-aggregates provide a unique combination of highly localized and enhanced electromagnetic field in metal constituent with large oscillator strength and extremely narrow exciton band of the organic component. The coherent coupling of localized plasmons of the multispiked gold nanoparticles (nanostars) and excitons of JC1 dye J-aggregates results in a Rabi splitting reaching 260 meV. Importantly, broad absorption features of nanostars extending over a visible and near-infrared spectral range allowed us to demonstrate double Rabi splitting resulting from the simultaneous coherent coupling between plasmons of the nanostars and excitons of J-aggregates of two different cyanine dyes.
Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010
Authors: Pabbaraju Kanti , Wong Sallene , Chan Eve N Y , Tellier Raymond
Published: March 2013

Background

An unusually high incidence of aseptic meningitis caused by enteroviruses was noted in Alberta, Canada between March and October 2010. Sequence based typing was performed on the enterovirus positive samples to gain a better understanding of the molecular characteristics of the Coxsackie A9 (CVA-9) strain responsible for most cases in this outbreak.

Methods

Molecular typing was performed by amplification and sequencing of the VP2 region. The genomic sequence of one of the 2010 outbreak isolates was compared to a CVA-9 isolate from 2003 and the prototype sequence to study genetic drift and recombination.

Results

Of the 4323 samples tested, 213 were positive for enteroviruses (4.93%). The majority of the positives were detected in CSF samples (n = 157, 73.71%) and 81.94% of the sequenced isolates were typed as CVA-9. The sequenced CVA-9 positives were predominantly (94.16%) detected in patients ranging in age from 15 to 29 years and the peak months for detection were between March and October. Full genome sequence comparisons revealed that the CVA-9 viruses isolated in Alberta in 2003 and 2010 were highly homologous to the prototype CVA-9 in the structural VP1, VP2 and VP3 regions but divergent in the VP4, non-structural and non-coding regions.

Conclusion

The increase in cases of aseptic meningitis was associated with enterovirus CVA-9. Sequence divergence between the prototype strain of CVA-9 and the Alberta isolates suggests genetic drifting and/or recombination events, however the sequence was conserved in the antigenic regions determined by the VP1, VP2 and VP3 genes. These results suggest that the increase in CVA-9 cases likely did not result from the emergence of a radically different immune escape mutant.
Invariance and optimality in the regulation of an enzyme
Authors: Reznik Ed , Yohe Stefan , Segrè Daniel
Published: March 2013

Background

The Michaelis-Menten equation, proposed a century ago, describes the kinetics of enzyme-catalyzed biochemical reactions. Since then, this equation has been used in countless, increasingly complex models of cellular metabolism, often including time-dependent enzyme levels. However, even for a single reaction, there remains a fundamental disconnect between our understanding of the reaction kinetics, and the regulation of that reaction through changes in the abundance of active enzyme.

Results

We revisit the Michaelis-Menten equation under the assumption of a time-dependent enzyme concentration. We show that all temporal enzyme profiles with the same average enzyme level yield identical substrate degradation– a simple analytical conclusion that can be thought of as an invariance principle, and which we validate experimentally using a β-galactosidase assay. The ensemble of all time-dependent enzyme trajectories with the same average concentration constitutes a space of functions. We develop a simple model of biological fitness which assigns a cost to each of these trajectories (in the form of a function of functions, i.e. a functional). We then show how one can use variational calculus to analytically infer temporal enzyme profiles that minimize the overall enzyme cost. In particular, by separately treating the static costs of amino acid sequestration and the dynamic costs of protein production, we identify a fundamental cellular tradeoff.

Conclusions

The overall metabolic outcome of a reaction described by Michaelis-Menten kinetics is ultimately determined by the average concentration of the enzyme during a given time interval. This invariance in analogy to path-independent phenomena in physics, suggests a new way in which variational calculus can be employed to address biological questions. Together, our results point to possible avenues for a unified approach to studying metabolism and its regulation.

Reviewers

This article was reviewed by Sergei Maslov, William Hlavacek and Daniel Kahn.
Effect of lateral meniscectomy and osteochondral grafting of a lateral femoral condylar defect on contact mechanics: a cadaveric study in dogs
Authors: Choate Christina J , Kim Stanley E , Hudson Caleb C , Spreng David , Pozzi Antonio
Published: March 2013

Background

Osteochondral autograft transfer (OAT) aims at restoring normal articular cartilage surface geometry and articular contact mechanics. To date, no studies have evaluated the contact mechanics of the canine stifle following OAT. Additionally, there are no studies that evaluated the role of the meniscus in contact mechanics following OAT in human or canine femorotibial joints. The objective of this study was to measure the changes in femorotibial contact areas (CA), mean contact pressure (MCP) and peak contact pressure (PCP) before and after osteochondral autograft transplantation (OAT) of a simulated lateral femoral condylar cartilage defect with an intact lateral meniscus and following lateral meniscectomy.

Results

With an intact lateral meniscus, creation of an osteochondral defect caused a decrease in MCP and PCP by 11% and 30%, respectively, compared to the intact stifle (p < 0.01). With an intact meniscus, implanting an osteochondral graft restored MCP and PCP to 96% (p = 0.56) and 92% (p = 0.41) of the control values. Lateral meniscectomy with grafting decreased CA by 54% and increased PCP by 79% compared to the intact stifle (p < 0.01).

Conclusions

OAT restored contact pressures in stifles with a simulated lateral condylar defect when the meniscus was intact. The lateral meniscus has a significant role in maintaining normal contact pressures in both stifles with a defect or following OAT. Meniscectomy should be avoided when a femoral condylar defect is present and when performing OAT.
Feasibility and efficacy of chemoradiotherapy for elderly patients with locoregionally advanced nasopharyngeal carcinoma: results from a matched cohort analysis
Authors: Liu Huai , Chen Qiu-Yan , Guo Ling , Tang Lin-Quan , Mo Hao-Yuan , Zhong Zong-Liang , Huang Pei-Yu , Luo Dong-Hua , Sun Rui , Guo Xiang , Cao Ka-Jia , Hong Ming-Huang , Mai Hai-Qiang
Published: March 2013

Background

To clarify the feasibility and efficacy of chemoradiotherapy (CRT) in elderly (age≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (NPC).

Methods

From January 2000 to December 2006, 101 newly diagnosed elderly non-metastatic NPC patients (age≥65 years) who received cisplatin 3-weekly or weekly concurrent CRT with/without sequential chemotherapy were recruited. Each patient from the CRT group was matched to another patient treated with radiotherapy (RT) alone based on age, gender, pathological type, performance status, overall stage, stage method, Adult Comorbidity Evaluation-27 (ACE-27) score and RT technique, from the same institute and time period. We also recruited 101 young patients (age<65 years) as the referent group, which had been matched to the CRT group based on patient characteristics and treatment parameters. Treatment tolerability and toxicity were clarified, and treatment outcomes were calculated and compared among groups.

Results

CRT was feasible in elderly NPC patients, while a concurrent regimen of weekly cisplatin was more tolerable. Grade≥3 acute toxicity in CRT group was similar with referent group, although it was significantly higher than the RT alone group (65.3% vs. 43.6%, P=0.002). Furthermore, patients with ACE-27 score≥2 in the CRT group had significantly higher severe acute toxicity and dose reduction. Survival was poorer in elderly patients than the referent group. Compared to RT alone, CRT significantly improved the 5-year overall survival (OS: 54.6% vs. 39.3%, P=0.009), cancer-specific survival (CSS: 56.6% vs. 42.7%, P=0.022), disease-free survival (DFS: 51.6% vs. 30.2%, P=0.028) and locoregional relapse-free survival (LRRFS: 78.4% vs. 52.2%, P=0.003), but not distant metastasis-free survival (DMFS: 69.6% vs. 63.6%, P=0.669). However, CRT did not significantly improve 5-year OS (43.6% vs. 27.3%, P=0.893) or CSS (43.6% vs. 34.1%, P=0.971) in elderly NPC patients with ACE-27 score≥2.

Conclusions

CRT is feasible and effective in elderly patients with locoregionally advanced NPC without severe comorbidities. CRT should be used under serious consideration and be further tested in elderly patients with severe comorbidities. As such, it is essential to perform a comprehensive evaluation of pretreatment comorbidity status for all elderly NPC patients.
Assessment of foot and ankle muscle strength using hand held dynamometry in patients with established rheumatoid arthritis
Authors: Carroll Matthew , Joyce William , Brenton‐Rule Angela , Dalbeth Nicola , Rome Keith
Published: March 2013

Background

The foot and ankle are frequently affected in patients with rheumatoid arthritis (RA). One of the negative consequences of RA on the physical function of patients is a decrease in muscle strength. However, little is known about foot and muscle strength in this population. The aim of the study was to evaluate significant differences in foot and ankle muscle strength between patients with established RA against age and sex‐matched controls using hand‐held dynamometry.

Methods

The maximal muscle strength of ankle plantarflexion, dorsiflexion, eversion and inversion was assessed in 14 patients with RA, mean (SD) disease duration of 22 (14.1) years, and 20 age and sex‐matched control participants using hand‐held dynamometry.

Results

Significant differences were observed in muscle strength between the two groups in plantarflexion (p = 0.00), eversion (p = 0.04) and inversion (p = 0.01). No significant difference was found in dorsiflexion (p > 0.05). The patients with RA displayed a significantly lower plantarflexion‐dorsiflexion ratio than the control participants (p = 0.03).

Conclusions

The results from this study showed that the RA patients displayed a significant decrease in ankle dorsiflexion, eversion and inversion when compared to the non‐RA control group suggesting that foot and ankle muscle strength may be affected by the pathological processes in RA. This study is a preliminary step for the measurement of muscle impairments within the RA population.