bluuebunny/crossref_metadata_2025 huggingface dataset:
p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages
Authors: Cudejko Céline , Wouters Kristiaan , Fuentes Lucía , Hannou Sarah Anissa , Paquet Charlotte , Bantubungi Kadiombo , Bouchaert Emmanuel , Vanhoutte Jonathan , Fleury Sébastien , Remy Patrick , Tailleux Anne , Chinetti-Gbaguidi Giulia , Dombrowicz David , Staels Bart , Paumelle Réjane
Published: June 2011

The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.
Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II
Authors: Abboud Miguel R. , Yim Eunsil , Musallam Khaled M. , Adams Robert J. ,   for the STOP II Study Investigators
Published: June 2011

In the STOP II trial, discontinuation of prophylactic transfusions in high risk children with sickle cell disease (SCD) resulted in a high rate of reversion to abnormal blood-flow velocities on transcranial Doppler (TCD) ultrasonography and strokes. We analyzed data from STOP II to determine the effect of discontinuing transfusions on the development or progression of silent brain infarcts on magnetic resonance imaging (MRI). At study entry, 21 of 79 (27%) patients had evidence of silent infarcts. There were no statistically significant differences in baseline characteristics between patients with normal brain MRI or silent infarcts at study entry. At study end, 3 of 37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11 of 40 (27.5%) in the transfusion-halted group (P = .03). The total number of lesions remained essentially unchanged decreasing from 25 to 24 in the continued-transfusion group while increasing from 27 to 45 in transfusion-halted patients. Thus, discontinuation of transfusions in children with SCD and abnormal TCD who revert to low-risk increases the risk of silent brain infarction. Together with data from STOP, these findings demonstrate that transfusions prevent the development of silent infarcts in patients with SCD and abnormal TCD but normal MRA.
Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation
Authors: Inamoto Yoshihiro , Flowers Mary E. D. , Lee Stephanie J. , Carpenter Paul A. , Warren Edus H. , Deeg H. Joachim , Storb Rainer F. , Appelbaum Frederick R. , Storer Barry E. , Martin Paul J.
Published: June 2011

This study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.
Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system
Authors: Luft Thomas , Dietrich Sascha , Falk Christine , Conzelmann Michael , Hess Michael , Benner Axel , Neumann Frank , Isermann Berend , Hegenbart Ute , Ho Anthony D. , Dreger Peter
Published: June 2011

Acute graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (SCT) and can be readily controlled by systemic high-dose steroids in many patients. However, patients whose GVHD is refractory to this therapy have a poor prognosis. Refractory patients have ongoing end-organ damage despite effective immunosuppression with second-line regimens, suggesting pathomechanisms independent from the initiating T-cell attack. To explore whether endothelial damage might contribute to GVHD refractoriness and to study the role of angiopoietin-2 (ANG2) in this process, we have compared kinetics of T-cell activation markers and markers of endothelial dysfunction in the serum of patients with sensitive (n = 23) and refractory GVHD (n = 25). Longitudinal measurements of soluble FAS ligand along with other immune markers demonstrate that refractory patients are not exposed to an overwhelming or unresponsive T-cell attack. However, in contrast to sensitive GVHD, refractory GVHD was associated with rising thrombomodulin levels and high ANG2/ vascular endothelial-derived growth factor ratios. Patients with refractory GVHD showed significantly increased ANG2 levels already before SCT. These results suggest that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD and opens new avenues for prediction and control of this devastating condition.
A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura
Authors: Scully Marie , McDonald Vickie , Cavenagh Jamie , Hunt Beverley J. , Longair Ian , Cohen Hannah , Machin Samuel J.
Published: June 2011

The safety and efficacy of weekly rituximab 375 mg/m2 (×4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n = 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 × 109/L and 38% > 150 × 109/L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P = .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P = .04), especially in whites, with a mean reduction of 7 days (P = .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P = .0011). There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713.
Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3
Authors: Lakshmikanthan Sribalaji , Sobczak Magdalena , Chun Changzoon , Henschel Angela , Dargatz Jillian , Ramchandran Ramani , Chrzanowska-Wodnicka Magdalena
Published: June 2011

Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin αvβ3. Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin αvβ3. These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs.
A single vaccination of commercial broilers does not reduce transmission of H5N1 highly pathogenic avian influenza
Authors: Poetri Okti , Bouma Annemarie , Claassen Ivo , Koch Guus , Soejoedono Retno , Stegeman Arjan , van Boven Michiel
Published: June 2011

Vaccination of chickens has become routine practice in Asian countries in which H5N1 highly pathogenic avian influenza (HPAI) is endemically present. This mainly applies to layer and breeder flocks, but broilers are usually left unvaccinated. Here we investigate whether vaccination is able to reduce HPAI H5N1 virus transmission among broiler chickens. Four sets of experiments were carried out, each consisting of 22 replicate trials containing a pair of birds. Experiments 1-3 were carried out with four-week-old birds that were unvaccinated, and vaccinated at day 1 or at day 10 of age. Experiment 4 was carried out with unvaccinated day-old broiler chicks. One chicken in each trial was inoculated with H5N1 HPAI virus. One chicken in each trial was inoculated with virus. The course of the infection chain was monitored by serological analysis, and by virus isolation performed on tracheal and cloacal swabs. The analyses were based on a stochastic SEIR model using a Bayesian inferential framework. When inoculation was carried out at the 28th day of life, transmission was efficient in unvaccinated birds, and in birds vaccinated at first or tenth day of life. In these experiments estimates of the latent period (~1.0 day), infectious period (~3.3 days), and transmission rate parameter (~1.4 per day) were similar, as were estimates of the reproduction number (~4) and generation interval (~1.4 day). Transmission was significantly less efficient in unvaccinated chickens when inoculation was carried out on the first day of life. These results show that vaccination of broiler chickens does not reduce transmission, and suggest that this may be due to the interference of maternal immunity.
Extensive production of Neospora caninum tissue cysts in a carnivorous marsupial succumbing to experimental neosporosis
Authors: King Jessica S , McAllan Bronwyn , Spielman Derek S , Lindsay Scott A , Hůrková-Hofmannová Lada , Hartigan Ashlie , Al-Qassab Sarwat E , Ellis John T , Šlapeta Jan
Published: June 2011

Experimental infections of Sminthopsis crassicaudata, the fat-tailed dunnart, a carnivorous marsupial widely distributed throughout the arid and semi-arid zones of Australia, show that this species can act as an intermediate host for Neospora caninum. In contrast to existing models that develop relatively few N. caninum tissue cysts, dunnarts offer a new animal model in which active neosporosis is dominated by tissue cyst production. The results provide evidence for a sylvatic life cycle of N. caninum in Australia between marsupials and wild dogs. It establishes the foundation for an investigation of the impact and costs of neosporosis to wildlife.
Binding Site Prediction for Protein-Protein Interactions and Novel Motif Discovery using Re-occurring Polypeptide Sequences
Authors: Amos-Binks Adam , Patulea Catalin , Pitre Sylvain , Schoenrock Andrew , Gui Yuan , Green James R , Golshani Ashkan , Dehne Frank
Published: June 2011

Background

While there are many methods for predicting protein-protein interaction, very few can determine the specific site of interaction on each protein. Characterization of the specific sequence regions mediating interaction (binding sites) is crucial for an understanding of cellular pathways. Experimental methods often report false binding sites due to experimental limitations, while computational methods tend to require data which is not available at the proteome-scale. Here we present PIPE-Sites, a novel method of protein specific binding site prediction based on pairs of re-occurring polypeptide sequences, which have been previously shown to accurately predict protein-protein interactions. PIPE-Sites operates at high specificity and requires only the sequences of query proteins and a database of known binary interactions with no binding site data, making it applicable to binding site prediction at the proteome-scale.

Results

PIPE-Sites was evaluated using a dataset of 265 yeast and 423 human interacting proteins pairs with experimentally-determined binding sites. We found that PIPE-Sites predictions were closer to the confirmed binding site than those of two existing binding site prediction methods based on domain-domain interactions, when applied to the same dataset. Finally, we applied PIPE-Sites to two datasets of 2347 yeast and 14,438 human novel interacting protein pairs predicted to interact with high confidence. An analysis of the predicted interaction sites revealed a number of protein subsequences which are highly re-occurring in binding sites and which may represent novel binding motifs.

Conclusions

PIPE-Sites is an accurate method for predicting protein binding sites and is applicable to the proteome-scale. Thus, PIPE-Sites could be useful for exhaustive analysis of protein binding patterns in whole proteomes as well as discovery of novel binding motifs. PIPE-Sites is available online at http://pipe-sites.cgmlab.org/.
The CDK9/Cyclin T1 subunits of P-TEFb in mouse oocytes and preimplantation embryos: A possible role in embryonic genome activation
Authors: Oqani Reza K , Kim Hong R , Diao Yun F , Park Chang S , Jin Dong I
Published: June 2011

Background

Two stages of genome activation have been identified in the mouse embryo. Specifically, minor transcriptional activation is evident at the one-cell stage and a second major episode of activation occurs at the two-cell stage. Nuclear translocation of RNA polymerase II and phosphorylation of the C-terminal domain (CTD) of the largest enzyme subunit are major determinants of embryonic genome activation. P-TEFb, the Pol II CTD kinase, regulates transcriptional elongation via phosphorylation of the serine 2 residues of the CTD.

Results

Here, we show that the CDK9 and cyclin T1 subunits of P-TEFb are present in mouse oocytes and preimplantation embryos. Both proteins translocate to pronuclei at the late one-cell stage and are predominantly localized in nuclei at the two-cell stage. We additionally examine the effects of the CDK9-specific inhibitor, flavopiridol, on mouse preimplantation development. Our data show that treatment with the drug results in mislocalization of CDK9, cyclin T1, and phosphorylated Pol II, as well as developmental arrest at the two-cell stage.

Conclusions

A change in CDK9 localization from the cytoplasm to the pronucleus occurs at the time of minor embryonic genome activation, and CDK9 accumulation at the two-cell stage is evident, concomitant with major transcriptional activation of the embryonic genome. Moreover, CDK9 inhibition triggers a developmental block at the two-cell stage. Our findings clearly indicate that CDK9 is essential for embryonic genome activation in the mouse.
A novel class of heat-responsive small RNAs derived from the chloroplast genome of Chinese cabbage (Brassica rapa)
Authors: Wang Lu , Yu Xiang , Wang Han , Lu Yi-Zhen , de Ruiter Marjo , Prins Marcel , He Yu-Ke
Published: June 2011

Background

Non-coding small RNAs play critical roles in various cellular processes in a wide spectrum of eukaryotic organisms. Their responses to abiotic stress have become a popular topic of economic and scientific importance in biological research. Several studies in recent years have reported a small number of non-coding small RNAs that map to chloroplast genomes. However, it remains uncertain whether small RNAs are generated from chloroplast genome and how they respond to environmental stress, such as high temperature. Chinese cabbage is an important vegetable crop, and heat stress usually causes great losses in yields and quality. Under heat stress, the leaves become etiolated due to the disruption and disassembly of chloroplasts. In an attempt to determine the heat-responsive small RNAs in chloroplast genome of Chinese cabbage, we carried out deep sequencing, using heat-treated samples, and analysed the proportion of small RNAs that were matched to chloroplast genome.

Results

Deep sequencing provided evidence that a novel subset of small RNAs were derived from the chloroplast genome of Chinese cabbage. The c hloroplast s mall RNAs (csRNAs) include those derived from mRNA, rRNA, tRNA and intergenic RNA. The rRNA-derived csRNAs were preferentially located at the 3'-ends of the rRNAs, while the tRNA-derived csRNAs were mainly located at 5'-termini of the tRNAs. After heat treatment, the abundance of csRNAs decreased in seedlings, except those of 24 nt in length. The novel heat-responsive csRNAs and their locations in the chloroplast were verified by Northern blotting. The regulation of some csRNAs to the putative target genes were identified by real-time PCR. Our results reveal that high temperature suppresses the production of some csRNAs, which have potential roles in transcriptional or post-transcriptional regulation.

Conclusions

In addition to nucleus, the chloroplast is another important organelle that generates a number of small RNAs. Many members of csRNA families are highly sensitive to heat stress. Some csRNAs respond to heat stress by silencing target genes. We suggest that proper temperature is important for production of chloroplast small RNAs, which are associated with plant resistance to abiotic stress.
Retraction Note: Molecular characterization of Legionella pneumophila-induced interleukin-8 expression in T cells
Authors: Takamatsu Reika , Teruya Hiromitsu , Takeshima Eriko , Ishikawa Chie , Matsumoto Kunihiro , Mukaida Naofumi , Li Jian-Dong , Heuner Klaus , Higa Futoshi , Fujita Jiro , Mori Naoki
Published: June 2011

Article Retracted
Retraction Note: NF-κB activation by Helicobacter pylorirequires Akt-mediated phosphorylation of p65
Authors: Takeshima Eriko , Tomimori Koh , Kawakami Hirochika , Ishikawa Chie , Sawada Shigeki , Tomita Mariko , Senba Masachika , Kinjo Fukunori , Mimuro Hitomi , Sasakawa Chihiro , Fujita Jiro , Mori Naoki
Published: June 2011

Article retracted
Premature ventricular contractions originating from the left ventricular septum: Results of Radiofrequency Catheter Ablation in twenty patients
Authors: Jia Li , Yue-Chun Li , Kang-Ting Ji , Na-Dan Zhou , Jia-Xuan Lin , Wen-Wu Zhang , Peng-Lin Yang , Ji-Fei Tang , Jia-Feng Lin
Published: June 2011

Background

RFCA has been established as an effective and curative therapy for severely symptomatic PVC from the outflow tract in structurally normal hearts. However, it is unknown whether PVCs originating from the left ventricular septum, are effectively eliminated by RFCA. This study aimed to investigate electrophysiologic characteristics and effects of Radiofrequency catheter ablation (RFCA) for patients with symptomatic premature ventricular contraction (PVC) originating from the left ventricular septum without including fascicular PVCs.

Methods

Characteristics of body surface electrocardiogram (ECG) and electrophysiologic recordings endocardiogram in a successful RFCA target were analyzed in 20 patients with symptomatic PVCs originating from the left ventricular septum. RFCA was performed using pace mapping and activation mapping.

Results

The QRS morphology of PVCs originating from the left ventricular septum is similar to that seen in fascicular tachycardia. Most of the PVCs originated from the left septum appears in the form of ventricular parasystole. The incidence of ventricular parasystole was 70%. Sustained ventricular tachycardia was not inducible by electrical stimulation and isoproterenol infusion in all 20 patients, ablation at the site recording the earliest Purkinje potential was not effective in all 20 patients, and Purkinje potentials were not identified at successful sites during point mapping. Sixteen patients were successful with RFCA using pace mapping and activation mapping, 3 failed, and 1 recurrent.

Conclusion

Although the ECG characteristics of the PVCs arising from the left ventricular septum are similar to that seen in fascicular tachycardia, the electrophysiologic characteristics are different between the two types of PVCs. The distinguishing characteristic of the PVCs is that Purkinje potentials were not present at the site of successful ablation, suggesting a myocardial as opposed to fascicular substrate. RFCA is an effective curative therapy for symptomatic PVCs originating from the left ventricular septum (not from the left anterior and posterior fascicle).
Untapped ethical resources for neurodegeneration research
Authors: Robillard Julie M , Federico Carole A , Tairyan Kate , Ivinson Adrian J , Illes Judy
Published: June 2011

Background

The research community has a mandate to discover effective treatments for neurodegenerative disorders. The ethics landscape surrounding this mandate is in a constant state of flux, and ongoing challenges place ever greater demands on investigators to be accountable to the public and to answer questions about the implications of their work for health care, society, and policy.

Methods

We surveyed US-based investigators involved in neurodegenerative diseases research about how they value ethics-related issues, what motivates them to give consideration to those issues, and the barriers to doing so. Using the NIH CRISP database we identified 1,034 researchers with relevant, active grants and invited them to complete an online questionnaire. We received 193 responses. We used exploratory factor analysis to transform individual survey questions into a smaller set of factors, and linear regression to understand the effect of key variables of interest on the factor scores.

Results

Ethics-related issues clustered into two groups: research ethics and external influences. Heads of research groups viewed issues of research ethics to be more important than the other respondents. Concern about external influences was related to overall interest in ethics. Motivators clustered into five groups: ensuring public understanding, external forces, requirements, values, and press and public. Heads of research groups were more motivated to ensure public understanding of research than the other respondents. Barriers clustered into four groups: lack of resources, administrative burden, relevance to the research, and lack of interest. Perceived lack of ethics resources was a particular barrier for investigators working in drug discovery.

Conclusions

The data suggest that senior level neuroscientists working in the field of neurodegeneration (ND), and drug discovery specifically, are motivated to consider ethics issues related to their work, but the perceived lack of ethics resources thwarts their efforts. With bioethics centres at more than 50% of the institutions at which these respondents reside, the neuroscience and bioethics communities appear to be disconnected. Dedicated ethical, legal and social implications (ELSI) programs, such as those fully integrated into genetics and regenerative medicine, provide models for achieving meaningful partnerships not yet adequately realized for scholars and trainees interested in drug discovery for ND.
Two-tier charging in Maputo Central Hospital: Costs, revenues and effects on equity of access to hospital services
Authors: McPake Barbara , Hongoro Charles , Russo Giuliano
Published: June 2011

Background

Special services within public hospitals are becoming increasingly common in low and middle income countries with the stated objective of providing higher comfort services to affluent customers and generating resources for under funded hospitals. In the present study expenditures, outputs and costs are analysed for the Maputo Central Hospital and its Special Clinic with the objective of identifying net resource flows between a system operating two-tier charging, and, ultimately, understanding whether public hospitals can somehow benefit from running Special Clinic operations.

Methods

A combination of step-down and bottom-up costing strategies were used to calculate recurrent as well as capital expenses, apportion them to identified cost centres and link costs to selected output measures.

Results

The results show that cost differences between main hospital and clinic are marked and significant, with the Special Clinic's cost per patient and cost per outpatient visit respectively over four times and over thirteen times their equivalent in the main hospital.

Discussion

While the main hospital cost structure appeared in line with those from similar studies, salary expenditures were found to drive costs in the Special Clinic (73% of total), where capital and drug costs were surprisingly low (2 and 4% respectively). We attributed low capital and drug costs to underestimation by our study owing to difficulties in attributing the use of shared resources and to the Special Clinic's outsourcing policy. The large staff expenditure would be explained by higher physician time commitment, economic rents and subsidies to hospital staff. On the whole it was observed that: (a) the flow of capital and human resources was not fully captured by the financial systems in place and stayed largely unaccounted for; (b) because of the little consideration given to capital costs, the main hospital is more likely to be subsidising its Special Clinic operations, rather than the other way around.

Conclusion

We conclude that the observed lack of transparency may create scope for an inequitable cross subsidy of private customers by public resources.
Focal Laser Ablation of Prostate Cancer: Numerical Simulation of Temperature and Damage Distribution
Authors: Marqa Mohamad-Feras , Colin Pierre , Nevoux Pierre , Mordon Serge R , Betrouni Nacim
Published: June 2011

Background

The use of minimally invasive ablative techniques in the management of patients with low grade and localized prostate tumours could represent a treatment option between active surveillance and radical therapy. Focal laser ablation (FLA) could be one of these treatment modalities. Dosimetry planning and conformation of the treated area to the tumor remain major issues, especially when, several fibers are required. An effective method to perform pre-treatment planning of this therapy is computer simulation. In this study we present an in vivo validation of a mathematical model.

Methods

The simulation model is based on finite elements method (FEM) to solve the bio-heat and the thermal damage equations. Laser irradiation was performed with a 980 nm laser diode system (5 W, 75 s). Light was transmitted using a cylindrical diffusing fiber inserted inside a preclinical animal prostate cancer model induced in Copenhagen rats. Non-enhanced T2-weighted and dynamic gadolinium-enhanced T1-weighted MR imaging examinations were performed at baseline and 48 hours after the procedure. The model was validated by comparing the simulated necrosis volume to the results obtained in vivo on (MRI) and by histological analysis. 3 iso-damage temperatures were considered 43° C, 45° C and 50° C.

Results

The mean volume of the tissue necrosis, estimated from the histological analyses was 0.974 ± 0.059 cc and 0.98 ± 0.052 cc on the 48 h MR images. For the simulation model, volumes were: 1.38 cc when T = 43° C, 1.1 cc for T = 45°C and 0.99 cc when T = 50 C°.

Conclusions

In this study, a clear correlation was established between simulation and in vivo experiments of FLA for prostate cancer.

Simulation is a promising planning technique for this therapy. It needs further more evaluation to allow to FLA to become a widely applied surgical method.
FLIP (Flice-like inhibitory protein) suppresses cytoplasmic double-stranded-RNA-induced apoptosis and NF-κB and IRF3-mediated signaling
Authors: Handa Priya , Tupper Joan C , Jordan Katherine C , Harlan John M
Published: June 2011

Background

Cytoplasmic viral double-stranded RNA (dsRNA) is detected by a class of ubiquitous cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen-5 (MDA5), which initiate a signaling cascade via their common adaptor called interferon-β (IFN-β) promoter stimulator-1 (IPS-1). This leads to the production of proinflammatory and antiviral cytokines, the type I Interferons, via mainly nuclear factor kappa B (NF-κB) and interferon response factor-3 (IRF3) transcription factors. Fas-associated death domain (FADD) protein, receptor-interacting protein (RIP1), caspase-8 and tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) protein, all traditionally associated with death receptor signaling, are also involved in RIG-I/MDA5 signaling pathway. We previously showed that FLIP (Flice-like inhibitory protein), also designated as cflar (CASP8 and FADD-like apoptosis regulator), negatively regulates lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling in endothelial cells and mouse embryonic fibroblasts (MEFs) and protected against TLR4-mediated apoptosis.

Results

In this study, we investigated the role of FLIP in cellular response to cytoplasmic polyinosinic:polycytidylic acid, poly(I:C), a synthetic analog of dsRNA. C onsistent with the previously described role of FADD in RIG-I/MDA5-mediated apoptosis, we found that FLIP-/- MEFs were more susceptible to killing by cytoplasmic poly(I:C). However, FLIP-/- MEFs also exhibited markedly increased expression of NF-κB-and IRF3- dependent genes in response to cytoplasmic poly(I:C). Importantly, reconstitution of FLIP in FLIP-/-MEFs reversed the hyper-activation of IRF3- and NF-κB-mediated gene expression. Further, we found that caspase-8 catalytic activity was not required for cytoplasmic poly(I:C)-mediated NF-κB and IRF3 signaling.

Conclusions

These results provide evidence for a crucial dual role for FLIP in antiviral responses to cytoplasmic dsRNA: it protects from cytoplasmic dsRNA-mediated cell death while down-regulating IRF3-and NF-κB-mediated gene expression. Since the pathogenesis of several viral infections involves a heightened and dysregulated cytokine response, a possible therapy could involve modulating FLIP levels.
Nanoscale surface modifications to control capillary flow characteristics in PMMA microfluidic devices
Authors: Mukhopadhyay Subhadeep , Roy Susanta S , D'Sa Raechelle A , Mathur Ashish , Holmes Richard J , McLaughlin James A
Published: June 2011

Polymethylmethacrylate (PMMA) microfluidic devices have been fabricated using a hot embossing technique to incorporate micro-pillar features on the bottom wall of the device which when combined with either a plasma treatment or the coating of a diamond-like carbon (DLC) film presents a range of surface modification profiles. Experimental results presented in detail the surface modifications in the form of distinct changes in the static water contact angle across a range from 44.3 to 81.2 when compared to pristine PMMA surfaces. Additionally, capillary flow of water (dyed to aid visualization) through the microfluidic devices was recorded and analyzed to provide comparison data between filling time of a microfluidic chamber and surface modification characteristics, including the effects of surface energy and surface roughness on the microfluidic flow. We have experimentally demonstrated that fluid flow and thus filling time for the microfluidic device was significantly faster for the device with surface modifications that resulted in a lower static contact angle, and also that the incorporation of micro-pillars into a fluidic device increases the filling time when compared to comparative devices.
Distinct different expression of Th17 and Th9 cells in coxsackie virus B3-induced mice viral myocarditis
Authors: Qing Kong , Weifeng Wu , Fan Yang , Yuluan Yan , Yu Pang , Yanlan Huang
Published: June 2011

Background

Recently, a new subset of CD4+T helper(Th) cell that predominantly secret cytokine interleukin-9(IL-9) is identified, termed Th9 cell. It has been reported to participate in tissue inflammation and autoimmune responses, and induce disease which differed from Th17 cells. Th17 cells have been shown to play a critical role in viral myocarditis (VMC), but whether Th9 cells are involved in the pathogenesis of VMC remains unclear.

Results

BALB/c mice were intraperitoneally (i.p) injected with coxsackie virus B3(CVB3) for establishing VMC models. Control mice were treated with phosphate-buffered saline i.p. On day 0,7,14,21,28,35,42 after injection, myocardial histopathological changes were evaluated by hematoxylin-eosin staining. Splenic Th17 and Th9 cells subsets were analyzed by flow cytometry. And cardiac IL-17, IL-9 mRNA were measured by semi-quantitative reverse transcription-PCR and nested PCR, respectively. Results showed the levels of Th17 cells and IL-17 mRNA obviously increased in VMC mice on 7 day after infection, peaked on day 28, and highly persisted to at least day 42 (p < 0.05). While the frequencies of Th9 cells and IL-9 mRNA showed no significant difference between VMC and control group throughout the course of the experiment(p > 0.05).

Conclusions

It was differentiated Th17 but not Th9 cells significantly elevated in the development of CVB3-induced VMC. The microenvironment of VMC seemed to contribute to the differentiation and proliferation of Th17 rather than Th9 cells. Our preliminary data implied Th9 cells could not protect against VMC nor promote the disease.
Oncogenic potential of Human Papillomavirus (HPV) and its relation with cervical cancer
Authors: Faridi Rabia , Zahra Amreen , Khan Khalida , Idrees Muhammad
Published: June 2011

Human Papillomavirus (HPV) is the most common cause of cervical cancer. Cervical cancer being the second most common cancer after lung cancer, affecting women of different age groups; has a prevalence of about 20% in young sexually active women. Among different types of HPV, HPV16 the major strain causing this cancer and is sexually transmitted had been unnoticed for decades. Keeping in mind the multiple risk factors related with cervical cancer such as early age sexual activities, teenage pregnancies, smoking, use of oral contraceptives, having multiple sex partners, hormone replacement therapies and various other unknown factors lead to the onset of the disease. Awareness for various diagnostic procedures such as Pap smears screening prove to be an effective way in eradicating the oncogenic potential of HPV.
Elevated IL-6 Receptor Expression on CD4+ T Cells contributes to the increased Th17 Responses in patients with Chronic Hepatitis B
Authors: Zhang Fan , Yao Simin , Yuan Jing , Zhang Mingxia , He Qing , Yang Guilin , Gao Zhiliang , Liu Hong , Chen Xinchun , Zhou Boping
Published: June 2011

Background

Increased numbers of Interleukin-17-producing CD4+T cells (Th17) have been found in association with hepatitis B virus (HBV)-induced liver injury. However, the mechanism underlying the increase of Th17 responses in patients with HBV infection remains unclear. In this study, we investigate the possible regulatory mechanisms of increased Th17 responses in patients with chronic hepatitis B(CHB).

Methods

Th17 response and IL-6R expression on CD4+T cells in peripheral blood samples were determined by flow cytometry. Cytokines TGF-β, IL-1β, IL-6 and IL-17 in plasma and/or supernatant samples were determined by ELISA and the IL-17 and IL-6R mRNA levels were quantified by quantitative real-time reverse polymerase chain reaction.

Results

All these data indicated that the frequency of periphery Th17 cells is significantly correlated with the percentage of CD4+T cells expressing IL-6R in CHB patients. CD4+T cells from patients with CHB, but not those from healthy donors, produced higher levels of IL-17 and had more IL-6R expression upon stimulation with the HBV core antigen (HBcAg) in vitro. The PMA/ionomycin and HBcAg -stimulated up-regulation of IL-17 production by CD4+T cells could be reversed by a neutralizing antibody against IL-6R.

Conclusion

we showed that enhancement of IL-6R expression on CD4+T cells upon HBV infection contributes to increased Th17 response in patients with CHB.
Two-step intensity modulated arc therapy (2-step IMAT) with segment weight and width optimization
Authors: Sun Jidi , Chew Theam Yong , Meyer Juergen
Published: June 2011

Background

2-step intensity modulated arc therapy (IMAT) is a simplified IMAT technique which delivers the treatment over typically two continuous gantry rotations. The aim of this work was to implement the technique into a computerized treatment planning system and to develop an approach to optimize the segment weights and widths.

Methods

2-step IMAT was implemented into the Prism treatment planning system. A graphical user interface was developed to generate the plan segments automatically based on the anatomy in the beam's-eye-view. The segment weights and widths of 2-step IMAT plans were subsequently determined in Matlab using a dose-volume based optimization process. The implementation was tested on a geometric phantom with a horseshoe shaped target volume and then applied to a clinical paraspinal tumour case.

Results

The phantom study verified the correctness of the implementation and showed a considerable improvement over a non-modulated arc. Further improvements in the target dose uniformity after the optimization of 2-step IMAT plans were observed for both the phantom and clinical cases. For the clinical case, optimizing the segment weights and widths reduced the maximum dose from 114% of the prescribed dose to 107% and increased the minimum dose from 87% to 97%. This resulted in an improvement in the homogeneity index of the target dose for the clinical case from 1.31 to 1.11. Additionally, the high dose volume V105 was reduced from 57% to 7% while the maximum dose in the organ-at-risk was decreased by 2%.

Conclusions

The intuitive and automatic planning process implemented in this study increases the prospect of the practical use of 2-step IMAT. This work has shown that 2-step IMAT is a viable technique able to achieve highly conformal plans for concave target volumes with the optimization of the segment weights and widths. Future work will include planning comparisons of the 2-step IMAT implementation with fixed gantry intensity modulated radiotherapy (IMRT) and commercial IMAT implementations.
A new cultivation method for microbial oil production: cell pelletization and lipid accumulation by Mucor circinelloides
Authors: Xia Chunjie , Zhang Jianguo , Zhang Weidong , Hu Bo
Published: June 2011

The recent energy crisis has triggered significant attention on the microbial synthesis of lipids, which comprise the raw material for biodiesel production. Microbial oil accumulation with filamentous fungi has great potential because filamentous fungi can form pellets during cell growth, and these pellets are much easier to harvest from cell broth. This paper focuses on the cell pelletization process of the oleaginous Mucor circinelloides. We have studied the effect of various cultural conditions on pelletized cell growth and lipid accumulation. This study is the first to report that pH adjustment during cell growth plays a key role in pellet formation of M. circinelloides and describes a handy method by which to induce cell pelletization in submerged fungal cultivation. Our study reveals that cell growth and lipid production are not significantly affected by pelletization and that lipid accumulation is triggered at stressed conditions, such as a high carbon-to-nitrogen ratio and high temperature.
mRNA binding protein staufen 1-dependent regulation of pyramidal cell spine morphology via NMDA receptor-mediated synaptic plasticity
Authors: Lebeau Geneviève , DesGroseillers Luc , Sossin Wayne , Lacaille Jean-Claude
Published: June 2011

Staufens (Stau) are RNA-binding proteins involved in mRNA transport, localization, decay and translational control. The Staufen 1 (Stau1) isoform was recently identified as necessary for the protein synthesis-dependent late phase long-term potentiation (late-LTP) and for the maintenance of mature dendritic spines and synaptic activity in hippocampal CA1 pyramidal cells, strongly suggesting a role of mRNA regulation by Stau1 in these processes. However, the causal relationship between these impairments in synaptic function (spine shape and basal synaptic activity) and plasticity (late-LTP) remains unclear. Here, we determine that the effects of Stau1 knockdown on spine shape and size are mimicked by blocking NMDA receptors (or elevating extracellular Mg2+) and that Stau1 knockdown in the presence of NMDA receptor blockade (or high Mg2+) has no further effect on spine shape and size. Moreover, the effect of Stau1 knockdown on late-LTP cannot be explained by these effects, since when tested in normal medium, slice cultures that had been treated with high Mg2+ (to impair NMDA receptor function) in combination with a control siRNA still exhibited late-LTP, while siRNA to Stau1 was still effective in blocking late-LTP. Our results indicate that Stau1 involvement in spine morphogenesis is dependent on ongoing NMDA receptor-mediated plasticity, but its effects on late-LTP are independent of these changes. These findings clarify the role of Stau1-dependent mRNA regulation in physiological and morphological changes underlying long-term synaptic plasticity in pyramidal cells.
Certified reduced basis approximation for parametrized partial differential equations and applications
Authors: Quarteroni Alfio , Rozza Gianluigi , Manzoni Andrea
Published: June 2011

Reduction strategies, such as model order reduction (MOR) or reduced basis (RB) methods, in scientific computing may become crucial in applications of increasing complexity. In this paper we review the reduced basis methods (built upon a high-fidelity ‘truth’ finite element approximation) for a rapid and reliable approximation of parametrized partial differential equations, and comment on their potential impact on applications of industrial interest. The essential ingredients of RB methodology are: a Galerkin projection onto a low-dimensional space of basis functions properly selected, an affine parametric dependence enabling to perform a competitive Offline-Online splitting in the computational procedure, and a rigorousa posteriorierror estimation used for both the basis selection and the certification of the solution. The combination of these three factors yields substantial computational savings which are at the basis of an efficient model order reduction, ideally suited for real-time simulation and many-query contexts (for example, optimization, control or parameter identification). After a brief excursus on the methodology, we focus on linear elliptic and parabolic problems, discussing some extensions to more general classes of problems and several perspectives of the ongoing research. We present some results from applications dealing with heat and mass transfer, conduction-convection phenomena, and thermal treatments.
A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome
Authors: Hodgson Carol L , Tuxen David V , Davies Andrew R , Bailey Michael J , Higgins Alisa M , Holland Anne E , Keating Jenny L , Pilcher David V , Westbrook Andrew J , Cooper David J , Nichol Alistair D
Published: June 2011

Introduction

Tidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration.

Method

Twenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined.

Results

There were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups.

Conclusions

This open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted.

Trial registration

ACTRN12607000465459