bluuebunny/crossref_metadata_2025 huggingface dataset:
Coinfection withRickettsia helveticaand Herpes Simplex Virus 2 in a Young Woman with Meningoencephalitis
Authors: Nilsson Kenneth , Wallménius Katarina , Påhlson Carl
Published: October 2011

Herpes virus type 2 DNA was detected by PCR in the cerebrospinal fluid in a young woman presenting with headache, stiff neck and pleocytosis, and serological findings consistent with reactivation. Since she was exposed to ticks, Lyme disease and tick-borne encephalitis were excluded. Further investigation in an ongoing project, using PCR and sequencing of the amplified products, showed the presence ofRickettsia helveticain the cerebrospinal fluid. The bacteria were also isolated in Vero cell culture, and microimmunofluorescence confirmed the development of antibodies againstRickettsiaspp. with predominance of IgM reactivity consistent with recent infection. She was treated with antibiotics and improved rapidly. The patient could easily have been judged to have isolated herpes meningitis. Because Sweden and other European countries are endemic areas for rickettsioses, the paper reaffirms the importance of investigating for the presence of rickettsial infections in endemic areas in cases of meningitis of uncertain aetiology.
Methaemoglobinemia Induced by MDMA?
Authors: Verhaert L. L. W.
Published: October 2011

Case. A 45-year-old man with a blank medical history presented at the emergency room with dizziness and cyanosis. Physical examination showed cyanosis with a peripheral saturation (SpO2) of 85%, he did not respond to supplemental oxygen. Arterial blood gas analysis showed a striking chocolate brown colour. Based on these data, we determined the arterial methaemoglobin concentration. This was 32%. We gave 100% oxygen and observed the patient in a medium care unit. The next day, patient could be discharged in good condition. Further inquiry about exhibitions and extensive history revealed that the patient used MDMA (3,4- methylenedioxymethamphetamine, the active ingredient of ecstasy).Conclusion. Acquired methaemoglobinemia is a condition that occurs infrequently, but is potentially life threatening. Different nutrients, medications, and chemicals can induce methaemoglobinemia by oxidation of haemoglobin. The clinical presentation of a patient with methaemoglobinemia is due to the impossibility of O2binding and transport, resulting in tissue hypoxia. Important is to think about methaemoglobin in a patient who presents with cyanosis, a peripheral saturation of 85% that fails to respond properly to the administration of O2. Because methaemoglobin can be reduced physiologically, it is usually sufficient to remove the causative agent, to give O2, and to observe the patient.
Cyclin-Dependent Kinase 5/p35/p39: A Novel and Imminent Therapeutic Target for Diabetes Mellitus
Authors: Ahmed Danish , Sharma Manju
Published: October 2011

Present therapies to minify hyperglycaemia and insulin resistance mainly target ATP-sensitive K+channels () of pancreatic cells and PPAR-γto enhance the insulin secretion and potential for GLUT expression, respectively. These current approaches are frequently associated with the various side effects such as hypoglycaemia and cardiovascular adverse events. CDK5 is a serine/threonine protein kinase, which forms active complexes with p35 or p39 found principally in neurons and in pancreaticβcells. Pieces of evidence from recent studies recommend the vital role of CDK5 in physiological functions in nonneuronal cells such as glucose-stimulated insulin secretion in pancreatic cells. Inhibition of CDK5 averts the decrease of insulin gene expression through the inhibition of nuclear translocation of PDX-1 which is a transcription factor for the insulin gene. The present pieces of evidence designate that CDK5 might be a potential drug target for the regulation of glucose-stimulated insulin secretion in the treatment of diabetes mellitus.
Timing of Colonization of Caries-Producing Bacteria: An Approach Based on Studying Monozygotic Twin Pairs
Authors: Bockmann Michelle R. , Harris Abbe V. , Bennett Corinna N. , Odeh Ruba , Hughes Toby E. , Townsend Grant C.
Published: October 2011

Findings are presented from a prospective cohort study of timing of primary tooth emergence and timing of oral colonization ofStreptococcus mutans(S. mutans) in Australian twins. The paper focuses on differences in colonization timing in genetically identical monozygotic (MZ) twins. Timing of tooth emergence was based on parental report. Colonization timing ofS. mutanswere established by plating samples of plaque and saliva on selective media at 3 monthly intervals and assessing colony morphology. In 25% of individuals colonization occurred prior to emergence of the first tooth. A significant proportion of MZ pairs (21%) was discordant for colonization occurring before or after first tooth emergence, suggesting a role of environmental or epigenetic factors in timing of tooth emergence, colonization byS. mutans, or both. These findings and further application of the MZ co-twin model should assist in development of strategies to prevent or delay infection withS. mutansin children.
ObliqueCorpectomyto Manage Cervical Myeloradiculopathy
Authors: Salvatore Chibbaro , Orphee Makiese , Damien Bresson , Alisha Reiss , Pavel Poczos , Bernard George
Published: October 2011

Background. The authors describe a lateral approach to the cervical spine for the management of spondylotic myeloradiculopathy. The rationale for this approach and surgical technique are discussed, as well as the advantages, disadvantages, complications, and pitfalls based on the author's experience over the last two decades.Methods. Spondylotic myelo-radiculopathy may be treated via a lateral approach to the cervical spine when there is predominant anterior compression associated with either spine straightening or kyphosis, but without vertebral instability.Results. By using a lateral approach, the lateral aspect of the cervical spine and the vertebral artery are easily reached and visualized. Furthermore, the lateral part of the affected intervertebral disc(s), uncovertebral joint(s), vertebral body(ies), and posterior longitudinal ligament can be removed as needed to decompress nerve root(s) and/or the spinal cord.Conclusion. Multilevel cervical oblique corpectomy and/or lateral foraminotomy allow wide decompression of nervous structures, while maintaining optimal stability and physiological motion of the cervical spine.
Lunar Tractive Forces and Renal Stone Incidence
Authors: Arampatzis Spyridon , Thalmann George N. , Zimmermann Heinz , Exadaktylos Aristomenis K.
Published: October 2011

Background.Several factors are implicated in renal stone formation and peak incidence of renal colic admissions to emergency departments (ED). Little is known about the influence of potential environmental triggers such as lunar gravitational forces. We conducted a retrospective study to test the hypothesis that the incidence of symptomatic renal colics increases at the time of the full and new moon because of increased lunar gravitational forces.Methods.We analysed 1500 patients who attended our ED between 2000 and 2010 because of nephrolithiasis-induced renal colic. The lunar phases were defined as full moon ± 1 day, new moon ± 1 day, and the days in-between as “normal” days.Results.During this 11-year period, 156 cases of acute nephrolithiasis were diagnosed at the time of a full moon and 146 at the time of a new moon (mean of 0.4 per day for both). 1198 cases were diagnosed on “normal” days (mean 0.4 per day). The incidence of nephrolithiasis in peak and other lunar gravitational phases, the circannual variation and the gender-specific analysis showed no statistically significant differences.Conclusion.In this adequate powered longitudinal study, changes in tractive force during the different lunar phases did not influence the incidence of renal colic admissions in emergency department.
A New Efficient Ordering Scheme for Sphere Detection
Authors: Haiyan Cao , Jun Li
Published: October 2011

The decoding order has a deep impact in the complexity of sphere detection. A new ordering scheme for sphere detection is presented in this paper, which is based on SIC (serial interference canceling) and the gradient defined by the accumulated probability of the absolute difference between symbol element and the zero-forcing solution. The simulation results show that the proposed ordering scheme can achieve a significant complexity reduction, especially for high numbers of antennas and large constellation sizes in the low SNR region. Compared with sphere detection complexity under BSQR (balanced sorted QR) decomposition and GB (gradient-based) orderings atSNR=5 dB, the average number of visited nodes under our proposed ordering is reduced by almost 30% and 33% in4×416QAM system and by almost 30% and 50% reduction in6×616QAM system, respectively. For4×464QAM system, almost 75% and 80% reduction atSNR=0 dBand more than 40% and 50% reduction atSNR=5 dBcan be achieved, respectively.
On the Generalized Weighted Lebesgue Spaces of Locally Compact Groups
Authors: Akbarbaglu I. , Maghsoudi S.
Published: October 2011

Let G be a locally compact group with a fixed left Haar measure λ and Ω be a system of weights on G. In this paper, we deal with locally convex space Lp(G, Ω) equipped with the locally convex topology generated by the family of norms . We study various algebraic and topological properties of the locally convex space Lp(G, Ω). In particular, we characterize its dual space and show that it is a semireflexive space. Finally, we give some conditions under which Lp(G, Ω) with the convolution multiplication is a topological algebra and then characterize its closed ideals and its spectrum.
DNA Damage Response is Prominent in Ovarian High-Grade Serous Carcinomas, Especially Those with Rsf-1 (HBXAP) Overexpression
Authors: Kshirsagar Malti , Jiang Wei , Shih Ie-Ming
Published: October 2011

DNA damage commonly occurs in cancer cells as a result of endogenous and tumor microenvironmental stress. In this study, we applied immunohistochemistry to study the expression of phosphorylated Chk2 (pChk2), a surrogate marker of the DNA damage response, in high grade and low grade of ovarian serous carcinoma. A phospho-specific antibody specific for threonine 68 of Chk2 was used for immunohistochemistry on a total of 292 ovarian carcinoma tissues including 250 high-grade and 42 low-grade serous carcinomas. Immunostaining intensity was correlated with clinicopathological features. We found that there was a significant correlation between pChk2 immunostaining intensity and percentage of pChk2 positive cells in tumors and demonstrated that high-grade serous carcinomas expressed an elevated level of pChk2 as compared to low-grade serous carcinomas. Normal ovarian, fallopian tube, ovarian cyst, and serous borderline tumors did not show detectable pChk2 immunoreactivity. There was no significant difference in pChk2 immunoreactivity between primary and recurrent high-grade serous carcinomas. In high-grade serous carcinomas, a significant correlation (P<0.0001) in expression level (both in intensity and percentage) was found between pChk2 and Rsf-1 (HBXAP), a gene involved in chromatin remodeling that is amplified in high-grade serous carcinoma. Our results suggest that the DNA damage response is common in high-grade ovarian serous carcinomas, especially those with Rsf-1 overexpression, suggesting that Rsf-1 may be associated with DNA damage response in high-grade serous carcinomas.
Immune Aspects and Myometrial Actions of Progesterone and CRH in Labor
Authors: Vrachnis Nikolaos , Malamas Fotodotis M. , Sifakis Stavros , Tsikouras Panayiotis , Iliodromiti Zoe
Published: October 2011

Progesterone and corticotropin-releasing hormone (CRH) have a critical role in pregnancy and labor, as changes related to these hormones are crucial for the transition from myometrial quiescence to contractility. The mechanisms related to their effect differ between humans and other species, thus, despite extensive research, many questions remain to be answered regarding their mediation in human labor. Immune responses to progesterone and CRH are important for labor. Progesterone acts as an immunomodulator which controls many immune actions during pregnancy, and its withdrawal releases the inhibitory action on inflammatory pathways. In humans, a “functional” progesterone withdrawal occurs with onset of labor through changes in progesterone metabolism, progesterone receptors, and other molecules that either facilitate or antagonize progesterone function. Placental CRH acts on the fetal pituitary-adrenal axis to stimulate adrenal production of androgens and cortisol and also acts directly on myometrial cells via its receptors. CRH also affects inflammatory signals and vice versa. Interactions between progesterone and CRH additionally occur during labor. We describe the role of these two hormones in human myometrium and their interactions with the immune system during labor.
Important Role of Caspase-8 for Chemosensitivity of ALL Cells
Authors: Ehrhardt Harald , Wachter Franziska , Maurer Martina , Stahnke Karsten , Jeremias Irmela
Published: October 2011

Purpose: Sensitivity of tumor cells toward chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemosensitivity remain poorly understood. Here, we aimed at characterizing the role of caspase-8 for chemosensitivity of B- and T-ALL cells.

Experimental Design: Primary tumor cells from children with ALL were evaluated for expression levels of the caspase-8 protein, were amplified in nonobese diabetic/severe combined immunodeficient mice, transfected with siRNA, and evaluated for their chemosensitivity in vitro.

Results: Effective cell death in B- and T-ALL cells depended on the presence of caspase-8 for the majority of cytotoxic drugs routinely used in antileukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of caspase-8 protein correlated with cell death sensitivity toward defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells, with low expression of caspase-8, methotrexate (MTX) upregulated the expression of caspase-8 mediated by the transcription factor p53, suggesting epigenetic silencing of caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving MTX depended on the presence of caspase-8.

Conclusion: Our results indicate that caspase-8 is crucial for the high antileukemic efficiency of numerous routine cytotoxic drugs. Reexpression of epigenetically downregulated caspase-8 represents a promising approach to increase efficiency of antileukemic therapy. Clin Cancer Res; 17(24); 7605–13. ©2011 AACR.
Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells
Authors: Azad Arun , Jackson Susan , Cullinane Carleen , Natoli Anthony , Neilsen Paul M. , Callen David F. , Maira Sauveur-Michel , Hackl Wolfgang , McArthur Grant A. , Solomon Benjamin
Published: October 2011

DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-galactosidase staining, G2–M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res; 9(12); 1696–707. ©2011 AACR.
Nuclear Receptor LXR as a Novel Therapeutic Antitumoral Target in Glioblastoma
Authors: Moschetta Antonio
Published: October 2011

Both primary and transformed cells need cholesterol for their growth. Guo and colleagues unraveled the connection between epidermal growth factor receptor mutations in glioblastoma and increased cholesterol influx via sterol regulatory element-binding protein 1 and low-density lipoprotein receptor (LDLR) increase. They propose the activation of the liver X receptor–inducible degrader of LDLR–LDLR axis as a therapeutic approach to reduce intracellular cholesterol, block tumor growth, and induce cell death. Cancer Discovery; 1(5): 381–2. ©2011 AACR.

Commentary on Guo et al., p. 442.
Blockade of Mineralocorticoid and Glucocorticoid Receptors Reverses Stress-Induced Motor Impairments
Authors: Jadavji Nafisa M. , Supina Rebecca D. , Metz Gerlinde A.
Published: October 2011

Aim: Stress and glucocorticoids can influence movement performance and pathologies of the motor system. The classic notion assumes that the glucocorticoid receptor (GR) mediates the majority of stress-induced behavioral changes. Nevertheless, recent findings have attributed a more prominent role to the mineralocorticoid receptor (MR) in modulating behavior. The purpose of this study was to dissociate the impact of MR versus GR activation in movement and stress-associated motor disruption. Methods: Groups of male and female rats were tested in skilled reaching and open field behavior and treated peri-orally with either agonists or antagonists for MR and GR, respectively. Results: Selective acute activation of MR (aldosterone) and GR (dexamethasone) decreased movement success with a magnitude similar to stress-induced impairment in male and female animals. By contrast, antagonist treatment to block MR (RU-28318) or GR (Mifepristone, RU-486) prevented motor impairments caused by acute restraint stress or corticosterone treatment. Moreover, both antagonists reversed chronic stress- and glucocorticoid-induced motor impairments to values comparable to baseline levels. Higher success rates in treated animals were accompanied by improved performance of skilled limb movements. In addition, combined treatment with MR and GR antagonists had additive benefit on aim and advance towards the reaching target. Conclusion: These observations suggest that MR or GR equally influence motor system function with partially synergistic effects. Males and females show comparable responses to MR and GR activation or blockade. The need for balanced activation of MRs and GRs in motor control requires consideration in intervention strategies to improve performance in health and disease.
Inferior Survival of Advanced Pancreatic Cancer Patients Who Received Gemcitabine-Based Chemotherapy but Did Not Participate in Clinical Trials
Authors: Yang Shih-Hung , Kuo Yu-Hsuan , Tien Yu-Wen , Hsu Chiun , Hsu Chih-Hung , Kuo Sung-Hsin , Cheng Ann-Lii
Published: October 2011

Background: Advanced pancreatic cancer, even when treated, is highly lethal. The best choice of gemcitabine-based therapy and the prognostic factors affecting the success of treatment remain uncertain. Methods: We identified 159 of 1,475 patients with pancreatic cancer diagnosed in our institution and receiving gemcitabine-based chemotherapy between January 1995 and June 2007. Univariate and multivariate analyses were used to evaluate the prognostic significance of various clinical parameters for overall survival (OS). Results: The median survival after gemcitabine-based therapy was 5.4 months; 89.9% (n = 143) had ductal adenocarcinoma, 55.3% (n = 88) with stage IV. Gemcitabine alone was given to 60 (38%) patients, and gemcitabine with high-dose infusional fluorouracil (5-FU) with (n = 25) or without (n = 39) oxaliplatin was given to 64 (40%) patients. All regimens correlated with OS (p = 0.042) but not with the response rate (RR; p = 0.3). The overall RR was 11.1%, and all responders had a good performance status (PS). The RRs to gemcitabine with infusional 5-FU, and gemcitabine with oxaliplatin and infusional 5-FU were 5.3 and 20.8%, respectively. In a multivariate analysis, old age, advanced stage, poor PS and no enrollment in clinical trials were associated with inferior survival. Conclusions: The outcome for patients who did not participate in clinical trials, regardless of gemcitabine-based treatment, is still bleak.
Circulating MicroRNAs
Authors: Fichtlscherer Stephan , Zeiher Andreas M. , Dimmeler Stefanie
Published: October 2011

MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally control gene expression by inhibiting protein translation or inducing target mRNA destabilization. Besides their intracellular function, recent studies demonstrate that miRs can be exported or released by cells and circulate with the blood in a remarkably stable form. The discovery of circulating miRs opens up intriguing possibilities to use the circulating miR patterns as biomarker for cardiovascular diseases. Cardiac injury as it occurs after acute myocardial infarction increases the circulating levels of several myocardial-derived miRs (eg, miR-1, miR-133, miR-499, miR-208), whereas patients with coronary artery disease or diabetes showed reduced levels of endothelial-enriched miRs, such as miR-126. This review article summarizes the current clinical and experimental studies addressing the role of circulating miRs as a diagnostic or prognostic biomarker in cardiovascular disease. In addition, the mechanisms by which miRs are released and their putative function as long-distance communicators are discussed.
Selective MicroRNA Suppression in Human Thoracic Aneurysms
Authors: Jones Jeffrey A. , Stroud Robert E. , O'Quinn Elizabeth C. , Black Laurel E. , Barth Jeremy L. , Elefteriades John A. , Bavaria Joseph E. , Gorman Joseph H. , Gorman Robert C. , Spinale Francis G. , Ikonomidis John S.
Published: October 2011

Background—

Increasing evidence points to a direct role for altered microRNA (miRNA or miR) expression levels in cardiovascular remodeling and disease progression. Although alterations in miR expression levels have been directly linked to cardiac hypertrophy, fibrosis, and remodeling, their role in regulating gene expression during thoracic aortic aneurysm (TAA) development has yet to be explored.

Methods and Results—

The present study examined miR expression levels in aortic tissue specimens collected from patients with ascending TAAs by quantitative real-time PCR, and observed decreased miR expression (miRs -1, -21, -29a, -133a, and -486) as compared with normal aortic specimens. A significant relationship between miR expression levels (miRs -1, -21, -29a, and -133a) and aortic diameter was identified; as aortic diameter increased, miR expression decreased. Through the use of a bioinformatics approach, members of the matrix metalloproteinase (MMP) family, proteins involved in TAA development, were examined for putative miR binding sites. MMP-2 and MMP-9 were identified as potential targets for miR-29a and miR-133a, respectively, and MMP-2 was subsequently verified as a miR-29a target in vitro. A significant inverse relationship between miR-29a and total MMP-2 was then identified in the clinical TAA specimens.

Conclusions—

These findings demonstrate altered miR expression patterns in clinical TAA specimens, suggesting that the loss of specific miR expression may allow for the elaboration of specific MMPs capable of driving aortic remodeling during TAA development. Importantly, these data suggest that these miRs have biological and clinical relevance to the behavior of TAAs and may provide significant targets for therapeutic and diagnostic applications.
Effect of Heparin Administration on Metabolomic Profiles in Samples Obtained During Cardiac Catheterization
Authors: Brunner Michael P. , Shah Svati H. , Craig Damian M. , Stevens Robert D. , Muehlbauer Michael J. , Bain James R. , Newgard Christopher B. , Kraus William E. , Granger Christopher B. , Sketch Michael H. , Newby L. Kristin
Published: October 2011

Background—

Metabolic profiling holds promise for early detection of coronary artery disease and assessing risk for ischemic events. Heparin is frequently administered (1) to treat acute coronary syndromes; and (2) during routine cardiac catheterization procedures. Because it stimulates lipolysis, heparin is a potential confounder of metabolic profiling in these populations.

Methods and Results—

Using mass spectrometry and conventional immunoassays, we evaluated how unfractionated heparin administration affected 69 peripheral blood metabolites (acylcarnitines, amino acids, nonesterified fatty acids and their oxidation byproducts, conventional lipids, glucose, and C-reactive protein) in samples obtained pre- and postcardiac catheterization from 19 patients who received heparin and 10 patients who did not. Using unpaired
t
tests, we compared the changes in mean metabolite levels before and after the procedure between the nonheparin and heparin groups. Clinical characteristics of the nonheparin and heparin groups, indication for cardiac catheterization, procedure performed, and other periprocedural variables were similar. The mean change between pre- and postprocedure β-hydroxybutyrate (5.43 versus 66.84 μmol/L;
P
=0.009), ketones (21.17 versus 98.49 μmol/L;
P
=0.009), nonesterified fatty acids (0.37 versus 1.20 mmol/L;
P
=0.017), and triglycerides (−9.33 versus −36.50 mg/dL;
P
=0.007) was significantly different between the nonheparin and heparin groups, respectively. There were no significant differences between groups in the other metabolites measured.

Conclusions—

Heparin administration during cardiac catheterization induced changes in peripheral blood metabolites that were consistent with known lipolytic effects of heparin and define a metabolite signature associated with heparin administration. These findings are important for accurate interpretation of future metabolic profiling studies in populations exposed to heparin.
Marine Downscaling of a Future Climate Scenario for Australian Boundary Currents
Authors: Sun Chaojiao , Feng Ming , Matear Richard J. , Chamberlain Matthew A. , Craig Peter , Ridgway Ken R. , Schiller Andreas
Published: October 2011

Ocean boundary currents are poorly represented in existing coupled climate models, partly because of their insufficient resolution to resolve narrow jets. Therefore, there is limited confidence in the simulated response of boundary currents to climate change by climate models. To address this issue, the eddy-resolving Ocean Forecasting Australia Model (OFAM) was used, forced with bias-corrected output in the 2060s under the Special Report on Emissions Scenarios (SRES) A1B from the CSIRO Mark version 3.5 (Mk3.5) climate model, to provide downscaled regional ocean projections. CSIRO Mk3.5 captures a number of robust changes that are common to most climate models that are consistent with observed changes, including the weakening of the equatorial Pacific zonal wind stress and the strengthening of the wind stress curl in the Southern Pacific, important for driving the boundary currents around Australia.

The 1990s climate is downscaled using air–sea fluxes from the 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40). The current speed, seasonality, and volume transports of the Australian boundary currents show much greater fidelity to the observations in the downscaled model. Between the 1990s and the 2060s, the downscaling with the OFAM simulates a 15% reduction in the Leeuwin Current (LC) transport, a 20% decrease in the Indonesian Throughflow (ITF) transport, a 12% increase in the East Australian Current (EAC) core transport, and a 35% increase in the EAC extension. The projected changes by the downscaling model are consistent with observed trends over the past several decades and with changes in wind-driven circulation derived from Sverdrup dynamics. Although the direction of change projected from downscaling is usually in agreement with CSIRO Mk3.5, there are important regional details and differences that will impact the response of ecosystems to climate change.
Component-based approach for programming and running scientific applications on grids and clouds
Authors: Malawski Maciej , Gubała Tomasz , Bubak Marian
Published: October 2011

This paper presents an approach to programming and running scientific applications on grid and cloud infrastructures based on two principles: the first one is to follow a component-based programming model, the second is to apply a flexible technology which allows for virtualization of the underlying infrastructure. The solutions described in this paper include high-level composition and deployment consisting of a scripting-based environment and a manager system based on an architecture description language (ADL), a dynamically managed pool of component containers, and interoperability with other component models such as Grid Component Model (GCM). We demonstrate how the proposed methodology can be implemented by combining the unique features of the Common Component Architecture (CCA) model together with the H2O resource sharing platform, resulting in the MOCCA component framework. Applications and tests include data mining using the Weka library, Monte Carlo simulation of the formation of clusters of gold atoms, as well as a set of synthetic benchmarks. The conclusion is that the component approach to scientific applications can be successfully applied to both grid and cloud infrastructures.
The strategy for the diagnosis of invasive pulmonary aspergillosis should depend on both the underlying condition and the leukocyte count of patients with hematologic malignancies
Authors: Bergeron Anne , Porcher Raphaël , Sulahian Annie , de Bazelaire Cédric , Chagnon Karine , Raffoux Emmanuel , Vekhoff Anne , Cornet Muriel , Isnard Françoise , Brethon Benoit , Lacroix Claire , Poirot Jean Louis , Bouges Claire , Derouin Francis , Tazi Abdellatif , Ribaud Patricia
Published: October 2011

The identification of the causative organism in invasive pulmonary aspergillosis (IPA) is recommended. We investigated whether a mycologic diagnostic strategy could be optimized based on patient characteristics. Fifty-five patients were enrolled in a prospective study. The presence of Aspergillus in respiratory samples occurred more frequently in non-acute leukemia (AL) patients than in AL patients (P = .0003), and in patients with leukocyte counts more than 100/mm3 (P = .002). In a logistic regression model, these 2 factors appeared to be independent, with an adjusted odds ratio of 7.14 (95% confidence interval, 1.40-36.5) for non-AL patients and an adjusted odds ratio of 6.97 (95% confidence interval, 1.33-36.5) for patients with leukocyte counts more than 100/mm3. A positive mycologic result was also more frequent among patients with lung CT scan signs of airway-invasive disease than among other patients (P = .043). Airway-invasive signs were more frequent among non-AL patients (P = .049), whereas angioinvasive disease was more frequent among both AL patients (P = .01) and patients with leukocyte counts less than 100/mm3 (P = .001). A concomitant pulmonary infection was identified more frequently among non-AL patients (P = .005 vs allogeneic hematopoietic stem cell transplant and P = .048 vs others). Our results suggest that different strategies for diagnosing IPA should be considered based on the underlying condition.
Distinct Ldb1/NLI complexes orchestrate γ-globin repression and reactivation through ETO2 in human adult erythroid cells
Authors: Kiefer Christine M. , Lee Jongjoo , Hou Chunhui , Dale Ryan K. , Lee Y. Terry , Meier Emily R. , Miller Jeffrey L. , Dean Ann
Published: October 2011

The Ldb1/GATA-1/TAL1/LMO2 complex mediates long-range interaction between the β-globin locus control region (LCR) and gene in adult mouse erythroid cells, but whether this complex mediates chromatin interactions at other developmental stages or in human cells is unknown. We investigated NLI (Ldb1 homolog) complex occupancy and chromatin conformation of the β-globin locus in human erythroid cells. In addition to the LCR, we found robust NLI complex occupancy at a site downstream of the Aγ-globin gene within sequences of BGL3, an intergenic RNA transcript. In cells primarily transcribing β-globin, BGL3 is not transcribed and BGL3 sequences are occupied by NLI core complex members, together with corepressor ETO2 and by γ-globin repressor BCL11A. The LCR and β-globin gene establish proximity in these cells. In contrast, when γ-globin transcription is reactivated in these cells, ETO2 participation in the NLI complex at BGL3 is diminished, as is BCL11A occupancy, and both BGL3 and γ-globin are transcribed. In these cells, proximity between the BGL3/γ-globin region and the LCR is established. We conclude that alternative NLI complexes mediate γ-globin transcription or silencing through long-range LCR interactions involving an intergenic site of noncoding RNA transcription and that ETO2 is critical to this process.
Risk factors for acute GVHD and survival after hematopoietic cell transplantation
Authors: Jagasia Madan , Arora Mukta , Flowers Mary E. D. , Chao Nelson J. , McCarthy Philip L. , Cutler Corey S. , Urbano-Ispizua Alvaro , Pavletic Steven Z. , Haagenson Michael D. , Zhang Mei-Jie , Antin Joseph H. , Bolwell Brian J. , Bredeson Christopher , Cahn Jean-Yves , Cairo Mitchell , Gale Robert Peter , Gupta Vikas , Lee Stephanie J. , Litzow Mark , Weisdorf Daniel J. , Horowitz Mary M. , Hahn Theresa
Published: October 2011

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.
Identification of RNA binding motif proteins essential for cardiovascular development
Authors: Maragh Samantha , Miller Ronald A , Bessling Seneca L , McGaughey David M , Wessels Marja W , de Graaf Bianca , Stone Eric A , Bertoli-Avella Aida M , Gearhart John D , Fisher Shannon , McCallion Andrew S
Published: October 2011

Background

We recently identified Rbm24 as a novel gene expressed during mouse cardiac development. Due to its tightly restricted and persistent expression from formation of the cardiac crescent onwards and later in forming vasculature we posited it to be a key player in cardiogenesis with additional roles in vasculogenesis and angiogenesis.

Results

To determine the role of this gene in cardiac development, we have identified its zebrafish orthologs (rbm24a and rbm24b), and functionally evaluated them during zebrafish embryogenesis. Consistent with our underlying hypothesis, reduction in expression of either ortholog through injection of morpholino antisense oligonucleotides results in cardiogenic defects including cardiac looping and reduced circulation, leading to increasing pericardial edema over time. Additionally, morphant embryos for either ortholog display incompletely overlapping defects in the forming vasculature of the dorsal aorta (DA), posterior caudal vein (PCV) and caudal vein (CV) which are the first blood vessels to form in the embryo. Vasculogenesis and early angiogenesis in the trunk were similarly compromised in rbm24 morphant embryos at 48 hours post fertilization (hpf). Subsequent vascular maintenance was impaired in both rbm24 morphants with substantial vessel degradation noted at 72 hpf.

Conclusion

Taken collectively, our functional data support the hypothesis that rbm24a and rbm24b are key developmental cardiac genes with unequal roles in cardiovascular formation.
A comparative assessment of mandible shape in a consomic strain panel of the house mouse (Mus musculus) - implications for epistasis and evolvability of quantitative traits
Authors: Boell Louis , Gregorova Sona , Forejt Jiri , Tautz Diethard
Published: October 2011

Background

Expectations of repeatedly finding associations between given genes and phenotypes have been borne out by studies of parallel evolution, especially for traits involving absence or presence of characters. However, it has rarely been asked whether the genetic basis of quantitative trait variation is conserved at the intra- or even at the interspecific level. This question is especially relevant for shape, where the high dimensionality of variation seems to require a highly complex genetic architecture involving many genes.

Results

We analyse here the genetic effects of chromosome substitution strains carrying M. m. musculus chromosomes in a largely M. m. domesticus background on mandible shape and compare them to the results of previously published QTL mapping data between M. m. domesticus strains. We find that the distribution of genetic effects and effect sizes across the genome is consistent between the studies, while the specific shape changes associated with the chromosomes are different. We find also that the sum of the effects from the different M. m. musculus chromosomes is very different from the shape of the strain from which they were derived, as well as all known wild type shapes.

Conclusions

Our results suggest that the relative chromosome-wide effect sizes are comparable between the long separated subspecies M. m. domesticus and M. m. musculus, hinting at a relative stability of genes involved in this complex trait. However, the absolute effect sizes and the effect directions may be allele-dependent, or are context dependent, i.e. epistatic interactions appear to play an important role in controlling shape.
Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa
Authors: Enroth Stefan , Rada-Iglesisas Alvaro , Andersson Robin , Wallerman Ola , Wanders Alkwin , Påhlman Lars , Komorowski Jan , Wadelius Claes
Published: October 2011

Background

Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples.

Methods

Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29.

Results

By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors.

Conclusions

Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.
Doctors and local media: a synergy for public health information? A controlled trial to evaluate the effects of a multifaceted campaign on antibiotic prescribing (protocol)
Authors:   LOcal Campaign on Antibiotics ALliance (LOCAAL) study group
Published: October 2011

Background

Use of information campaigns and educational interventions directed to citizens and supported by physicians, aimed at promoting the appropriate use of medicines, have been evaluated by several studies with conflicting results. These interventions are potentially relevant, favouring the reduction of unnecessary use of medicines and related risks. Several studies have specifically evaluated the promotion of the appropriate use of antibiotics in adults and children, with variable results. A controlled study is proposed to evaluate the feasibility and effectiveness of a multifaceted intervention aimed at reducing antibiotic prescription by increasing awareness on risks of their unnecessary use.

Methods/design

Information will be provided to citizens through several media (posters, local TV, radio and newspapers, video terminals, websites of Local Health Authorities). Brochures with information on expected benefits and risks of antibiotics will be also available, either with direct access in waiting rooms and pharmacies or handed out and mediated by doctors. Physicians and pharmacists will get specific data on local antibiotic resistance. A small group of representative doctors have also actively participated in defining the campaign key messages. A sample of general practitioners and paediatricians will be trained in patient counselling strategies.

The information campaign will be implemented in two Provinces of Emilia-Romagna during the fall-winter season (November 2011-February 2012). Change in the overall prescribing rate of antibiotics (expressed as DDD per 1000 inhabitants/day) in the intervention area will be compared versus other areas in the same Region. Knowledge and attitudes of the general population will be evaluated through a phone and internet survey on a representative sample.

Discussion

While the campaign messages will be mainly directed to the general population, doctors' prescribing will be assessed. The main rationale for this apparent discrepancy lies in the influence patients may have on physicians' prescribing behaviour (directly or indirectly) and in physicians' endorsement of the campaign goals, considering their participation in its design.

This study could observe a reduction lower than 5% in the prescribing rate of antibiotics. Such a reduction would be of public health relevance and would determine average savings of almost twice as much as the campaign costs.
Protocol for Northern Ireland Caries Prevention in Practice Trial (NIC-PIP) trial: a randomised controlled trial to measure the effects and costs of a dental caries prevention regime for young children attending primary care dental services
Authors: Tickle Martin , Milsom Keith M , Donaldson Michael , Killough Seamus , O'Neill Ciaran , Crealey Grainne , Sutton Matthew , Noble Solveig , Greer Margaret , Worthington Helen V
Published: October 2011

Background

Dental caries is a persistent public health problem with little change in the prevalence in young children over the last 20 years. Once a child contracts the disease it has a significant impact on their quality of life. There is good evidence from Cochrane reviews including trials that fluoride varnish and regular use of fluoride toothpaste can prevent caries.

The Northern Ireland Caries Prevention in Practice Trial (NIC-PIP) trial will compare the costs and effects of a caries preventive package (fluoride varnish, toothpaste, toothbrush and standardised dental health education) with dental health education alone in young children.

Methods/Design

A randomised controlled trial on children initially aged 2 and 3 years old who are regular attenders at the primary dental care services in Northern Ireland. Children will be recruited and randomised in dental practices. Children will be randomised to the prevention package of both fluoride varnish (twice per year for three years), fluoride toothpaste (1,450 ppm F) (supplied twice per year), a toothbrush (supplied twice a year) or not; both test and control groups receive standardised dental health education delivered by the dentist twice per year. Randomisation will be conducted by the Belfast Trust Clinical Research Support Centre ([CRSC] a Clinical Trials Unit).

1200 participants will be recruited from approximately 40 dental practices. Children will be examined for caries by independent dental examiners at baseline and will be excluded if they have caries. The independent dental examiners will examine the children again at 3 years blinded to study group.

The primary end-point is whether the child develops caries (cavitation into dentine) or not over the three years. One secondary outcome is the number of carious surfaces in the primary dentition in children who experience caries. Other secondary outcomes are episodes of pain, extraction of primary teeth, other adverse events and costs which will be obtained from parental questionnaires.

Discussion

This is a pragmatic trial conducted in general dental practice. It tests a composite caries prevention intervention, which represents an evidence based approach advocated by current guidance from the English Department of Health which is feasible to deliver to all low risk (caries free) children in general dental practice. The trial will provide valuable information to policy makers and clinicians on the costs and effects of caries prevention delivered to young children in general dental practice.

Trial registration

EudraCT No: 2009 - 010725 - 39

ISRCTN: ISRCTN36180119

Ethics Reference No: 09/H1008/93: