bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple sclerosis and pregnancy: experience from a nationwide database in Germany
Authors: Hellwig Kerstin , Haghikia Aiden , Rockhoff Milena , Gold Ralf 
Published: July 2012

Objective: The objective of this study was to evaluate exposure to disease-modifying therapies (DMTs) during pregnancy in 335 pregnancies of multiple sclerosis (MS) patients and to further determine whether exclusive breastfeeding of MS mothers has any relevant influence on postpartum relapse rate. Background: Only limited data are available on whether DMT exposure during pregnancy affects relapse rate during pregnancy or after birth. Currently, findings on beneficial effect of exclusive breastfeeding on MS disease course are controversially discussed. Methods: We enrolled pregnant women with MS who contacted us directly or via their treating physicians to be included in our nationwide MS and pregnancy database. Results: We identified 78 pregnancies under interferon-beta (IFNβ) preparations, 41 under glatiramer acetate (GLAT), and 216 pregnancies without DMT exposure during pregnancy. As expected, annualized relapse rate (ARR) decreased continuously during pregnancy in nonexposed mothers ( p < 0.001) to then increase after birth. In IFNβ- or GLAT-exposed women this typical pattern was not as obvious. Congenital anomalies were within normal ranges in exposed pregnancies. In total, 170 women were identified who exclusively breastfed (EBF). Significantly reduced postpartum relapse rate during the first 3 months after birth were registered in the EBF group as compared with nonexclusively breastfeeding (NEBF) or nonbreastfeeding women (NBF) women with MS ( p < 0.0001). Relapse rate (RR) in the year before pregnancy had been similar throughout all groups. We did not observe any significant differences in RR of NEBF and NBF women. Conclusion: Exclusive breastfeeding showed some beneficial effects on postpartum relapse rate in our cohort. Our data support that IFNβ and GLAT do not seem to represent a major teratogenic risk in pregnancy.
Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway
Authors: Krisinger Michael J. , Goebeler Verena , Lu Zhen , Meixner Scott C. , Myles Timothy , Pryzdial Edward L. G. , Conway Edward M. 
Published: July 2012

AbstractThe coagulation and complement pathways simultaneously promote homeostasis in response to injury but cause tissue damage when unregulated. Mechanisms by which they cooperate are poorly understood. To delineate their interactions, we studied the effects of thrombin and C5 convertase on C5 in purified and plasma-based systems, measuring release of the anaphylatoxin C5a, and generation of C5b, the initial component of the lytic membrane attack complex. Thrombin cleaved C5 poorly at R751, yielding minimal C5a and C5b. However, thrombin efficiently cleaved C5 at a newly identified, highly conserved R947 site, generating previously undescribed intermediates C5T and C5bT. Tissue factor-induced clotting of plasma led to proteolysis of C5 at a thrombin-sensitive site corresponding to R947 and not R751. Combined treatment of C5 with thrombin and C5 convertase yielded C5a and C5bT, the latter forming a C5bT-9 membrane attack complex with significantly more lytic activity than with C5b-9. Our findings provide a new paradigm for complement activation, in which thrombin and C5 convertase are invariant partners, enhancing the terminal pathway via the generation of newly uncovered C5 intermediates. Delineating the molecular links between coagulation and complement will provide new therapeutic targets for diseases associated with excess fibrin deposition and complement activation.
A comparative transcriptomic, fluxomic and metabolomic analysis of the response of Saccharomyces cerevisiae to increases in NADPH oxidation
Authors: Celton Magalie , Sanchez Isabelle , Goelzer Anne , Fromion Vincent , Camarasa Carole , Dequin Sylvie 
Published: July 2012

AbstractBackgroundRedox homeostasis is essential to sustain metabolism and growth. We recently reported that yeast cells meet a gradual increase in imposed NADPH demand by progressively increasing flux through the pentose phosphate (PP) and acetate pathways and by exchanging NADH for NADPH in the cytosol, via a transhydrogenase-like cycle. Here, we studied the mechanisms underlying this metabolic response, through a combination of gene expression profiling and analyses of extracellular and intracellular metabolites and13 C-flux analysis.ResultsNADPH oxidation was increased by reducing acetoin to 2,3-butanediol in a strain overexpressing an engineered NADPH-dependent butanediol dehydrogenase cultured in the presence of acetoin. An increase in NADPH demand to 22 times the anabolic requirement for NADPH was accompanied by the intracellular accumulation of PP pathway metabolites consistent with an increase in flux through this pathway. Increases in NADPH demand were accompanied by the successive induction of several genes of the PP pathway. NADPH-consuming pathways, such as amino-acid biosynthesis, were upregulated as an indirect effect of the decrease in NADPH availability. Metabolomic analysis showed that the most extreme modification of NADPH demand resulted in an energetic problem. Our results also highlight the influence of redox status on aroma production.ConclusionsCombined13 C-flux, intracellular metabolite levels and microarrays analyses revealed that NADPH homeostasis, in response to a progressive increase in NADPH demand, was achieved by the regulation, at several levels, of the PP pathway. This pathway is principally under metabolic control, but regulation of the transcription of PP pathway genes can exert a stronger effect, by redirecting larger amounts of carbon to this pathway to satisfy the demand for NADPH. No coordinated response of genes involved in NADPH metabolism was observed, suggesting that yeast has no system for sensing NADPH/NADP+ratio. Instead, the induction of NADPH-consuming amino-acid pathways in conditions of NADPH limitation may indirectly trigger the transcription of a set of PP pathway genes.
Health-related quality of life and strain in caregivers of Australians with Parkinson’s disease: An observational study
Authors: Kelly David H , McGinley Jennifer L , Huxham Frances E , Menz Hylton B , Watts Jennifer J , Iansek Robert , Murphy Anna T , Danoudis Mary , Adair Brooke , Morris Meg E 
Published: July 2012

Abstract

Background
The relationship between health-related quality of life (HRQoL) in people with Parkinson’s disease and their caregivers is little understood and any effects on caregiver strain remain unclear. This paper examines these relationships in an Australian sample.

Methods
Using the generic EuroQol (EQ-5D) and disease-specific Parkinson’s Disease Questionnaire-39 Item (PDQ-39), HRQoL was evaluated in a sample of 97 people with PD and their caregivers. Caregiver strain was assessed using the Modified Caregiver Strain Index. Associations were evaluated between: (i) caregiver and care-recipient HRQoL; (ii) caregiver HRQoL and caregiver strain, and; (iii) between caregiver strain and care-recipient HRQoL.

Results
No statistically significant relationships were found between caregiver and care-recipient HRQoL, or between caregiver HRQoL and caregiver strain. Although this Australian sample of caregivers experienced relatively good HRQoL and moderately low strain, a significant correlation was found between HRQoL of people with PD and caregiver strain (rho 0.43, p < .001).

Conclusion
Poor HRQoL in people with PD is associated with higher strain in caregivers. Therapy interventions may target problems reported as most troublesome by people with PD, with potential to reduce strain on the caregiver.
Cardiac Troponin I elevation after epileptic seizure
Authors: Sieweke Nicole , Allendörfer Jens , Franzen Wolfgang , Feustel Andreas , Reichenberger Frank , Pabst Wolfgang , Krämer Heidrun Heidi , Kaps Manfred , Tanislav Christian 
Published: July 2012

Abstract

Background
Cardiac troponin-I (cTNI) is highly specific biomarker to prove myocardial damage, e.g. in acute coronary syndrome (ACS). However, it occurs in other conditions as well. We therefore analysed cTNI increase in patients after generalized convulsive seizure.

Methods
Consecutive patients admitted with acute generalized convulsive seizure were included in case of cTNI measurement on admission. Among 898 selected cases, 53 patients were referred secondary to our department; in 845 cases cTNI measurements on admission were available. In case of multiple admissions (81 cases), only the first admission entered our analysis. In 17 patients elevated cTNI was determined due to ACS; in one patient a myocarditis was found. 5 patients suffered of relevant renal insufficiency. Finally 741 patients were included in the analysis. A cTNI cut-off level of ≥ 0.1 ng/ml was considered. Factors associated with a cTNI increase were analysed subsequently.

Results
The mean age of the study population (n = 741) was 47.8 years (SD ± 18.6), 40.9% were female. In 50 patients (6.7%) a cTNI elevation of unknown origin was found; no obvious cardiac involvement could be detected in these patients who all remained asymptomatic. A vascular risk profile (including at least hypertension, hypercholesterolemia or diabetes) (OR = 3.62; CI: 1.59 to 8.21; p = 0.001) and elevated creatine kinase on admission (OR = 2.36; CI: 1.26 to 4.39; p = 0.002) were independent factors associated with cTNI release.

Conclusion
cTNI release occurs in patients with generalized convulsive seizure with predominance in patients with vascular risk profile.
Evaluation of filtering blebs using the ‘Wuerzburg bleb classification score’ compared to clinical findings
Authors: Furrer Sandra , Menke Marcel N , Funk Jens , Töteberg-Harms Marc 
Published: July 2012

Abstract

Background
To determine the agreement between intraocular pressure and the ‘Wuerzburg bleb classification score’, as well as between single items of the score and intraocular pressure. Interobserver variability was analyzed.

Methods
57 post-trabeculectomy eyes were included. Colour photographs were used to score the filtering bleb in accordance to the Wuerzburg bleb classification score by two different examiners. At the same visit, clinical data such as intraocular pressure, best corrected visual acuity, slit lamp biomicroscopy and medical history were obtained by another examiner.

Results
After trabeculectomy, 42 out of 57 eyes (73.7%) reached the target pressure (≤21mmHg, and intraocular pressure reduction of at least 20%, without antiglaucoma medication, and without any additional intervention). Fair agreement was found between intraocular pressure and Wuerzburg bleb classification score ≥8 points and ≥7 points (kappa 0.24 and 0.27, respectively). Analyzing the subgroups of the morphological criteria, best agreement was found between occurrence of microcysts and target intraocular pressure (к 0.22 – 0.34).

Conclusions
Evaluating filtering blebs after trabeculectomy by using the Wuerzburg bleb classification score is a good technique for predicting intraocular pressure control in eyes attaining a minimum score of seven points. The presence of microcysts on the filtering bleb predicts that the eye is likely to attain target pressure.
In Arabidopsis thaliana codon volatility scores reflect GC3 composition rather than selective pressure
Authors: O'Connell Mary J , Doyle Aisling M , Juenger Thomas E , Donoghue Mark TA , Keshavaiah Channa , Tuteja Reetu , Spillane Charles 
Published: July 2012

Abstract

Background
Synonymous codon usage bias has typically been correlated with, and attributed to translational efficiency. However, there are other pressures on genomic sequence composition that can affect codon usage patterns such as mutational biases. This study provides an analysis of the codon usage patterns in Arabidopsis thaliana in relation to gene expression levels, codon volatility, mutational biases and selective pressures.

Results
We have performed synonymous codon usage and codon volatility analyses for all genes in the A. thaliana genome. In contrast to reports for species from other kingdoms, we find that neither codon usage nor volatility are correlated with selection pressure (as measured by dN/dS), nor with gene expression levels on a genome wide level. Our results show that codon volatility and usage are not synonymous, rather that they are correlated with the abundance of G and C at the third codon position (GC3).

Conclusions
Our results indicate that while the A. thaliana genome shows evidence for synonymous codon usage bias, this is not related to the expression levels of its constituent genes. Neither codon volatility nor codon usage are correlated with expression levels or selective pressures but, because they are directly related to the composition of G and C at the third codon position, they are the result of mutational bias. Therefore, in A. thaliana codon volatility and usage do not result from selection for translation efficiency or protein functional shift as measured by positive selection.
Participation of heparin binding proteins from the surface of Leishmania (Viannia) braziliensis promastigotes in the adhesion of parasites to Lutzomyia longipalpis cells (Lulo) in vitro
Authors: de Castro Côrtes Luzia Monteiro , de Souza Pereira Mirian Claudia , da Silva Franklin Souza , Pereira Bernardo Acácio Santini , de Oliveira Junior Francisco Odêncio , de Araújo Soares Renata Oliveira , Brazil Reginaldo Peçanha , Toma Leny , Vicente Carolina Meloni , Nader Helena Bonciani , de Fátima Madeira Maria , Bello Felio J , Alves Carlos Roberto 
Published: July 2012

AbstractBackgroundLeishmania (V.) braziliensisis a causative agent of cutaneous leishmaniasis in Brazil. During the parasite life cycle, the promastigotes adhere to the gut of sandflies, to avoid being eliminated with the dejection. The Lulo cell line, derived fromLutzomyia longipalpis(Diptera: Psychodidae), is a suitablein vitrostudy model to understand the features of parasite adhesion.Here, we analyze the role of glycosaminoglycans (GAGs) from Lulo cells and proteins from the parasites in this event.MethodsFlagellar (Ff) and membrane (Mf) fractions from promastigotes were obtained by differential centrifugation and the purity of fractions confirmed by western blot assays, using specific antibodies for cellular compartments. Heparin-binding proteins (HBP) were isolated from both fractions using a HiTrap-Heparin column. In addition, binding of promastigotes to Lulo cells or to a heparin-coated surface was assessed by inhibition assays or surface plasmon resonance (SPR) analysis.ResultsThe success of promastigotes subcellular fractionation led to the obtainment of Ffand Mfproteins, both of which presented two main protein bands (65.0 and 55.0kDa) with affinity to heparin. The contribution of HBPs in the adherence of promastigotes to Lulo cells was assessed through competition assays, using HS or the purified HBPs fractions. All tested samples presented a measurable inhibition rate when compared to control adhesion rate (17 ± 2.0% of culture cells with adhered parasites): 30% (for HS 20μg/ml) and 16% (for HS 10μg/ml); HBP Mf(35.2% for 10μg/ml and 25.4% for 20μg/ml) and HBP Ff(10.0% for 10μg/ml and 31.4% for 20μg/ml). Additionally, to verify the presence of sulfated GAGs in Lulo cells surface and intracellular compartment, metabolic labeling with radioactive sulfate was performed, indicating the presence of an HS and chondroitin sulfate in both cell sections. The SPR analysis performed further confirmed the presence of GAGs ligands onL. (V.) braziliensispromastigote surfaces.ConclusionsThe data presented here point to evidences that HBPs present on the surface ofL. (V.) braziliensispromastigotes participate in adhesion of these parasites to Lulo cells through HS participation.
Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial
Authors: Sonneveld Pieter , Schmidt-Wolf Ingo G.H. , van der Holt Bronno , el Jarari Laila , Bertsch Uta , Salwender Hans , Zweegman Sonja , Vellenga Edo , Broyl Annemiek , Blau Igor W. , Weisel Katja C. , Wittebol Shulamiet , Bos Gerard M.J. , Stevens-Kroef Marian , Scheid Christof , Pfreundschuh Michael , Hose Dirk , Jauch Anna , van der Velde Helgi , Raymakers Reinier , Schaafsma Martijn R. , Kersten Marie-Jose , van Marwijk-Kooy Marinus , Duehrsen Ulrich , Lindemann Walter , Wijermans Pierre W. , Lokhorst Henk M. , Goldschmidt Hartmut M. 
Published: July 2012

Purpose We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and Methods In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m2 (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. Results Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003). Conclusion Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.
Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging
Authors: Armstrong Gregory T. , Plana Juan Carlos , Zhang Nan , Srivastava Deokumar , Green Daniel M. , Ness Kirsten K. , Daniel Donovan F. , Metzger Monika L. , Arevalo Alejandro , Durand Jean-Bernard , Joshi Vijaya , Hudson Melissa M. , Robison Leslie L. , Flamm Scott D. 
Published: July 2012

Purpose To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function. Patients and Methods Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy. Results In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR. Conclusion CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.
The Price We Pay for Progress: A Meta-Analysis of Harms of Newly Approved Anticancer Drugs
Authors: Niraula Saroj , Seruga Bostjan , Ocana Alberto , Shao Tiffany , Goldstein Robyn , Tannock Ian F. , Amir Eitan 
Published: July 2012

Purpose Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration. Patients and Methods We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed. Results Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS. Conclusion New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.