bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic Analysis of Enterococcus faecium
l
,
d
-Transpeptidase Inactivation by Carbapenems
Authors: Dubée Vincent , Arthur Michel , Fief Hélène , Triboulet Sébastien , Mainardi Jean-Luc , Gutmann Laurent , Sollogoub Matthieu , Rice Louis B. , Ethève-Quelquejeu Mélanie , Hugonnet Jean-Emmanuel 
Published: March 2012

ABSTRACT

Bypass of classical penicillin-binding proteins by the
l
,
d
-transpeptidase of
Enterococcus faecium
(Ldt
fm
) leads to high-level ampicillin resistance in
E. faecium
mutants, whereas carbapenems remain the lone highly active β-lactams. Kinetics of Ldt
fm
inactivation was determined for four commercial carbapenems and a derivative obtained by introducing a minimal ethyl group at position 2. We show that the bulky side chains of commercial carbapenems have both positive and negative effects in preventing hydrolysis of the acyl enzyme and impairing drug binding.
FlaA Proteins in Leptospira interrogans Are Essential for Motility and Virulence but Are Not Required for Formation of the Flagellum Sheath
Authors: Lambert Ambroise , Picardeau Mathieu , Haake David A. , Sermswan Rasana W. , Srikram Amporn , Adler Ben , Murray Gerald A. 
Published: March 2012

ABSTRACT

Spirochetes have periplasmic flagella composed of a core surrounded by a sheath. The pathogen
Leptospira interrogans
has four
flaB
(proposed core subunit) and two
flaA
(proposed sheath subunit) genes. The
flaA
genes are organized in a locus with
flaA2
immediately upstream of
flaA1
. In this study,
flaA1
and
flaA2
mutants were constructed by transposon mutagenesis. Both mutants still produced periplasmic flagella. The
flaA1
mutant did not produce FlaA1 but continued to produce FlaA2 and retained normal morphology and virulence in a hamster model of infection but had reduced motility. The
flaA2
mutant did not produce either the FlaA1 or the FlaA2 protein. Cells of the
flaA2
mutant lacked the distinctive hook-shaped ends associated with
L. interrogans
and lacked translational motility in liquid and semisolid media. These observations were confirmed with a second, independent
flaA2
mutant. The
flaA2
mutant failed to cause disease in animal models of acute infection. Despite lacking FlaA proteins, the flagella of the
flaA2
mutant were of the same thickness as wild-type flagella, as measured by electron microscopy, and exhibited a normal flagellum sheath, indicating that FlaA proteins are not essential for the synthesis of the flagellum sheath, as observed for other spirochetes. This study shows that FlaA subunits contribute to leptospiral translational motility, cellular shape, and virulence.
Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response
Authors: Brudecki Laura , Ferguson Donald A. , McCall Charles E. , El Gazzar Mohamed 
Published: March 2012

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are a heterogeneous Gr1+CD11b+population of immature cells containing granulocytic and monocytic progenitors, which expand under nearly all inflammatory conditions and are potent repressors of T-cell responses. Studies of MDSCs during inflammatory responses, including sepsis, suggest they can protect or injure. Here, we investigated MDSCs during early and late sepsis. To do this, we used our published murine model of cecal ligation and puncture (CLP)-induced polymicrobial sepsis, which transitions from an early proinflammatory phase to a late anti-inflammatory and immunosuppressive phase. We confirmed that Gr1+CD11b+MDSCs gradually increase after CLP, reaching ∼88% of the bone marrow myeloid series in late sepsis. Adoptive transfer of early (day 3) MDSCs from septic mice into naive mice after CLP increased proinflammatory cytokine production, decreased peritoneal bacterial growth, and increased early mortality. Conversely, transfer of late (day 12) MDSCs from septic mice had the opposite effects. Early and late MDSCs studiedex vivoalso differed in their inflammatory phenotypes. Early MDSCs expressed nitric oxide and proinflammatory cytokines, whereas late MDSCs expressed arginase activity and anti-inflammatory interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Late MDSCs had more immature CD31+myeloid progenitors and, when treatedex vivowith granulocyte-macrophage colony-stimulating factor (GM-CSF), generated fewer macrophages and dendritic cells than early MDSCs. We conclude that as the sepsis inflammatory process progresses, the heterogeneous MDSCs shift to a more immature state and from being proinflammatory to anti-inflammatory.
Why do so few patients with heart failure participate in cardiac rehabilitation? A cross-sectional survey from England, Wales and Northern Ireland
Authors: Dalal Hasnain M , Wingham Jennifer , Palmer Joanne , Taylor Rod , Petre Corinna , Lewin Robert 
Published: March 2012

ObjectivesTo determine why so few patients with chronic heart failure in England, Wales and Northern Ireland take part in cardiac rehabilitation.DesignTwo-stage, postal questionnaire-based national survey.Participants and settingStage 1: 277 cardiac rehabilitation centres that provided phase 3 cardiac rehabilitation in England, Wales and Northern Ireland registered on the National Audit of Cardiac Rehabilitation register. Stage 2: 35 centres that indicated in stage 1 that they provide a separate cardiac rehabilitation programme for patients with heart failure.ResultsFull data were available for 224/277 (81%) cardiac rehabilitation centres. Only 90/224 (40%) routinely offered phase 3 cardiac rehabilitation to patients with heart failure. Of these 90 centres that offered rehabilitation, 43% did so only when heart failure was secondary to myocardial infarction or revascularisation. Less than half (39%) had a specific rehabilitation programme for heart failure. Of those 134 centres not providing for patients with heart failure, 84% considered a lack of resources and 55% exclusion from commissioning contracts as the reason for not recruiting patients with heart failure. Overall, only 35/224 (16%) centres provided a separate rehabilitation programme for people with heart failure.ConclusionsPatients with heart failure as a primary diagnosis are excluded from most cardiac rehabilitation programmes in England, Wales and Northern Ireland. A lack of resources and direct exclusion from local commissioning agreements are the main barriers for not offering rehabilitation to patients with heart failure.
Efficacy of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen in women with moderate-to-severe primary dysmenorrhoea: an open-label, multicentre, randomised, controlled study
Authors: Strowitzki Thomas , Kirsch Bodo , Elliesen Jörg 
Published: March 2012

ObjectivesThe aim of this Phase III, multicentre, open-label, randomised study was to compare the efficacy and safety of ethinylestradiol (EE)/drospirenone (DRSP) in a new flexible extended regimen that allowed the management of intracyclic (breakthrough) bleeding (MIB) with that of EE/DRSP in a conventional 28-day regimen in women with moderate-to-severe primary dysmenorrhoea.MethodsWomen (aged 18–40 years) with moderate-to-severe primary dysmenorrhoea-related pain received a flexible extended regimen with MIB (flexibleMIB; minimum 24, maximum 120 days of continuous tablet intake for a flexible number of cycles to reach a treatment duration of at least 140 days with 4-day breaks between cycles) or a conventional 28-day regimen (24 active and four placebo tablets for five cycles) of EE/DRSP. The primary outcome was the number of days with dysmenorrhoeic pain over 140 days. Secondary outcomes included other dysmenorrhoea-related pain outcomes, bleeding profile, satisfaction and safety.ResultsOverall, 223 patients received study medication. There were significantly fewer days with dysmenorrhoeic pain with the flexibleMIBregimen than the conventional regimen (difference −4.2 days, 95% CI −6.5 to −2.0;p=0.0003), as well as considerably fewer days with at least moderate dysmenorrhoeic pain (difference −2.5 days, 95% CI −3.7 to −1.3), dysmenorrhoeic pain that interfered with daily activities (difference −2.2 days, 95% CI −4.2 to −0.1) and pelvic pain (difference −3.4 days, 95% CI −5.9 to −0.9). Adverse events were similar with both regimens.ConclusionsCompared with the conventional regimen, the flexible extended regimen of EE/DRSP with MIB was associated with a significantly greater reduction in days with dysmenorrhoeic pain in women with moderate-to-severe primary dysmenorrhoea. The flexibleMIBregimen was also associated with greater improvements in dysmenorrhea according to the Clinical Global Impression rating scale and was generally well tolerated.
CAPTURING INTERFACE PROTOCOLS TO SUPPORT COMPREHENSION AND EVALUATION OF C++ LIBRARIES
Authors: MALLOY BRIAN A. , LLOYD ERROL L. , HALLSTROM JASON O. , DUFFY EDWARD B. 
Published: March 2012

Developing and maintaining reliable object-oriented software requires a precise understanding of how individual classes must be used. Unfortunately, for many systems, especially those that are large, the available documentation is inadequate. Developers are left with incomplete information concerning the allowable set of call sequences that each class can accommodate. Techniques for reverse engineering this information and presenting it to developers in an intellectually scalable manner are critical.In this paper, we present four contributions to address this challenge. First, we describe a runtime trace collection system for large C++ applications. Second, we present a methodology for reverse engineering interface protocols from collected trace data. Third, we present a scalable, tunable algorithm for generating compact specifications of these protocols. Finally, we present a detailed case study involving the Mozilla Necko library. We consider popular applications in common use constructed using this library. The results are promising both in terms of the performance of the approach and the utility of the identified protocols.
Information Leaks in Structured Peer-to-Peer Anonymous Communication Systems
Authors: Mittal Prateek , Borisov Nikita 
Published: March 2012

We analyze information leaks in the lookup mechanisms of structured peer-to-peer (P2P) anonymous communication systems and how these leaks can be used to compromise anonymity. We show that the techniques used to combat active attacks on the lookup mechanism dramatically increase information leaks and the efficacy of passive attacks, resulting in a tradeoff between robustness to active and passive attacks.
We study this tradeoff in two P2P anonymous systems: Salsa and AP3. In both cases, we find that, by combining both passive and active attacks, anonymity can be compromised much more effectively than previously thought, rendering these systems insecure for most proposed uses. Our results hold even if security parameters are changed or other improvements to the systems are considered. Our study, therefore, shows the importance of considering these attacks in P2P anonymous communication.
Abiraterone in Prostate Cancer: A New Angle to an Old Problem
Authors: Stein Mark N. , Goodin Susan , DiPaola Robert S. 
Published: March 2012

Abstract
Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17), which is essential for synthesis of testosterone from cholesterol. Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with luteinizing hormone-releasing hormone agonists or antagonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself. An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo-controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone's efficacy shows the importance of androgen signaling in patients with castrate-resistant metastatic disease, with additional confirmation from recent studies of other novel agents such as MDV3100, an androgen receptor signaling inhibitor. These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel agents. Clin Cancer Res; 18(7); 1848–54. ©2012 AACR.
In Search of a Real “Targeted” Therapy for Thyroid Cancer
Authors: Brose Marcia S. 
Published: March 2012

Abstract
Over the past 5 years, patients with progressive radioactive iodine–refractory thyroid cancer have responded to “targeted” multikinase inhibitors, which inhibit angiogenesis and not the tumor cell. Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the V600EBRAF mutation. Clin Cancer Res; 18(7); 1827–9. ©2012 AACR.
Nonspatial Cueing of Tactile STM Causes Shift of Spatial Attention
Authors: Katus Tobias , Andersen Søren K. , Müller Matthias M. 
Published: March 2012

Abstract
The focus of attention can be flexibly altered in mnemonic representations of past sensory events. We investigated the neural mechanisms of selection in tactile STM by applying vibrotactile sample stimuli of different intensities to both hands, followed by a symmetrically shaped visual retro-cue. The retro-cue indicated whether the weak or strong sample was relevant for subsequent comparison with a single tactile test stimulus. Locations of tactile stimuli were randomized, and the required response did not depend upon the spatial relation between cued sample and test stimulus. Selection between spatially segregated items in tactile STM was mirrored in lateralized activity following visual retro-cues (N2pc) and influenced encoding of task-irrelevant tactile probe stimuli (N140). Our findings support four major conclusions. First, retrospective selection results in transient shifts of spatial attention. Second, retrospective selection is functionally dissociable from attention-based rehearsal of locations. Third, selection mechanisms are linked across processing stages, as attention shifts in STM influence encoding of sensory signals. Fourth, selection in tactile STM recruits attentional control mechanisms that are, at least partially, supramodal.
Observational and Synoptic Analyses of the Winter Precipitation Regime Change over Utah
Authors: Gillies Robert R. , Wang Shih-Yu , Booth Marty R. 
Published: March 2012

Abstract
Previous studies have indicated a widespread decline in snowpack over Utah accompanied by a decline in the snow–precipitation ratio while anecdotal evidence claims have been put forward that measured changes in Utah’s snowpack are spurious and do not reflect actual change. Using two distinct lines of investigation, this paper further analyzes the winter precipitation regime in the state of Utah. First, by means of observation-based, gridded daily temperature, precipitation, and remotely sensed data, as well as utilizing a climatological rain–snow threshold (RST) temperature method, the precipitation regime of Utah was scrutinized. Second, a comprehensive synoptic analysis was conducted as an alternate means that is independent from surface observations. It was found that the proportion of winter (January–March) precipitation falling as snow has decreased by 9% during the last half century, a combined result from a significant increase in rainfall and a minor decrease in snowfall. Meanwhile, observed snow depth across Utah has decreased and is accompanied by consistent decreases in snow cover and surface albedo. Weather systems with the potential to produce precipitation in Utah have decreased in number with those producing snowfall decreasing at a considerably greater rate. Further circulation analysis showed that an anomalous anticyclone has developed over western North America, which acts to reduce the frequency of cyclone waves impacting Utah. Combined with the increased precipitation, this feature suggests that the average precipitation per event has intensified with more of it falling as rain than as snow. Trends in the hydroclimate such as these have implications for present and future regional water policy in the state of Utah.
Is Pacific Storm-Track Activity Correlated with the Strength of Upstream Wave Seeding?
Authors: Chang Edmund K. M. , Guo Yanjuan 
Published: March 2012

Abstract
In this paper, the relationship between upstream seeding over north Asia and downstream storm-track activity over the North Pacific in midwinter and spring/fall has been analyzed using 45 years of variance and feature-tracking statistics. It is shown that for each season, interannual variations in upstream seeding and downstream storm-track activity are largely uncorrelated. Moreover, during midwinter months in which the upstream seeding from north Asia is about as strong as that during a typical spring/fall month, the downstream storm track in central Pacific is still significantly weaker during midwinter than that during spring/fall. In addition, during cool seasons in which the midwinter suppression is more pronounced in the upstream seeding region, the suppression is not significantly enhanced in the downstream Pacific storm track.
A recent study suggested that reduced upstream seeding from north Asia is the main “source” of the midwinter suppression of the Pacific storm track. Results presented in this study suggest that it is unlikely that the weakness in upstream seeding is the primary cause of the midwinter suppression.
Towards a reliable animal model of migraine
Authors: Olesen Jes , Jansen-Olesen Inger 
Published: March 2012

The pharmaceutical industry shows a decreasing interest in the development of drugs for migraine. One of the reasons for this could be the lack of reliable animal models for studying the effect of acute and prophylactic migraine drugs. The infusion of glyceryl trinitrate (GTN) is the best validated and most studied human migraine model. Several attempts have been made to transfer this model to animals. The different variants of this model are discussed as well as other recent models.
Rationale and design of PATRO Adults, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope® for the treatment of adult patients with growth hormone deficiency
Authors: Beck-Peccoz Paolo , Minuto Francesco , Leal-Cerro Alfonso , Zabransky Markus , Stalla Günter 
Published: March 2012

Objective: To describe the rationale and design of PATRO Adults, a postmarketing surveillance study of the long-term efficacy and safety of somatropin (Omnitrope®) for the treatment of adult patients with growth hormone deficiency (GHD). Methods: PATRO Adults is an observational, multicentre, open, longitudinal, noninterventional study being conducted in hospitals and specialized endocrinology clinics across several European countries. The primary objective is to assess the safety and efficacy of Omnitrope® in adults treated in routine clinical practice. Eligible patients are male or female adults who are receiving treatment with Omnitrope® and who have provided informed consent. Patients who have been treated with another human growth hormone (hGH) product before starting Omnitrope® therapy will also be eligible for inclusion. Efficacy assessments will be based on the analysis of the following: insulin-like growth factor-1 levels within age- and gender-adjusted normal ranges; anthropometric measures (weight, waist circumference, total fat mass, lean body mass, total body water); bone mineral density; lipids; effects on cardiovascular risk factors such as glucose metabolism, blood pressure and inflammatory markers (e.g. C-reactive protein); and quality of life. All adverse events will be monitored and recorded. Particular emphasis will be placed on long-term safety, the recording of malignancies, the occurrence and clinical impact of antirecombinant hGH antibodies, the incidence, severity and duration of hyperglycaemia, and the development of diabetes during treatment with Omnitrope®. Conclusions: PATRO Adults is a large, long-term, postmarketing surveillance study that will extend the safety database for Omnitrope®, as well as contributing to the available data for all recombinant hGH products. Of particular interest, the study will provide important data on the impact of long-term GH replacement therapy on the development of diabetes mellitus, the recurrence/regrowth of hypothalamic–pituitary tumours, and de novo malignancy or recurrence of other (non-hypothalamic–pituitary) tumours.
Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study
Authors: Lentzsch Suzanne , O'Sullivan Amy , Kennedy Ryan C. , Abbas Mohammad , Dai Lijun , Pregja Silvana Lalo , Burt Steve , Boyiadzis Michael , Roodman G. David , Mapara Markus Y. , Agha Mounzer , Waas John , Shuai Yongli , Normolle Daniel , Zonder Jeffrey A. 
Published: March 2012

Abstract
This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.