bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recovery of a Medieval Brucella melitensis Genome Using Shotgun Metagenomics
Authors: Kay Gemma L. , Sergeant Martin J. , Giuffra Valentina , Bandiera Pasquale , Milanese Marco , Bramanti Barbara , Bianucci Raffaella , Pallen Mark J. 
Published: July 2014

ABSTRACT

Shotgun metagenomics provides a powerful assumption-free approach to the recovery of pathogen genomes from contemporary and historical material. We sequenced the metagenome of a calcified nodule from the skeleton of a 14th-century middle-aged male excavated from the medieval Sardinian settlement of Geridu. We obtained 6.5-fold coverage of a
Brucella melitensis
genome. Sequence reads from this genome showed signatures typical of ancient or aged DNA. Despite the relatively low coverage, we were able to use information from single-nucleotide polymorphisms to place the medieval pathogen genome within a clade of
B. melitensis
strains that included the well-studied Ether strain and two other recent Italian isolates. We confirmed this placement using information from deletions and IS
711
insertions. We conclude that metagenomics stands ready to document past and present infections, shedding light on the emergence, evolution, and spread of microbial pathogens.

IMPORTANCE
Infectious diseases have shaped human populations and societies throughout history. The recovery of pathogen DNA sequences from human remains provides an opportunity to identify and characterize the causes of individual and epidemic infections. By sequencing DNA extracted from medieval human remains through shotgun metagenomics, without target-specific capture or amplification, we have obtained a draft genome sequence of an ~700-year-old
Brucella melitensis
strain. Using a variety of bioinformatic approaches, we have shown that this historical strain is most closely related to recent strains isolated from Italy, confirming the continuity of this zoonotic infection, and even a specific lineage, in the Mediterranean region over the centuries.
Comparison of endovascular treatment approaches for acute ischemic stroke: cost effectiveness, technical success, and clinical outcomes
Authors: Turk Aquilla S , Turner Raymond , Spiotta Alejandro , Vargas Jan , Holmstedt Christine , Ozark Shelly , Chalela Julio , Turan Tanya , Adams Robert , Jauch Edward C , Battenhouse Holly , Whitsitt Brian , Wain Matt , Chaudry M Imran 
Published: July 2014

IntroductionThe use of mechanical thrombectomy for the treatment of acute ischemic stroke has significantly advanced over the last 5 years. Few data are available comparing the cost and clinical and angiographic outcomes associated with available techniques. The aim of this study is to compare the cost and efficacy of current endovascular stroke therapies.MethodsA single-center retrospective review was performed of the medical record and hospital financial database of all ischemic stroke cases admitted from 2009 to 2013. Three discrete treatment methodologies used during this time were compared: traditional Penumbra System (PS), stent retriever with local aspiration (SRLA) and A Direct Aspiration first Pass Technique (ADAPT). Statistical analyses of clinical and angiographic outcomes and costs for each group were performed.Results222 patients (45% men) underwent mechanical thrombectomy. Successful revascularization was defined as Thrombolysis In Cerebral Infarction (TICI) 2b/3 flow, which was achieved in 79% of cases with PS, 83% of cases with SRLA, and 95% of cases with ADAPT. The average total cost of hospitalization for patients was $51 599 with PS, $54 700 with SRLA, and $33 611 with ADAPT (p<0.0001). Average times to recanalization were 88 min with PS, 47 min with SRLA, and 37 min with ADAPT (p<0.0001). Similar rates of good functional outcomes were seen in the three groups (PS 36% vs SRLA 43% vs ADAPT 47%; p=0.4).ConclusionsThe ADAPT technique represents the most technically successful yet cost-effective approach to revascularization of large vessel intracranial occlusions.
A questionnaire‐based survey on the uptake and use of cattle vaccines in the UK
Authors: Cresswell E. , Brennan M. L. , Barkema H. W. , Wapenaar W. 
Published: July 2014

BackgroundVaccination is a widely used strategy for disease control in cattle in the UK and abroad. However, there has been limited research describing the uptake and use of cattle vaccines on UK farms.AimTo describe the current uptake and usage of cattle vaccines in the UK.DesignA questionnaire, available in paper and online format, was distributed to cattle farmers by convenience sampling.ParticipantsAll UK cattle farmers were eligible to participate in the study.ResultsEighty‐six per cent of respondents (n=229/266) had vaccinated their cattle in the past year. Diseases most commonly vaccinated against were Bovine Viral Diarrhoea, Leptospirosis and Infectious Bovine Rhinotracheitis. Vaccination compliance was limited in certain areas, for example only 48 per cent of respondents stated that they administered the second dose in the primary course within the recommended timeframe, and 14 per cent of respondents stated that they vaccinated earlier than the youngest recommended age. Although outside the scope of this study, further work is needed to establish the extent of inadequate compliance and the effect this has on vaccine efficacy. The role of the veterinarian was highlighted as the main supplier of vaccines and preferred source of vaccination information. Respondents preferred to receive recommendations regarding vaccination by face‐to‐face communication with the veterinarian.ConclusionsThe results provide a description of the current uptake and usage of cattle vaccines in the UK. Uptake is generally high but there are areas of usage of vaccines which could be improved upon. The veterinarian plays a key role as supplier of vaccines and a source of information for the majority of farmers. Although outside the scope of this study, further work is needed to establish the extent of inadequate compliance and the effect this has on vaccine efficacy. Although the respondents in this study represent a biased population of farmers, the findings indicate areas for future investigation in order to improve vaccination strategies in cattle in the UK.
The Role of Age on Dose-Limiting Toxicities in Phase I Dose-Escalation Trials
Authors: Schwandt A. , Harris P.J. , Hunsberger S. , Deleporte A. , Smith G.L. , Vulih D. , Anderson B.D. , Ivy S.P. 
Published: July 2014

Abstract
Purpose: Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT.
Experimental Design: We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which &lt;33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables.
Results: Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P &lt; 0.05). There was no association between dose level administered and age (P = 0.57).
Conclusions: This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels. Clin Cancer Res; 20(18); 4768–75. ©2014 AACR.
Antiproliferative Effects of CDK4/6 Inhibition inCDK4-Amplified Human LiposarcomaIn VitroandIn Vivo
Authors: Zhang Yi-Xiang , Sicinska Ewa , Czaplinski Jeffrey T. , Remillard Stephen P. , Moss Samuel , Wang Yuchuan , Brain Christopher , Loo Alice , Snyder Eric L. , Demetri George D. , Kim Sunkyu , Kung Andrew L. , Wagner Andrew J. 
Published: July 2014

AbstractWell-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (RB) phosphorylation and dramatically decreased liposarcoma cell growth. Cell-cycle analysis demonstrated arrest at G0–G1. siRNA-mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor 18F-fluorodeoxyglucose uptake with decreased tumor biomarkers, including RB phosphorylation and bromodeoxyuridine incorporation in vivo. Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight. After prolonged continuous dosing, reestablishment of RB phosphorylation and cell-cycle progression was noted. These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function, and suggest its potential function in the regulation of survival and metabolism of liposarcoma, supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS. Mol Cancer Ther; 13(9); 2184–93. ©2014 AACR.
Las críticas de Kant al modelo teórico del estado westfaliano
Authors: Marey Macarena 
Published: July 2014

Neste artigo defendo a tese de que a crítica de Kant ao quadro teórico que serviu para apoiar o Estado moderno westfaliano consiste em mostrar a conexão entre a ilegitimidade do decisionismo e os equívocos do positivismo jurídico. Para tanto, proponho uma estrutura do argumento geral de Kantiano contra as teorias jusnaturalistas racionais modernas da tradição grociano-hobbesiana extraída dos escritos políticos de Kant da década de 1790.
Atrial Natriuretic Peptide Locally Counteracts the Deleterious Effects of Cardiomyocyte Mineralocorticoid Receptor Activation
Authors: Nakagawa Hitoshi , Oberwinkler Heike , Nikolaev Viacheslav O. , Gaßner Birgit , Umbenhauer Sandra , Wagner Helga , Saito Yoshihiko , Baba Hideo A. , Frantz Stefan , Kuhn Michaela 
Published: July 2014

Background—
The endocrine balance between atrial natriuretic peptide (ANP) and the renin–angiotensin–aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, toward increased mineralocorticoid receptor (MR) signaling, contributes to adverse left ventricular remodeling in response to pressure overload.

Methods and Results—

We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload–induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21 days of transverse aortic constriction, mice with cardiomyocyte-restricted inactivation (knockout) of the ANP receptor (guanylyl cyclase [GC]-A) or the downstream cGMP-dependent protein kinase I developed enhanced left ventricular hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/d) attenuated left ventricular hypertrophy and fully prevented fibrosis, dilatation, and failure. Transverse aortic constriction induced the cardiac expression of profibrotic connective tissue growth factor and attenuated the expression of SERCA2a (sarcoplasmic reticulum Ca
2+
-ATPase) in knockout mice, but not in controls. These genotype-dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGMP-dependent protein kinase I in transfected HEK 293 (human embryonic kidney) cells. Coimmunoprecipitation and fluorescence resonance energy transfer experiments demonstrated that a population of MRs were membrane associated in close interaction with GC-A and cGMP-dependent protein kinase I and, moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP.

Conclusions—
ANP counter-regulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload.
Heart Failure With Anemia
Authors: O’Meara Eileen , Rouleau Jean L. , White Michel , Roy Karine , Blondeau Lucie , Ducharme Anique , Neagoe Paul-Eduard , Sirois Martin G. , Lavoie Joël , Racine Normand , Liszkowski Mark , Madore François , Tardif Jean-Claude , de Denus Simon ,   List of the ANCHOR Co-Principal Investigators:, Bergeron Dr , Dion Dr , Dupuis Dr , Giannetti Dr , Huynh Dr , Nadeau Dr 
Published: July 2014

Background—
Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia.

Methods and Results—
In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia–HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF.

Conclusions—
Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00834691.
Trends in 10-Year Survival of Patients With Stroke Hospitalized Between 1980 and 2000
Authors: Lakshminarayan Kamakshi , Berger Alan K. , Fuller Candace C. , Jacobs David R. , Anderson David C. , Steffen Lyn M. , Sillah Arthur , Luepker Russell V. 
Published: July 2014

Background and Purpose—
We report on trends in poststroke survival, both in the early period after stroke and over the long term. We examine these trends by stroke subtype.

Methods—
The Minnesota Stroke Survey is a study of all hospitalized patients with acute stroke aged 30 to 74 years in the Minneapolis–St Paul metropolis. Validated stroke events were sampled for survey years 1980, 1985, 1990, 1995, and 2000 and subtyped as ischemic or hemorrhagic by neuroimaging for survey years 1990, 1995, and 2000. Survival was obtained by linkage to vital statistics data through the year 2010.

Results—

There were 3773 acute stroke events. Age-adjusted 10-year survival improved from 1980 to 2000 (men 29.5% and 46.5%;
P
<0.0001; women 32.6% and 50.5%;
P
<0.0001). Ten-year ischemic stroke survival (n=1667) improved from 1990 to 2000 (men 35.3% and 50%;
P
=0.0001; women 38% and 55.3%;
P
<0.0001). Ten-year hemorrhagic stroke survival showed a trend toward improvement, but this (n=489) did not reach statistical significance, perhaps because of their smaller number (men 29.7% and 45.8%;
P
=0.06; women 39.2% and 49.6%;
P
=0.2). Markers of stroke severity including unconsciousness or major neurological deficits at admission declined from 1980 to 2000 while neuroimaging use increased.

Conclusions—
These poststroke survival trends are likely because of multiple factors, including more sensitive case ascertainment shifting the case mix toward less severe strokes, improved stroke care and risk factor management, and overall improvements in population health and longevity.
Clinical Features and Outcomes of Spinal Cord Arteriovenous Malformations
Authors: Lee Young-Jun , Terbrugge Karel G. , Saliou Guillaume , Krings Timo 
Published: July 2014

Background and Purpose—
As a result of the rarity of spinal cord arteriovenous malformations (AVM), there are only a few series available that describe clinical features, outcome after treatment, and natural history of these lesions. In this article, we aim to describe our experience with both nidus- and fistulous-type spinal cord AVMs.

Methods—
Forty-four consecutive patients with spinal cord AVMs were retrospectively reviewed. There were 26 patients with a nidus-type and 18 patients with a fistulous-type AVM. Treatments were performed with embolization (n=23), surgery (n=13), combined embolization–surgery (n=3), or conservative management (n=5). Clinical features, radiological findings, treatment results, and clinical outcomes were assessed.

Results—

Patients with nidus-type AVMs were younger at presentation and more often presented with hemorrhage, with a higher proportion of hematomyelia than fistulous-type AVMs (
P
<0.05). Progression of clinical presentation from hemorrhage to congestive myelopathy during follow-up was noted in 5 patients, all of which had AVMs of the nidus type. Complete obliteration could be achieved more often in the fistulous type (72%) than in the nidus type (27%). Improved or stable clinical status at last follow-up was noted in 100% of fistulous-type and 77% of nidus-type patients. Long-term clinical deterioration was noted in 6 of 26 patients with nidus-type (23%) AVMs and was related to recurrent bleeding (n=3) or progressive venous congestion (n=3). Overall rebleed rate after presentation with hemorrhage was 7 in 145.5 patient-years (4.8%/y) if the lesion was not treated, 3 in 102 patient-years (2.9%/y) after partial treatment, and 0 in 47.5 patient-years (0%) after complete treatment.

Conclusions—
Nidus and fistulous spinal cord AVMs have different clinical features and obliteration rates, which may affect their long-term prognosis.
Stable Boundary Layer in Complex Terrain. Part I: Linking Fluxes and Intermittency to an Average Stability Index
Authors: Medeiros Luiz E. , Fitzjarrald David R. 
Published: July 2014

AbstractAverage heat and momentum fluxes observed by a network of surface stations during the Hudson Valley Ambient Meteorology Study (HVAMS) were found as functions of a spatially representative bulk Richardson number Ribr. Preferential sites were identified for the occurrence of strong turbulence under mesoscale stability conditions common to all stations. Locally sensed turbulence intermittency depends on the mesoscale flow stability. Nearly continuous turbulence with few long-lived intermittent events occurs when Ribr < Ricr, the critical gradient Richardson number. Less-continuous mixing associated with a larger number of events occurs when Ricr < Ribr < 5, with the weakest turbulence and fewer events observed for Ribr ≫ Ricr. It was found that the need to allow for extra mixing above the conventional critical bulk Richardson number in numerical weather prediction models is primarily a consequence of spatial averaging in a heterogeneous landscape and is secondarily the result of turbulence above Ricr at locations with “nonideal fetch.”
Water Vapor Budget in a Developing Tropical Cyclone and Its Implication for Tropical Cyclone Formation
Authors: Fritz Cody , Wang Zhuo 
Published: July 2014

Abstract
Evolution of the water vapor budget from the tropical wave stage to the tropical cyclone stage is examined using a high-resolution numerical model simulation. The focus is on a time window from 27 h prior to genesis to 9 h after genesis, and the diagnoses are carried out in the framework of the marsupial paradigm. Analysis shows that the vertically integrated inward moisture flux accounts for a majority of the total condensation and that its fractional contribution increases from the tropical wave stage to the tropical cyclone stage. The fractional contribution of the local evaporation is much smaller and decreases from the tropical wave stage to the tropical cyclone stage. It is also shown that the radial moisture flux above 850 hPa is rather weak prior to genesis but increases significantly after genesis because of the deepening of the inflow layer. The decrease in the fractional contribution of the local evaporation, or the increase in the fractional contribution of the vertically integrated inward moisture flux, is due to the strengthening of the low-level convergence associated with the secondary circulation. The intensification of the secondary circulation can be attributed to the organized convection and concentrated diabatic heating near the circulation center. The results suggest that the local evaporation and its positive interaction with the primary circulation may not be as important as generally appreciated for tropical cyclone development. By contrast, the increase in the fractional contribution by the inward moisture flux with the storm intensification implies the importance of the positive feedback among the primary circulation, the secondary circulation, and convection for tropical cyclone development.