bluuebunny/crossref_metadata_2025_split huggingface dataset:
Killed but Metabolically Active Leishmania infantum as a Novel Whole-Cell Vaccine for Visceral Leishmaniasis
Authors: Bruhn Kevin W. , Birnbaum Ron , Haskell Jacquelyn , Vanchinathan Veena , Greger Stephanie , Narayan Rupa , Chang Pei-Lin , Tran Thu Anh , Hickerson Suzanne M. , Beverley Stephen M. , Wilson Mary E. , Craft Noah 
Published: February 2012

ABSTRACTThere are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach usingLeishmania infantum chagasipromastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results inLeishmaniaorganisms termed killed but metabolically active (KBMA). In this report, we characterize thein vitrogrowth characteristics of both KBMAL. majorand KBMAL. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like liveL. infantum chagasi, KBMAL. infantum chagasiparasites were able to initially enter liver cellsin vivoafter intravenous infection. However, whereas liveL. infantum chagasiinfection leads to hepatosplenomegaly in mice after 6 months, KBMAL. infantum chagasiparasites were undetectable in the organs of mice at this time point.In vitro, KBMAL. infantum chagasiretained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMAL. infantum chagasicorrelated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either liveL. infantum chagasior KBMAL. infantum chagasidisplayed similar cytokine patternsin vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoanL. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.
Diagnostic Performance of a Multiple Real-Time PCR Assay in Patients with Suspected Sepsis Hospitalized in an Internal Medicine Ward
Authors: Pasqualini Leonella , Mencacci Antonella , Leli Christian , Montagna Paolo , Cardaccia Angela , Cenci Elio , Montecarlo Ines , Pirro Matteo , di Filippo Francesco , Cistaro Emma , Schillaci Giuseppe , Bistoni Francesco , Mannarino Elmo 
Published: February 2012

ABSTRACT

Early identification of causative pathogen in sepsis patients is pivotal to improve clinical outcome. SeptiFast (SF), a commercially available system for molecular diagnosis of sepsis based on PCR, has been mostly used in patients hospitalized in hematology and intensive care units. We evaluated the diagnostic accuracy and clinical usefulness of SF, compared to blood culture (BC), in 391 patients with suspected sepsis, hospitalized in a department of internal medicine. A causative pathogen was identified in 85 patients (22%). Sixty pathogens were detected by SF and 57 by BC. No significant differences were found between the two methods in the rates of pathogen detection (
P
= 0.74), even after excluding 9 pathogens which were isolated by BC and were not included in the SF master list (
P
= 0.096). The combination of SF and BC significantly improved the diagnostic yield in comparison to BC alone (
P
< 0.001). Compared to BC, SF showed a significantly lower contamination rate (0 versus 19 cases;
P
< 0.001) with a higher specificity for pathogen identification (1.00, 95% confidence interval [CI] of 0.99 to 1.00, versus 0.94, 95% CI of 0.90 to 0.96;
P
= 0.005) and a higher positive predictive value (1.00, 95% CI of 1.00 to 0.92%, versus 0.75, 95% CI of 0.63 to 0.83;
P
= 0.005). In the subgroup of patients (
n
= 191) who had been receiving antibiotic treatment for ≥24 h, SF identified more pathogens (16 versus 6;
P
= 0.049) compared to BC. These results suggest that, in patients with suspected sepsis, hospitalized in an internal medicine ward, SF could be a highly valuable adjunct to conventional BC, particularly in patients under antibiotic treatment.
Immunodominant “Asymptomatic” Herpes Simplex Virus 1 and 2 Protein Antigens Identified by Probing Whole-ORFome Microarrays with Serum Antibodies from Seropositive Asymptomatic versus Symptomatic Individuals
Authors: Dasgupta Gargi , Chentoufi Aziz A. , Kalantari Mina , Falatoonzadeh Payam , Chun Sookhee , Lim Chang Hyun , Felgner Philip L. , Davies D. Huw , BenMohamed Lbachir 
Published: February 2012

ABSTRACTHerpes simplex virus 1 (HSV-1) and HSV-2 are medically significant pathogens. The development of an effective HSV vaccine remains a global public health priority. HSV-1 and HSV-2 immunodominant “asymptomatic” antigens (ID-A-Ags), which are strongly recognized by B and T cells from seropositive healthy asymptomatic individuals, may be critical to be included in an effective immunotherapeutic HSV vaccine. In contrast, immunodominant “symptomatic” antigens (ID-S-Ags) may exacerbate herpetic disease and therefore must be excluded from any HSV vaccine. In the present study, proteome microarrays of 88 HSV-1 and 84 HSV-2 open reading frames(ORFs) (ORFomes) were constructed and probed with sera from 32 HSV-1-, 6 HSV-2-, and 5 HSV-1/HSV-2-seropositive individuals and 47 seronegative healthy individuals (negative controls). The proteins detected in both HSV-1 and HSV-2 proteome microarrays were further classified according to their recognition by sera from HSV-seropositive clinically defined symptomatic (n= 10) and asymptomatic (n= 10) individuals. We found that (i) serum antibodies recognized an average of 6 ORFs per seropositive individual; (ii) the antibody responses to HSV antigens were diverse among HSV-1- and HSV-2-seropositive individuals; (iii) panels of 21 and 30 immunodominant antigens (ID-Ags) were identified from the HSV-1 and HSV-2 ORFomes, respectively, as being highly and frequently recognized by serum antibodies from seropositive individuals; and (iv) interestingly, four HSV-1 and HSV-2 cross-reactive asymptomatic ID-A-Ags, US4, US11, UL30, and UL42, were strongly and frequently recognized by sera from 10 of 10 asymptomatic patients but not by sera from 10 of 10 symptomatic patients (P< 0.001). In contrast, sera from symptomatic patients preferentially recognized the US10 ID-S-Ag (P< 0.001). We have identified previously unreported immunodominant HSV antigens, among which were 4 ID-A-Ags and 1 ID-S-Ag. These newly identified ID-A-Ags could lead to the development of an efficient “asymptomatic” vaccine against ocular, orofacial, and genital herpes.
Clinical decision making in a high-risk primary care environment: a qualitative study in the UK
Authors: Balla John , Heneghan Carl , Thompson Matthew , Balla Margaret 
Published: February 2012

ObjectiveExamine clinical reasoning and decision making in an out of hours (OOH) primary care setting to gain insights into how general practitioners (GPs) make clinical decisions and manage risk in this environment.DesignSemi-structured interviews using open-ended questions.SettingA 2-month qualitative interview study conducted in Oxfordshire, UK.Participants21 GPs working in OOH primary care.ResultsThe most powerful themes to emerge related to dealing with urgent potentially high-risk cases, keeping patients safe and responding to their needs, while trying to keep patients out of hospital and the concept of ‘fire fighting’. There were a number of well-defined characteristics that GPs reported making presentations easy or difficult to deal with. Severely ill patients were straightforward, while the older people, with complex multisystem diseases, were often difficult. GPs stopped collecting clinical information and came to clinical decisions when high-risk disease and severe illness requiring hospital attention has been excluded; they had responded directly to the patient's needs and there was a reliable safety net in place. Learning points that GPs identified as important for trainees in the OOH setting included the importance of developing rapport in spite of time pressures, learning to deal with uncertainty and learning about common presentations with a focus on critical cues to exclude severe illness.ConclusionsThe findings support suggestions that improvements in primary care OOH could be achieved by including automated and regular timely feedback system for GPs and individual peer and expert clinician support for GPs with regular meetings to discuss recent cases. In addition, trainee support and mentoring to focus on clinical skills, knowledge and risk management issues specific to OOH is currently required. Investigating the stopping rules used for diagnostic closure may provide new insights into the root causes of clinical error in such a high-risk setting.
Change in physical activity and weight in relation to retirement: the French GAZEL Cohort Study
Authors: Sjösten Noora , Kivimäki Mika , Singh-Manoux Archana , Ferrie Jane E , Goldberg Marcel , Zins Marie , Pentti Jaana , Westerlund Hugo , Vahtera Jussi 
Published: February 2012

ObjectivesTo examine the trajectories of physical activity from preretirement to postretirement and to further clarify whether the changes in physical activity are associated with changes in body weight.DesignProspective.SettingFrench national gas and electricity company (GAZEL cohort).ParticipantsFrom the original sample of 20 625 employees, only those retiring between 2001 and 2008 on a statutory basis were selected for the analyses (analysis 1: n=2711, 63% men; analysis 2: n=3812, 75% men). Persons with data on at least one preretirement and postretirement measurement of the outcome were selected.Primary and secondary outcome measuresAll outcome data were gathered by questionnaires. In analysis 1, the annual prevalence of higher physical activity (walking ≥5 km/week) 4 years before and after retirement was analysed. In analysis 2, changes in leisure-time sport activities (engagement, frequency and manner) from preretirement to postretirement were analysed with simultaneous changes in body weight (kilogram).ResultsIn analysis 1 (n=2711), prevalence estimates for 4 years before and 4 years after retirement showed that higher leisure-time physical activity (walking at least 5 km/week) increased by 36% in men and 61% in women during the transition to retirement. This increase was also observed among people at a higher risk of physical inactivity, such as smokers and those with elevated depressive symptoms. In a separate sample (analysis 2, n=3812), change in weight as a function of preretirement and postretirement physical activity was analysed. Weight gain preretirement to postretirement was 0.85 (95% CI 0.48 to 1.21) to 1.35 (0.79 to 1.90) kg greater among physically inactive persons (decrease in activity or inactive) compared with those physically active (p<0.001).ConclusionsRetirement transition may be associated with beneficial changes in lifestyle and may thus be a good starting point to preventive interventions in various groups of individuals in order to maintain long-term changes.
Incomplete mechanical recanalization of middle cerebral artery occlusions facilitates endogenous recanalization within 5 h
Authors: Loh Yince , Shi Zhongsong , Liebeskind David , Jahan Reza , Gonzalez Nestor , Vespa Paul M , Starkman Sidney , Saver Jeffrey L , Tateshima Satoshi , Vinuela Fernando , Duckwiler Gary 
Published: February 2012

Background and purposeSuccessful revascularization can often improve functional outcome after large intracranial arterial occlusions. However, incomplete or unsuccessful recanalization is often the end result after attempted mechanical thrombectomy. A study was undertaken to determine whether partial recanalization of proximal isolated middle cerebral artery (MCA) occlusions facilitates endogenous thrombolysis and spontaneous recanalization.MethodsWe retrospectively analyzed consecutive patients with acute ischemic stroke undergoing mechanical thrombectomy using the Merci Retriever System for occlusions involving any portion of the M1 segment of the MCA. Only those patients with a residual obstruction of the proximal MCA segments were included. The rates of facilitated endogenous recanalization (FER5) by imaging within the 5 h following intervention were compared in patients with partial proximal recanalization and those in whom recanalization was unsuccessful.ResultsForty-two patients were included in the analysis. Twenty-six patients had good recanalization of the proximal aspect of the target lesion with an arterial occlusive lesion score of 2 or 3 but a residual partial or total occlusion of the MCA, while 16 patients failed to recanalize any portion of the target occlusion. Twelve patients (46%) in the first group and only one (5.9%) in the second group had facilitated endogenous recanalization on interval imaging 5 h after intervention (OR 12.9, 95% CI 1.5 to 112.2). Nine patients with proximal recanalization had good clinical outcomes at discharge (mRS ≤2) compared with none without recanalization (p=0.01), but FER did not have a relationship with clinical outcome.ConclusionsDespite initially incomplete proximal mechanical thrombectomy, nearly half of all patients with residual M1 occlusions will undergo further endogenous recanalization within the subsequent 5 h.
EIGENVALUES OF THE LAPLACIAN ON RIEMANNIAN MANIFOLDS
Authors: CHENG QING-MING , QI XUERONG 
Published: February 2012

For a bounded domain Ω with a piecewise smooth boundary in a complete Riemannian manifold M, we study eigenvalues of the Dirichlet eigenvalue problem of the Laplacian. By making use of a fact that eigenfunctions form an orthonormal basis of L2(Ω) in place of the Rayleigh–Ritz formula, we obtain inequalities for eigenvalues of the Laplacian. In particular, for lower order eigenvalues, our results extend the results of Chen and Cheng [D. Chen and Q.-M. Cheng, Extrinsic estimates for eigenvalues of the Laplace operator, J. Math. Soc. Japan 60 (2008) 325–339].
SKLB1206, a Novel Orally Available Multikinase Inhibitor Targeting EGFR Activating and T790M Mutants, ErbB2, ErbB4, and VEGFR2, Displays Potent Antitumor Activity Both In Vitro and In Vivo
Authors: Pan Youli , Xu Yong , Feng Shan , Luo Shidong , Zheng Renlin , Yang Jiao , Wang Lijiao , Zhong Lei , Yang Han-Yu , Wang Bing-Lin , Yu Yang , Liu Jingjing , Cao Zhixing , Wang Xiaoyan , Ji Pan , Wang Zerong , Chen Xin , Zhang Shuang , Wei Yu-Quan , Yang Sheng-Yong 
Published: February 2012

Abstract
Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here, we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and -resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative activity against a range of EGFR-mutant cell lines, including gefitinib-sensitive and -resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo, and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR-activating/resistance mutations or EGFR/ErbB2 overexpressed. Mol Cancer Ther; 11(4); 952–62. ©2012 AACR.
Serine-305 Phosphorylation Modulates Estrogen Receptor Alpha Binding to a Coregulator Peptide Array, with Potential Application in Predicting Responses to Tamoxifen
Authors: Houtman René , de Leeuw Renée , Rondaij Mariska , Melchers Diana , Verwoerd Desiree , Ruijtenbeek Rob , Martens John W.M. , Neefjes Jacques , Michalides Rob 
Published: February 2012

Abstract
With current techniques, it remains a challenge to assess coregulator binding of nuclear receptors, for example, the estrogen receptor alpha (ERα). ERα is critical in many breast tumors and is inhibited by antiestrogens such as tamoxifen in cancer therapy. ERα is also modified by acetylation and phosphorylation that affect responses to the antiestrogens as well as interactions with coregulators. Phosphorylation of ERα at Ser305 is one of the mechanisms causing tamoxifen resistance. Detection of resistance in patient samples would greatly facilitate clinical decisions on treatment, in which such patients would receive other treatments such as aromatase inhibitors or fulvestrant. Here we describe a coregulator peptide array that can be used for high-throughput analysis of full-length estrogen receptor binding. The peptide chip can detect ERα binding in cell and tumor lysates. We show that ERα phosphorylated at Ser305 associates stronger to various coregulator peptides on the chip. This implies that ERαSer305 phosphorylation increases estrogen receptor function. As this is also detected in a breast tumor sample of a tamoxifen-insensitive patient, the peptide array, as described here, may be applicable to detect tamoxifen resistance in breast tumor samples at an early stage of disease and contribute to personalized medicine. Mol Cancer Ther; 11(4); 805–16. ©2012 AACR.
The treatment of venous thromboembolism with low-molecular-weight heparins
Authors: Nizankowski Rafal , Bochenek Tomasz 
Published: February 2012

SummaryThe currently recommended method of venous thromboembolism (VTE) treatment is the application of vitamin K antagonists (VKA) in most patients, and low-molecular-weight heparins (LMWH) in selected groups. The VKA dose adjustment is difficult which might well render the treatment ineffective. The study aimed to compare LMWH with VKA in treating VTE in terms of efficacy and safety. A systematic review of literature and the meta-analysis of the treatment results were performed. The main differences between LMWH and VKA in terms of their respective effectiveness in treating VTE consist in appreciably more advantageous effects of LMWH in preventing deep venous thrombosis (DVT). The key difference in terms of respective safety is the greater effectiveness of LMWH in preventing minor bleedings. The advantage of LMWH in cancer patients consists predominantly in a significantly better protection against DVT episodes, whereas the advantage of LMWH in non-cancer patients is mainly owed to better protection against minor bleedings. In none of the analysed outcomes of VTE treatment, the application of VKA proved to hold any advantage over LMWH. Although, arguably, there might well be sufficient medical grounds to propose more widespread use of LMWH, it still remains a debatable issue whether the currently used therapeutic standard should also be modified accordingly. Apart from the actual findings of the present meta-analysis, pertinent economic considerations must also be addressed.
Emotional states and future risk of venous thromboembolism
Authors: Brækkan Sigrid K. , Hansen-Krone Ida J. , Hansen John-Bjarne , Enga Kristin F. 
Published: February 2012

SummaryEmotional states of depression and loneliness are reported to be associated with higher risk and optimism with lower risk of arterial cardiovascular disease (CVD) and death. The relation between emotional states and risk of venous thromboembolism (VTE) has not been explored previously. We aimed to investigate the associations between self-reported emotional states and risk of incident VTE in a population-based, prospective study. The frequency of feeling depressed, lonely and happy/optimistic were registered by self-administered questionnaires, along with major co-morbidities and lifestyle habits, in 25,964 subjects aged 25–96 years, enrolled in the Tromsø Study in 1994–1995. Incident VTE-events were registered from the date of inclusion until September 1, 2007. There were 440 incident VTE-events during a median of 12.4 years of follow-up. Subjects who often felt depressed had 1.6-fold (95% CI:1.02–2.50) higher risk of VTE compared to those not depressed in analyses adjusted for other risk factors (age, sex , body mass index, oes-trogens), lifestyle (smoking, alcohol consumption, educational level) and co-morbidities (diabetes, CVD, and cancer). Often feeling lonely was not associated with VTE. However, the incidence rate of VTE in subjects who concurrently felt often lonely and depressed was higher than for depression alone (age-and sex-adjusted incidence rate: 3.27 vs. 2.21). Oppositely, subjects who often felt happy/optimistic had 40% reduced risk of VTE (HR 0.60, 95% CI: 0.41–0.87). Our findings suggest that self-reported emotional states are associated with risk of VTE. Depressive feelings were associated with increased risk, while happiness/ optimism was associated with reduced risk of VTE.
Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH)
Authors: Joglekar Manali V. , Diez Pedro M. , Marcus Stephen , Qi Rui , Espinasse Benjamin , Wiesner Mark R. , Pempe Elizabeth , Liu Jian , Monroe Dougald M. , Arepally Gowthami M. 
Published: February 2012

SummaryRecent studies have shown that ultra-large complexes (ULCs) of platelet factor 4 (PF4) and heparin (H) play an essential role in the pathogenesis of heparin-induced thrombocytopenia (HIT), an immune-mediated disorder caused by PF4/H antibodies. Because antigenic PF4/H ULCs assemble through non-specific electrostatic interactions, we reasoned that disruption of charge-based interactions can modulate the immune response to antigen. We tested a minimally anticoagulant compound (2-O, 3-O desulfated heparin, ODSH) with preserved charge to disrupt PF4/H complex formation and immunogenicity. We show that ODSH disrupts complexes when added to pre-formed PF4/H ULCs and prevents ULC formation when incubated simultaneously with PF4 and UFH. In other studies, we show that excess ODSH reduces HIT antibody (Ab) binding in immunoassays and that PF4/ODSH complexes do not cross-react with HIT Abs. When ODSH and unfractionated heparin (UFH) are mixed at equimolar concentrations, we show that there is a negligible effect on amount of protamine required for heparin neutralisation and reduced immunogenicity of PF4/UFH in the presence of ODSH. Taken together, these studies suggest that ODSH can be used concurrently with UFH to disrupt PF4/H charge interactions and provides a novel strategy to reduce antibody mediated complications in HIT.Presented in part at the 52nd American Society of Hematology Annual Meeting and Exposition, December 6th, 2010, Orlando, Florida, USA.