bluuebunny/crossref_metadata_2025_split huggingface dataset:
Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes
Authors: Hammerschmidt Claudia , Koenigs Arno , Siegel Corinna , Hallström Teresia , Skerka Christine , Wallich Reinhard , Zipfel Peter F. , Kraiczy Peter 
Published: November 2013

ABSTRACTCspA of the Lyme disease spirocheteBorrelia burgdorferirepresents a key molecule in immune evasion, protecting borrelial cells from complement-mediated killing. As previous studies focused almost exclusively on CspA ofB. burgdorferi, here we investigate the different binding capacities of CspA orthologs ofBorrelia burgdorferi,B. afzelii, andB. spielmaniifor complement regulator factor H and plasminogen and their ability to inhibit complement activation by either binding these host-derived plasma proteins or independently by direct interaction with components involved in formation of the lethal, pore-like terminal complement complex. To further examine their function in serum resistancein vivo, a serum-sensitiveB. gariniistrain was used to generate spirochetes, ectopically producing functional CspA orthologs. Irrespective of their species origin, all three CspA orthologs impart resistance to complement-mediated killing when produced in a serum-sensitiveB. gariniisurrogate strain. To analyze the inhibitory effect on complement activation and to assess the potential to inactivate C3b by binding of factor H and plasminogen, recombinant CspA orthologs were also investigated. All three CspA orthologs simultaneously bound factor H and plasminogen but differed in regard to their capacity to inactivate C3b via bound plasmin(ogen) and inhibit formation of the terminal complement complex. CspA ofB. afzeliibinds plasmin(ogen) and inhibits the terminal complement complex more efficiently than CspA ofB. burgdorferiandB. spielmanii. Taken together, CspA orthologs of serum-resistant Lyme disease spirochetes act as multifunctional evasion molecules that inhibit complement on two central activation levels, C3b generation and assembly of the terminal complement complex.
Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria
Authors: Kim Hani , Erdman Laura K. , Lu Ziyue , Serghides Lena , Zhong Kathleen , Dhabangi Aggrey , Musoke Charles , Gerard Craig , Cserti-Gazdewich Christine , Liles W. Conrad , Kain Kevin C. 
Published: November 2013

ABSTRACT

The host immune response plays an important role in the onset and progression of cerebral malaria (CM). The complement system is an essential component of the innate immune response to malaria, and its activation generates the anaphylatoxin C5a. To test the hypothesis that C5a signaling contributes to the pathogenesis of CM, we investigated a causal role for the C5a receptors C5aR and C5L2 in a mouse model of experimental CM (ECM) induced by
Plasmodium berghei
ANKA infection, and using a case-control design, we examined levels of C5a in plasma samples from Ugandan children presenting with CM or uncomplicated malaria (UM). In the ECM model,
C5aR
−/−
mice displayed significantly improved survival compared to their wild-type (WT) counterparts (
P
= 0.004), whereas
C5L2
−/−
mice showed no difference in survival from WT mice. Improved survival in
C5aR
−/−
mice was associated with reduced levels of the proinflammatory cytokines tumor necrosis factor (TNF) and gamma interferon (IFN-γ) and the chemokine, monocyte chemoattractant protein 1 (MCP-1) (CCL2). Furthermore, endothelial integrity was enhanced, as demonstrated by increased levels of angiopoietin-1, decreased levels of angiopoietin-2 and soluble ICAM-1, and decreased Evans blue extravasation into brain parenchyma. In the case-control study, the median levels of C5a at presentation were significantly higher in children with CM versus those in children with UM (43.7 versus 22.4 ng/ml;
P
< 0.001). These findings demonstrate that C5a is dysregulated in human CM and contributes to the pathogenesis of ECM via C5aR-dependent inflammation and endothelial dysfunction.
Radiologically isolated syndrome: an uncommon finding at a university clinic in a high-prevalence region for multiple sclerosis
Authors: Granberg Tobias , Martola Juha , Aspelin Peter , Kristoffersen-Wiberg Maria , Fredrikson Sten 
Published: November 2013

ObjectiveThe improved availability of MRI in medicine has led to an increase in incidental findings. Unexpected brain MRI findings suggestive of multiple sclerosis (MS) without typical symptoms of MS were recently defined as radiologically isolated syndrome (RIS). The prevalence of RIS is uncertain. The aim of this study was to determine the prevalence of RIS at a university hospital in a region with a high prevalence for MS and describe the long-term prognosis of the identified patients.DesignRetrospective cohort study conducted in 2012.SettingAll brain MRI examinations performed at Karolinska University Hospital in Huddinge, Stockholm, Sweden during 2001 were retrospectively screened by a single rater for findings fulfilling the Okuda criteria. The sample year was chosen in order to establish the long-term prognosis of the patients identified. The examinations of interest were re-evaluated according to the Barkhof criteria by a neuroradiologist with long experience in MS.ParticipantsIn total 2105 individuals were included in the study. Ages ranged from 0 to 90 years with a median age of 48 years. Only one patient with RIS was identified, equivalent to a prevalence of 0.05% in the studied population, or 0.15% among patients aged 15–40 years. The patient with RIS developed symptoms consistent with MS within 3 months accompanied with radiological progression and was diagnosed with MS.ConclusionsRIS, according to present criteria, is an uncommon finding in a tertiary hospital setting in a high-prevalence region for MS where awareness and clinical suspicion of MS is common. In order to study the prognosis of RIS, multicentre studies, or case–control studies are recommended.
At cancer diagnosis: a ‘window of opportunity’ for behavioural change towards physical activity. A randomised feasibility study in patients with colon and breast cancer
Authors: Møller Tom , Lillelund Christian , Andersen Christina , Ejlertsen Bent , Nørgaard Lone , Christensen Karl Bang , Vadstrup Eva , Diderichsen Finn , Hendriksen Carsten , Bloomquist Kira , Adamsen Lis 
Published: November 2013

IntroductionChallenges exist in identifying, recruiting and motivating sedentary patients with cancer to initiate physical activity towards recommended levels. We hypothesise that the onset period of adjuvant chemotherapy can be ‘the open window of opportunity’ to identify and motivate sedentary patients with breast and colon cancers, at risk for developing coronary heart disease, to initiate and sustain lifestyle changes.AimsTo investigate the feasibility of oncologists/nurses screening for physical inactivity, in order to identify and recruit an at-risk population of sedentary patients with breast or colon cancer at the onset of adjuvant chemotherapy. Furthermore, the study will examine the adherence to one of two multimodal exercise interventions lasting 12 weeks; (1) hospital-based, high intensity, group exercise intervention (2) home-based, low intensity, individual, pedometer intervention. Both arms will be compared with a control group.Methods and analysesAll newly referred patients will be screened for sedentary behaviour, using national recommendations. Testing at baseline, 6, 12 and 39 weeks will include; (1) physiological testing (VO2-peak, one repetition maximum muscle strength and lung function (2) fasting full body dual-energy X-ray absorptiometry scan (3) fasting blood glucose, insulin, lipids and cholesterols, (4) psychometric questionnaires (general well-being, quality of life, anxiety and depression, motivational readiness). The randomised controlled trial feasibility design is selected in order to examine barriers for recruitment, programme adherence, safety aspects and potential efficacy to the interventions during adjuvant chemotherapy.Ethics and disseminationThe Scientific Committee of the Capital Region (case No. H-1-2011-131) and the Danish Data Protection Agency (j. No. 2011-41-6349) approved the study. Data will be entered and locked into a database hosted by the Copenhagen Trial Unit, Rigshosptialet. Data will be available for analyses to project members and the trial statistician after the 45 included patients have completed the 12-week test. Results will be published in peer-reviewed scientific journals.Trial registrationCurrent Controlled TrialsISRCTN24901641.
Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial
Authors: Armstrong Matthew J , Barton Darren , Gaunt Piers , Hull Diana , Guo Kathy , Stocken Deborah , Gough Stephen C L , Tomlinson Jeremy W , Brown Rachel M , Hübscher Stefan G , Newsome Philip N ,   on behalf of the LEAN trial team
Published: November 2013

IntroductionNon-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH.Methods and analysisLiraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis.Ethics and disseminationThe protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.Trial registrationclinicaltrials.govNCT01237119.
Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs
Authors: Jardim Denis L. , Hess Kenneth R. , LoRusso Patricia , Kurzrock Razelle , Hong David S. 
Published: November 2013

Abstract
Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990–October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials. Clin Cancer Res; 20(2); 281–8. ©2013 AACR.
Restricted Expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Cell Carcinomas Enhances HIF2α Activity
Authors: Mathew Lijoy K. , Lee Samuel S. , Skuli Nicolas , Rao Shilpa , Keith Brian , Nathanson Katherine L. , Lal Priti , Simon M. Celeste 
Published: November 2013

Abstract
Inactivation of the von-Hippel Lindau (VHL) tumor suppressor gene occurs in 90% of human clear cell renal cell carcinomas (ccRCC) and leads to the stable expression of the hypoxia-inducible factors HIF1α and HIF2α. The constitutive expression of HIF1α in a majority of VHL-deficient tumors is counterintuitive, given that HIF1α functions as a tumor suppressor in ccRCC, whereas HIF2α clearly enhances tumor growth. We demonstrate here that miR-30c-2-3p and miR-30a-3p specifically bind and inhibit expression of HIF2A transcripts, and that the locus encoding miR-30c-2-3p and miR-30a-3p is selectively repressed in “H1H2” VHL-deficient tumors expressing both HIF1α and HIF2α proteins. Inhibiting miR-30a-3p expression increases HIF2α levels in H1H2 ccRCC cells and promotes cellular proliferation, angiogenesis, and xenograft tumor growth. Our results indicate that miR-30c-2-3p and miR-30a-3p repression enhances HIF2α expression and suggests a mechanism whereby the tumor-suppressive effects of constitutive HIF1α expression are attenuated in VHL-deficient H1H2 tumors.
Significance: HIF1α is constitutively expressed in a majority of VHL-deficient ccRCCs, despite its tumor suppressor activity in these malignancies. This study demonstrates that repression of miR-30c-2-3p/miR-30a-3p increases HIF2α levels to promote tumor growth, thereby ameliorating the inhibitory effects of HIF1α in ccRCCs. Cancer Discov; 4(1); 53–60. ©2013 AACR.
See related commentary by Moch and Lukamowicz-Rajska, p. 22
This article is highlighted in the In This Issue feature, p. 1
Characteristics and Outcomes of Sudden Cardiac Arrest During Sports in Women
Authors: Marijon Eloi , Bougouin Wulfran , Celermajer David S. , Périer Marie-Cécile , Dumas Florence , Benameur Nordine , Karam Nicole , Lamhaut Lionel , Tafflet Muriel , Mustafic Hazrije , de Deus Natalia Machado , Le Heuzey Jean-Yves , Desnos Michel , Avillach Paul , Spaulding Christian , Cariou Alain , Prugger Christof , Empana Jean-Philippe , Jouven Xavier 
Published: November 2013

Background—
No specific data are available on characteristics and outcome of sudden cardiac death (SCD) during sport activities among women in the general population.

Methods and Results—

From a prospective 5-year national survey, involving 820 subjects 10 to 75 years old who presented with SCD (resuscitated or not) during competitive or recreational sport activities, 43 (5.2%) such events occurred in women, principally during jogging, cycling, and swimming. The level of activity at the time of SCD was moderate to vigorous in 35 cases (81.4%). The overall incidence of sport-related SCD, among 15- to 75-year-old women, was estimated as 0.59 (95% confidence interval [CI], 0.39–0.79) to 2.17 (95% CI, 1.38–2.96) per year per million female sports participants for the 80th and 20th percentiles of reporting districts, respectively. Compared with men, the incidence of SCDs in women was dramatically lower, particularly in the 45- to 54-year range (relative risk, 0.033; 95% CI, 0.015–0.075). Despite similar circumstances of occurrence, survival at hospital admission (46.5%; 95% CI, 31.0–60.0) was significantly higher than that for men (30.0%; 95% CI, 26.8–33.2;
P
=0.02), although this did not reach statistical significance for hospital discharge. Favorable neurological outcomes were similar (80%). Cause of death seemed less likely to be associated with structural heart disease in women compared with men (58.3% versus 95.8%;
P
=0.003).

Conclusions—
Sports-related SCDs in women participants seems dramatically less common (up to 30-fold less frequent) compared with men. Our results also suggest a higher likelihood of successful resuscitation as well as less frequency of structural heart disease in women compared with men.
Mental Disorders Across the Adult Life Course and Future Coronary Heart Disease
Authors: Gale Catharine R. , Batty G. David , Osborn David P. J. , Tynelius Per , Rasmussen Finn 
Published: November 2013

Background—
Depression, anxiety, and psychotic disorders have been associated with an increased risk of coronary heart disease (CHD). It is unclear whether this association between mental health and CHD is present across a wider range of mental disorders.

Methods and Results—
Participants were 1 107 524 Swedish men conscripted at a mean age of 18.3 years. Mental disorders were assessed by psychiatric interview on conscription, and data on hospital admissions for mental disorder and CHD were obtained from national registers during 22.6 years of follow-up. An increased risk of incident CHD was evident across a range of mental disorders whether diagnosed at conscription or on later hospital admission. Age-adjusted hazard ratios (95% confidence intervals) according to diagnoses at conscription ranged from 1.30 (1.05–1.62) (depressive disorders) to 1.90 (1.58–2.28) (alcohol-related disorders). The equivalent figures according to diagnoses during hospital admission ranged from 1.49 (1.24–1.80) (schizophrenia) to 2.82 (2.53–3.13) (other substance use disorders). Associations were little changed by adjustment for parental socioeconomic status, or body mass index, diabetes mellitus, and blood pressure measured at conscription, but they were partially attenuated by the adjustment for smoking, alcohol intake, and intelligence measured at conscription, and for education and own socioeconomic position.

Conclusions—
Increased risk of incident CHD is present across a range of mental disorders and is observable when the disorders are diagnosed at a young age.
Role of Small-Conductance Calcium-Activated Potassium Channels in Atrial Electrophysiology and Fibrillation in the Dog
Authors: Qi Xiao-Yan , Diness Jonas G. , Brundel Bianca J.J.M. , Zhou Xiao-Bo , Naud Patrice , Wu Chia-Tung , Huang Hai , Harada Masahide , Aflaki Mona , Dobrev Dobromir , Grunnet Morten , Nattel Stanley 
Published: November 2013

Background—

Recent evidence points to functional Ca
2+
-dependent K
+
(SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.

Methods and Results—

Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC
50
of ≈5 μmol/L, without affecting Na
+
, Ca
2+
, or other K
+
currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (
P
o
), whereas AT-P enhanced both whole-cell SK currents and single-channel
P
o
. SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.

Conclusions—
SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.
Regional Assessment of Sampling Techniques for More Efficient Dynamical Climate Downscaling
Authors: Pinto James O. , Monaghan Andrew J. , Delle Monache Luca , Vanvyve Emilie , Rife Daran L. 
Published: November 2013

Abstract
Dynamical downscaling is a computationally expensive method whereby finescale details of the atmosphere may be portrayed by running a limited area numerical weather prediction model (often called a regional climate model) nested within a coarse-resolution global reanalysis or global climate model output. The goal of this study is to assess using sampling techniques to dynamically downscale a small subset of days to approximate the statistical properties of the entire period of interest. Two sampling techniques are explored: one where days are randomly selected and another where representative days are chosen (or targeted) based on a set of selection criteria. The relative merit of using random sampling versus targeted random sampling is demonstrated using daily mean 2-m air temperature (T2M). The first two moments of dynamically downscaled T2M can be approximated within 0.3 K using just 5% of the population of available days during a 20-yr period. Targeted random sampling can reduce the mean absolute error of these estimates by as much as 30% locally. Estimation of the more extreme values of T2M is more uncertain and requires a larger sample size. The potential reduction in computational cost afforded by these sampling techniques could greatly benefit applications requiring high-resolution dynamically downscaled depictions of regional climate, including situations in which an ensemble of regional climate simulations is required to properly characterize uncertainty in the model physics assumptions, scenarios, and so on.