bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capillary zone electrophoresis for haemoglobinopathy diagnosis
Authors: Borbely Nicole , Phelan Lorraine , Szydlo Richard , Bain Barbara 
Published: October 2012

AimsCapillary zone electrophoresis (CE) at alkaline pH is increasingly used in haemoglobinopathy diagnosis. We report our evaluation of automated CE, using the Capillarys 2 Flex Piercing instrument, as a routine diagnostic method for the detection of variant haemoglobins and the diagnosis of β thalassaemia.MethodsA Capillarys 2 Flex Piercing instrument with Phoresis software was evaluated in our laboratory over a 6-week period, comparisons being made with high performance liquid chromatography (HPLC) and, for haemoglobin A2quantification, with microcolumn chromatography.ResultsThe instrument was easy to use and was suitable for the quantification of haemoglobin A2. Quantification of A2was precise and the percentage was stable with ageing of the blood specimen. Results differ among HPLC, CE and microcolumn chromatography and use of an instrument-specific, method-specific reference range is therefore recommended until such time as there is standardisation between methods and manufacturers. Common variant haemoglobins were provisionally identified without difficulty. There are some uncommon variant haemoglobins that are detected by HPLC but not by capillary electrophoresis, but the reverse also occurs.ConclusionsCapillary electrophoresis using a Capillarys 2 Flex Piercing instrument is suitable for haemoglobinopathy diagnosis.
The financial costs to patients of diagnosing and excluding ectopic pregnancy
Authors: Unger Holger W , Starrs Lisa , Scott Linda , Critchley Hilary O D , Duncan W Colin , Horne Andrew W 
Published: October 2012

ObjectivesHealth care costs are one of the greatest challenges in modern medicine. In gynaecology, diagnosing and excluding ectopic pregnancy (EP) has been shown to be a financial burden to health services because it commonly requires multiple investigations and hospital visits. However, the full economic costs are not captured by an analysis of health care costs alone. This study therefore aimed to assess the indirect costs to patients of diagnosing and excluding EP.MethodsPatients presenting to a Pregnancy Support Centre in a large UK teaching hospital with abdominal pain and/or bleeding and a positive pregnancy test were recruited during the period June 2010–February 2011. Patients were provided with questionnaires to be completed at home and designed to record and quantify costs that they had incurred until a final diagnosis of their condition was made. A cost–description analysis was performed.Results52/203 (26%) recruited patients returned completed questionnaires. The mean cost to patients of diagnosing or excluding EP was £135.13±£51.60 (median £20.70). The main cost drivers identified were hospital visits, holiday cancellations, income loss and household help.ConclusionsQuantification of the indirect costs of diagnosing and excluding EP is challenging because it relies on questionnaire feedback from patients at a time when they have suffered from the emotional impact of pregnancy loss. However, initial estimates suggest that such costs are significant due to diagnostic delays. This further highlights the importance of the development of potential biomarkers of EP to allow prompt diagnosis.
Advanced modality imaging evaluation in acute ischemic stroke may lead to delayed endovascular reperfusion therapy without improvement in clinical outcomes
Authors: Sheth Kevin N , Terry John B , Nogueira Raul G , Horev Anat , Nguyen Thanh N , Fong Albert K , Gandhi Dheeraj , Prabhakaran Shyam , Wisco Dolora , Glenn Brenda A , Tayal Ashis H , Ludwig Bryan , Hussain Muhammad Shazam , Jovin Tudor G , Clemmons Paul F , Cronin Carolyn , Liebeskind David S , Tian Melissa , Gupta Rishi 
Published: October 2012

PurposeAdvanced neuroimaging techniques may improve patient selection for endovascular stroke treatment but may also delay time to reperfusion. We studied the effect of advanced modality imaging with CT perfusion (CTP) or MRI compared with non-contrast CT (NCT) in a multicenter cohort.Materials and methodsThis is a retrospective study of 10 stroke centers who select patients for endovascular treatment using institutional protocols. Approval was obtained from each institution's review board as only de-identified information was used. We collected demographic and radiographic data, selected time intervals, and outcome data. ANOVA was used to compare the groups (NCT vs CTP vs MRI). Binary logistic regression analysis was performed to determine factors associated with a good clinical outcome.Results556 patients were analyzed. Mean age was 66±15 years and median National Institutes of Health Stroke Scale score was 18 (IQR 14–22). NCT was used in 286 (51%) patients, CTP in 190 (34%) patients, and MRI in 80 (14%) patients. NCT patients had significantly lower median times to groin puncture (61 min, IQR (40–117)) compared with CTP (114 min, IQR (81–152)) or MRI (124 min, IQR (87–165)). There were no differences in clinical outcomes, hemorrhage rates, or final infarct volumes among the groups.ConclusionsThe current retrospective study shows that multimodal imaging may be associated with delays in treatment without reducing hemorrhage rates or improving clinical outcomes. This exploratory analysis suggests that prospective randomised studies are warranted to support the hypothesis that advanced modality imaging is superior to NCT in improving clinical outcomes.
Sensory neuromodulators in functional nausea and vomiting: predictors of response
Authors: Patel Amit , Sayuk Gregory S , Kushnir Vladimir M , Gyawali C Prakash 
Published: October 2012

Abstract

Background
Tricyclic antidepressants (TCAs) are known to benefit subjects with functional nausea and vomiting (FNV), but it is not known if alternate neuromodulators are also beneficial. We retrospectively evaluated outcomes and clinical predictors of response in FNV subjects treated with any neuromodulator, including TCAs.

Methods
We identified 94 subjects (43.8±1.4 year, 79 F) with FNV (Rome III criteria) over a 12 year period, treated with neuromodulators and followed up for 8.5±1.1 months. Clinical presentation, demographics and gastric emptying study (GES) findings (when available) were extracted. Likert scales determined symptom severity at baseline and symptom response or remission at follow-up. Outcomes and predictors of response were evaluated using univariate and multivariate analyses.

Results
At least moderate symptom improvement was reported by 72.3%, and 22.3% had symptom remission. Proportions achieving moderate improvement and remission, and mean outcome Likert scores were similar regardless of neuromodulator agent used or GES status. On univariate and multivariate logistic regression analysis, baseline symptom severity affected symptom response, and pain negatively impacted symptom remission to treatment (p≤0.04 for each); GES status failed to predict treatment response or remission.

Conclusions
Symptom improvement with neuromodulators may be seen in over two-thirds of subjects with FNV regardless of the specific agent administered. Response may be suboptimal in pain predominant presentations.
A new infectious disease model for estimating and projecting HIV/AIDS epidemics
Authors: Bao Le 
Published: October 2012

ObjectivesAs the global HIV pandemic enters its fourth decade, countries have collected longer time series of surveillance data, and the AIDS-specific mortality has been substantially reduced by the increasing availability of antiretroviral treatment. A refined model with a greater flexibility to fit longer time series of surveillance data is desired.MethodsIn this article, we present a new epidemiological model that allows the HIV infection rate, r(t), to change over years. The annual change of infection rate is modelled by a linear combination of three key factors: the past prevalence, the past infection rate and a stabilisation condition. We focus on fitting the antenatal clinic (ANC) data and household surveys which are the most commonly available data source for generalised epidemics defined by the overall prevalence being above 1%. A hierarchical model is used to account for the repeated measurement within a clinic. A Bayesian approach is used for the parameter estimation.ResultsWe evaluate the performance of the newly proposed model on the ANC data collected from urban and rural areas of 31 countries with generalised epidemics in sub-Sahara Africa. The three factors in the proposed model all have significant contributions to the reconstruction of r(t) trends. It improves the prevalence fit over the classic Estimation and Projection Package model and provides more realistic projections when the classic model encounters problems.ConclusionsThe proposed model better captures the main pattern of the HIV/AIDS dynamic. It also retains the simplicity of the classic model with a few interpretable parameters that are easy to interpret and estimate.
Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab
Authors: Bates David O. , Catalano Paul J. , Symonds Kirsty E. , Varey Alex H.R. , Ramani Pramila , O'Dwyer Peter J. , Giantonio Bruce J. , Meropol Neal J. , Benson Al Bowen , Harper Steven J. 
Published: October 2012

Abstract
Purpose: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab.
Experimental Design: Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio.
Results: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P &lt; 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio &gt;median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3months).
Conclusion: Low VEGF165b:VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. Clin Cancer Res; 18(22); 6384–91. ©2012 AACR.
Simultaneous Targeting of COX-2 and AKT Using Selenocoxib-1-GSH to Inhibit Melanoma
Authors: Gowda Raghavendra , Madhunapantula SubbaRao V. , Desai Dhimant , Amin Shantu , Robertson Gavin P. 
Published: October 2012

Abstract
Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting the COX-2, PI3K/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways that are deregulated in up to 70% of sporadic melanomas might be an effective treatment, but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium-containing glutathione (GSH) analogue of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC50 of 7.66 μmol/L compared with control celecoxib at 55.6 μmol/L. The IC50 range for normal cells was 36.3 to 41.2 μmol/L compared with 7.66 μmol/L for cancer cells. Selenocoxib-1-GSH reduced development of xenografted tumor by approximately 70% with negligible toxicity by targeting COX-2, like celecoxib, and having novel inhibitory properties by acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an approximately 80% decrease in cultured cell proliferation and an approximately 200% increase in apoptosis following 24-hour treatment with 15.5 μmol/L of drug. Thus, this study details the development of selenocoxib-1-GSH, which is a nontoxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development. Mol Cancer Ther; 12(1); 3–15. ©2012 AACR.
Mitochondrial Motility and Vascular Smooth Muscle Proliferation
Authors: Chalmers Susan , Saunter Christopher , Wilson Calum , Coats Paul , Girkin John M. , McCarron John G. 
Published: October 2012

Objective—
Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.

Methods and Results—
High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (≈2 μm by 0.5 μm), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.

Conclusion—
These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.
Circulating Nucleosomes and Neutrophil Activation as Risk Factors for Deep Vein Thrombosis
Authors: van Montfoort Maurits L. , Stephan Femke , Lauw Mandy N. , Hutten Barbara A. , Van Mierlo Gerard J. , Solati Shabnam , Middeldorp Saskia , Meijers Joost C.M. , Zeerleder Sacha 
Published: October 2012

Objective—
The formation of neutrophil extracellular traps and the exposure of nucleosomes on these neutrophil extracellular traps contribute to coagulation activation and the propagation of deep vein thrombosis (DVT) in animal models. However, no data are available on the role of neutrophil extracellular traps or nucleosomes in patients with thrombosis.

Methods and Results—
We conducted a case–control study, in which levels of circulating nucleosomes and neutrophil elastase–α1-antitrypsin complexes were assessed in plasma from 150 patients with objectified symptomatic DVT (cases) and compared with 195 patients with a clinical suspicion of DVT but in whom DVT was excluded (controls). We explored the association between both nucleosomes and elastase–α1-antitrypsin complexes, and the presence of DVT by calculating the odds ratio with corresponding 95% CIs. Elevated levels of both circulating nucleosomes and elastase–α1-antitrypsin complexes were associated with a 3-fold risk of DVT, and the associations remained similar after adjustment for potential confounders (malignancy, smoking, recent immobilization, recent hospitalization). The risk increased with higher nucleosome and elastase–α1-antitrypsin complex levels, suggesting a dose-dependent relationship among circulating nucleosomes, activated neutrophils, and DVT.

Conclusion—
Our study suggests an association among circulating nucleosomes, activated neutrophils, and presence of DVT in humans, which might have implications for treatment and prevention.
Omega 3 Fatty Acids and Cardiovascular Outcomes
Authors: Kotwal Sradha , Jun Min , Sullivan David , Perkovic Vlado , Neal Bruce 
Published: October 2012

Background—
Early trials evaluating the effect of omega 3 fatty acids (ω-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of ω-3 FA on cardiovascular and other important clinical outcomes.

Methods and Results—

We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end-stage kidney disease. Twenty studies including 63030 participants were included. There was no overall effect of ω-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90–1.03;
P
=0.24) or on total mortality (RR=0.95; 95% CI, 0.86–1.04;
P
=0.28). ω-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75–0.99;
P
=0.03) but not coronary events (RR=0.86; 95% CI, 0.67–1.11;
P
=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85–1.16;
P
=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92–1.16;
P
=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02–1.37;
P
=0.03), predominantly because of an excess of gastrointestinal side effects.

Conclusions—
ω-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed.
Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension
Authors: Valbuena-Diez Ana C. , Blanco Francisco J. , Oujo Barbara , Langa Carmen , Gonzalez-Nuñez María , Llano Elena , Pendas Alberto M. , Díaz Mercedes , Castrillo Antonio , Lopez-Novoa José M. , Bernabeu Carmelo 
Published: October 2012

Background—
Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng.

Methods and Results—
Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice.

Conclusions—
These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia.
Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort
Authors: Horsfall Laura J. , Nazareth Irwin , Petersen Irene 
Published: October 2012

Background—
Serum bilirubin is an endogenous antioxidant that is routinely measured before a statin is prescribed primarily to assess liver function, but the association with cardiovascular disease (CVD) in this population has not been explored.

Method and Results—
We identified patients from a United Kingdom primary care database (The Health Improvement Network) with measurements of serum total bilirubin levels recorded 3 months before the first statin treatment between January 1, 2000, and December 31, 2010, and no history of liver disease or CVD. In total, 130 052 patients met the inclusion criteria, and after a median follow-up of 43 months, there were 7850 CVD events. In men, the incidence of CVD in the lowest decile category of bilirubin (1–6 μmol/L [0.06–0.35 mg/dL]) was 215 per 10 000 person-years compared with 163 per 10 000 person-years in the highest decile (19–40 μmol/L [1.1–2.3 mg/dL]). Similar differences were seen for women. After conventional CVD risk factors were accounted for, the associations with bilirubin were nonlinear (L shaped), and the models predicted that, compared with patients with a bilirubin level of 10 μmol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 μmol/L (0.3 mg/dL) had an 18% (95% confidence interval, 9–27) higher risk of any CVD event, a 34% (95% confidence interval, 13–56) higher risk of myocardial infarction, and a 33% (95% confidence interval, 21–46) higher risk of death resulting from any cause.

Conclusions—
Serum bilirubin level measured before a statin prescription to assess liver function is an independent risk factor for CVD and death in both men and women.