bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability in parathyroid hormone assays confounds clinical practice in chronic kidney disease patients
Authors: Eddington Helen , Hudson Julie E , Oliver Robert L , Fraser William D , Hutchison Alastair J , Kalra Philip A 
Published: September 2013

Background Intact parathyroid hormone (iPTH) measurements are used to guide therapy in renal patients, but variability in results can occur depending on the assay used. This study has investigated iPTH assay variation in North West England and paired data with regional audit data to determine clinical relevance of assay variability. Methods Thirty-seven haemodialysis patients had blood taken (EDTA plasma, and serum), and samples were processed at 17 laboratories that analyse iPTH for North West dialysis patients. Correction factors were calculated and applied to the iPTH assay results to enable direct comparisons. These correction factors were also applied to Regional Audit data to determine if iPTH assay variability explains the variation in unit performance in achieving PTH targets. Results The iPTH results from the 37 patients were significantly different when either analysed by different assays and/or different laboratories ( P < 0.001). The Abbott Architect method consistently produced the highest iPTH results. Of the 37 patients, between 49% and 65% would achieve the Kidney Disease: Improving Global Outcomes (KDIGO) iPTH target depending on the assay used. When results were adjusted using correction factors, 21% of the patients would require a change of management according to guidelines. Data from all haemodialysis units submitted for the regional audit were adjusted to the Roche assay and this led to a small change in achievement of KDIGO iPTH targets in individual units when compared to each other. Conclusions A combination of iPTH assay variability and diversity in clinical management leads to variation in achieving iPTH targets. Both need to be improved and/or standardized to improve patient care.
Acute changes to biomarkers as a consequence of prolonged strenuous running
Authors: Bird Stephen R , Linden Matthew , Hawley John A 
Published: September 2013

Background A single bout of strenuous running exercise results in perturbations to numerous biomarkers. An understanding of these is important when analysing samples from individuals who have recently performed such exercise. Methods A literature search was undertaken using the search terms, exercise, marathon and delayed onset of muscle soreness. The search was then refined using the terms for key biomarkers known to be altered by exercise. Results The magnitude of changes to biomarkers is proportional to the severity of the running bout. Familiar, moderate intensity running exercise produces brief transient changes in common biomarkers such as lactate, whereas more severe bouts of running exercise, such as marathons and ultra-marathon events can produce changes to biomarkers that are normally associated with pathology of the muscles, liver and heart. Examples being changes to concentrations and/or activity of myoglobin, leucocytes, creatine kinase, bilirubin, cardiac troponins, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase. While persisting for longer, these changes are also transient and full recovery occurs within days, without any apparent long-term adverse consequences. Additionally, unfamiliar exercise involving forceful eccentric muscle contractions, such as running downhill, can cause increases in creatine kinase and delayed onset of muscle soreness that peaks 36–72 h after the exercise bout. Conclusions Strenuous running exercise can produce changes to biomarkers that are normally associated with disease and injury, but these do not necessarily reflect chronic pathology.
Enhanced 3-epi-25-hydroxyvitamin D3 signal leads to overestimation of its concentration and amplifies interference in 25-hydroxyvitamin D LC-MS/MS assays
Authors: Flynn N , Lam F , Dawnay A 
Published: September 2013

Background 3-epi-25-hydroxyvitamin D3 (3-epi-25OHD3) interferes in most liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for 25-hydroxyvitamin D (25OHD). The clinical significance of this is unclear, with concentrations from undetectable to 230 nmol/L reported. Many studies have quantified 3-epi-25OHD3 based on 25OHD3 calibrators or other indirect methods, and we speculated that this contributes to the observed variability in reported 3-epi-25OHD3 concentrations. Methods We compared continuous MS/MS infusions of 3-epi-25OHD3 and 25OHD3 solutions, spiked both analytes into the same serum matrix and analysed patient samples to assess the effect of three different quantitation methods on 3-epi-25OHD3 concentration. Experiments were performed on an LC-MS/MS system using a phenyl column which does not resolve 3-epi-25OHD3, and a modified method utilizing a Zorbax SB-CN column that chromatographically resolves 3-epi-25OHD3 from 25OHD3. Results A greater 3-epi-25OHD3 signal, compared with 25OHD3, was observed during equimolar post-column continuous infusion of analyte solutions, and following analysis of a serum pool spiked with both analytes. 3-epi-25OHD3 signal enhancement was dependent on mobile phase composition. Compared with 3-epi-25OHD3 calibrators, indirect quantitation methods resulted in up to 10 times as many samples having 3-epi-25OHD3 concentrations ≥ 10 nmol/L, and an approximately fourfold increase in the maximum observed 3-epi-25OHD3 concentration to 95 nmol/L. Conclusions Enhanced 3-epi-25OHD3 signal leads to overestimation of its concentrations in the indirect quantitation methods used in many previous studies. The enhanced signal may contribute to greater interference in some 25OHD LC-MS/MS assays than others. We highlight that equimolar responses cannot be assumed in LC-MS/MS systems, even if two molecules are structurally similar.
Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation
Authors: Ramachandran Roshni , Bhatt Deepak Kumar , Ploug Kenneth Beri , Hay-Schmidt Anders , Jansen-Olesen Inger , Gupta Saurabh , Olesen Jes 
Published: September 2013

Background and aim Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model. Materials and methods The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring nNOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation. Results GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC). Upregulation of Fos was observed in TNC four hours after the infusion. This activation was inhibited by pre-treatment with olcegepant. Pre-treatment with L-NAME and L-733060 also significantly inhibited GTN induced Fos expression. Conclusion The present study indicates that blockers of CGRP, NOS and NK-1 receptors all inhibit GTN induced Fos activation. These findings also predict that pre-treatment with olcegepant may be a better option than post-treatment to study its inhibitory effect in GTN migraine models.
Cytomegalovirus seropositivity is negatively associated with multiple sclerosis
Authors: Sundqvist E , Bergström T , Daialhosein H , Nyström M , Sundström P , Hillert J , Alfredsson L , Kockum I , Olsson T 
Published: September 2013

Background: Epidemiological data suggest a role for common viruses in the pathogenesis of multiple sclerosis (MS), and recent data showed a negative association of past cytomegalovirus (CMV) infection on pediatric MS risk. Objective: Our aim was to analyze the association of CMV infection with MS risk in an adult case-control material. A meta-analysis was performed to validate our findings. Methods: Epidemiological Investigation in MS (EIMS) is a case-control study with incident cases and population-based controls. Anti-CMV antibody titers were measured with ELISA, and HLA-A and DRB1 genotyping was performed with SSP-PCR, in 658 MS cases, who all fulfilled the McDonald criteria for MS, and 786 controls. Results: CMV seropositivity was associated with a decreased MS risk, OR = 0.73 (0.58–0.92 95% CI), p = 0.005, adjusted for index age, gender, smoking, sun exposure, EBNA1 IgG titer and HLA-A*02 and DRB1*15. When we removed all cases and controls younger than 18 years at index, the protective effect was still apparent. Conclusions: CMV is negatively associated with adult-onset MS pathology, consistent with results from a study on pediatric MS cases. It remains to be shown whether this negative association is due to a true protective effect of CMV infection on MS risk.
Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis
Authors: Prosperini Luca , Mancinelli Chiara Rosa , De Giglio Laura , De Angelis Floriana , Barletta Valeria , Pozzilli Carlo 
Published: September 2013

Objective: The objective of this paper is to investigate four-year outcomes of interferon beta (IFNB)-treated patients with multiple sclerosis (MS) according to their clinical or magnetic resonance imaging (MRI) activity status at first year of treatment. Methods: A total of 370 patients with MS duration ≤5 years before IFNB start were followed-up for four years. The optimal threshold for one-year MRI activity that more accurately predicted subsequent relapses or disability worsening was identified. The risk of relapses and disability worsening after the first year was then estimated by propensity score (PS)-adjusted analyses in patients fulfilling European Medicines Agency (EMA) criteria for second-line escalation and in those with isolated MRI activity. Results: A total of 192 (51.9%) patients relapsed, and 66 (17.8%) worsened in disability from year 1 to 4 of follow-up. The more accurate threshold for one-year MRI activity was the occurrence of ≥1 enhancing or ≥2 new T2-lesions. An increased risk of relapses and disability worsening was found in either patients fulfilling EMA criteria (hazard ratio (HR) = 3.69, and HR = 6.02) and in those experiencing isolated MRI activity (HR = 3.15, and HR = 5.31) at first year of treatment, when compared with stable patients (all p values <0.001). Conclusion: The four-year outcomes of patients with isolated MRI activity did not differ from those fulfilling EMA criteria at first year of IFNB treatment.
How good does the science have to be in proposals submitted to Institutional Review Boards? An Interview Study of Institutional Review Board personnel
Authors: Klitzman Robert 
Published: September 2013

Background Institutional Review Boards (IRBs) have been increasingly criticized for how they review protocols, but how IRBs perceive, and make decisions about, the quality of the science of protocols has not been examined. Purpose To explore how and when IRBs view and make decisions about the quality of the science of studies they review. Methods I contacted the leadership of 60 IRBs (every fourth one in the list of the top 240 institutions by National Institutes of Health (NIH) funding) and interviewed IRB chairs, co-chairs, administrators, and a director from 34 IRBs (response rate = 55%), and an additional 7 members. Results Interviewees faced several ambiguities and questions concerning the quality of the science of protocols. IRBs are often not sure how and to what extent to evaluate the science of protocols, whether the science should be ‘good enough’ (and if so, what that means) versus as good as possible. Federal regulations state that IRBs should ensure that risks are minimized, and commensurate with benefits. Thus, at times IRBs feel that changing the science is ethically necessary. But IRBs also then struggle with whether to adopt a higher threshold (1) that social and thus scientific benefits be maximized and (2) that scientific efforts and resources should not be wasted. Committees face dilemmas – for example, if a ‘perfect’ study is not feasible. For protocols already approved elsewhere (e.g., by the NIH), IRBs vary in how much they feel they can request alterations, and sometimes make changes nonetheless. Larger institutional contexts and biases can shape these issues, and IRBs differ in how much they are ‘pro-research’, and have sufficient expertise. IRBs at times also approve studies despite reservations about the science. Limitations This study includes interviews with IRBs, but not observations of IRB meetings. Conclusions IRBs often face ambiguities and conflicting goals in assessing scientific quality. Many IRBs try to improve the science beyond what the regulations mandate. These data have important implications for improving practice, education, research, and policy.
Selflessness is sexy: reported helping behaviour increases desirability of men and women as long-term sexual partners
Authors: Moore David , Wigby Stuart , English Sinead , Wong Sonny , Székely Tamás , Harrison Freya 
Published: September 2013

AbstractBackgroundDespite its short-term costs, behaviour that appears altruistic can increase an individual’s inclusive fitness by earning direct (selfish) and/or indirect (kin-selected) benefits. An evolved preference for other-regarding or helping behaviour in potential mates has been proposed as an additional mechanism by which these behaviours can yield direct fitness benefits in humans.ResultsWe asked 32 heterosexual women and 35 heterosexual men to rate the attractiveness of members of the opposite sex in the presence and the absence of information about helping behaviours. Reports of helping behaviour were associated with a significant increase in the attractiveness of both men and women as potential long-term sexual partners. Altruism also increased the attractiveness of men as potential partners for short-term flings, but to a lesser extent than when the same men were being considered for long-term relationships. Altruism did not affect the attractiveness of women as partners for short-term flings.ConclusionsOur results unite two important areas of evolutionary theory – social evolution and sexual selection – and extend the list of means by which helping behaviours, which appear at first glance to be costly to the actor, can in fact earn direct fitness benefits. Helping behaviours may be attractive because they signal ‘good genes’ and/or because they are perceived as a signal of likely provision of non-genetic benefits (e.g. parental care). Exactly why helping behaviours in a non-mating context might be attractive to potential mates, and whether they are honest signals of mate quality, remains to be elucidated.
Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogues
Authors: Salomão Kelly , De Santana Natalia A , Molina Maria Teresa , De Castro Solange L , Menna-Barreto Rubem F S 
Published: September 2013

AbstractBackgroundNaphthoquinones (NQs) are privileged structures in medicinal chemistry due to the biological effects associated with the induction of oxidative stress. The present study evaluated the activities of sixteen NQs derivatives onTrypanosoma cruzi.ResultsFourteen NQs displayed higher activity against bloodstream trypomastigotes ofT. cruzithan benznidazole. Further assays with NQ1, NQ8, NQ9 and NQ12 showed inhibition of the proliferation of axenic epimastigotes and intracelulluar amastigotes interiorized in macrophages and in heart muscle cells. NQ8 was the most active NQ against both proliferative forms ofT. cruzi. In epimastigotes the four NQs induced mitochondrial swelling, vacuolization, and flagellar blebbing. The treatment with NQs also induced the appearance of large endoplasmic reticulum profiles surrounding different cellular structures and of myelin-like membranous contours, morphological characteristics of an autophagic process. At IC50concentration, NQ8 totally disrupted the ΔΨm of about 20% of the parasites, suggesting the induction of a sub-population with metabolically inactive mitochondria. On the other hand, NQ1, NQ9 or NQ12 led only to a discrete decrease of TMRE + labeling at IC50values. NQ8 led also to an increase in the percentage of parasites labeled with DHE, indicative of ROS production, possibly the cause of the observed mitochondrial swelling. The other three NQs behaved similarly to untreated controls.ConclusionsNQ1, NQ8, NQ9 and NQ12 induce an autophagic phenotype inT. cruziepimastigoted, as already observed with others NQs. The absence of oxidative stress in NQ1-, NQ9- and NQ12-treated parasites could be due to the existence of more than one mechanism of action involved in their trypanocidal activity, leaving ROS generation suppressed by the detoxification system of the parasite. The strong redox effect of NQ8 could be associated to the presence of the acetyl group in its structure facilitating quinone reduction, as previously demonstrated by electrochemical analysis. Further experiments using biochemical and molecular approaches are needed to better characterize ROS participation in the mechanism of action of these NQs.
AFLP analysis reveals high genetic diversity but low population structure in Coccidioides posadasiiisolates from Mexico and Argentina
Authors: Duarte-Escalante Esperanza , Zúñiga Gerardo , Frías-De-León María Guadalupe , Canteros Cristina , Castañón-Olivares Laura Rosio , Reyes-Montes María Rocío del 
Published: September 2013

AbstractBackgroundCoccidioides immitisandC. posadasiicause coccidioidomycosis, a disease that is endemic to North and South America, but for Central America, the incidence of coccidioidomycosis has not been clearly established. Several studies suggest genetic variability in these fungi; however, little definitive information has been discovered about the variability ofCoccidioidesfungi in Mexico (MX) and Argentina (AR). Thus, the goals for this work were to study 32Coccidioidesspp. isolates from MX and AR, identify the species of theseCoccidioidesspp. isolates, analyse their phenotypic variability, examine their genetic variability and investigate theCoccidioidesreproductive system and its level of genetic differentiation.MethodsCoccidioidesspp. isolates from MX and AR were taxonomically identified by phylogenetic inference analysis using partial sequences of theAg2/PRAgene and their phenotypic characteristics analysed. The genetic variability, reproductive system and level of differentiation were estimated using AFLP markers. The level of genetic variability was assessed measuring the percentage of polymorphic loci, number of effective allele, expected heterocygosity and Index of Association (IA). The degree of genetic differentiation was determined by AMOVA. Genetic similarities among isolates were estimated using Jaccard index. The UPGMA was used to contsruct the corresponding dendrogram. Finally, a network of haplotypes was built to evaluate the genealogical relationships among AFLP haplotypes.ResultsAll isolates ofCoccidioidesspp. from MX and AR were identified asC. posadasii. No phenotypic variability was observed among theC. posadasiiisolates from MX and AR. Analyses of genetic diversity and population structure were conducted using AFLP markers. Different estimators of genetic variability indicated that theC. posadasiiisolates from MX and AR had high genetic variability. Furthermore, AMOVA, dendrogram and haplotype network showed a small genetic differentiation among theC. posadasiipopulations analysed from MX and AR. Additionally, theIAcalculated for the isolates suggested that the species has a recombinant reproductive system.ConclusionsNo phenotypic variability was observed among theC. posadasiiisolates from MX and AR. The high genetic variability observed in the isolates from MX and AR and the small genetic differentiation observed among theC. posadasiiisolates analysed, suggest that this species could be distributed as a single genetic population in Latin America.
Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution
Authors: Michaelsen Signe Regner , Christensen Ib Jarle , Grunnet Kirsten , Stockhausen Marie-Thérése , Broholm Helle , Kosteljanetz Michael , Poulsen Hans Skovgaard 
Published: September 2013

Abstract

Background
Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been identified. More studies and new approaches to identify the best and worst performing patients are therefore in great demand.

Methods
This study examined 225 consecutive, non-selected GBM patients with performance status (PS) 0–2 receiving postoperative radiotherapy with concomitant and adjuvant TMZ as primary therapy. At relapse, patients with PS 0–2 were mostly treated by reoperation and/or combination with bevacizumab/irinotecan (BEV/IRI), while a few received TMZ therapy if the recurrence-free period was >6 months.

Results
Median overall survival and time to progression were 14.3 and 8.0 months, respectively. Second-line therapy indicated that reoperation and/or BEV/IRI increased patient survival compared with untreated patients and that BEV/IRI was more effective than reoperation alone. Patient age, ECOG PS, and use of corticosteroid therapy were significantly correlated with patient survival and disease progression on univariate analysis, whereas p53, epidermal growth factor receptor, and O6-methylguanine-DNA methyltransferase expression (all detected by immunohistochemistry), tumor size or multifocality, and extent of primary operation were not. A model based on age, ECOG PS, and corticosteroids use was able to predict survival probability for an individual patient.

Conclusion
The survival of RT/TMZ-treated GBM patients can be predicted based on patient age, ECOG PS, and corticosteroid therapy status.