Biomarkers of Cerebral Injury for Prediction of Postoperative Cognitive Dysfunction in Patients Undergoing Cardiac Surgery

OBJECTIVES: To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery. DESIGN: Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial. SETTING: Single-center study from a primary heart center in Denmark. PARTICIPANTS: Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement. INTERVENTIONS: Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD. MEASUREMENTS AND MAIN RESULTS: A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability. CONCLUSIONS: Postoperative serum levels of tau and GFAP were elevated significantly in patients with POCD who underwent cardiac surgery at discharge; however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge

A systematic review of randomised controlled trials on the effectiveness of exercise programs on lumbo pelvic pain among postnatal women

Background: A substantial number of women tend to be affected by Lumbo Pelvic Pain (LPP) following child birth. Physical exercise is indicated as a beneficial method to relieve LPP, but individual studies appear to suggest mixed findings about its effectiveness. This systematic review aimed to synthesise evidence from randomised controlled trials on the effectiveness of exercise on LPP among postnatal women to inform policy, practice and future research. Methods: A systematic review was conducted of all randomised controlled trials published between January 1990 and July 2014, identified through a comprehensive search of following databases: PubMed, PEDro, Embase, Cinahl, Medline, SPORTDiscus, Cochrane Pregnancy and Childbirth Group’s Trials Register, and electronic libraries of authors’institutions. Randomised controlled trials were eligible for inclusion if the intervention comprised of postnatal exercise for women with LPP onset during pregnancy or within 3 months after delivery and the outcome measures included changes in LPP. Selected articles were assessed using the PEDro Scale for methodological quality and findings were synthesised narratively as meta-analysis was found to be inappropriate due to heterogeneity among included studies. Results: Four randomised controlled trials were included, involving 251 postnatal women. Three trials were rated as of ‘good’ methodological quality. All trials, except one, were at low risk of bias. The trials included physical exercise programs with varying components, differing modes of delivery, follow up times and outcome measures. Intervention in one trial, involving physical therapy with specific stabilising exercises, proved to be effective in reducing LPP intensity. An improvement in gluteal pain on the right side was reported in another trial and a significant difference in pain frequency in another. Conclusion: Our review indicates that only few randomised controlled trials have evaluated the effectiveness of exercise on LPP among postnatal women. There is also a great amount of variability across existing trials in the components of exercise programs, modes of delivery, follow up times and outcome measures. While there is some evidence to indicate the effectiveness of exercise for relieving LPP, further good quality trials are needed to ascertain the most effective elements of postnatal exercise programs suited for LPP treatment

Neuronal Toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro.

BACKGROUND: The innate immune response in the brain is initiated by pathogen-associated molecular patterns (PAMPS) or danger-associated molecular patterns (DAMPS) produced in response to central nervous system (CNS) infection or injury. These molecules activate members of the Toll-like receptor (TLR) family, of which TLR4 is the receptor for bacterial lipopolysaccharide (LPS). Although neurons have been reported to express TLR4, the function of TLR4 activation in neurons remains unknown. METHODS: TLR4 mRNA expression in primary mouse glial and neuronal cultures was assessed by RT-PCR. Mouse mixed glial, neuronal or endothelial cell cultures were treated with LPS in the absence or the presence of a TLR4 specific antagonist (VIPER) or a specific JNK inhibitor (SP600125). Expression of inflammatory mediators was assayed by cytometric bead array (CBA) and ELISA. Activation of extracellular-signal regulated kinase 1/2 (ERK1/2), p38, c-Jun-N-terminal kinase (JNK) and c-Jun was assessed by Western blot. The effect of conditioned media of untreated- versus LPS-treated glial or neuronal cultures on endothelial activation was assessed by neutrophil transmigration assay, and immunocytochemistry and ELISA were used to measure expression of intercellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1). RESULTS: LPS induces strong release of the chemokines RANTES and CXCL1 (KC), tumor necrosis factor-α (TNFα) and IL-6 in primary mouse neuronal cultures. In contrast, LPS induced release of IL-1α, IL-1β and granulocyte-colony stimulating factor (G-CSF) in mixed glial, but not in neuronal cultures. LPS-induced neuronal KC expression and release were completely blocked by VIPER. In glial cultures, LPS induced activation of ERK1/2, p38 and JNK. In contrast, in neuronal cultures, LPS activated JNK but not ERK1/2 or p38, and the specific JNK inhibitor SP600125 significantly blocked LPS-induced KC expression and release. Finally, conditioned medium of LPS-treated neuronal cultures induced strong expression of ICAM-1 and VCAM-1 on endothelial cells, and induced infiltration of neutrophils across the endothelial monolayer, which was inhibited by VIPER. CONCLUSION: These data demonstrate for the first time that neurons can play a role as key sensors of infection to initiate CNS inflammation

Charcoal does not change the decomposition rate of mixed litters in a mineral cambisol: a controlled conditions study

It has been recently shown that the presence of charcoal might promote humus decomposition in the soil. We investigated the decomposition rate of charcoal and litters of different biochemical quality mixed together in a soil incubation under controlled conditions. Despite the large range of organic substrate quality used in this study, we did not find any difference in the decomposition between the average of two individual substrates decomposing separately and the same substrates mixed together. We concluded that charcoal does not always promote other organic matter decomposition and that its particular effect might depend on various factors, for example, soil properties

Screening for C3 Deficiency in Newborns Using Microarrays

BACKGROUND: Dried blood spot samples (DBSS) from newborns are widely used in neonatal screening for selected metabolic diseases and diagnostic possibilities for additional disorders are continuously being evaluated. Primary immunodeficiency disorders comprise a group of more than one hundred diseases, several of which are fatal early in life. Yet, a majority of the patients are not diagnosed due to lack of high-throughput screening methods. METHODOLOGY/PRINCIPAL FINDINGS: We have previously developed a system using reverse phase protein microarrays for analysis of IgA levels in serum samples. In this study, we extended the applicability of the method to include determination of complement component C3 levels in eluates from DBSS collected at birth. Normal levels of C3 were readily detected in 269 DBSS from healthy newborns, while no C3 was detected in sera and DBSS from C3 deficient patients. CONCLUSIONS/SIGNIFICANCE: The findings suggest that patients with deficiencies of specific serum proteins can be identified by analysis of DBSS using reverse phase protein microarrays.QC 20120213</p

Contribution of Chondroitin Sulfate A to the Binding of Complement Proteins to Activated Platelets

Exposure of chondroitin sulfate A (CS-A) on the surface of activated platelets is well established. The aim of the present study was to investigate to what extent CS-A contributes to the binding of the complement recognition molecule C1q and the complement regulators C1 inhibitor (C1INH), C4b-binding protein (C4BP), and factor H to platelets.Human blood serum was passed over Sepharose conjugated with CS-A, and CS-A-specific binding proteins were identified by Western blotting and mass spectrometric analysis. C1q was shown to be the main protein that specifically bound to CS-A, but C4BP and factor H were also shown to interact. Binding of C1INH was dependent of the presence of C1q and then not bound to CS-A from C1q-depleted serum. The specific interactions observed of these proteins with CS-A were subsequently confirmed by surface plasmon resonance analysis using purified proteins. Importantly, C1q, C4BP, and factor H were also shown to bind to activated platelets and this interaction was inhibited by a CS-A-specific monoclonal antibody, thereby linking the binding of C1q, C4BP, and factor H to exposure of CS-A on activated platelets. CS-A-bound C1q was also shown to amplify the binding of model immune complexes to both microtiter plate-bound CS-A and to activated platelets.This study supports the concept that CS-A contributes to the binding of C1q, C4BP, and factor H to platelets, thereby adding CS-A to the previously reported binding sites for these proteins on the platelet surface. CS-A-bound C1q also seems to amplify the binding of immune complexes to activated platelets, suggesting a role for this molecule in immune complex diseases

BSE can propagate in sheep co-infected or pre-infected with scrapie

To understand the possible role of mixed-prion infections in disease presentation, the current study reports the co-infection of sheep with bovine spongiform encephalopathy (BSE) and scrapie. The bovine BSE agent was inoculated subcutaneously into sheep with ARQ/ARQ or VRQ/ARQ PRNP genotypes either at the same time as subcutaneous challenge with scrapie, or three months later. In addition, VRQ/VRQ sheep naturally infected with scrapie after being born into a scrapie-affected flock were challenged subcutaneously with BSE at eight or twenty one months-of-age. Sheep were analysed by incubation period/attack rate, and western blot of brain tissue determined the presence of BSE or scrapie-like PrP Sc. Serial protein misfolding cyclic amplification (sPMCA) that can detect very low levels of BSE in the presence of an excess of scrapie agent was also applied to brain and lymphoreticular tissue. For VRQ/ARQ sheep challenged with mixed infections, scrapie-like incubation periods were produced, and no BSE agent was detected. However, whilst ARQ/ARQ sheep developed disease with BSE-like incubation periods, some animals had a dominant scrapie western blot phenotype in brain, but BSE was detected in these sheep by sPMCA. In addition, VRQ/VRQ animals challenged with BSE after natural exposure to scrapie had scrapie-like incubation periods and dominant scrapie PrP Sc in brain, but one sheep had BSE detectable by sPMCA in the brain. Overall, the study demonstrates for the first time that for scrapie/BSE mixed infections, VRQ/ARQ sheep with experimental scrapie did not propagate BSE but VRQ/VRQ sheep with natural scrapie could propagate low levels of BSE, and whilst BSE readily propagated in ARQ/ARQ sheep it was not always the dominant PrP Sc strain in brain tissue. Indeed, for several animals, a dominant scrapie biochemical phenotype in brain did not preclude the presence of BSE prion

Male × Female Interaction for a Pre-Copulatory Trait, but Not a Post-Copulatory Trait, among Cosmopolitan Populations of Drosophila melanogaster

Sexual coevolution occurs when changes in the phenotype of one sex select for changes in the other sex. We can identify the “footprint” of this coevolution by mating males and females from different populations and testing for a male-female genotype interaction for a trait associated with male (or female) performance. Here we mated male Drosophila melanogaster from five different continents with females from their own and different continents to test for a male-female interaction for mating speed, a pre-copulatory trait, and female reproductive investment, a post-copulatory trait. We found a strong male-female interaction for mating speed, consistent with previous studies using different populations, suggesting that the potential for sexual coevolution for this trait is present in this species. In contrast, we did not detect a male-female interaction for female reproductive investment. Although a male-female interaction for mating speed is compatible with the hypothesis of ongoing sexual coevolution, the nature of our experimental design is unable to exclude alternate explanations. Thus, the evolutionary mechanisms promoting male-female genotype interactions for pre-copulatory mating traits in D. melanogaster warrant further investigation

Assessment of ePrescription quality: an observational study at three mail-order pharmacies

<p>Abstract</p> <p>Background</p> <p>The introduction of electronic transfer of prescriptions (ETP) or ePrescriptions in ambulatory health care has been suggested to have a positive impact on the prescribing and dispensing processes. Thereby, implying that ePrescribing can improve safety, quality, efficiency, and cost-effectiveness. In December 2007, 68% of all new prescriptions were transferred electronically in Sweden. The aim of the present study was to assess the quality of ePrescriptions by comparing the proportions of ePrescriptions and non-electronic prescriptions necessitating a clarification contact (correction, completion or change) with the prescriber at the time of dispensing.</p> <p>Methods</p> <p>A direct observational study was performed at three Swedish mail-order pharmacies which were known to dispense a large proportion of ePrescriptions (38–75%). Data were gathered on all ePrescriptions dispensed at these pharmacies over a three week period in February 2006. All clarification contacts with prescribers were included in the study and were classified and assessed in comparison with all drug prescriptions dispensed at the same pharmacies over the specified period.</p> <p>Results</p> <p>Of the 31225 prescriptions dispensed during the study period, clarification contacts were made for 2.0% (147/7532) of new ePrescriptions and 1.2% (79/6833) of new non-electronic prescriptions. This represented a relative risk (RR) of 1.7 (95% CI 1.3–2.2) for new ePrescriptions compared to new non-electronic prescriptions. The increased RR was mainly due to 'Dosage and directions for use', which had an RR of 7.6 (95% CI 2.8–20.4) when compared to other clarification contacts. In all, 89.5% of the suggested pharmacist interventions were accepted by the prescriber, 77.7% (192/247) as suggested and an additional 11.7% (29/247) after a modification during contact with the prescriber.</p> <p>Conclusion</p> <p>The increased proportion of prescriptions necessitating a clarification contact for new ePrescriptions compared to new non-electronic prescriptions indicates the need for an increased focus on quality aspects in ePrescribing deployment. ETP technology should be developed towards a two-way communication between the prescriber and the pharmacist with automated checks of missing, inaccurate, or ambiguous information. This would enhance safety and quality for the patient and also improve efficiency and cost-effectiveness within the health care system.</p

Experimental evolution of sperm competitiveness in a mammal

<p>Abstract</p> <p>Background</p> <p>When females mate with multiple partners, sperm from rival males compete to fertilise the ova. Studies of experimental evolution have proven the selective action of sperm competition on male reproductive traits. However, while reproductive traits may evolve in response to sperm competition, this does not necessarily provide evidence that sperm competitive ability responds to selection. Indeed, a study of <it>Drosophila </it>failed to observe divergence in sperm competitive ability of males in lines selected for enhanced sperm offence and defence.</p> <p>Results</p> <p>Adopting the naturally polygamous house mouse (<it>Mus domesticus</it>) as our vertebrate model, we performed an experimental evolution study and observed genetic divergence in sperm quality; males from the polygamous selection lines produced ejaculates with increased sperm numbers and greater sperm motility compared to males from the monogamous lines. Here, after 12 generations of experimental evolution, we conducted competitive matings between males from lineages evolving under sperm competition and males from lineages subject to relaxed selection. We reduced variation in paternity arising from embryo mortality by genotyping embryos <it>in utero </it>at 14 days gestation. Our microsatellite data revealed a significant paternity bias toward males that evolved under the selective regime of sperm competition.</p> <p>Conclusion</p> <p>We provide evidence that the sperm competitiveness phenotype can respond to selection, and show that improved sperm quality translates to greater competitive fertilisation success in house mice.</p