Temperature and time-dependent effects of delayed blood processing on oxylipin concentrations in human plasma.

BACKGROUND:Oxidized derivatives of polyunsaturated fatty acids, collectively known as oxylipins, are labile bioactive mediators with diverse roles in human physiology and pathology. Oxylipins are increasingly being measured in plasma collected in clinical studies to investigate biological mechanisms and as pharmacodynamic biomarkers for nutrient-based and drug-based interventions. Whole blood is generally stored either on ice or at room temperature prior to processing. However, the potential impacts of delays in processing, and of temperature prior to processing, on oxylipin concentrations are incompletely understood. OBJECTIVE:To evaluate the effects of delayed processing of blood samples in a timeframe that is typical of a clinical laboratory setting, using typical storage temperatures, on concentrations of representative unesterified oxylipins measured by liquid chromatography-tandem mass spectrometry. DESIGN:Whole blood (drawn on three separate occasions from a single person) was collected into 5 mL purple-top potassium-EDTA tubes and stored for 0, 10, 20, 30, 60 or 120 min at room temperature or on wet ice, followed by centrifugation at 4 °C for 10 min with plasma collection. Each sample was run in duplicate, therefore there were six tubes and up to six data points at each time point for each oxylipin at each condition (ice/room temperature). Representative oxylipins derived from arachidonic acid, docosahexaenoic acid, and linoleic acid were quantified by liquid chromatography tandem mass spectrometry. Longitudinal models were used to estimate differences between temperature groups 2 h after blood draw. RESULTS:We found that most oxylipins measured in human plasma in traditional potassium-EDTA tubes are reasonably stable when stored on ice for up to 2 h prior to processing, with little evidence of auto-oxidation in either condition. By contrast, in whole blood stored at room temperature, substantial time-dependent increases in the 12-lipoxygenase-derived (12-HETE, 14-HDHA) and platelet-derived (thromboxane B2) oxylipins were observed. CONCLUSION:These findings suggest that certain plasma oxylipins can be measured with reasonable accuracy despite delayed processing for up to 2 h when blood is stored on ice prior to centrifugation. 12-Lipoxygenase- and platelet-derived oxylipins may be particularly sensitive to post-collection artifact with delayed processing at room temperature. Future studies are needed to determine impacts of duration and temperature of centrifugation on oxylipin concentrations

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies

Perfect state distinguishability and computational speedups with postselected closed timelike curves

Bennett and Schumacher's postselected quantum teleportation is a model of closed timelike curves (CTCs) that leads to results physically different from Deutsch's model. We show that even a single qubit passing through a postselected CTC (P-CTC) is sufficient to do any postselected quantum measurement, and we discuss an important difference between "Deutschian" CTCs (D-CTCs) and P-CTCs in which the future existence of a P-CTC might affect the present outcome of an experiment. Then, based on a suggestion of Bennett and Smith, we explicitly show how a party assisted by P-CTCs can distinguish a set of linearly independent quantum states, and we prove that it is not possible for such a party to distinguish a set of linearly dependent states. The power of P-CTCs is thus weaker than that of D-CTCs because the Holevo bound still applies to circuits using them regardless of their ability to conspire in violating the uncertainty principle. We then discuss how different notions of a quantum mixture that are indistinguishable in linear quantum mechanics lead to dramatically differing conclusions in a nonlinear quantum mechanics involving P-CTCs. Finally, we give explicit circuit constructions that can efficiently factor integers, efficiently solve any decision problem in the intersection of NP and coNP, and probabilistically solve any decision problem in NP. These circuits accomplish these tasks with just one qubit traveling back in time, and they exploit the ability of postselected closed timelike curves to create grandfather paradoxes for invalid answers.Comment: 15 pages, 4 figures; Foundations of Physics (2011

Towards A Holographic Model of Color Superconductivity

In this note, we discuss the basic elements that should appear in a gravitational system dual to a confining gauge theory displaying color superconductivity at large baryon density. We consider a simple system with these minimal elements, and show that for a range of parameters, the phase structure of this model as a function of temperature and baryon chemical potential exhibits phases that can be identified with confined, deconfined, and color superconducting phases in the dual field theory. We find that the critical temperature at which the superconducting phase disappears is remarkably small (relative to the chemical potential). This small number arises from the dynamics, and is unrelated to any small parameter in the model that we study. We discuss similar models which exhibit flavor superconductivity.Comment: 34 pages, 14 figure

Reframing Kurtz’s Painting: Colonial Legacies and Minority Rights in Ethnically Divided Societies

Minority rights constitute some of the most normatively and economically important human rights. Although the political science and legal literatures have proffered a number of constitutional and institutional design solutions to address the protection of minority rights, these solutions are characterized by a noticeable neglect of, and lack of sensitivity to, historical processes. This Article addresses that gap in the literature by developing a causal argument that explains diverging practices of minority rights protections as functions of colonial governments’ variegated institutional practices with respect to particular ethnic groups. Specifically, this Article argues that in instances where colonial governments politicize and institutionalize ethnic hegemony in the pre-independence period, an institutional legacy is created that leads to lower levels of minority rights protections. Conversely, a uniform treatment and depoliticization of ethnicity prior to independence ultimately minimizes ethnic cleavages post-independence and consequently causes higher levels of minority rights protections. Through a highly structured comparative historical analysis of Botswana and Ghana, this Article builds on a new and exciting research agenda that focuses on the role of long-term historio-structural and institutional influences on human rights performance and makes important empirical contributions by eschewing traditional methodologies that focus on single case studies that are largely descriptive in their analyses. Ultimately, this Article highlights both the strength of a historical approach to understanding current variations in minority rights protections and the varied institutional responses within a specific colonial government

A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch

Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z-pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy-(10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch

HLA-Identical Sibling Allogeneic Transplants versus Chemotherapy in Acute Myelogenous Leukemia with t(8;21) in First Complete Remission: Collaborative Study between the German AML Intergroup and CIBMTR

AbstractWe studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) acute myelogenous leukemia (AML) in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from 8 German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality (TRM; relative risk [RR] 6.76, 95% confidence interval [CI] 2.95-15.45, P < .001), lower relapse (RR 0.47, 95% CI 0.25-0.85, P = .01), and similar relapse-free survival (P = .2). Loss of sex chromosomes (LOS) in addition to t(8;21) had a negative impact on overall survival (OS) in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, P = .02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis >25 × 109/L was associated with a higher relapse risk (RR = 2.09, P = .03), lower relapse-free (RR = 1.9, P = .008), and OS (RR = 1.91, P = .01). In this cohort of patients with t(8;21) AML, HCT did not improve OS, because reduction of relapse was offset by high TRM. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT