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Glioblastomas are the most frequent and aggressive primary brain tumor in adults and despite recent therapeutic advances, they are resistant to treatment. Increasing malignancy of gliomas correlates with an increase in cellularity and a poorly organized tumor vasculature, leading to insufficient blood supply, hypoxic areas, and ultimately to the formation of necrosis. Hypoxia induces direct or indirect changes in the biology of solid tumor and their microenvironment through the activation of HIF transcription factors, leading to increased aggressiveness and tumor resistance to therapy. Not much is known about the epigenetic alterations induced by hypoxia and how they could alter tumor biology. In the present study, we have utilized PIMO as a specific marker of hypoxia in glioblastoma patients, treated with PIMO preoperatively. We have estimated PIMO positivity in each tumor (5-45%) and determined that it positively correlates with the hypoxia marker CA IX (r=0.57). In addition, 10 surgical PIMO cases were dissociated, immune labeled using PIMO antibody, followed by DNA isolation and methylation profiling. Our analysis of differentially top 4000 differentially methylated probes suggests that PIMO-positive (hypoxic) cells are differentially methylated compared to the PIMO-negative cells and these changes are associated with genes involved in hypoxic cellular response. We will validate these findings in additional glioblastoma cases and assess the mechanism of these epigenetic alterations in vitro in glioma stem cell culture conditions and upon exposure of the cells hypoxic conditions.
Introduction: Hypertensive disorders of pregnancy (HDP), including preeclampsia, can develop or worsen in the early postpartum period, often following discharge from hospital, resulting in severe preventable maternal morbidity and mortality. Due to a lack of routine early out-patient follow-up, many women with postpartum HDP present to the emergency department (ED) with severe hypertension or symptoms of preeclampsia (e.g., headache). In the ED, postpartum HDP can be difficult for clinicians to recognize (due to vague presenting symptom) and manage (due to lower blood pressure targets and concern of medication safety). ED clinicians recognized a need for timely recognition and effective treatments for postpartum HDP in the ED to improve maternal outcomes. As such, as part of a multi-step quality improvement initiative, an interdisciplinary team developed and implemented a postpartum HDP management protocol (consisting of nursing and physician protocols and an electronic order set embedded in the electronic medical record). The aims of this specific project were to assess: 1) the use of this clinical management protocol in the ED; and 2) its impacts on clinical care. Methods: This quality improvement project used electronic medical records to identify: 1) ED visits for postpartum HDP for postpartum women ages 20-50; 2) utilization of the postpartum HDP order set; and 3) clinical care outcomes (consultation and admission). Patient population characteristics and clinical care measures were summarized with descriptive statistics and compared using a before and after design. Changes in the utilization of the protocol were assessed using run charts. Results: 540 women with postpartum HDP were seen in the four Calgary EDs in the 16-month period following protocol implementation compared with 335 women in the preceding 12 months. The protocol was used in 46% of these 540 women, and increased over the 16 month follow-up period. We found an increase in the frequency of consultation of specialists (47% to 52%) and admissions (26% to 29%) amongst these women after protocol implementation. Conclusion: This initial assessment demonstrated good uptake of a postpartum HDP management protocol including referral for consultation and admission to hospital for blood pressure management. Future steps include evaluation of the impacts of this management protocol on important patient outcomes.
To determine the patterns and predictors of treatment response trajectories for veterans with post-traumatic stress disorder (PTSD).
Conditional latent growth mixture modelling was used to identify classes and predictors of class membership. In total, 2686 veterans treated for PTSD between 2002 and 2015 across 14 hospitals in Australia completed the PTSD Checklist at intake, discharge, and 3 and 9 months follow-up. Predictor variables included co-morbid mental health problems, relationship functioning, employment and compensation status.
Five distinct classes were found: those with the most severe PTSD at intake separated into a relatively large class (32.5%) with small change, and a small class (3%) with a large change. Those with slightly less severe PTSD separated into one class comprising 49.9% of the total sample with large change effects, and a second class comprising 7.9% with extremely large treatment effects. The final class (6.7%) with least severe PTSD at intake also showed a large treatment effect. Of the multiple predictor variables, depression and guilt were the only two found to predict differences in response trajectories.
These findings highlight the importance of assessing guilt and depression prior to treatment for PTSD, and for severe cases with co-morbid guilt and depression, considering an approach to trauma-focused therapy that specifically targets guilt and depression-related cognitions.
North American studies show bipolar disorder is associated with elevated
rates of problem gambling; however, little is known about rates in the
different presentations of bipolar illness.
To determine the prevalence and distribution of problem gambling in
people with bipolar disorder in the UK.
The Problem Gambling Severity Index was used to measure gambling problems
in 635 participants with bipolar disorder.
Moderate to severe gambling problems were four times higher in people
with bipolar disorder than in the general population, and were associated
with type 2 disorder (OR = 1.74, P = 0.036), history of
suicidal ideation or attempt (OR = 3.44, P = 0.02) and
rapid cycling (OR = 2.63, P = 0.008).
Approximately 1 in 10 patients with bipolar disorder may be at moderate
to severe risk of problem gambling, possibly associated with suicidal
behaviour and a rapid cycling course. Elevated rates of gambling problems
in type 2 disorder highlight the probable significance of modest but
unstable mood disturbance in the development and maintenance of such
A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1 % total fatty acids) associated with a 12 % increase in the probability of remission at any time during the study period (hazard ratio (HR)=1·12; 95 % CI 1·02, 1·23; P=0·02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and ‘shared epitope’ HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0·85; 95 % CI 0·72, 0·99; P=0·047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.
Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40), and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility.
Solar irradiance and precipitation are the most likely drivers of the seasonal variation of net primary productivity (NPP) in tropical forests. Since their roles remain poorly understood, we use litter traps, dendrometer bands and census data collected from one hectare permanent plots to quantify the seasonality of above-ground NPP components and weather parameters in 13 sites distributed along a 2800-m altitudinal gradient ranging from lowland Amazonia to the high Andes. We combine canopy leaf area index and litterfall data to describe the seasonality of canopy production. We hypothesize that solar irradiance is the primary driver of canopy phenology in wetter sites, whereas precipitation drives phenology in drier systems. The seasonal rhythm of canopy NPP components is in synchrony with solar irradiance at all altitudes. Leaf litterfall peaks in the late dry season, both in lowland (averaging 0.54 ± 0.08 Mg C ha y−1, n = 5) and montane forests (averaging 0.29 ± 0.04 Mg C ha y−1, n = 8). Peaks in above-ground coarse woody NPP appears to be triggered by the onset of rainfall in seasonal lowland rain forests (averaging 0.26 ± 0.04 Mg C ha y−1, n = 5, in November), but not in montane cloud forests.
Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose–response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose–response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.
We use a WISE-2MASS-Pan-STARRS1 galaxy catalog to search for a supervoid in the direction of the Cosmic Microwave Background Cold Spot. We obtain photometric redshifts using our multicolor data set to create a tomographic map of the galaxy distribution. The radial density profile centred on the Cold Spot shows a large low density region, extending over 10's of degrees. Motivated by previous Cosmic Microwave Background results, we test for underdensities within two angular radii, 5°, and 15°. Our data, combined with an earlier measurement by Granett et al. 2010, are consistent with a large Rvoid=(192 ± 15)h−1 Mpc (2σ) supervoid with δ ≃ −0.13 ± 0.03 centered at z=0.22 ± 0.01. Such a supervoid, constituting a ∼3.5 σ fluctuation in the ΛCDM model, is a plausible cause for the Cold Spot.
High-redshift quasars are unique probes of the evolution of supermassive black holes and the intergalactic medium at the end of the epoch of reionization. We present the optical spectra of eight new z ~ 6 quasars selected from the Panoramic Survey Telescope & Rapid Response System 1 (Pan-STARRS1). Details of the selection strategy can be found in Bañados et al. (2014). With this work we increase the number of known quasars at z < 5.7 by more than 10%. The quasars discovered here span a large range of luminosities (19.6 ≤ zP1 ≤ 21.2) and are remarkably heterogeneous in their spectral features: half of them show bright emission lines whereas the other half show weak or no Lyα emission line. We find a larger fraction of weak–line emission quasars than in lower redshift studies, although still based on low number statistics, this may imply that the quasar population could be more diverse than previously thought.
The dynamo process is believed to drive the magnetic activity of stars like the Sun that have an outer convection zone. Large spectroscopic surveys showed that there is a relation between the rotation periods and the cycle periods: the longer the rotation period is, the longer the magnetic activity cycle period will be. We present the analysis of F stars observed by Kepler for which individual p modes have been measure and with surface rotation periods shorter than 12 days. We defined magnetic indicators and proxies based on photometric observations to help characterise the activity levels of the stars. With the Kepler data, we investigate the existence of stars with cycles (regular or not), stars with a modulation that could be related to magnetic activity, and stars that seem to show a flat behaviour.
Programmes for the geological disposal of radioactive wastes are by nature extremely complex. A structured approach for making and documenting varied kinds of decisions is required to support programme design and implementation. At each programme stage, the decision-making process must be able to identify and justify key priorities for work, to reduce uncertainties.
To support structured decision-making evidence support logic (ESL) has been developed and applied to varied complex projects, nationally and internationally, in several industries. Evidence support logic involves breaking down a hypothesis that informs a decision into a hierarchical 'decision tree'. Examples of hypotheses are 'the geology associated with site x will provide sufficient disposal capacity', 'container x will contain waste form y for z years' and 'the engineered barrier system will provide the required safety functions'. Independent evaluations of confidence 'for' and 'against' bottom-level hypotheses allow the level of remaining uncertainty (or conflict) to be recognized explicitly, and the overall confidence (and uncertainty) relevant to the overall decision, and key sensitivities, to be represented clearly and succinctly.
Thus ESL can help (1) break down decisions into a manageable and logical structure, assisting clear presentation; (2) identify key uncertainties and sensitivities to inform prioritization; and (3) test whether the outcomes of specific studies have improved confidence.
This is a concise history of India since the time of the Mughals. It comprises the history of what was known as British India from the late eighteenth century until 1947, when the subcontinent was split into the two independent countries of India and Pakistan, and of the Republic of India thereafter. (The history of Pakistan and, after 1971, of Bangladesh, is taken up in a separate volume in this series.)
In this work we hope to capture something of the excitement that has characterized the field of India studies in recent decades. Any history written today differs markedly from that of the late 1950s and early 1960s when we, as graduate students, first ‘discovered’ India. The history of India, like histories everywhere, is now at its best written as a more inclusive story, one with fewer determining narratives. Not only do historians seek to include more of the population in their histories – women, minorities, the dispossessed – but they are also interested in alternative historical narratives, those shaped by distinctive cosmologies or by local experiences. Historians question, above all, the historical narratives that were forged – as they were everywhere in the modern world – by the compelling visions of nationalism. The first histories of India, written from the early decades of the nineteenth century, were the handmaiden of British nationalism. They were subsequently challenged, and rewritten, by Indian nationalist historians. All of these histories, including those written from a Marxist perspective, were shaped by notions of ‘progress’ and what was seen as an inevitable progression toward presumably already known models of ‘modernity’ that included economic development and democracy. In recent years, Indian historians have taken the lead in breaking apart the old narratives, at the cost, some would argue, of a cherished cultural continuity and the stirring stories of heroism that foster patriotism. What they have given us in its place is what the leading ‘subalternist’ Partha Chatterjee calls ‘fragments’ of history. But such a history is no less critical for the formation of an informed citizenry of an individual nation, or of the world.
The revolt of 1857–8, which swept across much of north India in opposition to British rule, has conventionally been taken as the dividing point that marks the beginning of modern India. Historical periodization is, however, always somewhat arbitrary. With greater distance from the colonial period, when the searing chaos of the uprising was understood either as ‘Mutiny’ to the colonial rulers or as the ‘First War of Independence’ to many nationalists, it is possible to focus on substantial, long-term transformations rather than on a single event. Such an emphasis, moreover, places India in the context of changes taking place in the larger world, not just in terms of events and personalities in India itself. Far from modernity ‘happening’ in Europe and then being transplanted to a country like India, many of these changes took place in relation to each other.
Modern technological changes, among them canals, railways, and telegraph, were introduced into India within years of their introduction in Europe. Changes essential to the modern state, including the unification of sovereignty, the surveying and policing of the population, and institutions meant to create an educated citizenry were also, broadly speaking, introduced during the same period in India and in parts of Europe. Indeed, certain modern practices and institutions were either stimulated by the Indian experience or originated in India itself. Municipal cemeteries, as noted above, appeared in India before they did in England; the same is true of English literature as a curricular subject, and of state-sponsored scientific and surveying institutions. The colonial relationship with India was essential, moreover, as Gauri Vishwanathan recently argued, to one of the fundamental characteristics of modern states, namely the practice of state secularism. At the same time, new religious organizations in both India and Britain shared the common pattern of an unprecedented involvement of the laity. In both countries too, the spread of electoral politics was accompanied by debate over the place of religion in public life. Above all, the economic lives of both countries were profoundly, and increasingly, intertwined.