Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions.

BACKGROUND:Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). OBJECTIVE:To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. METHODS:We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. RESULTS:Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. CONCLUSION:We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p < 0.001), from Week 0‒24 by 33% (p < 0.001) and from Week 24‒96 by 72% (p < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p < 0.001).ConclusionSuperior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab

New Pyridine Derivatives from Essential Oils

Four new pyridines 1–4 have been isolated from jonquil absolute and their structures confirmed by synthesis. These pyridines also occur in other essential oils

Negotiating daughterhood and strangerhood: retrospective accounts of serial migration

Most considerations of daughtering and mothering take for granted that the subjectivities of mothers and daughters are negotiated in contexts of physical proximity throughout daughters’ childhoods. Yet many mothers and daughters spend periods separated from each other, sometimes across national borders. Globally, an increasing number of children experience life in transnational families. This paper examines the retrospective narratives of four women who were serial migrants as children (whose parents migrated before they did) . It focuses on their accounts of the reunion with their mothers and how these fit with the ways in which they construct their mother-daughter relationships. We take a psychosocial approach by using a psychoanalytically-informed reading of these narratives to acknowledge the complexities of the attachments produced in the context of migration and to attend to the multi-layered psychodynamics of the resulting relationships. The paper argues that serial migration positioned many of the daughters in a conflictual emotional landscape from which they had to negotiate ‘strangerhood’ in the context of sadness at leaving people to whom they were attached in order to join their mothers (or parents). As a result, many were resistant to being positioned as daughters, doing daughtering and being mothered in their new homes

Selfish or altruistic? An analysis of alarm call function in wild capuchin monkeys, Cebus apella nigritus

Alarm calls facilitate some antipredatory benefits of group living but may endanger the caller by attracting the predator's attention. A number of hypotheses invoking kin selection and individual selection have been proposed to explain how such behaviour could evolve. This study tests eight hypotheses for alarm call evolution by examining the responses of tufted capuchin monkeys to models of felids, perched raptors and vipers. Specifically, this study examines: (1) differences between individuals in their propensity to call in response to different threat types, (2) whether there is an audience effect for alarm calling and (3) the response of conspecifics to alarms. Results indicate that the benefits likely to be afforded to the caller vary with stimulus type. Alarm calling in response to felids is most likely selfish, with calls apparently directed towards both the predator and potential conspecific mobbers. Alarm calling in response to vipers attracts additional mobbers as well, but also appears to be driven by kin selection in the case of males and parental care benefits in the case of females. Alarm responses to perched raptors are rare, but seem to be selfish, with callers benefiting by recruiting additional mobbers

Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using √s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-p T jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in s√=8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb−1. Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate (single light-flavour) squarks. In mSUGRA/CMSSM models with tan β = 30, A 0 = −2m 0 and μ > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector