This meta-analysis, spanning 5 decades of Draw-A-Scientist studies, examined U.S. children's gender-science stereotypes linking science with men. These stereotypes should have weakened over time ...because women's representation in science has risen substantially in the United States, and mass media increasingly depict female scientists. Based on 78 studies (N = 20,860; grades K-12), children's drawings of scientists depicted female scientists more often in later decades, but less often among older children. Children's depictions of scientists therefore have become more gender diverse over time, but children still associate science with men as they grow older. These results may reflect that children observe more male than female scientists in their environments, even though women's representation in science has increased over time.
Summary The diagnosis of multiple sclerosis is based on neurological symptoms and signs, alongside evidence of dissemination of CNS lesions in space and time. MRI is often sufficient to confirm the ...diagnosis when characteristic lesions accompany a typical clinical syndrome, but in some patients, further supportive information is obtained from cerebrospinal fluid examination and neurophysiological testing. Differentiation is important from other diseases in which demyelination is a feature (eg, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis) and from non-demyelinating disorders such as chronic small vessel disease and other inflammatory, granulomatous, infective, metabolic, and genetic causes that can mimic multiple sclerosis. Advances in MRI and serological and genetic testing have greatly increased accuracy in distinguishing multiple sclerosis from these disorders, but misdiagnosis can occur. In this Series paper we explore the progress and challenges in the diagnosis of multiple sclerosis with reference to diagnostic criteria, important differential diagnoses, controversies and uncertainties, and future prospects.
A ferroelectric is a material with a polar structure whose polarity can be reversed (switched) by applying an electric field
. In metals, itinerant electrons screen electrostatic forces between ions, ...which explains in part why polar metals are very rare
. Screening also excludes external electric fields, apparently ruling out the possibility of ferroelectric switching. However, in principle, a thin enough polar metal could be sufficiently penetrated by an electric field to have its polarity switched. Here we show that the topological semimetal WTe
provides an embodiment of this principle. Although monolayer WTe
is centro-symmetric and thus non-polar, the stacked bulk structure is polar. We find that two- or three-layer WTe
exhibits spontaneous out-of-plane electric polarization that can be switched using gate electrodes. We directly detect and quantify the polarization using graphene as an electric-field sensor
. Moreover, the polarization states can be differentiated by conductivity and the carrier density can be varied to modify the properties. The temperature at which polarization vanishes is above 350 kelvin, and even when WTe
is sandwiched between graphene layers it retains its switching capability at room temperature, demonstrating a robustness suitable for applications in combination with other two-dimensional materials
.
Multiple sclerosis (MS) is an inflammatory disorder of the CNS that affects both the brain and the spinal cord. MRI studies in MS focus more often on the brain than on the spinal cord, owing to the ...technical challenges in imaging this smaller, mobile structure. However, spinal cord abnormalities at disease onset have important implications for diagnosis and prognosis. Furthermore, later in the disease course, in progressive MS, myelopathy becomes the primary characteristic of the clinical presentation, and extensive spinal cord pathology--including atrophy, diffuse abnormalities and numerous focal lesions--is common. Recent spinal cord imaging studies have employed increasingly sophisticated techniques to improve detection and quantification of spinal cord lesions, and to elucidate their relationship with physical disability. Quantitative MRI measures of cord size and tissue integrity could be more sensitive to the axonal loss and other pathological processes in the spinal cord than is conventional MRI, putting quantitative MRI in a key role to elucidate the association between disability and spinal cord abnormalities seen in people with MS. In this Review, we summarize the most recent MS spinal cord imaging studies and discuss the new insights they have provided into the mechanisms of neurological impairment. Finally, we suggest directions for further and future research.
Optic neuritis Toosy, Ahmed T, Dr; Mason, Deborah F, FRACP; Miller, David H, Prof
Lancet neurology,
2014, January 2014, 2014-Jan, 2014-01-00, 20140101, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Summary Acute optic neuritis is the most common optic neuropathy affecting young adults. Exciting developments have occurred over the past decade in understanding of optic neuritis pathophysiology, ...and these developments have been translated into treatment trials. In its typical form, optic neuritis presents as an inflammatory demyelinating disorder of the optic nerve, which can be associated with multiple sclerosis. Atypical forms of optic neuritis can occur, either in association with other inflammatory disorders or in isolation. Differential diagnosis includes various optic nerve and retinal disorders. Diagnostic investigations include MRI, visual evoked potentials, and CSF examination. Optical coherence tomography can show retinal axonal loss, which correlates with measures of persistent visual dysfunction. Treatment of typical forms with high-dose corticosteroids shortens the period of acute visual dysfunction but does not affect the final visual outcome. Atypical forms can necessitate prolonged immunosuppressive regimens. Optical coherence tomography and visual evoked potential measures are suitable for detection of neuroaxonal loss and myelin repair after optic neuritis. Clinical trials are underway to identify potential neuroprotective or remyelinating treatments for acutely symptomatic inflammatory demyelinating CNS lesions.
Summary Clinically isolated syndrome (CIS) is a term that describes a first clinical episode with features suggestive of multiple sclerosis (MS). It usually occurs in young adults and affects optic ...nerves, the brainstem, or the spinal cord. Although patients usually recover from their presenting episode, CIS is often the first manifestation of MS. The most notable risk factors for MS are clinically silent MRI lesions and CSF oligoclonal bands; weak or uncertain risk factors include vitamin D deficiency, Epstein-Barr virus infection, smoking, HLA genes, and miscellaneous immunological abnormalities. Diagnostic investigations including MRI aim to exclude alternative causes and to define the risk for MS. MRI findings incorporated into diagnostic criteria in the past decade enable MS to be diagnosed at or soon after CIS presentation. The course of MS after CIS is variable: after 15–20 years, a third of patients have a benign course with minimal or no disability and a half will have developed secondary progressive MS with increasing disability. Prediction of the long-term course at disease onset is unreliable. Disease-modifying treatments delay the development from CIS to MS. Their use in CIS is limited by uncertain long-term clinical prognosis and treatment benefits and adverse effects, although they have the potential to prevent or delay future tissue damage, including demyelination and axonal loss. Targets for future therapeutic progress are to achieve safe and effective long-term immunomodulation with neuroprotection and repair.
Summary Background More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis ...represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. Methods Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5–6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov , number NCT00395200. Findings We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×106 cells per kg bodyweight (range 1·1–2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3–4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change −0·02 logMAR units, 95% CI −0·03 to −0·01; p=0·003) and visual evoked response latency (−1·33 ms, −2·44 to −0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm2 , 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. Interpretation Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. Funding Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.
Summary Background No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple ...sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. Methods In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov , number NCT00731692 . The study is now closed. Findings 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years SD 8·4, mean EDSS 4·67 SD 1·03, 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). Interpretation The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. Funding Novartis Pharma AG.
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 ...within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.
•AML cases with DNMT3A mutations at R882 exhibit focal hypomethylation•R882H DNMT3A is a dominant-negative inhibitor of WT DNMT3A•WT DNMT3A forms stable, active homotetramers•R882H DNMT3A dominantly disrupts DNMT3A tetramerization
Heterozygous DNMT3A R882H mutation is common in acute myeloid leukemia (AML). Russler-Germain et al. show that DNMT3AR882H inhibits wild-type DNMT3A activity in cells, but not in vitro, and that AML cells with the R882H mutation have reduced de novo methyltransferase activity and focal CpG hypomethylation.
Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum ...and regulates downstream pathways including sphingolipids, metalloproteases, remodeling genes, and chemokines. ORMDL3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis. In addition, ORMDL3 activates the ATF6α branch of the unfolded protein response which regulates SERCA2b and IL-6, pathways of potential importance to asthma. The SNP-linking chromosome 17q21 to asthma is associated with increased ORMDL3 and GSDMB expression. Mice expressing either increased levels of human ORMDL3, or human GSDMB, have an asthma phenotype characterized by increased airway responsiveness and increased airway remodeling (increased smooth muscle and fibrosis) in the absence of airway inflammation. GSDMB regulates expression of 5-LO and TGF-β1 which are known pathways involved in the pathogenesis of asthma. GSDMB is one of four members of the GSDM family (GSDMA, GSDMB, GSDMC, and GSDMD). GSDMD (located on chromosome 8q24 and not linked to asthma) has emerged as a key mediator of pyroptosis. GSDMD is a key component of the NLPR3 inflammasome and is required for its activation. GSDMD undergoes proteolytic cleavage by caspase-1 to release its N-terminal fragment, which in turn mediates pyroptosis and IL-1β secretion. Chromosome 17q21 has not only been linked to asthma but also to type 1 diabetes, inflammatory bowel disease, and primary biliary cirrhosis suggesting that future insights into the biology of genes located in this region will increase our understanding of these diseases.
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