Search

The objective is to demonstrate feasibility of separating magnetic sources in quantitative susceptibility mapping (QSM) by incorporating magnitude decay ratesmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:mathin gradient echo (GRE) MRI.Magnetic susceptibility source separation was developed usingmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:mathand compared with a prior method usingmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:mo=/mml:momml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:mo-/mml:momml:msubmml:miR/mml:mimml:mn2/mml:mn/mml:msub/mml:mrowmml:annotation${R^{\prime}_2} = R_2^* - {R_2}$/mml:annotation/mml:semantics/mml:maththat required an additional sequence to measure the transverse relaxation rate Rsub2/sub. Both susceptibility separation methods were compared in multiple sclerosis (MS) patients (n = 17). Susceptibility values of negative sources estimated withmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:math-based source separation in a set of enhancing MS lesions (n = 44) were correlated against longitudinal myelin water fraction (MWF) changes.In in vivo data, linear regression of the estimatedmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo+/mml:mo/mml:msupmml:annotation${\chi}^{+}$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathsusceptibility values between themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^*$/mml:annotation/mml:semantics/mml:math- and themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:annotation${R^{\prime}_2}$/mml:annotation/mml:semantics/mml:math-based separation methods performed across 182 segmented lesions revealed correlation coefficient r = .96 and slope close .99. Correlation analysis in enhancing lesions revealed a significant positive association between themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathincrease at 1-year post-onset relative to 0 year and the MWF increase at 1 year relative to 0 year (β = -0.144, 95% confidence interval: [-0.199, -0.1], p = .0008) and good agreement betweenmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:annotation${R^{\prime}_2}$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^*$/mml:annotation/mml:semantics/mml:mathmethods (r = .79, slope = .95).Separation of magnetic sources based solely on GRE complex data is feasible by combining magnitude decay rate modeling and phase-based QSM andmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathchange may serve as a biomarker for myelin recovery or damage in acute MS lesions.

Retirement village contracts are complex, blending together financial options on real estate, life annuities and life insurance. We analyse the structure of the cash flows involved in a retirement village contract and distil the cost components into an equivalent monthly comparison rent. In general, we observe lower monthly rents when the maintenance fees and deferred management fees are lower, when higher rates of capital gain are evident, and, importantly, when retirees reside in the retirement village for a longer period. Our analysis provides a framework to meaningfully compare the relative merits of the finances incorporated into retirement village contracts.

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease-modifying therapies. Proton MRS (1 H-MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ-aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H-MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N-acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing-remitting (N = 26) or progressive (N = 21) multiple sclerosis or healthy control adults (N = 25) in a cross-sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate (F2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine (F2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA (F2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione (F2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p

Background The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. Purpose To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. Study type Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. Population/specimens Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. Field strength/sequence 3D T 2 * -weighted spoiled multiecho gradient echo scans performed at 3T. Assessment Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. Statistical tests Not applicable. Results MBP degradation by trypsin increased the QSM measurement by an average of 112 ± 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 ± 3.7 days, their susceptibility increased by an average of 7.5 ± 6.3 ppb. Data conclusion Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. Level of evidence 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287.

OBJECTIVE Myeloid cells, including macrophages and dendritic cells, are a prominent component of central nervous system (CNS) infiltrates during multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Although myeloid cells are generally thought to be proinflammatory, alternatively polarized subsets can serve noninflammatory and/or reparative functions. Here we investigate the heterogeneity and biological properties of myeloid cells during central nervous system autoimmunity. METHODS Myeloid cell phenotypes in chronic active MS lesions were analyzed by immunohistochemistry. In addition, immune cells were isolated from the CNS during exacerbations and remissions of EAE and characterized by flow cytometric, genetic, and functional assays. RESULTS Myeloid cells expressing inducible nitric oxide synthase (iNOS), indicative of a proinflammatory phenotype, were detected in the actively demyelinating rim of chronic active MS lesions, whereas macrophages expressing mannose receptor (CD206), a marker of alternatively polarized human myeloid cells, were enriched in the quiescent lesion core. During EAE, CNS-infiltrating myeloid cells, as well as microglia, shifted from expression of proinflammatory markers to expression of noninflammatory markers immediately prior to clinical remissions. Murine CNS myeloid cells expressing the alternative lineage marker arginase-1 (Arg1) were partially derived from iNOS+ precursors and were deficient in activating encephalitogenic T cells compared with their Arg1- counterparts. INTERPRETATION These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. Level of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951–971.

Purpose Within multiple sclerosis (MS) lesions iron is present in chronically activated microglia. Thus, iron detection with MRI might provide a biomarker for chronic inflammation within lesions. Here, we examine contributions of iron and myelin to magnetic susceptibility of lesions on quantitative susceptibility mapping (QSM). Methods Fixed MS brain tissue was assessed with MRI including gradient echo data, which was processed to generate field (phase), R2* and QSM. Five lesions were sectioned and evaluated by immunohistochemistry for presence of myelin, iron and microglia/macrophages. Two of the lesions had an elemental analysis for iron concentration mapping, and their phospholipid content was estimated from the difference in the iron and QSM data. Results Three of the five lesions had substantial iron deposition that was associated with microglia and positive susceptibility values. For the two lesions with elemental analysis, the QSM derived phospholipid content maps were consistent with myelin labeled histology. Conclusion Positive susceptibility values with respect to water indicate the presence of iron in MS lesions, although both demyelination and iron deposition contribute to QSM. Magn Reson Med 74:564–570, 2015. © 2014 Wiley Periodicals, Inc.

Summary In this article, we study the Monty Hall three doors problem. A fully general solution and several new approaches are presented, including a Bayesian analysis.

A number of philosophers endorse, without argument, the view that there’s something it’s like consciously to think that p, which is distinct from what it’s like consciously to think that q. This thesis, if true, would have important consequences for philosophy of mind and cognitive science. In this paper I offer two arguments for it. The first argument claims it would be impossible introspectively to distinguish conscious thoughts with respect to their content if there weren’t something it’s like to think them. This argument is defended against several objections. The second argument uses what I call “minimal pair” experiences—sentences read without and with understanding—to induce in the reader an experience of the kind I claim exists. Further objects are considered and rebutted.

This communication brings the number of recognized cases of the C (trigonocephaly) syndrome to 11. The pattern of findings includes an anomaly of the anterior cranium and frontal cortex (trigonocephaly), the root of the nose (broad nasal bridge, epicanthus, and short nose), and palate (thick anterior alveolar ridges); abnormalities of the limbs (polysyndactyly, bridged palmar creases, short limbs, and joint dislocations and/or contractures); visceral defects (congenital heart defects, cryptorchidism, and abnormal lobulations of the lungs and kidneys). Auricular, mandibular, skin, and genital abnormalities also occur. Consistent neurological findings are hypotonia, strabismus, and psychomotor retardation; seizures have been reported. Normal chromosomes, normal parents with multiple affected offspring, equal sex ratio of affected individuals, and consanguineous matings all support autosomal recessive inheritance of the C syndrome. In autopsied cases, there has been a suggestion of defective central nervous system myelination. About 1/2 of the case have died within the first year. All survivors have severe to profound mental retardation except for one child who has moderate retardation.

SUMMARY We have studied 116 patients in Heber's Category VII (encephalopathy due to unknown cause, with neurological signs). 4 of these had a progressive neurological disease of obscure type, 53 had motor disorders, and 59 were epileptic. 19 of the 53 cases of cerebral palsy were also epileptic. In this group, when compared with a control series, the incidence of prematurity, of twins and of neonatal symptoms were increased, suggesting the possible operation of perinatal factors. There was also the usual tendency to a small head (80.6%) with circumferences more than 3 standard deviations below the mean. In the 59 cases of epilepsy without motor disorders there were 7 cases without overt seizures but an abnormal EEG. In the whole group, the incidence of prematurity and of twins were again raised, and there was also an excess of complications of pregnancy. However, in addition to this evidence that prenatal factors are involved, there was some evidence of genetic factors, for in 10 families there were relatives with epilepsy and/or mental retardation. The tendency to have a small head (27.6%) was less marked than in the cerebral palsy group, but the incidence of psychiatric disorders (64.4%) was high. Among these disorders there were two groups (a) those with hyperactive explosive behaviour, and (b) those who showed psychotic, autistic or withdrawn features. It is considered that brain damage has played a major role in these psychiatric features.