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Oak Ridge Y-12 Plant Review of Lessons Learned of the Tokaimura Criticality Accident
Narrowband UVB phototherapy for clinically isolated syndrome: A trial to deliver the benefits of Vitamin D and other UVB-Induced molecules
Low vitamin D and insufficient sun exposure are additive independent risk factors for the development of multiple sclerosis (MS). The usual measure of vitamin D status, serum 25-hydroxy vitamin D [25(OH)D], is also a marker of recent exposure to the UVB rays of sunshine. The main evidence for a protective effect for MS development of higher 25(OH)D comes from observational studies, but this study design cannot separate out whether 25(OH)D is acting as a marker of vitamin D status, sun exposure, or both. In light of a lack of definitive outcomes in MS patients after trials of vitamin D supplementation and the ability of narrowband UVB to induce vitamin D, as well as other immune-regulatory molecules in skin, the Phototherapy for Clinically Isolated Syndrome (PhoCIS) trial was established to investigate the benefits of narrowband UVB, in addition to supplemented vitamin D, on MS development in individuals with Clinically Isolated Syndrome. We propose that the PhoCIS trial provides a fresh approach to re-defining the reported associations of 25(OH)D levels with MS development and progression
Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome
Objective
To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT).
Methods
sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes.
Results
Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7â161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2â212.2) than in HC (10.7 pg/ml [IQR] 4.9â21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT â10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall.
Conclusions
Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT
Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS
BACKGROUND:
Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire.
OBJECTIVE:
The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT.
METHODS:
Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT.
RESULTS:
CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naĂŻve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years.
CONCLUSION:
This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients
Autologous stem cell transplantation in multiple sclerosis: Results from a single centre
Background: In the last 2 decades, intensive immunosuppression followed by autologous stem cell transplantation (ASCT) has been proposed as a possible strategy for treatment of severe immune-mediated disorders, including multiple sclerosis (MS).
Objective: To review the outcome of ASCT for MS in Western Australia. Methods: Eligibility criteria for ASCT were (1) progression of sustained disability with expanded disability status scale (EDSS) score increase of more than 1/10 over a 12 month period, (2) advanced MS with threatened loss of ambulation and (3) rapidly progressive disease not adequately assessed by EDSS. Stem cell mobilization was with cyclophosphamide (CY) 2g/m 2 and granu - locyte-colony stimulating factor 5ug/kg bd. conditioning chemo - therapy was with CY 50mg/kg and rabbit antithymocyte globulin 1mg/kg days -5 to -2. Patients were assessed at 3, 6, 12 and 24 months post-transplant.
Results: Fourteen patients underwent ASCT. Median age was 47 years; median time from diagnosis to transplant was 12 years. Diagnosis at transplant was secondary progressive MS (12), pri - mary progressive MS (1) and neuromyelitis optica (1). About half the cohorts were neurologically stable at 24 months while the remainder had clinically relevant neurological deterioration. Two patients had meaningful improvement in bladder function. Follow-up MRI showed no Gd-enhancing lesions, but two patients developed new cerebral lesions on T2 weighted imaging.
Conclusion: In this group of patients with advanced MS, neuro - logical function 24 months post-ASCT was essentially stable in half the cohort while the remainder experienced clinical progres - sion. It is not possible to conclude whether ASCT altered the natu - ral history of the disease
Higher serum immunoglobulin G3 levels may predict the development of multiple sclerosis in individuals with Clinically Isolated Syndrome
Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgG1â4 were measured in 20 people with CIS and compared with those in 10 healthy controls (HC) and 8 people with MS. Serum Ig levels in individuals with CIS were compared with (a) the time to their conversion from CIS to MS, (b) serum levels of antibodies to EpsteinâBarr virus, (c) frequencies of T regulatory (Treg), T follicular regulatory (Tfr), and B cell subsets, and (d) Treg/Tfr expression of Helios. Serum IgG, IgM, and IgG2 levels were significantly lower in people with CIS than HC, and IgG, IgM, and IgG1 levels were significantly lower in people with CIS than MS. After adjusting for age, sex, and serum 25(OH) vitamin D3 [25(OH)D] levels, CIS was associated with lower serum levels of IgG and IgG2 compared with HC (p = 0.001 and p < 0.001, respectively). People with MS had lower IgG2 levels (p < 0.001) and IgG2 proportions (%IgG; p = 0.007) compared with HC. After adjusting for age, sex, and 25(OH)D, these outcomes remained, in addition to lower serum IgA levels (p = 0.01) and increased IgG3 levels (p = 0.053) in people with MS compared with HC. Furthermore, serum from people with MS had increased proportions of IgG1 and IgG3 (p = 0.03 and p = 0.02, respectively), decreased proportions of IgG2 (p = 0.007), and greater ratios of âupstreamâ to âdownstreamâ IgG subclasses (p = 0.001) compared with HC. Serum IgG3 proportions (%IgG) from people with CIS correlated with the frequency of plasmablasts in peripheral blood (p = 0.02). Expression of Helios by Treg and Tfr cell subsets from individuals with CIS correlated with levels of serum IgG2 and IgG4. IgG3 levels and proportions of IgG3 (%IgG) in serum at CIS diagnosis were inversely correlated with the time until conversion to MS (p = 0.018 and p < 0.001, respectively), suggesting they may be useful prognostic markers of individuals with CIS who rapidly convert to MS
Gravitational Coupling and Dynamical Reduction of The Cosmological Constant
We introduce a dynamical model to reduce a large cosmological constant to a
sufficiently small value. The basic ingredient in this model is a distinction
which has been made between the two unit systems used in cosmology and particle
physics. We have used a conformal invariant gravitational model to define a
particular conformal frame in terms of large scale properties of the universe.
It is then argued that the contributions of mass scales in particle physics to
the vacuum energy density should be considered in a different conformal frame.
In this manner, a decaying mechanism is presented in which the conformal factor
appears as a dynamical field and plays a key role to relax a large effective
cosmological constant. Moreover, we argue that this model also provides a
possible explanation for the coincidence problem.Comment: To appear in GR
Is the evidence for dark energy secure?
Several kinds of astronomical observations, interpreted in the framework of
the standard Friedmann-Robertson-Walker cosmology, have indicated that our
universe is dominated by a Cosmological Constant. The dimming of distant Type
Ia supernovae suggests that the expansion rate is accelerating, as if driven by
vacuum energy, and this has been indirectly substantiated through studies of
angular anisotropies in the cosmic microwave background (CMB) and of spatial
correlations in the large-scale structure (LSS) of galaxies. However there is
no compelling direct evidence yet for (the dynamical effects of) dark energy.
The precision CMB data can be equally well fitted without dark energy if the
spectrum of primordial density fluctuations is not quite scale-free and if the
Hubble constant is lower globally than its locally measured value. The LSS data
can also be satisfactorily fitted if there is a small component of hot dark
matter, as would be provided by neutrinos of mass 0.5 eV. Although such an
Einstein-de Sitter model cannot explain the SNe Ia Hubble diagram or the
position of the `baryon acoustic oscillation' peak in the autocorrelation
function of galaxies, it may be possible to do so e.g. in an inhomogeneous
Lemaitre-Tolman-Bondi cosmology where we are located in a void which is
expanding faster than the average. Such alternatives may seem contrived but
this must be weighed against our lack of any fundamental understanding of the
inferred tiny energy scale of the dark energy. It may well be an artifact of an
oversimplified cosmological model, rather than having physical reality.Comment: 12 pages, 5 figures; to appear in a special issue of General
Relativity and Gravitation, eds. G.F.R. Ellis et al; Changes: references
reformatted in journal style - text unchange
The -essence scalar field in the context of Supernova Ia Observations
A -essence scalar field model having (non canonical) Lagrangian of the
form where
with constant is shown to be consistent with luminosity
distance-redshift data observed for type Ia Supernova. For constant ,
satisfies a scaling relation which is used to set up a differential
equation involving the Hubble parameter , the scale factor and the
-essence field . and are extracted from SNe Ia data and using
the differential equation the time dependence of the field is found to
be: . The constants
have been determined. The time dependence is similar to that of the
quintessence scalar field (having canonical kinetic energy) responsible for
homogeneous inflation. Furthermore, the scaling relation and the obtained time
dependence of the field is used to determine the -dependence of the
function .Comment: 8 pages, 5 figures, Late
Star Models with Dark Energy
We have constructed star models consisting of four parts: (i) a homogeneous
inner core with anisotropic pressure (ii) an infinitesimal thin shell
separating the core and the envelope; (iii) an envelope of inhomogeneous
density and isotropic pressure; (iv) an infinitesimal thin shell matching the
envelope boundary and the exterior Schwarzschild spacetime. We have analyzed
all the energy conditions for the core, envelope and the two thin shells. We
have found that, in order to have static solutions, at least one of the regions
must be constituted by dark energy. The results show that there is no physical
reason to have a superior limit for the mass of these objects but for the ratio
of mass and radius.Comment: 20 pages, 1 figure, references and some comments added, typos
corrected, in press GR
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