67 research outputs found
HTLV-I-Infected T Cells Evade the Antiproliferative Action of IFN-β
AbstractHuman T-cell lymphotropic virus type I (HTLV-I)-infected T-cell clones enter the S-phase of the cell cycle in the absence of exogenous IL-2. The pathway by which HTLV-I activates the host T cell may circumvent normal immunoregulatory mechanisms and thus be important for the pathogenesis of HTLV-I-induced diseases. The early control of viral infections is in part mediated by interferons (IFNs), which possess both antiviral and antiproliferative functions. In order to investigate the antiproliferative effect of IFN-β on HTLV-I-induced T-cell activation, we generated T-cell clones from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis by single-cell cloning under limiting dilution conditions. Here we demonstrate that HTLV-I-induced T-cell proliferation is resistant to the antiproliferative action of IFN-β. Moreover, HTLV-I-infected T-cell clones continue to constitutively secrete IFN-γ in the presence of high doses of IFN-β. HTLV-I-infected T cells express normal levels of IFNAR1 and are able to respond to IFN-β by phosphorylation of STAT1 on Tyr701, although they display a relative increase in phosphorylation of the transcriptionally inactive STAT1β when compared with STAT1α. Thus, HTLV-I promotes cell cycle progression in G1by a mechanism that overcomes inhibitory signals, thereby circumventing an innate immune defense mechanism
Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis.
Background: In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia.
Objective: We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate in routine practice.
Methods: Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6-month intervals following dimethyl fumarate initiation.
Results: Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 10
Conclusion: Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia
“I think we need to get a better generator”: Household resilience to disruption to power supply during storm events
AbstractElectricity is becoming ever more central to the everyday practices of households. As the energy system decarbonises, it is likely that electricity will supply even more services, thereby increasing the dependence of communities on reliable electricity supply. In this situation, the risk of power outages during extreme weather events poses a serious challenge to the safety and wellbeing of communities. However, little is known of the capacity of households to manage normal day-to-day life in such circumstances. This paper focuses on the UK winter storms that occurred in February 2014, the result of which 80,000 homes were left without power and communities not reconnected for several days. We outline the impacts these power outages had on households, describing the challenges faced and the strategies adopted to alleviate impacts. This provides insight into everyday household-level resilience achieved through social and material elements that constitute everyday life
Radio continuum observations of Class I protostellar disks in Taurus: constraining the greybody tail at centimetre wavelengths
We present deep 1.8 cm (16 GHz) radio continuum imaging of seven young
stellar objects in the Taurus molecular cloud. These objects have previously
been extensively studied in the sub-mm to NIR range and their SEDs modelled to
provide reliable physical and geometrical parametres.We use this new data to
constrain the properties of the long-wavelength tail of the greybody spectrum,
which is expected to be dominated by emission from large dust grains in the
protostellar disk. We find spectra consistent with the opacity indices expected
for such a population, with an average opacity index of beta = 0.26+/-0.22
indicating grain growth within the disks. We use spectra fitted jointly to
radio and sub-mm data to separate the contributions from thermal dust and radio
emission at 1.8 cm and derive disk masses directly from the cm-wave dust
contribution. We find that disk masses derived from these flux densities under
assumptions consistent with the literature are systematically higher than those
calculated from sub-mm data, and meet the criteria for giant planet formation
in a number of cases.Comment: submitted MNRA
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
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Female hormonal exposures and neuromyelitis optica symptom onset in a multicenter study
Objective: To study the association between hormonal exposures and disease onset in a cohort of women with neuromyelitis optica spectrum disorder (NMOSD). Methods: Reproductive history and hormone use were assessed using a standardized reproductive survey administered to women with NMOSD (82% aquaporin-4 antibody positive) at 8 clinical centers. Using multivariable regression, we examined the association between reproductive exposures and age at first symptom onset (FS). Results: Among 217 respondents, the mean age at menarche was 12.8 years (SD 1.7). The mean number of pregnancies was 2.1 (SD 1.6), including 0.3 (SD 0.7) occurring after onset of NMOSD symptoms. In the 117 participants who were postmenopausal at the time of the questionnaire, 70% reported natural menopause (mean age: 48.9 years [SD 3.9]); fewer than 30% reported systemic hormone therapy (HT) use. Mean FS age was 40.1 years (SD 14.2). Ever-use of systemic hormonal contraceptives (HC) was marginally associated with earlier FS (39 vs 43 years, p = 0.05). Because HC use may decrease parity, when we included both variables in the model, the association between HC use and FS age became more significant (estimate = 2.7, p = 0.007). Among postmenopausal participants, 24% reported NMOSD onset within 2 years of (before or after) menopause. Among these participants, there was no association between age at menopause or HT use and age at NMOSD onset. Conclusions: Overall, age at NMOSD onset did not show a strong relationship with endogenous hormonal exposures. An earlier onset age did appear to be marginally associated with systemic HC exposure, an association that requires confirmation in future studies
AMI-LA radio continuum observations of Spitzer c2d small clouds and cores: Serpens region
We present deep radio continuum observations of the cores identified as
deeply embedded young stellar objects in the Serpens molecular cloud by the
Spitzer c2d programme at a wavelength of 1.8cm with the Arcminute Microkelvin
Imager Large Array (AMI-LA). These observations have a resolution of ~30arcsec
and an average sensitivity of 19microJy/beam. The targets are predominantly
Class I sources, and we find the detection rate for Class I objects in this
sample to be low (18%) compared to that of Class 0 objects (67%), consistent
with previous works. For detected objects we examine correlations of radio
luminosity with bolometric luminosity and envelope mass and find that these
data support correlations found by previous samples, but do not show any
indiction of the evolutionary divide hinted at by similar data from the Perseus
molecular cloud when comparing radio luminosity with envelope mass. We conclude
that envelope mass provides a better indicator for radio luminosity than
bolometric luminosity, based on the distribution of deviations from the two
correlations. Combining these new data with archival 3.6cm flux densities we
also examine the spectral indices of these objects and find an average spectral
index of 0.53+/-1.14, consistent with the canonical value for a partially
optically thick spherical or collimated stellar wind. However, we caution that
possible inter-epoch variability limits the usefulness of this value, and such
variability is supported by our identification of a possible flare in the radio
history of Serpens SMM 1.Comment: accepted MNRA
AMI radio continuum observations of young stellar objects with known outflows
We present 16 GHz (1.9 cm) deep radio continuum observations made with the Arcminute Microkelvin Imager (AMI) of a sample of low-mass young stars driving jets. We combine these new data with archival information from an extensive literature search to examine spectral energy distributions (SEDs) for each source and calculate both the radio and sub-mm spectral indices in two different scenarios: (1) fixing the dust temperature (Td) according to evolutionary class; and (2) allowing Td to vary. We use the results of this analysis to place constraints on the physical mechanisms responsible for the radio emission. From AMI data alone, as well as from model fitting to the full SED in both scenarios, we find that 80 per cent of the objects in this sample have spectral indices consistent with freefree emission. We find an average spectral index in both Td scenarios, consistent with freefree emission. We examine correlations of the radio luminosity with bolometric luminosity, envelope mass and outflow force, and find that these data are consistent with the strong correlation with envelope mass seen in lower luminosity samples. We examine the errors associated with determining the radio luminosity and find that the dominant source of error is the uncertainty on the opacity index, beta. We examine the SEDs for variability in these young objects, and find evidence for possible radio flare events in the histories of L1551 IRS 5 and Serpens SMM 1
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
Background:
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods:
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings:
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation:
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
Background:
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods:
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings:
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation:
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention
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