From Department of Haematology, Barts & The London, Queen Marys School of Medicine and Dentistry, Whitechapel, London, UK (DP, TB, ACN); Department of Medical Sciences, Ospedale "Regina ...Apostolorum", Albano Laziale (MLE, RS); Dept. of Hematology, "Tor Vergata" University Hospital, Rome, Italy (SA)
Correspondence: Adrian Newland, Department of Haematology, The Royal London Hospital, Whitechapel, London El 2ES, UK. E-mail: a.c.newland{at}qmul.ac.uk
We conducted a retrospective analysis of 11 consecutive patients with various autoimmune cytopenias who failed to respond to conventional treatments and received a fixed-dose regimen of rituximab (100 mg weekly for 4 consecutive weeks). Sustained complete responses were achieved in 4 out of 7 patients with idiopathic thrombocytopenic purpura and in 1 patient with autoimmune pancytopenia. A partial response was observed in 1 patient with autoimmune hemolytic anemia. The immunotherapy had no effect in 1 patient with pure red cell aplasia or in 1 patient with autoimmune neutropenia. No infusion-related or delayed toxicities attributable to rituximab were experienced by any of the patients.
Key words: autoimmune disease, cytopenias, rituximab, low dose.
Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be quite effective in the treatment of immune disorders resulting from autoantibodies. We prospectively studied the long-term ...effects of rituximab in 10 patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis refractory to conventional therapy (n=3) or in second or subsequent relapse (n=7).
The median age of patients was 53 yrs (range 38-70 yrs). Eight were classified as Wegener's granulomatosis, and two as microscopic polyangiitis. Clinical activity was assessed using the Birmingham Vasculitis Activity Score modification for Wegener's granulomatosis. Treatment consisted of intravenous infusions of rituximab given at the dose of 375 mg/m2 weekly for four consecutive weeks.
All patients experienced a rapid clinical improvement following the administration of rituximab, with nine complete responses and one partial response at 6 months. With a median follow-up of 33.5 months (range 26-45 months), three patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. Rituximab therapy resulted in prolonged B-cell depletion. The ANCA titres decreased significantly in all patients, with eight out of 10 becoming ANCA-negative and three remaining ANCA-negative even after B-cell recovery. Infusion-related side effects were observed in one patient, but were of mild intensity and did not require discontinuation of treatment.
Rituximab is an effective and well-tolerated treatment for patients with ANCA-associated vasculitis and should be strongly considered in severely affected patients who do not respond to standard therapy or in those in whom cytotoxic therapy bears a high risk of morbidity.
We report the first data set of atmospheric abundances for the following four perfluoroalkanes: n-decafluorobutane (n-C4F10), n-dodecafluoropentane (n-C5F12), n-tetradecafluorohexane (n-C6F14) and ...n-hexadecafluoroheptane (n-C7F16). All four compounds could be detected and quantified in air samples from remote locations in the Southern Hemisphere (at Cape Grim, Tasmania, archived samples dating back to 1978) and the upper troposphere (a passenger aircraft flying from Germany to South Africa). Further observations originate from air samples extracted from deep firn in Greenland and allow trends of atmospheric abundances in the earlier 20th century to be inferred. All four compounds were not present in the atmosphere prior to the 1960s. n-C4F10 and n-C5F12 were also measured in samples collected in the stratosphere with the data indicating that they have no significant sinks in this region. Emissions were inferred from these observations and found to be comparable with emissions from the EDGAR database for n-C6F14. However, emissions of n-C4F10, n-C5F12 and n-C7F16 were found to differ by up to five orders of magnitude between our approach and the database. Although the abundances of the four perfluorocarbons reported here are currently small (less than 0.3 parts per trillion) they have strong Global Warming Potentials several thousand times higher than carbon dioxide (on a 100-yr time horizon) and continue to increase in the atmosphere. We estimate that the sum of their cumulative emissions reached 325 million metric tonnes CO2 equivalent at the end of 2009.
The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune ...conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database.
Using the General Practice Research Database, 1,070 adults (>or=18 years) with coded records for primary immune thrombocytopenia first referenced between January 1(st) 1992 and November 30(th) 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox's proportional hazards regression.
Over a median 47.6 months of follow-up (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00), and 1.41 (95% CI, 1.04-1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia.
Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.
Air samples collected at Cape Grim, Tasmania between 1978 and 2008 and during a series of more recent aircraft sampling programmes have been analysed to determine the atmospheric abundance and trend ...of octafluorocyclobutane (c-C4F8 or PFC-318). c-C4F8 has an atmospheric lifetime in excess of 3000 yr and a global warming potential (GWP) of 10 300 (100 yr time horizon), making it one of the most potent greenhouse gases detected in the atmosphere to date. The abundance of c-C4F8 in the Southern Hemisphere has risen from 0.35 ppt in 1978 to 1.2 ppt in 2010, and is currently increasing at a rate of around 0.03 ppt yr−1. It is the third most abundant perfluorocarbon (PFC) in the present day atmosphere, behind CF4 (~75 ppt) and C2F6 (~4 ppt). Although a number of potential sources of c-C4F8 have been reported, including the electronics and semi-conductor industries, there remains a large discrepancy in the atmospheric budget. Using a 2-D global model to derive top-down global emissions based on the Cape Grim measurements yields a recent (2007) emission rate of around 1.1 Gg yr−1 and a cumulative emission up to and including 2007 of 38.1 Gg. Emissions reported on the EDGAR emissions database for the period 1986–2005 represent less than 1% of the top-down emissions for the same period, which suggests there is a large unaccounted for source of this compound. It is also apparent that the magnitude of this source has varied considerably over the past 30 yr, declining sharply in the late 1980s before increasing again in the mid-1990s.
The Indian megacity of Delhi suffers from some of the
poorest air quality in the world. While ambient NO2 and particulate
matter (PM) concentrations have received considerable attention in the city,
...high ground-level ozone (O3) concentrations are an often overlooked
component of pollution. O3 can lead to significant ecosystem damage and
agricultural crop losses, and adversely affect human health. During October 2018,
concentrations of speciated non-methane hydrocarbon volatile organic
compounds (C2–C13), oxygenated volatile organic compounds
(o-VOCs), NO, NO2, HONO, CO, SO2, O3, and photolysis rates,
were continuously measured at an urban site in Old Delhi. These observations
were used to constrain a detailed chemical box model utilising the Master
Chemical Mechanism v3.3.1. VOCs and NOx (NO + NO2) were varied
in the model to test their impact on local O3 production rates,
P(O3), which revealed a VOC-limited chemical regime. When only NOx
concentrations were reduced, a significant increase in P(O3) was
observed; thus, VOC co-reduction approaches must also be considered in
pollution abatement strategies. Of the VOCs examined in this work, mean
morning P(O3) rates were most sensitive to monoaromatic compounds,
followed by monoterpenes and alkenes, where halving their concentrations in
the model led to a 15.6 %, 13.1 %, and 12.9 % reduction in
P(O3), respectively. P(O3) was not sensitive to direct changes in
aerosol surface area but was very sensitive to changes in photolysis rates,
which may be influenced by future changes in PM concentrations. VOC and
NOx concentrations were divided into emission source sectors, as
described by the Emissions Database for Global Atmospheric Research (EDGAR) v5.0 Global Air Pollutant Emissions and EDGAR
v4.3.2_VOC_spec inventories, allowing for the
impact of individual emission sources on P(O3) to be investigated.
Reducing road transport emissions only, a common strategy in air pollution
abatement strategies worldwide, was found to increase P(O3), even when
the source was removed in its entirety. Effective reduction in P(O3)
was achieved by reducing road transport along with emissions from combustion
for manufacturing and process emissions. Modelled P(O3) reduced by
∼ 20 ppb h−1 when these combined sources were halved. This study
highlights the importance of reducing VOCs in parallel with NOx and PM
in future pollution abatement strategies in Delhi.
Protease‐activated receptor‐2 (PAR‐2) belongs to a family of G‐coupled receptors activated by proteolytic cleavage to reveal a tethered ligand. PAR‐2 is activated by trypsin and trypsin‐like serine ...proteases and experimentally, by receptor‐activating peptides (APs), which mimic the tethered ligand. PAR‐2 has recently been implicated in proinflammatory immune responses. For example, PAR‐2−/− mice exhibit markedly diminished contact hypersensitivity reactions and are completely resistant to adjuvant‐induced arthritis. The present study shows that human blood monocytes express low‐level cell‐surface PAR‐2 ex vivo, which is up‐regulated upon cell purification by the mobilization of intracellular stores of PAR‐2 protein. PAR‐2 expression is also present on monocyte‐derived macrophages, but only a small proportion of monocyte‐derived dendritic cells (DC) is PAR‐2+, and blood DC are PAR–. Freshly isolated monocytes responded to the PAR‐2 AP ASKH 95 (2‐furoyl‐LIGKV‐OH) with the generation of a calcium flux and production of interleukin (IL)‐1β, IL‐6, and IL‐8. The results presented thus suggest that PAR‐2 contributes to inflammatory responses by inducing the production of proinflammatory cytokines in peripheral blood monocytes.
We report the first measurements of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), a substitute for ozone depleting compounds, in air samples originating from remote regions of the atmosphere and ...present evidence for its accelerating growth. Observed mixing ratios ranged from below 0.01 ppt in deep firn air to 0.59 ppt in the current northern mid-latitudinal upper troposphere. Firn air samples collected in Greenland were used to reconstruct a history of atmospheric abundance. Year-on-year increases were deduced, with acceleration in the growth rate from 0.029 ppt per year in 2000 to 0.056 ppt per year in 2007. Upper tropospheric air samples provide evidence for a continuing growth until late 2009. Furthermore we calculated a stratospheric lifetime of 370 years from measurements of air samples collected on board high altitude aircraft and balloons. Emission estimates were determined from the reconstructed atmospheric trend and suggest that current "bottom-up" estimates of global emissions for 2005 are too high by a factor of three.
Long term measurements in background air (Cape Grim, Tasmania) and firn air (NEEM, Greenland) of the potent long-lived greenhouse gas SF5 CF3 show that emissions declined after the late 1990s, having ...grown since the 1950s, and became indistinguishable from zero after 2003. The timing of this decline suggests that emissions of this gas may have been related to the production of certain fluorochemicals; production of which have been recently phased out. An earlier observation of closely correlated atmospheric abundances of SF5 CF3 and SF6 are shown here to have likely been purely coincidental, as their respective trends diverged after 2002. Due to its long lifetime (ca. 900 yr), atmospheric concentrations of SF5 CF3 have not declined, and it is now well mixed between hemispheres, as is also shown here from interhemispheric aircraft measurements. Total cumulative emissions of SF5 CF3 amount to around 5 kT.
The impact of emissions of volatile organic compounds (VOCs) to the
atmosphere on the production of secondary pollutants, such as ozone and
secondary organic aerosol (SOA), is mediated by the ...concentration of nitric
oxide (NO). Polluted urban atmospheres are typically considered to be
“high-NO” environments, while remote regions such as rainforests, with
minimal anthropogenic influences, are considered to be “low NO”. However,
our observations from central Beijing show that this simplistic separation
of regimes is flawed. Despite being in one of the largest megacities in the
world, we observe formation of gas- and aerosol-phase oxidation products
usually associated with low-NO “rainforest-like” atmospheric oxidation
pathways during the afternoon, caused by extreme suppression of NO
concentrations at this time. Box model calculations suggest that during
the morning high-NO chemistry predominates (95 %) but in the afternoon
low-NO chemistry plays a greater role (30 %). Current emissions
inventories are applied in the GEOS-Chem model which shows that such models,
when run at the regional scale, fail to accurately predict such an extreme
diurnal cycle in the NO concentration. With increasing global emphasis on
reducing air pollution, it is crucial for the modelling tools used to
develop urban air quality policy to be able to accurately represent such
extreme diurnal variations in NO to accurately predict the formation of
pollutants such as SOA and ozone.
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