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101.
Timothy?M?CoxEmail author Dominick?Amato Carla?EM?Hollak Cecile?Luzy Mariabeth?Silkey Ruben?Giorgino Robert?D?Steiner for the Miglustat Maintenance Study Group 《Orphanet journal of rare diseases》2012,7(1):102
Background
Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy.Methods
Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count.Results
Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3–765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (–1.1%; 95%CI ?6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, –0.95 (?1.38, –0.53) g/dL and ?44.1 (–57.6, –30.7) ×109/L, respectively.Conclusions
The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice.Trial registration
Clinicaltrials.gov identifier NCT00319046102.
AE Clarke S Bernatsky KH Costenbader MB Urowitz DD Gladman PR Fortin M Petri S Manzi DA Isenberg A Rahman D Wallace C Gordon C Peschken MA Dooley EM Ginzler C Aranow SM Edworthy O Nived S Jacobsen G Ruiz-Irastorza E Yelin SG Barr L Criswell G Sturfelt L Dreyer I Blanco L Gottesman CH Feldman R Ramsey-Goldman 《Arthritis research & therapy》2012,14(Z3):A16
103.
Tuula Jyske Markku Manner Harri Mäkinen Pekka Nöjd Heli Peltola Tapani Repo 《Trees - Structure and Function》2012,26(2):405-419
We studied the effects of artificial soil frost on cambial activity and xylem formation on 47-year-old Norway spruce [Picea abies (L.) Karst.] trees grown on medium fertile site type (with moraine soil) in eastern Finland (62°42′N; 29°45′E). Different
soil frost treatments applied were: (1) natural snow accumulation and melting (control, CTRL); (2) artificial removal of snow
from soil surface during two consecutive winters (OPEN); and (3) snow clearing and insulation (FROST), which was in other
ways similar to OPEN, but the ground was insulated in early spring to delay soil thawing. Each treatment was replicated in
three blocks, and two sample trees in each plot were repeatedly microcored during growing seasons of 2006–2007 for the analysis
of the onset, cessation and the duration of xylem formation. The phases of tracheid differentiation (tracheids in radial enlargement,
secondary cell wall formation, and mature tracheids) were measured from the microcores of 2007. The intra-ring growth and
wood density variables were analysed based on X-ray densitometry. In FROST in 2006, xylem formation started a week later than
in the other treatments. In 2007, no difference was found between the treatments. The discrepancy in results between the two
study years may be explained by between-years variation in weather, i.e., the winter was colder in 2005/2006 than in 2006/2007.
No effects of soil frost treatments on tracheid differentiation and on most of the intra-ring growth and density variables
were discovered. Our results suggest that the delayed thawing of moraine soil may slightly affect the onset, timing and duration
of xylem formation in Norway spruce. However, the effects of delayed soil frost may depend also on the soil type and become
more evident with increasing water holding capacity of the soil. 相似文献
104.
105.
Z. -M. Ge X. Zhou S. Kellom?ki H. Peltola P. J. Martikainen K. Y. Wang 《Photosynthetica》2012,50(1):141-151
The aim of this work was to study the acclimation of photosynthesis in a boreal grass (Phalaris arundinacea L.) grown in controlled environment chambers under elevated temperature (ambient + 3.5°C) and CO2 (700 μmol mol−1) with varying soil water regimes. More specifically, we studied, during two development stages (early: heading; late: florescence
completed), how the temperature response of light-saturated net photosynthetic rate (P
sat), maximum rate of ribulose-1,5-bisphosphate carboxylase/oxygenase activity (V
cmax) and potential rate of electron transport (J
max) acclimatized to the changed environment. During the early growing period, we found a greater temperature-induced enhancement
of P
sat at higher measurement temperatures, which disappeared during the late stage. Under elevated growth temperature, V
cmax and J
max at lower measurement temperatures (5–15°C) were lower than those under ambient growth temperature during the early period.
When the measurements were done at 20–30°C, the situation was the opposite. During the late growing period, V
cmax and J
max under elevated growth temperature were consistently lower across measurement temperatures. CO2 enrichment significantly increased P
sat with higher intercellular CO2 compared to ambient CO2 treatment, however, elevated CO2 slightly decreased V
cmax and J
max across measurement temperatures, probably due to down-regulation acclimation. For two growing periods, soil water availability
affected the variation in photosynthesis and biochemical parameters much more than climatic treatment did. Over two growing
periods, V
cmax and J
max were on average 36.4 and 30.6%, respectively, lower with low water availability compared to high water availability across
measurement temperatures. During the late growing period, elevated growth temperature further reduced the photosynthesis under
low water availability. V
cmax and J
max declined along with the decrease in nitrogen content of leaves as growing period progressed, regardless of climatic treatment
and water regime. We suggest that, for grass species, seasonal acclimation of the photosynthetic parameters under varying
environmental conditions needed to be identified to fairly estimate the whole-life photosynthesis. 相似文献
106.
High-dimensional datasets with large amounts of redundant information are nowadays available for hypothesis-free exploration of scientific questions. A particular case is genome-wide association analysis, where variations in the genome are searched for effects on disease or other traits. Bayesian variable selection has been demonstrated as a possible analysis approach, which can account for the multifactorial nature of the genetic effects in a linear regression model.Yet, the computation presents a challenge and application to large-scale data is not routine. Here, we study aspects of the computation using the Metropolis-Hastings algorithm for the variable selection: finite adaptation of the proposal distributions, multistep moves for changing the inclusion state of multiple variables in a single proposal and multistep move size adaptation. We also experiment with a delayed rejection step for the multistep moves. Results on simulated and real data show increase in the sampling efficiency. We also demonstrate that with application specific proposals, the approach can overcome a specific mixing problem in real data with 3822 individuals and 1,051,811 single nucleotide polymorphisms and uncover a variant pair with synergistic effect on the studied trait. Moreover, we illustrate multimodality in the real dataset related to a restrictive prior distribution on the genetic effect sizes and advocate a more flexible alternative. 相似文献
107.
The aim of this study was to analyze the effects of intensive management and forest landscape structure (in terms of age class distribution) on timber and energy wood production (m3?ha?1), net present value (NPV, ? ha?1) with implications on net CO2 emissions (kg CO2 MWh?1 per energy unit) from energy wood use of Norway spruce grown on medium to fertile sites. This study employed simulations using a forest ecosystem model and the Emission Calculation Tool, considering in its analyses: timber (saw logs, pulp) and energy wood (small-sized stem wood and/or logging residuals for top part of stem, branches, and needles) from the first thinning and harvesting residuals and stumps from the final felling. At the stand level, both fertilization and high pre-commercial stand density clearly increased timber production and the amount of energy wood. Short rotation length (40 and 60?years) outputted, on average, the highest annual stem wood production (most fertile and medium fertile sites), the 60?year rotation also outputted the highest average annual net present value (NPV with interest rates of 1?C4%). On the other hand, even longer rotation lengths, up to 80 and 100?years, were needed to output the lowest net CO2 emissions per year in energy wood use. At the landscape level, the largest productivity (both for timber and energy wood) was obtained using rotation lengths of 60 and 80?years with an initial forest landscape structure dominated by older mature stands (a right-skewed age-class distribution). If the rotation length was 120?years, the initial forest landscape dominated by young stands (a left-skewed age-class distribution) provided the highest productivity. However, the NPV with interest rate of 2% was, on average, the highest with a right-skewed distribution regardless of the rotation length. If the rotation length was 120?years, normal age class distribution provided, on average, the highest NPV. On the other hand, the lowest emissions (kg CO2 MWh?1a?1) were obtained with the left-skewed age-class distribution using the rotation lengths of 60 and 80?years, and with the normal age-class distribution using the rotation length of 120?years. Altogether, the management regimes integrating both timber and energy wood production and using fertilization provided, on average, the lowest emissions over all management alternatives considered. 相似文献
108.
Latifu?A?Sanni Catherine?EM?Allsopp Lieke?Reubsaet Ambaliou?Sanni Chris?Newbold Virander?S?Chauhan Jean?LanghorneEmail author 《Malaria journal》2002,1(1):7
Background
Plasmodium falciparum erythrocyte membrane protein-1, a variant antigen of the malaria parasite, is potentially a target for the immune response. It would be important to determine whether there are CD4 T cells that recognise conserved regions. However, within the relatively conserved region, there is variation. It is not possible to test T cell responses from small field samples with all possible peptides.Methods
We have aligned sequences that are relatively conserved between several PfEMP1 molecules, and chosen a representative sequence similar to most of the PfEMP1 variants. Using these peptides as pools representing CIDRα, CIDRβ and DBLβ-δ domains, DBLα domain, and EXON 2 domain of PfEMP1, we measured the CD4 T cell responses of malaria-exposed donors from Benin, West Africa by a FACS based assay.Results
All the three peptide pools elicited a CD4 T cell response in a proportion of malaria-exposed and non-exposed donors. CD4 T cell proliferation occurs at a relatively higher magnitude to peptide pools from the DBLα and EXON 2 in the malaria-exposed donors living in Benin than in the UK malaria-unexposed donors.Conclusions
These findings suggest that an immunological recall response to conserved peptides of a variant antigen can be measured. Further testing of individual peptides in a positive pool will allow us to determine those conserved sequences recognised by many individuals. These types of assays may provide information on conserved peptides of PfEMP1 which could be useful for stimulating T cells to provide help to P. falciparum specific B cells.109.
van Lent PL Nabbe KC Blom AB Sloetjes A Holthuysen AE Kolls J Van De Loo FA Holland SM Van Den Berg WB 《Arthritis research & therapy》2005,7(4):R885-R895
In previous studies we have found that FcγRI determines chondrocyte death and matrix metalloproteinase (MMP)-mediated cartilage
destruction during IFN-γ-regulated immune complex arthritis (ICA). Binding of immune complexes (ICs) to FcγRI leads to the
prominent production of oxygen radicals. In the present study we investigated the contribution of NADPH-oxidase-driven oxygen
radicals to cartilage destruction by using p47phox-/- mice lacking a functional NADPH oxidase complex. Induction of a passive ICA in the knee joints of p47phox-/- mice resulted in a significant elevation of joint inflammation at day 3 when compared with wild-type (WT) controls as studied
by histology. However, when IFN-γ was overexpressed by injection of adenoviral IFN-γ in the knee joint before ICA induction,
a similar influx of inflammatory cells was found at days 3 and 7, comprising mainly macrophages in both mouse strains. Proteoglycan
depletion from the cartilage layers of the knee joints in both groups was similar at days 3 and 7. Aggrecan breakdown in cartilage
caused by MMPs was further studied by immunolocalisation of MMP-mediated neoepitopes (VDIPEN). VDIPEN expression in the cartilage
layers of arthritic knee joints was markedly lower (between 30 and 60%) in IFN-γ-stimulated arthritic p47phox-/- mice at day 7 than in WT controls, despite significant upregulation of mRNA levels of various MMPs such as MMP-3, MMP-9,
MMP-12 and MMP-13 in synovia and MMP-13 in cartilage layers as measured with quantitative RT-PCR. The latter observation suggests
that oxygen radicals are involved in the activation of latent MMPs. Chondrocyte death, determined as the percentage of empty
lacunae in articular cartilage, ranged between 20 and 60% at day 3 and between 30 and 80% at day 7 in WT mice, and was completely
blocked in p47phox-/- mice at both time points. FcγRI mRNA expression was significantly lower, and FcγRII and FcγRIII were higher, in p47phox-/- mice than in controls. NADPH-oxidase-driven oxygen radical production determines chondrocyte death and aggravates MMP-mediated
cartilage destruction during IFN-γ-stimulated IC-mediated arthritis. Upregulation of FcγRI by oxygen radicals may contribute
to cartilage destruction. 相似文献
110.