Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, ...which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.
This analysis provides an up‐to‐date assessment of long‐term (1990–2010) rural ozone trends using all available data in the western (12 sites) and eastern (41 sites) USA. Rather than focus solely on ...average ozone values or air quality standard violations, we consider the full range of ozone values, reporting trends for the 5th, 50th and 95th percentiles. Domestic ozone precursor emissions decreased strongly during 1990–2010. Accordingly 83%, 66% and 20% of summertime eastern U.S. sites experienced statistically significant ozone decreases in the 95th, 50th and 5th percentiles, respectively. During spring 43% of the eastern sites have statistically significant ozone decreases for the 95th percentile with no sites showing a significant increase. At the 50th percentile there is little overall change in the eastern U.S. In contrast, only 17% (2 sites) and 8% (1 site) of summertime western U.S. sites have statistically significant ozone decreases in the 95th and 50th percentiles, respectively. During spring no western site has a significant decrease, while 50% have a significant median increase. This dichotomy in U.S. ozone trends is discussed in terms of changing anthropogenic and biomass burning emissions. Consideration is given to the concept that increasing baseline ozone flowing into the western U.S. is counteracting ozone reductions due to domestic emission reductions. An update to the springtime free tropospheric ozone trend above western North America shows that ozone has increased significantly from 1995 to 2011 at the rate of 0.41 ± 0.27 ppbv yr−1. Finally, the ozone changes are examined in relation to regional temperature trends.
Key Points
Median ozone in the eastern US is decreasing in summer but unchanged in spring
Half of the western US rural sites have increasing median ozone in spring
Increasing western ozone is inconsistent with decreasing US precursor emissions
Diamond-Blackfan anemia Da Costa, Lydie M; Marie, Isabelle; Leblanc, Thierry M
Hematology,
12/2021, Letnik:
2021, Številka:
1
Journal Article
Odprti dostop
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in ...erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit-erythroid and colony forming unit-erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.
Relative humidity (RH) measurements from Vaisala RS92 radiosondes are widely used in research and operational applications, but their accuracy is not well characterized as a function of height, RH, ...and time of day (or solar altitude angle). This study compares RS92 RH measurements to simultaneous water vapor measurements from three reference instruments of known accuracy. Cryogenic frost point hygrometer measurements are used to characterize the RS92 accuracy above the 700‐mbar level, microwave radiometer measurements characterize the RS92 accuracy averaged over essentially the lower troposphere, and the RS92 accuracy at the surface is characterized by a system of 6 RH probes with National Institute of Standards and Technology–traceable calibrations. The three RS92 accuracy assessments are combined to yield a detailed estimate of RS92 accuracy for all RH conditions from the surface to the lowermost stratosphere. An empirical correction is derived to remove the mean bias error, yielding corrected RS92 measurements whose bias uncertainty is independent of height or RH and is estimated to be ±4% of the measured RH value for nighttime soundings and ±5% for daytime soundings, plus an RH offset uncertainty of ±0.5% RH that is significant for dry conditions. The accuracy of an individual RS92 sounding is further characterized by the 1‐σ “random production variability,” estimated to be ±1.5% of the measured RH value. The daytime bias correction must be used with caution, as it is only accurate for clear‐sky or near‐clear conditions owing to the complicated effect of clouds on the solar radiation error.
We present a 20 year time series of in situ free tropospheric ozone observations above western North America during springtime and interpret results using hindcast simulations (1980–2014) conducted ...with the Geophysical Fluid Dynamics Laboratory global chemistry‐climate model (GFDL AM3). Revisiting the analysis of Cooper et al. (), we show that sampling biases can substantially influence calculated trends. AM3 cosampled in space and time with observations reproduces the observed ozone trend (0.65 ± 0.32 ppbv yr−1) over 1995–2008 (in simulations either with or without time‐varying emissions), whereas AM3 “true median” with continuous temporal and spatial sampling indicates an insignificant trend (0.25 ± 0.32 ppbv yr−1). Extending this analysis to 1995–2014, we find a weaker ozone trend of 0.31 ± 0.21 ppbv yr−1 from observations and 0.36 ± 0.18 ppbv yr−1 from AM3 “true median.” Rising Asian emissions and global methane contribute to this increase. While interannual variability complicates the attribution of ozone trends, multidecadal hindcasts can aid in the estimation of robust confidence limits for trends based on sparse observational records.
Key Points
Multidecadal hindcast simulations to interpret O3 trends based on incomplete observations
Large variability in meteorology and sparse in situ sampling complicates O3 trend estimates
While rising Asian emissions raise U.S. O3 background, the model “true median” indicates weaker or insignificant trends
Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and ...psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with initial platelet counts of.
Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated ...clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.
PDF
