Glennvang3680

Thus, our data suggest an important role for IL-3 in early human hematopoiesis by supporting the endothelial to hematopoietic transition of hemato-endothelial progenitor cells and highlight the potential of a hemanoid-based model to study human hematopoietic development. Copyright © 2020, Ferrata Storti Foundation.Severe congenital neutropenia (CN) is a rare heterogeneous group of diseases, characterized by a granulocytic maturation arrest. Autosomal recessive mutations in the HAX1 gene are frequently detected in affected individuals. However, the precise role of HAX1 during neutrophil differentiation is poorly understood. To date, no reliable animal model has been established to study HAX1-associated CN. Here we show that knockdown of zebrafish hax1 impairs neutrophil development without affecting other myeloid cells and erythrocytes. Furthermore, we have found that interference with the Hax1 function decreases the expression level of key target genes of the granulocyte-colony stimulating factor (G-CSF) signaling pathway. The reduced neutrophil numbers in the morphants could be reversed by G-CSF, which is also the main therapeutic intervention for patients who have CN. Our results demonstrate that zebrafish is a suitable model for HAX1-associated neutropenia. We anticipate that this model will serve as an in vivo platform to identify new avenues for developing tailored therapeutic strategies for CN patients, particularly for those individuals that do not respond to the G-CSF treatment. Copyright © 2020, Ferrata Storti Foundation.Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics explaining these variabilities. Patients (n=92) were treated according to the DCOG ALL-11 protocol, using therapeutic drug monitoring to individualize the PEGasparaginase doses. HA15 purchase Non-linear mixed effects modeling (NONMEM) was used to analyze the popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time-dependent clearance adequately described the popPK. Normalization of clearance and volume of distribution by body surface are (BSA) reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing with 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than intensification and maintenance (p less then 0.001). Targeting an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by BSA, treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account these covariates and the dosing guidelines provided. Copyright © 2020, Ferrata Storti Foundation.OBJECTIVE To determine the impact of socioeconomic status (SES) on sudden unexpected death in epilepsy (SUDEP) rates. METHODS We queried all decedents presented for medico-legal investigation at 3 medical examiner (ME) offices across the country (New York City, Maryland, San Diego County) in 2009 to 2010 and 2014 to 2015. We identified all decedents for whom epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate. We then reviewed all available reports. Decedents determined to have SUDEP were included for analysis. We used median income in the ZIP code of residence as a surrogate for SES. For each region, zip code regions were ranked by median household income and divided into quartiles based on total population for 2 time periods. Region-, age-, and income-adjusted epilepsy prevalence was estimated in each zip code. SUDEP rates in the highest and lowest SES quartiles were evaluated to determine disparity. Examined SUDEP rates in 2 time periods were also compared. RESULTS There were 159 and 43 SUDEP cases in the lowest and highest SES quartiles. ME-investigated SUDEP rate ratio between the lowest and highest SES quartiles was 2.6 (95% confidence interval [CI] 1.7-4.1, p less then 0.0001) in 2009 to 2010 and 3.3 (95% CI 1.9-6.0, p less then 0.0001) in 2014 to 2015. There was a significant decline in overall SUDEP rate between the 2 study periods (36% decrease, 95% CI 22%-48%, p less then 0.0001). CONCLUSION ME-investigated SUDEP incidence was significantly higher in people with the lowest SES compared to the highest SES. The difference persisted over a 5-year period despite decreased overall SUDEP rates. © 2020 American Academy of Neurology.OBJECTIVE This case series describes and discusses the potential clinical utility of a prominent vein (index vein) found on susceptibility-weighted MRI during migraine aura that drains the cortical area responsible for patients' symptoms. METHODS Six patients with acute migraine aura had a prominent draining sulcal vein on emergency MRI done initially for suspected stroke. The location of the prominent vein was correlated to patients' symptoms, and the diameter was compared to the corresponding contralateral vein. RESULTS In our patients with typical migraine aura, an accentuated sulcal vein pointed towards the cortical area correlating with the clinical presentation. Such an index vein outstands the ipsilateral area of hypoperfusion and exceeds the corresponding contralateral vessel in diameter by a factor 2.0 ± 1.6 (mean ± SD). CONCLUSION This case series provides a definition of an index vein in MRI pointing to the area where the patients' symptoms originate. Although confirmation in a larger systematic study is necessary, the presence of such an index vein might support that, in patients with an acute neurologic deficit, migraine aura is the underlying etiology. © 2020 American Academy of Neurology.OBJECTIVE To evaluate the risk of death in relation to incident antiepileptic drug (AED) use compared with nonuse in people with Alzheimer disease (AD) through the assessment in terms of duration of use, specific drugs, and main causes of death. METHODS The MEDALZ (Medication Use and Alzheimer Disease) cohort study includes all Finnish persons who received a clinically verified AD diagnosis (n = 70,718) in 2005-2011. Incident AED users were identified with 1-year washout period. For each incident AED user (n = 5,638), 1 nonuser was matched according to sex, age, and time since AD diagnosis. Analyses were conducted with Cox proportional regression models and inverse probability of treatment weighting (IPTW). RESULTS Nearly 50% discontinued AEDs within 6 months. Compared with nonusers, AED users had an increased relative risk of death (IPTW hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.12-1.36). This was mainly due to deaths from dementia (IPTW HR, 1.62; 95% CI, 1.42-1.86). There was no difference in cardiovascular and cerebrovascular deaths (IPTW HR, 0.