Hematopoietic stem cell (HSC) multipotency and self-renewal are typically defined through serial transplantation experiments. Host conditioning is necessary for robust HSC engraftment, likely by ...reducing immune-mediated rejection and by clearing limited HSC niche space. Because irradiation of the recipient mouse is non-specific and broadly damaging, there is a need to develop alternative models to study HSC performance at steady-state and in the absence of radiation-induced stress. We have generated and characterized two new mouse models where either all hematopoietic cells or only HSCs can be specifically induced to die in vivo or in vitro. Hematopoietic-specific Vav1-mediated expression of a loxP-flanked diphtheria-toxin receptor (DTR) renders all hematopoietic cells sensitive to diphtheria toxin (DT) in "Vav-DTR" mice. Crossing these mice to Flk2-Cre mice results in "HSC-DTR" mice which exhibit HSC-selective DT sensitivity. We demonstrate robust, rapid, and highly selective cell ablation in these models. These new mouse models provide a platform to test whether HSCs are required for long-term hematopoiesis in vivo, for understanding the mechanisms regulating HSC engraftment, and interrogating in vivo hematopoietic differentiation pathways and mechanisms regulating hematopoietic homeostasis.
ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the ...effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated.
Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well.
After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p=0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005). There was an increase>0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69–86% and 93–96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients.
Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters.
El ADV7103 es un nuevo tratamiento de liberación prolongada para la acidosis tubular renal distal (ATRd), que contiene citrato potásico y bicarbonato potásico. Dado que la acidosis puede afectar al contenido mineral óseo, se ha evaluado el efecto de dicho medicamento a lo largo de 24 meses sobre la densidad mineral ósea (DMO) y el crecimiento en pacientes con ATRd.
Se incluyeron treinta pacientes (24 pediátricos y seis adultos) en un estudio abierto de extensión tras un ensayo clínico de fase II/III. La DMO medida por densitometría se midió al inicio del estudio y los 24 meses. El crecimiento se evaluó a lo largo del estudio. Adicionalmente, se determinaron el bicarbonato plasmático, la parathormona, 25 hidroxivitamina D, 1,25 dihidroxivitamina D, fosfatasa alcalina ósea, calciuria y citraturia. La seguridad y el cumplimento terapéutico también fueron evaluados.
Tras 24 meses de tratamiento con ADV7103 la media del z-score de DMO de columna aumentó significativamente frente al valor basal (p = 0,024). En los adultos el z-score de la densitometría de columna y corporal total mostró una correlación significativa con los valores de bicarbonato plasmático (rS = 0,82 y rS = 0,97, respectivamente, p < 0,005). Se registró un incremento > 0,5 unidades de z-score para altura y peso en el 18 y 36%, respectivamente, de los pacientes pediátricos. Con el tratamiento, la concentración plasmática de bicarbonato y la calciuria fueron normales en las diferentes visitas en un 69-86% y un 93-96% de los pacientes, respectivamente. Solamente se notificaron nueve eventos adversos gastrointestinales relacionados con el tratamiento, todos de intensidad leve/moderada en cinco pacientes.
Dos años de tratamiento con ADV7103 mejoraron el crecimiento y la DMO de columna. Estos resultados sugieren que el control de la acidosis con dicho tratamiento provoca una mejora de parámetros óseos.
We study neutron-proton equilibration in dynamically deformed nuclear systems by investigating the correlations between the three largest fragments produced in collisions of 70Zn + 70Zn at 35 MeV per ...nucleon. In this work, the rotation angle is interpreted as a measure of the duration of contact between the regions of the excited projectile-like fragment as it decays. In this work we address questions of whether there is a simultaneous or a double rupture scenario, sizing of the fragments, and alignment of the configuration.
Isoscaling parameters α and β have been explored as a function of breakup angle in binary excited projectile-like fragment decays produced in collisions of 70Zn+ 70Zn and 64Zn+ 64Zn at 35 MeV per ...nucleon. In this analysis, focus was placed on isoscaling the second heaviest fragment with 4 ≤ ZL ≤ 8 emitted from the excited projectile-like fragment in events that contained a heavy fragment with ZH ≥ 12. The breakup orientation θprox was defined as the angle between the heavy and light fragments’ center-of-mass velocity and the fragment pairs’ relative velocity. Breakups between 0° < θprox ≤ 80° have been shown to be dominated by dynamical contributions, while break-up angles of θprox > 100° are predominantly statistical. Historically, isoscaling has often been understood and applied in a statistical context, assuming that the fragments are produced after statistical equilibrium is achieved. Finally, studying isoscaling parameters as a function of θprox reveals the sensitivity of α and β to the mechanism of fragment production.
Platelets are the terminal progeny of megakaryocytes, primarily produced in the bone marrow, and play critical roles in blood homeostasis, clotting, and wound healing. Traditionally, megakaryocytes ...and platelets are thought to arise from multipotent hematopoietic stem cells (HSCs) via multiple discrete progenitor populations with successive, lineage-restricting differentiation steps. However, this view has recently been challenged by studies suggesting that (1) some HSC clones are biased and/or restricted to the platelet lineage, (2) not all platelet generation follows the "canonical" megakaryocytic differentiation path of hematopoiesis, and (3) platelet output is the default program of steady-state hematopoiesis. Here, we specifically investigate the evidence that in vivo lineage tracing studies provide for the route(s) of platelet generation and investigate the involvement of various intermediate progenitor cell populations. We further identify the challenges that need to be overcome that are required to determine the presence, role, and kinetics of these possible alternate pathways.
Neutron-proton equilibration is a process which has been used to study the density dependence of the symmetry energy term in the nuclear equation-of-state. Here, this study utilizes constrained ...molecular dynamics (CoMD) simulations of 70Zn + 70Zn with collision energies of 35 and 45 MeV/nucleon. An algorithm is used which searches through CoMD events and identifies the PLF* after it separates from the target and determines its lifetime, Δt. It also determines the fragments that the PLF* breaks apart into and determines their angular alignment. This technique gives an opportunity to explore how the average alignment of dynamically produced fragments, $\langle$α $\rangle$dyn, evolves with PLF* lifetime. An approximately linear relationship was determined with d$\langle$α $\rangle$dyn/dΔt = 0.98 ± 0.08 rad / zs and 1.06 ± 0.09 rad / zs for the 35 and 45 MeV / nucleon, respectively, indicating a correlation with magnitude consistent with classically determined values which were used for prior experimental studies.
Some studies have been performed to assess the effects of levosimendan on cardiac function when administered to cardiac surgery patients with low cardiac output syndrome (LCOS) in the immediate ...postoperative period. Levosimendan is an inotropic agent for the treatment of low cardiac output syndrome that seems to have a protective effect on renal function.
It is a quasi-experimental study. A total of 100 patients with LCOS received either beta-agonists or levosimendan. We assessed the incidence of postoperative kidney failure in cardiac surgery patients. In patients who had kidney failure at diagnosis of LCOS, we examined whether differences existed in the evolution of kidney failure based on the treatment administered for LCOS. The parameters measured included haemodynamics, oxygen supply, and renal function as assessed by the AKI scale. ANOVA, Student's t-test and Wilcoxon or Friedman tests were used.
Up to 30% of cardiac surgery patients had kidney failure at diagnosis of LCOS. Kidney failure at discharge from the ICU was more frequent in patients who received beta-agonist drugs as compared to those who received levosimendan (p < 0.05).
The incidence of kidney failure decreased with the postoperative administration of levosimendan to cardiac surgery patients with LCOS, as compared to beta-agonists.
Current Controlled Trials ISRCTN 46058317. Date of registration: 7/10/2019. Retrospectively registered.
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