Specification of the haematopoietic stem cell lineage: From blood-fated mesodermal angioblasts to haemogenic endothelium.

Haematopoietic stem and progenitor cells emerge from specialized haemogenic endothelial cells in select vascular beds during embryonic development. Specification and commitment to the blood lineage, however, occur before endothelial cells are endowed with haemogenic competence, at the time of mesoderm patterning and production of endothelial cell progenitors (angioblasts). Whilst early blood cell fate specification has long been recognized, very little is known about the mechanisms that induce endothelial cell diversification and progressive acquisition of a blood identity by a subset of these cells. Here, we review the endothelial origin of the haematopoietic system and the complex developmental journey of blood-fated angioblasts. We discuss how recent technological advances will be instrumental to examine the diversity of the embryonic anatomical niches, signaling pathways and downstream epigenetic and transcriptional processes controlling endothelial cell heterogeneity and blood cell fate specification. Ultimately, this will give essential insights into the ontogeny of the cells giving rise to haematopoietic stem cells, that may aid in the development of novel strategies for their in vitro production for clinical purposes.

Intermediate progenitor cells provide a transition between hematopoietic progenitors and their differentiated descendants.

Genetic and genomic analysis in Drosophila suggests that hematopoietic progenitors likely transition into terminal fates via intermediate progenitors (IPs) with some characteristics of either, but perhaps maintaining IP-specific markers. In the past, IPs have not been directly visualized and investigated owing to lack of appropriate genetic tools. Here, we report a Split GAL4 construct, CHIZ-GAL4, that identifies IPs as cells physically juxtaposed between true progenitors and differentiating hemocytes. IPs are a distinct cell type with a unique cell-cycle profile and they remain multipotent for all blood cell fates. In addition, through their dynamic control of the Notch ligand Serrate, IPs specify the fate of direct neighbors. The Ras pathway controls the number of IP cells and promotes their transition into differentiating cells. This study suggests that it would be useful to characterize such intermediate populations of cells in mammalian hematopoietic systems.

Transmission Raman Spectroscopic Quantification of Active Pharmaceutical Ingredient in Coated Tablets of Hot-Melt Extruded Amorphous Solid Dispersion.

Transmission Raman spectroscopy is an emerging technique, capable of quantitative analysis of drug products nondestructively using a multivariate data analysis approach. We developed and validated a chemometric method to quantify the active pharmaceutical ingredient in coated tablets of hot-melt extruded amorphous solid dispersion. A partial least squares regression (PLSR) model was developed and validated based on transmission Raman spectra data collected from coated tablet samples with variations in the content of active pharmaceutical ingredient, excipients, water content, a key oxidative degradant, milled extrudate particle size distribution, and tablet hardness. The method was proven to be accurate, linear, specific, and robust. Our work demonstrates that transmission Raman spectroscopy (TRS) is a viable, cost-effective, secondary method to high-performance liquid chromatography (HPLC) for quantitation of active pharmaceutical ingredient (API) in coated tablets of hot-melt extruded amorphous solid dispersion.

Ischemic optic neuropathy following spine surgery.

Perioperative visual loss (POVL) is a devastating injury that has been reported infrequently after nonocular surgery. The most common cause of POVL is ischemic optic neuropathy (ION). Increasing numbers of cases of ION are being reported after spine surgery, but the etiology of postoperative ION remains poorly understood. After a MEDLINE search of the literature, we reviewed published case reports of ION, specifically those reported after spine surgery performed with the patient in the prone position. Most of the cases involved posterior ION (PION, n = 17), and the remainder anterior (AION, n = 5). Most patients had no or few preoperative vascular disease risk factors. All except one PION and 2 of 5 AION cases reported symptom onset within the first 24 hours after surgery. Visual loss was frequently bilateral (40% of AION, 47% of PION cases). Mean operative time exceeded 450 minutes. The lowest average intraoperative mean arterial blood pressure was 64 mm Hg and the mean lowest intraoperative hematocrit was 27%. The average blood loss was 1.7 L for AION and 5 L for PION patients. PION patients received an average of 8 L of crystalloid solution and 2.2 L of colloid intraoperatively. This compilation of case reports suggests that a combination of prolonged surgery in the prone position, decreased ocular perfusion pressure, blood loss and anemia/hemodilution, and infusion of large quantities of intravenous fluids are some of the potential factors involved in the etiology of postoperative ION. However, levels of blood pressure and anemia intraoperatively were frequently at levels considered acceptable in anesthesia practice. The etiology of postoperative ION remains incompletely understood. Potential strategies to avoid this complication are discussed.