Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis

Journal of Thrombosis and Thrombolysis - Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic...     

A Driver Training Program Intervention for Student Drivers with Autism Spectrum Disorder: A Multi-site Randomised Controlled Trial

The purpose of this multi-site randomised controlled trial was to evaluate the effectiveness of a Driving Training Program, an intervention designed for student drivers with autism spectrum disorder (ASD). Participants were 72 student drivers with ASD (ages 16–31) who were randomly assigned to an intervention or control group. Student drivers received ten driving lessons with a professional driving instructor via a standardised driving route. The Driving Performance Checklist was used as the outcome measure to evaluate the driving performance of student drivers during on-road pre- and post-observational drives. Both groups showed an improvement in driving performance, however, the extent of improvement between groups was not significant. Findings showed promising intervention efficacy for training student drivers with ASD to drive.

     

Hematologic Recovery after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors

Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34⁺ cells transplanted during the first and second HDCT/autoSCT were 4.3 × 10⁶/kg (range 0.6-220.2) and 4.1 × 10⁶/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34⁺ cells was lower, especially if it was < 2 × 10⁶/kg. A lower CD34⁺ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34⁺ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.     

FISSURE SEALANT IN A NUTSHELL. EVIDENCE-BASED META-EVALUATION OF SEALANTS’ EFFECTIVENESS IN CARIES PREVENTION AND ARREST

ObjectiveThis meta-evaluation aimed to summarize all available evidence regarding different fissure sealants on occlusal caries prevention, arrest, retention rate, adverse effect, and cost-effectiveness; when compared with no intervention, other preventive or minimally-invasive procedures.Materials and MethodsThe systematic reviews and meta-analyses were identified via four electronic databases and manual searching. Two independent reviewers performed study selection, data extraction, quality assessment with AMSTAR-2.ResultsAmong the 366 records yielded, 38 systematic reviews were identified as eligible 24 of them included meta-analyses. Moderate evidence has supported the efficacies of resin-based sealants (RBS) in occlusal caries prevention, arrest and cost-effectiveness compared to no interventions. Low to very low certainty of evidence suggested similar effectiveness of glass-ionomer cements in caries prevention with RBS and more superior performance of resin infiltration in arresting non-cavitated occlusal lesions.ConclusionThis meta-evaluation supports the use of RBS on permanent molars to reduce occlusal caries occurrence, arrest lesion progression and alleviate oral health inequalities between individuals of different socioeconomic status. This meta-evaluation also advocates further research on glass-ionomer cements and resin infiltration with respect to their efficacies in caries prevention and arrest.     

Pilot study of Sandostatin (octreotide) therapy of refractory HIV-associated diarrhea

Seventeen AIDS patients were enrolled in a prospective open-label dose-finding study of octreotide (Sandostatin) therapy for refractory diarrhea. Five were nonevaluable due to progression of AIDS symptomatology, and one was excluded because of lack of confirmation of HIV infection. Five of 11 evaluable patients responded to therapy (45%); two each at 50 g and 100 g, and one at 250 g thrice daily doses. A sixth patient demonstrated a moderate reduction in stool volume at 250 g thrice daily, which, although deemed clinically relevant, did not meet the criteria for response. On discontinuation of therapy, diarrhea recurred in all patients within 1–12 days, and responded to reinitiation of octreotide in those five patients who resumed treatment. Only one of the three patients with concurrent cryptosporidial infection responded to treatment. The drug was well tolerated, with mild symptomatology in three patients. Long-term treatment at a stable dose was effective in three of five treated patients for periods for seven months in one (moderate responder) and one year in two. One patient required dose increases to control symptoms, but after one year of treatment developed severe nausea following injections, which required dose cessation. One patient had partial control of his diarrhea for only three months despite two dose increases. These data suggest that octreotide may be of useful therapeutic value in HIV-associated diarrhea and that further studies are indicated.This study was supported by Sandoz Canada Inc.     

Fibrinogen Seoul (FGG Ala341Asp): a novel mutation associated with hypodysfibrinogenemia.

Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in fibrinogen function. The molecular basis of hypodysfibrinogenemia was investigated in a 66-year-old woman with peripheral artery obstructive disease and in her family members. Plasma level of functional fibrinogen determined using the Clauss method was lower (75 mg/dL; normal, 140-460 mg/dL) than that measured with immunologic nephelometric assay (137 mg/dL; normal, 180-400 mg/dL). Similar results were also observed in two family members through two generations. DNA was extracted from whole blood, and the coding regions and intron/exon boundaries of gamma chain gene (FGG) were amplified. A novel (Fibrinogen Seoul) heterozygous FGG mutation (GCT->GAT, Ala341Asp) was identified in all three affected family members. Thrombin-catalyzed polymerization was found to be defective on the analysis of purified fibinogen from the propositus. Molecular modeling also showed a conformational change of fibrinogen structure.     

The effect of lithium on growth factor production in long-term bone marrow cultures

We have previously reported that lithium chloride (LiCl) stimulates the production of granulocyte-macrophage colony-forming cells (GM-CFC), pluripotent stem cells (CFU-S), and differentiated granulocytes, macrophages and megakaryocytes in murine Dexter marrow cultures and that this effect appears to be mediated indirectly by a radioresistant adherent marrow cell. In this study we have established that exposure of murine Dexter cultures to LiCl (4 mEq/L) causes an increase of colony-forming cell megakaryocytes (CFU-meg) over 1 to 6 weeks of culture in both supernatant (188% to 611%) and stromal phases (123% to 246%). Moreover, we have shown that lithium treatment of either irradiated (1,100 rad) or unirradiated stromal cells increased production of activities stimulating formation of megakaryocyte, granulocyte, macrophage, and mixed lineage colonies and proliferation of the factor-dependent cell line, FDC-P1. This FDC-P1 stimulatory activity was completely blocked by an antibody to purified recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF). The baseline or lithium-induced--stromal-derived bone marrow colony stimulating activity was partially blocked by the antibody to rGM-CSF and by an antibody to purified colony stimulating factor I (CSF-1); the two antibodies combined resulted in greater than 90% inhibition of the lithium-induced marrow stimulatory activity. In addition, radioimmunoassay (RIA) showed that although CSF-1 was detectable in supernatants of these cultures, exposure to lithium did not increase CSF-1 levels. These data indicate that Dexter stromal cells produce CSF- 1 and GM-CSF and that lithium appears to exert its stimulatory effects on in vitro myelopoiesis by inducing production of GM-CSF.