Combinations of antioxidants and/or of epigenetic enzyme inhibitors allow for enhanced collection of mouse bone marrow hematopoietic stem cells in ambient air

Hematopoietic cell transplantation (HCT) is a treatment for malignant and non-malignant disorders. However, sometimes the numbers of donor hematopoietic stem cells (HSC) are limiting, which can compromise the success of HCT. We recently published that collection and processing of mouse bone marrow (BM) and human cord blood cells in a hypoxic atmosphere of 3% O2 or in ambient air (~21% O2) in the presence of cyclosporine A yields increased numbers of HSC. We now show that collection and processing of mouse BM cells in ambient air in the presence of specific combinations of anti-oxidants and/or inhibitors of epigenetic enzymes can also enhance the collection of HSC, information of potential relevance for enhanced efficacy of HCT

Mild Heat Treatment Primes Human CD34(+) Cord Blood Cells for Migration Toward SDF-1α and Enhances Engraftment in an NSG Mouse Model

Simple efforts are needed to enhance cord blood (CB) transplantation. We hypothesized that short-term exposure of CD34(+) CB cells to 39.5°C would enhance their response to stromal-derived factor-1 (SDF-1), by increasing lipid raft aggregation and CXCR4 expression, thus leading to enhanced engraftment. Mild hyperthermia (39.5°C) significantly increased the percent of CD34(+) CB that migrated toward SDF-1. This was associated with increased expression of CXCR4 on the cells. Mechanistically, mild heating increased the percent of CD34(+) cells with aggregated lipid rafts and enhanced colocalization of CXCR4 within lipid raft domains. Using methyl-β-cyclodextrin (MβCD), an agent that blocks lipid raft aggregation, it was determined that this enhancement in chemotaxis was dependent upon lipid raft aggregation. Colocalization of Rac1, a GTPase crucial for cell migration and adhesion, with CXCR4 to the lipid raft was essential for the effects of heat on chemotaxis, as determined with an inhibitor of Rac1 activation, NSC23766. Application-wise, mild heat treatment significantly increased the percent chimerism as well as homing and engraftment of CD34(+) CB cells in sublethally irradiated non-obese diabetic severe combined immunodeficiency IL-2 receptor gamma chain d (NSG) mice. Mild heating may be a simple and inexpensive means to enhance engraftment following CB transplantation in patients

Aristotle, Leopardi, Severino: the Endless Game of Nothingness

As Aristotle knew all too well, not being is an equivocal concept. This indeterminate character of nothingness turns out to be the main enemy of the principle of non-contradiction, especially due to its affnity to «chimeras» and poetic metaphors (Leopardi's «things that are notthings»). There is an age old philosophical debate about nothingness, at times to defend the reasons for the eternity of being, at others to disprove them. In particular, the work of Emanuele Severino throws some light on the dispute between two giants of thought, Aristotle and Leopardi, with whom the neo-Parmenidean philosopher debated from an impartial position. The article provides food for thought in support of the indefinite and disturbing character - positive, yet apocalyptic -“ of nothingness. What emerges is the ability of not being to resist both the univocal idea of nihil absolutum, as well as to the closure of a game in which the destiny of beings and the very sense of time remain at stake

Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen

Ames hypopituitary dwarf mice are deficient in growth hormone, thyroid-stimulating hormone, and prolactin. The phenotype of these mice demonstrates irregularities in the immune system with skewing of the normal cytokine milieu towards a more anti-inflammatory environment. However, the hematopoietic stem and progenitor cell composition of the bone marrow (BM) and spleen in Ames dwarf mice has not been well characterized. We found that there was a significant decrease in overall cell count when comparing the BM and spleen of 4-5 month old dwarf mice to their littermate controls. Upon adjusting counts to differences in body weight between the dwarf and control mice, the number of granulocyte-macrophage progenitors, confirmed by immunophenotyping and colony-formation assay was increased in the BM. In contrast, the numbers of all myeloid progenitor populations in the spleen were greatly reduced, as confirmed by colony-formation assays. This suggests that there is a shift of myelopoiesis from the spleen to the BM of Ames dwarf mice; however, this shift does not appear to involve erythropoiesis. The reasons for this unusual shift in spleen to marrow hematopoiesis in Ames dwarf mice are yet to be determined but may relate to the decreased hormone levels in these mice

THE EFFECTS OF CONTINUING BOND ON POSTTRAUMATIC STRESS DISORDER AND COMPLICATED GRIEF AMONG PARENTS BEREAVED BY THE SUICIDE OF THEIR CHILD

There is a paucity of research on the effect of parents maintaining a continuing bond with their child who died by suicide. Furthermore, there is a gap in the research literature regarding differences among the parental continuing bond, posttraumatic stress, and complicated grief between parents who directly witnessed the suicide or found the body of their child and parents who were notified of the suicide by indirect methods (police, clergy, family, media, etc). This quantitative study included a convenience sample of 219 participants (response rate = 63.29%) who self-identified as parents whose child died by suicide 6 or more months prior to the initiation of the study. Participants were predominately White (85.8%), married (67.1%), female (91.3%), and mostly between the ages of 51 and 60 (44.7%). Data were collected on the Internet using the REDCap software program. The survey, which was completed anonymously, contained viii demographic information and three questionnaires: The Impact of Event Scale—Revised (IES-R), 22 items (0-88); Inventory of Complicated Grief (ICG), 19 items (0-76); and Continuing Bond Scale (CBS), three items (0-15). The mean score for the IES- R was 34.75, mean score for ICG was 33.03, and mean score for CBS was 6.28. The results suggest that the higher the parents continuing bond was, the higher were the levels of posttraumatic stress disorder and complicated grief. There were no differences between the group who observed the suicide or found the body and the group who was notified by other methods

Toll-like receptor signaling in hematopoietic stem and progenitor cells

Purpose of review The innate immune system is essential in the protection against microbial infection and facilitating tissue repair mechanisms. During these stresses, the maintenance of innate immune cell numbers through stress-induced or emergency hematopoiesis is key for our survival. One major mechanism to recognize danger signals is through the activation of Toll-like receptors (TLRs) on the surface of hematopoietic cells, including hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC), and nonhematopoietic cells, which recognize pathogen-derived or damaged-induced compounds and can influence the emergency hematopoietic response. This review explores how direct pathogen-sensing by HSC/HPC regulates hematopoiesis, and the positive and negative consequences of these signals. Recent findings Recent studies have highlighted new roles for TLRs in regulating HSC and HPC differentiation to innate immune cells of both myeloid and lymphoid origin and augmenting HSC and HPC migration capabilities. Most interestingly, new insights as to how acute versus chronic stimulation of TLR signaling regulates HSC and HPC function has been explored. Summary Recent evidence suggests that TLRs may play an important role in many inflammation-associated diseases. This suggests a possible use for TLR agonists or antagonists as potential therapeutics. Understanding the direct effects of TLR signaling by HSC and HPC may help regulate inflammatory/danger signal-driven emergency hematopoiesis

Clinical population pharmacokinetics and toxicodynamics of linezolid

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxico-dynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs o

A study of Toray\u27s negative working driographic printing plate and the effect ink tack has on toning in the non-image area

Driography is a planographic printing process. A driographic printing plate differs from a conventional offset lithographic plate in that water is not required to keep the non-image area clean of ink during printing. Water, or fountain solution, is not required during printing because a silicone rubber coating which repels ink is used for the non-image area of a driographic plate. The first driographic plate was introduced in the early 1970\u27s by the 3M Company. The plate was a positive working printing plate and has since been discontinued. Driography has since been researched by a number of companies but only one is presently marketing a driographic plate. The Toray Company, a Japanese based firm, is producing a negative working driographic printing plate. The purpose of this study is to research Toray\u27s negative working driographic printing plate. It is hypothesized that as ink tack decreases, toning in the non-image area will increase. In this experiment, ink tack was monitored at the point of impression using a thermocouple device. The thermocouple was used to measure ink temperature on an inking form roller. Temperature/tack curves were developed and used to convert ink temperatures to tack readings. The actual experiment was performed on a duplicator offset printing press. A second technique using ink tack-reducer to alter ink tack was performed as an alternative test to support the initial method results.During the course of the study a number of variables could have altered the test results. These variables were monitored and kept constant during testing. The variable which affected test results most dramatically was the oil content in the ink. It was concluded that the amount of oil content in an ink had more influence on the degree of toning than ink tack did as originally hypothesized