Role of macrophage colony-stimulating factor in the differentiation and expansion of monocytes and dendritic cells from CD34+ progenitor cells

The present study focused on whether it is possible to expand monocytic cells from CD34+ progenitor cells by using macrophage colony-stimulating factor (M-CSF) in the absence and presence of mast cell growth factor (MGF) and IL-6. It was demonstrated that CD34+ cells differentiate without expansion to functional mature monocytic cells in the presence of M-CSF or combinations of M-CSF plus IL-6 and MGF. A different response pattern was observed for the number of clonogenic cells. The addition of IL-6 or both IL-6 and MGF to M-CSF containing cultures resulted in significant higher numbers of colony-forming unit-macrophage (CFU-M) as tested in clonogenic and 3H-thymidine assays. Furthermore, M-CSF plus both IL-6 and MGF appeared to be the most potent combination to preserve the monocytic precursor in cell suspension culture assays. These results indicate that IL-6 and MGF in conjunction with M-CSF affect CD34+ cells especially at precursor level without distinct effect on the more mature stages. Secondly we studied whether M-CSF is only critical for the monocytic lineage or also affects dendritic cell (DC) development. Indeed, we were able to culture CD83+ DC from CD34+ progenitor cells in the presence of M-CSF in conjunction with TNF-alpha, IL-4, and MGF although their absolute number is almost threefold lower than the number of CD83+ cells yielded from GM-CSF plus TNF-alpha, IL-4, and MGF stimulated CD34+ cells.     

Asthma symptoms in Hispanic children and daily ambient exposures to toxic and criteria air pollutants

Although acute adverse effects on asthma have been frequently found for the U.S. Environmental Protection Agency's principal criteria air pollutants, there is little epidemiologic information on specific hydrocarbons from toxic emission sources. We conducted a panel study of 22 Hispanic children with asthma who were 10-16 years old and living in a Los Angeles community with high traffic density. Subjects filled out symptom diaries daily for up to 3 months (November 1999 through January 2000). Pollutants included ambient hourly values of ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide and 24-hr values of volatile organic compounds (VOCs), particulate matter with aerodynamic diameter < 10 microm (PM10, and elemental carbon (EC) and organic carbon (OC) PM10 fractions. Asthma symptom severity was regressed on pollutants using generalized estimating equations, and peak expiratory flow (PEF) was regressed on pollutants using mixed models. We found positive associations of symptoms with criteria air pollutants (O3, NO2, SO2, PM10), EC-OC, and VOCs (benzene, ethylbenzene, formaldehyde, acetaldehyde, acetone, 1,3-butadiene, tetrachloroethylene, toluene, m,p-xylene, and o-xylene). Selected adjusted odds ratios for bothersome or more severe asthma symptoms from interquartile range increases in pollutants were, for 1.4 ppb 8-hr NO2, 1.27 [95% confidence interval (CI), 1.05-1.54]; 1.00 ppb benzene, 1.23 (95% CI, 1.02-1.48); 3.16 ppb formaldehyde, 1.37 (95% CI, 1.04-1.80); 37 microg/m3 PM10, 1.45 (95% CI, 1.11-1.90); 2.91 microg/m3 EC, 1.85 (95% CI, 1.11-3.08); and 4.64 microg/m3 OC, 1.88 (95% CI, 1.12-3.17). Two-pollutant models of EC or OC with PM10 showed little change in odds ratios for EC (to 1.83) or OC (to 1.89), but PM10 decreased from 1.45 to 1.0. There were no significant associations with PEF. Findings support the view that air toxins in the pollutant mix from traffic and industrial sources may have adverse effects on asthma in children.     

Medical education for students in compulsory education: the conception of the preparation of three graded textbooks and preliminary evaluation of lectures using these textbooks

The school pharmacist in our hospital pharmacy used three graded textbooks about medicine for students at the Sukagawa School for the Health-Impaired (Fukushima Medical University Hospital Branch (H. I. school)). A revised textbook for 4th-6th grade elementary school students containing 12 important items of information about medicine, a new picture textbook for 1st-3rd grade elementary school students, and a new textbook containing practical data for junior high school students were prepared by supplementing original information with illustrations, simplified expression and large type face. Additionally, the pronunciation of Chinese characters was included in the textbook for the 1st-3rd grade elementary school students. In this study, 9 students from H. I. school and 37 students from Koyase junior high school took part in a questionnaire and an examination evaluating the usefulness of the lectures, and these textbooks, in regard to the student's recognition and understanding of medicine. Most students answered that the lectures and textbooks helped them to understand medicine. Furthermore, the results of the examination indicated that the students had a general understanding of medicine. In conclusion, we suggest that it is important for students in compulsory education to learn about medicine, and that according to the preliminary result of questionnaires and examinations, both the lectures and textbooks were useful to help the students to understand more about medicine.     

Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis

The pathogenic role of the interleukin 21 (IL-21) in different autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit different activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining different clinical effects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective effect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modification of the immunological profile of the animals treated with the AAV8.sIL21R. The beneficial effect of the treatment was also observed when inducing the expression of the therapeutic molecule once the first neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the different clinical stages and its key role in the EAE immunopathogenesis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01279-8.     

New Oral Anticoagulants in Nonvalvular Atrial Fibrillation

The choice of an oral anticoagulant (OAC) for patients with nonvalvular atrial fibrillation (NVAF) is a major and complex clinical decision taking into account the individual risk‐benefit ratio and bearing in mind the chronicity of therapy. This review focuses on the safety and efficacy of new oral anticoagulants (NOACs) compared with conventional vitamin K antagonists (VKA) in patients with NVAF. Current data suggest that NOACs are at least as effective and safe as VKAs for most NVAF subjects. The NOACs do not mandate dietary restrictions and regular pharmacodynamic monitoring, and they seem to have lesser incidence of intracranial or fatal bleeding when compared with VKAs. However, both dabigatran 150 twice daily and rivaroxaban have a slightly higher incidence of gastrointestinal bleeding when compared with VKAs. The article will delineate the current knowledge as well as scientific gaps related to the choice and dosage of anticoagulation regimens for various NVAF subsets and will address certain common clinical scenarios requiring special considerations. The article also addresses the shortcomings of NOACs: lack of therapeutic pharmacokinetic and pharmacodynamic targets, absence of tools to assess compliance and efficacy, rigid and limited dosage options, and absence of effective and inexpensive reversal agents.     

ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance

ATP-binding cassette (ABC) transporters are known to play an important role in human physiology, toxicology, pharmacology, and numerous disorders including acute myeloid leukemia (AML). In AML only a few cells have properties allowing for ongoing proliferation and for expansion of this malignant disorder. These very primitive cells, referred to as leukemic stem cells, reside mostly in a quiescent cell cycle state. These cells have the capacity of self-renewal and are likely characterized by a high expression of a number of ABC transporters. In addition, over-expression of certain ABC transporters in leukemic cells has been associated with poor treatment outcome in AML patients. Therefore, to be able to improve diagnostics and therapies for AML patients, it may be important to better characterize this quiescent stem cell population. Particularly knowledge of the biology of highly expressed ABC transporters in these primitive leukemic cells might provide new insights to improve therapeutic options. This review provides an overview about ABC transporters and AML in general and particularly of the ABC transporters involved in multidrug resistance and cholesterol metabolism in primitive normal and leukemic cells.     

The decline in plasma leptin in response to calorie restriction predicts the effects of adjunctive leptin treatment on body weight in humans

BACKGROUND: Plasma leptin levels decline in response to food restriction. We hypothesized that the magnitude of this decline would predict the amount of weight lost in response to exogenous leptin administration. METHODS: Thirty obese subjects were mildly energy-restricted for 21 days. Subsequently, they were randomized to receive either recombinant human leptin [rL, 10 mg s.c. once (n=15) or twice (n=6) daily] or placebo (n=9) as an adjunct to the dietary measures for 12 weeks. RESULTS: Weight loss amounted to 2.8+/-1.1, 5.2+/-0.9, and 7.9+/-1.4 kg (mean+/-standard error) (p=0.035 vs. placebo) in placebo, rL once daily, and rL b.i.d. treated subjects, respectively. The reduction in plasma leptin concentrations during the initial 21 days was positively correlated with the loss of body weight following leptin treatment (r(2)=0.24, p=0.04). Plasma leptin concentration prior to the initiation of rL therapy was inversely associated with the amount of body weight lost in response to intervention (r(2)=0.36, p=0.003). CONCLUSION: Leptin administration counteracts the adaptations that are actuated by the drop in leptin concentrations and thereby disrupts energy balance to promote weight loss.