Several studies have demonstrated the anti-inflammatory potential of mesenchymal stromal cells (MSCs) isolated from bone marrow, adipose tissue, placenta, and other sources. Nevertheless, MSCs may ...also induce immunosuppression when administered systemically or directly to injured environments, as shown in different preclinical disease models. MSCs express certain receptors, including toll-like receptors and the aryl-hydrocarbon receptor, that are activated by the surrounding environment, thus leading to modulation of their immunosuppressive activity. Once MSCs are activated, they can affect a wide range of immune cells (e.g., neutrophils, monocytes/macrophages, dendritic cells, natural kill
e
r cells, T and B lymphocytes), a phenomenon that has been correlated to secretion of several mediators (e.g., indolamine 2,3-dioxygenase, galectins, prostaglandin E
2
, nitric oxide, and damage- and pathogen-associated molecular patterns) and stimulation of certain signaling pathways (e.g., protein kinase R, signal transducer and activator of transcription-1, nuclear factor-κB). Additionally, MSC manipulation and culture conditions, as well as the number of passages, duration of cryopreservation, and O
2
content available, can significantly affect the immunosuppressive properties of MSCs. This review sheds light on current knowledge regarding the mechanisms by which MSCs exert immunosuppressive effects both in vitro and in vivo, focusing on the receptors expressed by MSCs, the correlation between soluble factors secreted by MSCs and their immunosuppressive effects, and interactions between MSCs and immune cells.
Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert ...the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma.
C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 10
human AD-MSCs, or EVs (released by 10
AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated.
In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3
CD4
T cells, and pro-inflammatory mediators (interleukin IL-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3
CD4
T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3
CD4
T cells in the mediastinal lymph nodes.
In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different mechanisms of action of AD-MSCs versus their EVs.
Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem ...and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D
(RvD
), prostaglandin E
(PGE
), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated
. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD
, PGE
, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.
The incidence of Legionnaires' disease in the United States has been increasing since 2000. Outbreaks and clusters are associated with decorative, recreational, domestic, and industrial water ...systems, with the largest outbreaks being caused by cooling towers. Since 2006, 6 community-associated Legionnaires' disease outbreaks have occurred in New York City, resulting in 213 cases and 18 deaths. Three outbreaks occurred in 2015, including the largest on record (138 cases). Three outbreaks were linked to cooling towers by molecular comparison of human and environmental Legionella isolates, and the sources for the other 3 outbreaks were undetermined. The evolution of investigation methods and lessons learned from these outbreaks prompted enactment of a new comprehensive law governing the operation and maintenance of New York City cooling towers. Ongoing surveillance and program evaluation will determine if enforcement of the new cooling tower law reduces Legionnaires' disease incidence in New York City.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Addition of acetylcholine (ACh) or carbamylcholine (CCh) to suspensions of human endometrial carcinoma cells preincubated with (3H) -myoinositol promoted a rapid rise in levels of radiolabeled ...inositol mono- (IP1), bis- (IP2), and tris- (IP3) phosphates. The pattern of accumulation of these compounds suggests that the initial stimulated event was hydrolysis of phosphatidylinositol 4,5-bisphosphate. Levels of this phosphoinositide decreased significantly within 30 sec following exposure to CCh while no changes in the levels of phosphatidylinositol 4-monophosphate or phosphatidylinositol were observed for as long as 5 min. Stimulation of inositol phosphate (IP) accumulation by CCh or acetylcholine (ACh) was concentration-dependent and saturable. The Hill coefficients and EC50's of the concentration-response curves for CCh and ACh indicate interaction with a single class of low-affinity receptor. The Ki for atropine inhibition of these effects identifies the receptor as muscarinic. Both basal and CCh-stimulated levels of IP3 and IP2, as well as IP1, were increased in the presence of 10 mM LiCl. The effect on IP1 accumulation was observed under isosmotic and hyperosmolar conditions and was concentration-dependent between 1-100 mM LiCl. Vasopressin, oxytocin, histamine, phenylephrine, and PGF2@ had no apparent effect on IP levels following incubations for up to 1 hr. Estradiol, progesterone and sulfated estrogens were also without effect on IP levels during both long and short term incubations. Phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate inhibited up to 35% of the CCh-stimulated increase in IP accumulation. Triphenylethylene antiestrogens at micromolar concentrations increased IP levels in a concentration-dependent manner but inhibited the increase stimulated by CCh. A plasma membrane perturbing effect of these compounds is suggested by a concurrent loss of ability of the cells to exclude trypan blue. These studies demonstrate and characterize the plasma membrane signal transduction system involving phosphoinositide hydrolysis coupled to muscarinic receptors in Ishikawa cells. Several features of the transduction events not observed in similar model systems with respect to the actions of Li+ are described. Phorbol esters and triphenylethylene antiestrogens significantly altered phosphoinositide hydrolysis in Ishikawa cells. Suggestions are made concerning the possible presence and physiological role of phosphoinositide hydrolysis in human endometrium.
Cystic fibrosis (CF), the most prevalent, fatal genetic disorder in the Caucasian population, is caused by mutations of CF transmembrane conductance regulator (CFTR). The mutations of this chloride ...channel alter the transport of chloride and associated liquid and thereby impair lung defenses. Patients typically succumb to chronic bacterial infections and respiratory failure. Restoration of the abnormal CFTR function to CF airway epithelium is considered the most direct way to treat the disease. In this report, we explore the potential of adult stem cells from bone marrow, referred to as mesenchymal or marrow stromal stem cells (MSCs), to provide a therapy for CF. We found that MSCs possess the capacity of differentiating into airway epithelia. MSCs from CF patients are amenable to CFTR gene correction, and expression of CFTR does not influence the pluripotency of MSCs. Moreover, the CFTR-corrected MSCs from CF patients are able to contribute to apical Cl-secretion in response to cAMP agonist stimulation, suggesting the possibility of developing cell-based therapy for CF. The ex vivo coculture system established in this report offers an invaluable approach for selection of stem-cell populations that may have greater potency in lung differentiation.
•TGF beta2 heterozygosity synergizes with fibrillin1 hypomorphism to cause early death in mice.•Death is not from dissection and rupture.•Mortality is associated with abnormal aortic valves.
To ...assess the contribution of individual TGF-β isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-β1, 2, or 3 heterozygous null mutation. The loss of TGF-β2, and only TGF-β2, resulted in 80% of the double mutant animals dying earlier, by postnatal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-β2 in the postnatal development of the heart, aorta and lungs.
Objectives:
Nonpharmacologic pain management strategies are needed because of the growing opioid epidemic. While studies have examined the efficacy of virtual reality (VR) for pain reduction, there ...is little research in adult inpatient settings, and no studies comparing the relative efficacy of standard animated computer-generated imagery (CGI) VR to Video Capture VR (360 degrees 3D/stereoscopic Video Capture VR). Here, we report on a randomized controlled trial of the relative efficacy of standard CGI VR versus Video Capture VR (matched for content) and also compared the overall efficacy of VR to a waitlist control group.
Materials and Methods:
Participants (N=103 hospitalized inpatients reporting pain) were randomized to 1 of 3 conditions: (1) waitlist control, (2) CGI VR, or (3) Video Capture VR. The VR and waitlist conditions were 10 minutes in length. Outcomes were assessed pretreatment, post-treatment, and after a brief follow-up.
Results:
Consistent with hypotheses, both VR conditions reduced pain significantly more relative to the waitlist control condition (
d
=1.60,
P
<0.001) and pain reductions were largely maintained at the brief follow-up assessment. Both VR conditions reduced pain by ∼50% and led to improvements in mood, anxiety, and relaxation. Contrary to prediction, the Video Capture VR condition was not significantly more effective at reducing pain relative to the CGI VR condition (
d
=0.25,
P
=0.216). However, as expected, patients randomized to the Video Capture VR rated their experience as more positive and realistic (
d
=0.78,
P
=0.002).
Discussion:
Video Capture VR was as effective as CGI VR for pain reduction and was rated as more realistic.
We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.
An initial guidelines draft was created ...which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions.
Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended.
A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
