MicroRNA-125b potentiates macrophage activation Chaudhuri, Aadel A; So, Alex Yick-Lun; Sinha, Nikita ...
The Journal of immunology (1950),
2011-Nov-15, Letnik:
187, Številka:
10
Journal Article
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MicroRNA (miR)-125b expression is modulated in macrophages in response to stimulatory cues. In this study, we report a functional role of miR-125b in macrophages. We found that miR-125b is enriched ...in macrophages compared with lymphoid cells and whole immune tissues. Enforced expression of miR-125b drives macrophages to adapt an activated morphology that is accompanied by increased costimulatory factor expression and elevated responsiveness to IFN-γ, whereas anti-miR-125b treatment decreases CD80 surface expression. To determine whether these alterations in cell signaling, gene expression, and morphology have functional consequences, we examined the ability of macrophages with enhanced miR-125b expression to present Ags and found that they better stimulate T cell activation than control macrophages. Further indicating increased function, these macrophages were more effective at killing EL4 tumor cells in vitro and in vivo. Moreover, miR-125b repressed IFN regulatory factor 4 (IRF4), and IRF4 knockdown in macrophages mimicked the miR-125b overexpression phenotype. In summary, our evidence suggests that miR-125b is at least partly responsible for generating the activated nature of macrophages, at least partially by reducing IRF4 levels, and potentiates the functional role of macrophages in inducing immune responses.
Following our discovery that constitutional mutations in EED can cause overgrowth, we screened our cohort of patients with Weaver-like features for mutations in this gene. Here we describe a second ...patient with a different, rare and de novo mutation in EED. Phenotypic overlap with our first case of EED-associated overgrowth is significant. Now that we have found two unrelated families of different ethnicities, with a similar rare phenotype, both associated with de novo mutations in this member of the PRC2 complex, we are confident that EED is indeed a novel overgrowth gene.
The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a ...subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.
Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory ...disease. Consistent with a positive role for miR-155 in mediating inflammatory responses,
Mir155
−/− mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4
+ T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders.
► miR-155 promotes autoimmune inflammation ► miR-155 is involved in Th17 cell development during tissue inflammation ► miR-155 promotes DC expression of Th17 relevant cytokines
Male urinary incontinence (UI) is most prevalent in older men, with one in three men aged 65 and above having problems maintaining continence. Addressing health inequalities, male-female disparities ...in continence services, and low health-seeking among men emphasizes the necessity for co-creating an intervention that empowers them to self-manage their UI. We aim to co-create a self-management intervention with an older men and Health care provider (HCP) group and assess its usability and/or acceptability among older men with UI. The intervention mapping (IM) framework, a co-creation strategy, will be used to co-create a self-management tool, followed by usability and/or acceptability testing. The study will be guided by the first four IM steps: the logic model of the problem, the logic model of change, program/intervention design, and program/intervention production, followed by preliminary testing. A participatory group of older men with UI recruited from an existing group of patient partners, and continence care experts will be involved in all steps of the IM process. Usability and/or acceptability testing will be conducted on a sample of 20 users recruited through seniors’ associations and retirement living facilities. After accessing the self-management tool for a week, participants will complete a product usability testing scale (aka System Usability Scale-SUS) and/or an acceptability test, depending on the preferred mode(s) of intervention delivery. Data will be analyzed using descriptive statistics. A benchmark overall mean usability score of 70 represents a good/usable product, based on the large database of SUS scores.
Urinary incontinence (UI), characterized by involuntary urine leakage is a chronic, embarrassing and stigmatizing condition that is under-reported and under-treated). UI is under-prioritized and ...under-researched, particularly in older men (defined here as men 65+), and there have been calls for more targeted research focusing on this specific group. No existing self-management interventions focus on the needs of older men and none incorporate the perspectives of older men into their development. Furthermore, health inequalities and disparities in continence services for men, and a low level of health seeking behavior in men with UI make it crucial to incorporate their perspectives into intervention development to ensure optimal outcomes. The study will identify risk factors for UI that are potentially amenable to self-management in older men, assess their self-efficacy in managing UI, and determine what modifiable risk factors older men feel are pragmatic to include as part of a self-management program. We will conduct and report a sequential multi-method design consisting of a Delphi study among healthcare experts and a survey among older men with UI, according to the Guidance on Conducting and Reporting Delphi Studies (CREDES) Checklist and the Checklist for Reporting Of Survey Studies (CROSS). A geographically dispersed, multidisciplinary group of 30 health care professionals (urologists, geriatricians, family physicians, and nurses) involved in continence care and a representative sample of at least 128 ethnically diverse older men will participate in a Delphi survey and an older men’s survey respectively. The healthcare experts will evaluate an evidence-synthesized list of UI risk factors to determine those potentially amenable to self-management. Delphi rounds will be repeated until consensus threshold of 75% is reached. Thereafter, older men recruited via stratified sampling of population subgroups will rate a list of expert-identified potentially modifiable risk factors to indicate which factors they deem practicable and can prioritize. Older men’s survey questionnaires will capture information on patients’ characteristics (socio-demographics and UI-related items). The Geriatric Self-Efficacy Index for UI (GSE-UI Index) as well as a Likert scale to assess perceived capability and willingness to modify the expert-identified UI modifiable risk factors will be included. Data will be analyzed quantitatively and qualitatively.
For older people, and in particular frail older people, acute illness and hospitalization are associated with significant potential harm. One of the major drivers of iatrogenic harm in older adults ...is hospital-induced immobility, the so-called “pajama paralysis.” Older people in hospital are often confined to bed even after their acute illness has improved; not only by physical factors such as potentially unnecessary urinary catheters and monitoring equipment but also by the culture often found in hospital of keeping patients in bed for most of the day. Bed rest is associated with sarcopenia, infections, and greater length of stay, and early mobilization of patients is often overlooked as an intervention, despite being inexpensive and effective. In this article we review the evidence of the harm of unnecessary immobilization and discuss the innovations that have been developed to encourage a cultural shift away from pajama paralysis and toward early mobilization of older people in hospital.
Chez les personnes âgées, et en particulier celles qui sont plus fragiles, la maladie au stade aigu et l’hospitalisation peuvent causer des problèmes importants. L’une des principales causes des affections iatrogènes chez les adultes âgés est l’immobilité attribuable à l’hospitalisation, que l’on appelle parfois « paralysie du pyjama ». Les personnes âgées hospitalisées sont souvent confinées à leur lit même après l’amélioration de leur état de santé, non seulement en raison de facteurs d’ordre physique comme les cathéters urinaires et l’équipement de monitorage, qui ne sont pas toujours utiles, mais aussi à cause de la culture ayant cours dans le milieu hospitalier selon laquelle les patients doivent rester au lit pendant la plus grande partie de la journée. L’alitement est associé à la sarcopénie, aux infections et à une hospitalisation plus longue, et la mobilisation précoce des patients est rarement considérée comme une intervention, alors qu’elle est peu coûteuse et efficace. Dans cet article, nous passons en revue les données probantes sur les préjudices causés par l’immobilisation inutile et discutons des innovations qui ont été mises au point pour encourager un virage culturel visant à abandonner la « paralysie du pyjama » en faveur de la mobilisation précoce des patients âgés hospitalisés.
The clinical uses of electrocochleography are reviewed with some technical notes on the apparatus needed to get clear recordings under different conditions. Electrocochleography can be used to ...estimate auditory thresholds in difficult to test children and a golf club electrode is described. The same electrode can be used to obtain electrical auditory brainstem responses (EABR). Diagnostic testing in the clinic can be performed with a transtympanic needle electrode, and a suitable disposable monopolar electrode is described. The use of tone bursts rather than click stimuli gives a better means of diagnosis of the presence of endolymphatic hydrops. Electrocochleography can be used to monitor the cochlear function during surgery and a long coaxial cable, which can be sterilized, is needed to avoid electrical artifacts. Recently electrocochleography has been used to monitor cochlear implant insertion and to record residual hearing using an electrode on the cochlear implant array as the non-inverting (active) electrode.
Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical ...and animal support is equivocal.
We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots.
Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.
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