The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that ...microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease.
Objective
To define the functional significance of increased miR‐155 expression in myeloid cells in multiple sclerosis (MS).
Methods
miR‐155 expression levels were measured in CD14+ monocytes from ...untreated relapsing–remitting MS patients and compared to healthy controls. Similar microRNA (miRNA) analyses were performed in laser‐captured CD68+ cells from perivascular (blood‐derived macrophages) and parenchymal (microglia) brain regions in both active MS lesions and noninflammatory cases. Using human adult blood‐derived macrophages and brain‐derived microglia, in vitro experiments were performed to demonstrate how miR‐155 influences the polarization state, phenotype, and functional properties of myeloid cells, in addition to their ability to subsequently impact adaptive T‐cell responses.
Results
In MS, miR‐155 expression was significantly increased in both peripheral circulating CD14+ monocytes and active lesions (CD68+ cells) compared to control donor monocytes and parenchymal microglia, respectively. In vitro, miR‐155 was significantly increased in both M1‐polarized primary human macrophages and microglia. Transfection of an miR‐155 mimic increased proinflammatory cytokine secretion and costimulatory surface marker expression in both cell types; an miR‐155 inhibitor decreased proinflammatory cytokine expression. Coculture experiments demonstrated that allogeneic T‐cell responses were significantly enhanced in the presence of miR‐155–transfected myeloid cells compared to controls.
Interpretation
Our results demonstrate that miR‐155 regulates proinflammatory responses in both blood‐derived and central nervous system (CNS)‐resident myeloid cells, in addition to impacting subsequent adaptive immune responses. Differential miRNA expression may therefore provide insight into mechanisms responsible for distinct phenotypic and functional properties of myeloid cells, thus impacting their ability to influence CNS injury and repair. Ann Neurol 2013;74:709–720
In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, ...oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti-inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5(+) neural progenitors, resulting in decreased O4(+) and GalC(+) oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes.
Timely, in-person access to health care is a challenge for people living with conditions such as stroke that result in frailty, loss of independence, restrictions in driving and mobility, and ...physical and cognitive decline. In Southeastern Ontario, access is further complicated by rurality and the long travel distances to visit physician clinics. There is a need to make health care more accessible and convenient. Home virtual visits (electronic visits, eVisits) can conveniently connect physicians to patients. Physicians use a secure personal videoconferencing tool to connect to patients in their homes. Patients use their device of choice (smartphone, tablet, laptop, or desktop) for the visit.
This study aimed to assess the feasibility and logistics of implementing eVisits in a stroke prevention clinic for seniors.
A 6-month eVisit pilot study was initiated in the Kingston Health Sciences Centre stroke prevention clinic in August 2018. eVisits were used only for follow-up patient encounters. An integrated evaluation was used to test the impact of the program on clinic workflow and patient satisfaction. Patient satisfaction was evaluated by telephone interviews, using a brief questionnaire. Access and patient satisfaction metrics were compared with concurrent standard of care (patients' prior personal experience with in-person visits). Values are presented as median (interquartile range).
There were 75 subjects in the pilot. The patients were aged 65 (56-73.5) years, and 39% (29/75) resided in rural areas. There was a shorter wait for an appointment by eVisit versus in-person (mean 59.98 SD 48.36 days vs mean 78.36 SD 50.54 days; P<.001). The eVisit was also shorter, taking on an average of only 10 min to deliver follow-up care with a high degree of patient satisfaction versus 90 (60-112) min for in-person care. The total time saved by patients per eVisit was 80 (50-102) min, 44 (21-69) min of which was travel time. Travel distance avoided by the patients was 30.1 km (11.2-82.2). The estimated total out-of-pocket cost savings for patients per eVisit was Can $52.83 (31.26-94.53). The estimated savings (opportunity cost for in-person outpatient care) for our eVisit pilot project was Can $23,832-$28,584. The patient satisfaction with eVisits was very good compared with their prior personal experience with in-person outpatient care.
The eVisit program was well received by patients, deemed to be safe by physicians, and avoided unnecessary patient travel and expense. It also has the potential to reduce health care costs. We plan to scale the project within the department and the institution.
Tryptophan metabolism by the kynurenine pathway (KP) is important to the pathogenesis of inflammatory, infectious, and degenerative diseases. The 3-hydroxykynurenine (3-HK) branch of the KP is ...activated in macrophages and microglia, leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid, which are considered neurotoxic owing to their free radical–generating and N -methyl- d -aspartic acid receptor agonist activities. We investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human fetal central nervous system cultures treated with cytokines (IL-1 with or without interferon-γ) or with Toll-like receptor ligands mimicking the proinflammatory central nervous system environment. Results were analyzed by microarray, Western blot, immunostain, enzyme-linked immunosorbent assay, and neurotoxicity assays. 3-HAA suppressed glial cytokine and chemokine expression and reduced cytokine-induced neuronal death. 3-HK also suppressed cytokine-induced neuronal death. Unexpectedly, 3-HAA was highly effective in inducing in astrocytes the expression of hemeoxygenase-1 (HO-1), an antioxidant enzyme with anti-inflammatory and cytoprotective properties. Optimal induction of HO-1 required 3-HAA and cytokines. In human microglia, 3-HAA weakly induced HO-1 and lipopolysaccharide suppressed microglial HO-1 expression. 3-HAA–mediated HO-1 expression was confirmed in cultured adult human astrocytes and in vivo after 3-HAA injection to mouse brains. Together, our results demonstrate the novel neuroprotective activity of the tryptophan metabolite 3-HAA and have implications for future therapeutic approaches for neuroinflammatory disorders.
Surgery for Moyamoya Disease in Children Appireddy, Ramana; Ranjan, Manish; Durafourt, Bryce A. ...
Journal of Child Neurology,
08/2019, Letnik:
34, Številka:
9
Book Review, Journal Article
Recenzirano
Moyamoya disease is a chronic progressive cerebrovascular occlusive disease of the terminal portion of the internal carotid arteries associated with an acquired abnormal vascular network at the base ...of the brain, often leading to ischemic or hemorrhagic stroke. Moyamoya disease is a relatively common cause of pediatric stroke with a specific racial and well-identified clinical and imaging phenotype. Moyamoya disease is more prevalent in East Asian countries compared with other geographic regions with a higher incidence of familial cases and clinically more aggressive form. Moyamoya disease is one of the few causes of stroke that is amenable to effective surgical revascularization treatment. There are various surgical options available for revascularization, including the direct, indirect, or combined bypass techniques, each with variable responses. However, due to the heterogeneity of the diseases, different clinical course, geographical variables associated with the disease, and availability of a wide variety of surgical revascularization procedures, optimal selection of a surgical candidate and the surgical technique becomes challenging, particularly in the pediatric population. This brief review presents pertinent literature of clinical options for the diagnosis and surgical treatment of moyamoya disease in children.
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