Hematogenous recruitment of monocytes and macrophages has traditionally been viewed as a harmful process causing exacerbation of brain injury after stroke. However, emerging findings suggest equally ...important protective features. Inflammatory monocytes are rapidly recruited to ischemic brain via a CCR2-dependent pathway and undergo secondary differentiation in the target tissue towards non-inflammatory macrophages, mediating neuroprotection and repair of the ischemic neurovascular unit. In contrast, independent recruitment of non-inflammatory monocytes via CX3CR1 does not occur. Thus, protective features of hematogenous macrophages mainly depend on initial CCR2-dependent cell recruitment. Under therapeutic considerations, specific modulation of monocyte-derived macrophages will therefore be more appropriate than non-selectively blocking their hematogenous recruitment. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
•Hematogenous MO/MP are key players in postischemic brain repair and neuroprotection.•Repair-promoting MO/MP mainly derive from early invading inflammatory monocytes.•Therapeutic efforts should aim at stimulating protective features of MO/MP.
Controlling anisotropy is a key concept in the generation of complex functionality in advanced materials. For this concept, oriented attachment of nanocrystal building blocks, a self-assembly of ...particles into larger single-crystalline objects, is one of the most promising approaches in nanotechnology. We report here the two-dimensional oriented attachment of lead sulfide (PbS) nanocrystals into ultrathin single-crystal sheets with dimensions on the micrometer scale. We found that this process is initiated by cosolvents, which alter nucleation and growth rates during the primary nanocrystal formation, and is finally driven by dense packing of oleic acid ligands on {100} facets of PbS. The obtained nanosheets can be readily integrated in a photodetector device without further treatment.
Infarcted regions of the brain after stroke are segregated from the intact brain by scar tissue comprising both fibrous and glial components. The extent and quality of scarring is influenced by ...inflammation. The matricellular glycoprotein osteopontin (OPN) is strongly induced in myeloid cells after stroke and may contribute to repair of ischemic brain lesions. To elucidate the role of OPN in scar formation, we induced photothrombotic brain infarction, characterized by circumscribed cortical infarctions with a well‐defined border zone toward the intact brain parenchyma. The cellular source and functional role of OPN was addressed by studies in OPN null (OPN‐/‐) mice, wild‐type mice depleted of hematogenous monocytes/macrophages by clodronate‐filled liposome treatment, and CCR2‐/‐ bone marrow chimeric mice characterized by impaired hematogenous macrophage influx into the infarctions. OPN was mainly produced by hematogenous macrophages infiltrating into the inner border zone of the infarcts whereas astrocyte activation occurred in the outer border zone. In OPN‐/‐ as well as macrophage‐depleted mice, reactive astrocytes failed to properly extend processes from the periphery toward the center of the infarctions. This was associated with incomplete coverage of neovessels by astrocytic endfeet and persistent leakiness of the damaged blood brain barrier. In conclusion, OPN produced by hematogenous macrophages induces astrocyte process extension toward the infarct border zone, which may contribute to repair of the ischemic neurovascular unit. GLIA 2015;63:2198–2207
Main Points
OPN produced by hematogenous MO/MP induces astrocyte polarization toward the border zone of brain infarcts.
This is important for neovessel coverage by astrocytic endfeet and re‐establishment of the blood brain barrier.
Objective
A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion.
...Methods
ENDOSTROKE is an investigator‐initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction TICI score 2b–3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0–3) assessed after at least 3 months (median time to follow‐up = 120 days).
Results
Thirty‐four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b–3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome.
Interpretation
Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation. Ann Neurol 2015;77:415–424
Objective:
Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote ...beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion‐associated inflammation.
Methods:
We addressed the role of bone marrow‐derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell‐specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach.
Results:
Starting within 24 hours of stroke onset, immature Ly6chi monocytes infiltrated into the infarct border zone and differentiated into mature Ly6clo phagocytes within the lesion compartment. MO/MP infiltration was CCR2‐dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow‐derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin‐walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)‐β1 and collagen‐4, along with diminished activation of Smad2. Injection of TGF‐β1 into the lesion border zone greatly reduced infarct bleeding in MO/MP‐depleted mice.
Interpretation:
Bone marrow‐derived MOs/MPs recruited via CCR2 and acting via TGF‐β1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2+ MOs/MPs rather than blocking their hematogenous recruitment. ANN NEUROL 2012;71:743–752
We present the characterization of the organic ligand shell of CdSe/Cd x Zn1–x S/ZnS nanoparticles by means of fluorescence quenching experiments. Both electron scavengers and acceptors for resonance ...energy transfer were employed as probes. Different quenching behavior for short and long chain thiol ligands in water was found. It could be shown that poly(ethylene oxide) (PEO)-capping of the particles comprises a densely packed inner shell and a loosely packed outer shell in which ions and small molecules diffuse unhindered. A quantitative uptake of quencher molecules into the PEO shell was observed, through which the particle volume including the ligand sphere could be determined.
In this study, we developed and validated a new approach for in vivo visualization of inflammatory processes by magnetic resonance imaging using biochemically inert nanoemulsions of perfluorocarbons ...(PFCs).
Local inflammation was provoked in 2 separate murine models of acute cardiac and cerebral ischemia, followed by intravenous injection of PFCs. Simultaneous acquisition of morphologically matching proton ((1)H) and fluorine ((19)F) images enabled an exact anatomic localization of PFCs after application. Repetitive (1)H/(19)F magnetic resonance imaging at 9.4 T revealed a time-dependent infiltration of injected PFCs into the border zone of infarcted areas in both injury models, and histology demonstrated a colocalization of PFCs with cells of the monocyte/macrophage system. We regularly found the accumulation of PFCs in lymph nodes. Using rhodamine-labeled PFCs, we identified circulating monocytes/macrophages as the main cell fraction taking up injected nanoparticles.
PFCs can serve as a "positive" contrast agent for the detection of inflammation by magnetic resonance imaging, permitting a spatial resolution close to the anatomic (1)H image and an excellent degree of specificity resulting from the lack of any (19)F background. Because PFCs are nontoxic, this approach may have a broad application in the imaging and diagnosis of numerous inflammatory disease states.
Microglia are a major ghal component of the central nervous system (CNS) and are extremely sessile. Only a subtype, the perivascular microglia, are regularly replaced from the bone marrow in adult ...animals. Microglia respond to virtually any, even minor pathological events in the CNS. In most pathological settings microglia are aided by infiltrating hematogenous macrophages. Upon activation microglia and macrophages share most phenotypical markers and can exert similar effector functions. After transection of a CNS fibre tract microglia are insufficiently activated and hematogenous macrophages do not significantly enter the degenerating nerve stump. Thereby myelin debris that contains neurite outgrowth inhibiting activity persists for long time. This is in sharp contrast to the peripheral nervous system in which hematogenous macrophages are rapidly recruited in response to axotomy and clear myelin debris allowing regrowth of axons from the proximal stump. However, CNS lesion paradigms with breakdown of the blood-brain barrier such as cerebral ischemia, brain abscesses and stab wounds elicit prompt microglial activation, macrophage recruitment and debris clearance. There is increasing evidence that microglia play an active part in degenerative CNS diseases. In Alzheimer's disease activated microglia appear to be involved in plaque formation. In experimental globoid cell dystrophy T-cell independent induction of major histocompatibility complex class II molecules on microglia accelerates demyelination. In autoimmune diseases microglia probably have dual functions. Microglia present antigen to infiltrating T cells and exert effector functions thereby locally augmenting immune responses. On the other hand, microglia have the capacity to downregulate T cell responses. In the human acquired immunodeficiency syndrome (AIDS) virus infected macrophages probably introduce the virus to the CNS and in concert with microglia are involved in the pathophysiology of the AIDS dementia complex.
Rationale
Optimal secondary prevention of embolic stroke of undetermined source is not established. The current standard in these patients is acetylsalicylic acid, despite high prevalence of yet ...undetected paroxysmal atrial fibrillation.
Aim
The ATTICUS randomized trial is designed to determine whether the factor Xa inhibitor apixaban administered within 7 days after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of new ischemic lesions documented by brain magnetic resonance imaging within 12 months after index stroke.
Design
Prospective, randomized, blinded, parallel-group, open-label, German multicenter phase III trial in approximately 500 patients with embolic stroke of undetermined source. A key inclusion criterion is the presence or the planned implantation of an insertable cardiac monitor. Patients are 1:1 randomized to apixaban or acetylsalicylic acid and treated for a 12-month period. It is an event-driven trial aiming for core-lab adjudicated primary outcome events.
Study outcomes
The primary outcome is the occurrence of at least one new ischemic lesion identified by axial T2-weighted FLAIR magnetic resonance imaging and/or axial DWI magnetic resonance imaging at 12 months when compared with the baseline magnetic resonance imaging. Key secondary outcomes are the combination of recurrent ischemic strokes, hemorrhagic strokes, systemic embolism; combination of MACE including recurrent stroke, myocardial infarction, and cardiovascular death and combination of major and clinically relevant non-major bleeding defined according to ISTH, and change of cognitive function and quality of life (EQ-5D, Stroke Impact Scale).
Discussion
Embolic stroke of undetermined source is caused by embolic disease and associated with a high risk of recurrent ischemic strokes and clinically silent cerebral ischemic lesions. ATTICUS will investigate the impact of atrial fibrillation detected by insertable cardiac monitor and the effects of early anticoagulation with apixaban compared with antiplatelet therapy with acetylsalicylic acid on the incidence of new ischemic lesion after embolic stroke of undetermined source.
Endovascular therapy (EVT) with stent retrievers in addition to i.v. thrombolysis (IVT) has proven effective in acute stroke patients with middle cerebral artery (MCA, M1 segment) and distal internal ...carotid artery (ICA) occlusion. Limited data exist concerning acute cervical ICA occlusion, either alone or in combination with intracranial ICA occlusion (tandem occlusion). Therefore we analyzed outcome and treatment effects in stroke associated with cervical ICA occlusion, with specific focus on the impact of intracranial ICA or M1 patency.
Seventy-eight patients with cervical ICA occlusion from our local stroke unit registry were analyzed retrospectively. Thrombolysis in Cerebral Infarction (TICI) classification, infarct size, modified Rankin scale (mRS), symptomatic intracerebral hemorrhage (ICH), and death were assessed as outcome parameters.
Forty-three patients had isolated cervical ICA occlusion whereas 35 patients presented with extra-/intracranial tandem occlusion. Patients underwent IVT alone (n = 23), combined IVT/EVT (n = 28) or no treatment (n = 27). Treated and untreated patients with tandem occlusion had a worse outcome after 90 days compared to isolated cervical occlusion (OR for moderate outcome 0.29, 0.27-0.88, p = 0.01). Additional EVT improved outcome in patients with tandem occlusion (OR for moderate outcome: 15.43, 1.60-148.90, p = 0.008) but not isolated cervical occlusion (OR 1.33, 0.38-11.60, NS).
In contrast to tandem occlusion, stroke outcome in patients with isolated cervical ICA occlusion was generally more benign and not improved by combined IVT/EVT compared to IVT alone. Intracranial vessel patency may be critical for treatment decision in acute cervical ICA occlusion.
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