Pathophysiologic responses in brain after stroke are highly complex. Thus far, a singular focus on saving neurons alone has not revealed any clinically effective neuroprotectants. To address this limitation, the concept of a neurovascular unit was developed. Within this conceptual framework, brain function and dysfunction are manifested at the level of cell–cell signaling between neuronal, glial and vascular elements. For stroke, coordinated responses at the neurovascular interface will mediate acute as well as chronic events in ischemic and hemorrhagic brain tissue. In this minireview, we briefly survey two representative examples of neurovascular responses in stroke. During the early acute phase of neurovascular injury, blood– brain barrier perturbations should predominate with key roles for various matrix proteases. During the delayed phase, brain angiogenesis may provide the critical neurovascular substrates for neuronal remodeling. In this minireview, we propose the hypothesis that the biphasic nature of neuro-vascular responses represents an endogenous attempt by damaged parenchyma to trigger brain angiogenesis and repair. This phenomenon may allow acute deleterious signals to transition into beneficial effects during stroke recovery. Understanding how neurovascular signals and substrates make the transition from initial injury to angiogenic recovery will be important if we are to find new therapeutic approaches for stroke.

Background and Purpose-The natural product baicalein is a specific inhibitor of 12/15-lipoxygenase, but it also has antioxidant properties. The current study was designed to test if the neuroprotective properties of baicalein are related to its lipoxygenase inhibition. Methods

Background and Purpose Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters. Methods CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale. Results The international normalized ratio in nonanticoagulated mice was 0.8±0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5±0.9 and 7.2±3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (P=0.019) and 3.1-fold larger in W-30 mice (P<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was −1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice. Conclusions This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.

IntroductionCarcinogenesis is a consecutive process of multiple genetic and epigenetic alterations that affect the target cell to acquire growth advantages and dysregulated growth from tissue environment. 1 Plenty of genetic mutations have been discovered in both human and animal cancers. It should be noted that the mutations are cell-type specific and that there is specific genetic cooperation in the multi-step evolution of premalignant cells. The combination of genetic mutations alters cell fate, and specific genetic cooperation is therefore important for tumor phenotypes and biologic behaviors of cancer cells.Proper expression of AbdB-like Hox genes is a key molecular process in hematopoiesis and their deregulation perturbs myeloid differentiation, eventually resulting in leukemia with several cooperative genetic events. 2 One of the important Hox genes in myeloid leukemogenesis is Hoxa9, which has been identified as a target for ecotropic retroviral integration in BXH2 murine AML 3 as well as a fusion partner of NUP98 in human AML with t(7;11)(p15;p15) translocation. 4,5 Importantly, cooperative activation of the Hox cofactor Meis1 is important for both Hoxa9-and NUP98-HOXA9-induced transformation of murine bone marrow cells. 6,7 Recent studies have suggested that Meis1 might activate Flt3 receptor tyrosine kinase, which plays an important role in myeloid leukemogenesis. [8][9][10] However, it remains to be clarified what kinds of subsequent molecular processes are required for complete leukemogenesis, and it is important to understand subsequent molecular steps that are cooperative for Hoxa9 and Meis1 activation.We have addressed this issue by using retroviral insertional mutagenesis that has been applied for identification of oncogenes and tumor suppressor genes. 11 Plenty of important disease genes have been isolated by this technique and many of the genes are in fact involved in human cancers. Retroviral integration in the bone marrow cells is randomly distributed over the whole genome, and the cells with integrations that contribute growth advantages are subsequently selected and clonally expanded. Cooperative genetic effects in leukemogenesis can be achieved by multi-copy integration of retroviruses. The multiple integrations do not occur simultaneously, but it is likely that the process is consecutive, since such cooperative integrations are extremely rare without any predisposition. When there is a primary genetic alteration in the target cell, genetic cooperation for the first hit can be investigated by this technique. 12 Retrovirus-mediated gene transfer and bone marrow transfer of Hoxa9 and Meis1 induce AML at 100% penetrance. 6,13 In this study we have found that there is clonal selection of the transduced bone marrow cells at the transformation step, and we have systematically cloned retroviral integration sites in Hoxa9/Meis1-induced AML. Inverse polymerase chain reaction (PCR) experiments identified 6 common integration sites (CISs), and candidate cooperative genes for Hoxa9/Meis1 coactivation...

The outbreak of the COVID-19 virus in Wuhan, China, in January 2020 just before the Spring Festival and subsequent country-wide measures to contain the virus, effectively resulted in the lock-down of the country. Most industries and businesses were closed, traffic was largely reduced, and people were restrained to their homes. This resulted in the reduction of emissions of trace gases and aerosols, the concentrations of which were strongly reduced in many cities around the country. Satellite imagery from the TROPOspheric Monitoring Instrument (TROPOMI) showed an enormous reduction of tropospheric NO2 concentrations, but aerosol optical depth (AOD), as a measure of the amount of aerosols, was less affected, likely due to the different formation mechanisms and the influence of meteorological factors. In this study, satellite data and ground-based observations were used together to estimate the separate effects of the Spring Festival and the COVID-19 containment measures on atmospheric composition in the winter of 2020. To achieve this, data were analyzed for a period from 30 days before to 60 days after the Spring Festivals in 2017–2020. This extended period of time, including similar periods in previous years, were selected to account for both the decreasing concentrations in response to air pollution control measures, and meteorological effects on concentrations of trace gases and aerosols. Satellite data from TROPOMI provided the spatial distributions over mainland China of the tropospheric vertical column density (VCD) of NO2, and VCD of SO2 and CO. The MODerate resolution Imaging Spectroradiometer (MODIS) provided the aerosol optical depth (AOD). The comparison of the satellite data for different periods showed a large reduction of, e.g., NO2 tropospheric VCDs due to the Spring Festival of up to 80% in some regions, and an additional reduction due to the COVID-19 containment measures of up to 70% in highly populated areas with intensive anthropogenic activities. In other areas, both effects are very small. Ground-based in situ observations from 26 provincial capitals provided concentrations of NO2, SO2, CO, O3, PM2.5, and PM10. The analysis of these data was focused on the situation in Wuhan, based on daily averaged concentrations. The NO2 concentrations started to decrease a few days before the Spring Festival and increased after about two weeks, except in 2020 when they continued to be low. SO2 concentrations behaved in a similar way, whereas CO, PM2.5, and PM10 also decreased during the Spring Festival but did not trace NO2 concentrations as SO2 did. As could be expected from atmospheric chemistry considerations, O3 concentrations increased. The analysis of the effects of the Spring Festival and the COVID-19 containment measures was complicated due to meteorological influences. Uncertainties contributing to the estimates of the different effects on the trace gas concentrations are discussed. The situation in Wuhan is compared with that in 26 provincial capitals based on 30-day averages for four years, showing different effects across China.

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Glial scarring is traditionally thought to be detrimental after stroke. But emerging studies now suggest that reactive astrocytes may also contribute to neurovascular remodeling. Here, we assessed the effects and mechanisms of metabolic inhibition of reactive astrocytes in a mouse model of stroke recovery. Five days after stroke onset, astrocytes were metabolically inhibited with fluorocitrate (FC, 1 nmol). Markers of reactive astrocytes (glial fibrillary acidic protein (GFAP), HMGB1), markers of neurovascular remodeling (CD31, synaptophysin, PSD95), and behavioral outcomes (neuroscore, rotarod latency) were quantified from 1 to 14 days. As expected, focal cerebral ischemia induced significant neurological deficits in mice. But over the course of 14 days after stroke onset, a steady improvement in neuroscore and rotarod latencies were observed as the mice spontaneously recovered. Reactive astrocytes coexpressing GFAP and HMGB1 increased in peri-infarct cortex from 1 to 14 days after cerebral ischemia in parallel with an increase in the neurovascular remodeling markers CD31, synaptophysin, and PSD95. Compared with stroke-only controls, FC-treated mice demonstrated a significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery. Our results suggest that reactive astrocytes in peri-infarct cortex may promote neurovascular remodeling, and these glial responses may aid functional recovery after stroke.