A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.

The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.

[Outdoor activity and myopia among 681 primary students in urban and rural regions of Beijing].

OBJECTIVE: To explore the association between outdoor activity and myopia among 681 primary students from Beijing. METHODS: School-based, cross-sectional investigation. Eye examination includes the visual acuity test, auto-refractor, slit lamp, ocular biometry and non-mydriatic fundus camera. Questionnaire includes regular items, near work, outdoor activity and social-economic status. RESULTS: The mean time spent outdoors was 1.6 ± 0.8 hours daily. Time spent on outdoor sports and outdoor leisure were 0.7 ± 0.1 hours daily, 1.0 ± 0.8 hours daily, respectively. Mean time of outdoor activity in urban was 1.1 ± 0.4 hours daily, compared with 2.2 ± 0.8 hours daily in rural (P = 0.000). In grade-1, total time spent outdoors is significantly different between myopia and non-myopia (1.4 ± 0.6 vs 1.8 ± 0.8 hours daily, P = 0.000), similar to outdoor leisure (0.8 ± 0.6 vs 1.1 ± 0.9 hours daily, P = 0.000). The same trend was also found in grade-4. CONCLUSION: The mean time spent outdoors was 1.6 ± 0.8 hours daily. Myopia spent a lower outdoor activity compared with non-myopia. More outdoor activity, e.g., in schools, may potentially be helpful to reduce the high prevalence of myopia in the young generation.

Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury.

Interferon regulatory factor 8 (IRF8), a transcriptional regulator in the IRF family, has been implicated in innate immunity, immune cell differentiation and tumour cell apoptosis. In the present study, we found that IRF8 is constitutively expressed in the brain and suppressed after cerebral ischaemia in a time-dependent manner. IRF8 knockout (IRF8-KO) mice, wild type (WT) mice, neuron-specific IRF8 transgenic (TG) mice and non-transgenic mice were used in a transient cerebral ischaemic model. The IRF8 knockout mice exhibited aggravated apoptosis, inflammation and oxidative injury in the ischaemic brain, eventually leading to poorer stroke outcomes, whereas neuron-specific IRF8 transgenic mice showed a marked inhibition of apoptosis and improved stroke outcomes. To model ischaemia/reperfusion conditions in vitro, primary cortical neurons were cultured and subjected to transient oxygen and glucose deprivation for 60 min. Similar to the in vivo study, IRF8 knockdown by Ad-shIRF8 resulted in increased apoptosis, whereas IRF8 over-expression by Ad-IRF8 significantly decreased neuronal apoptosis. These data indicate that IRF8 is strongly protective in ischaemic stroke by regulating neuronal apoptosis, the inflammatory response and oxidative stress. In the present study, we found that the transcriptional factor IRF8 plays a protective role in the cerebral ischaemic-reperfusion injury by attenuating neuronal apoptosis, oxidative stress and inflammation. Besides the known function of IRF8 in regulating the inflammatory gene expression, we first demonstrated that IRF8 can directly modulate apoptosis and oxidative stress by controlling the relative genes expression.

TRAF1 is a critical regulator of cerebral ischaemia-reperfusion injury and neuronal death.

Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.

Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction.

Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily and plays important roles in regulating multiple signaling pathways. This study was conducted to investigate the role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury. Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron-specific TRAF5 transgene (TG), and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood-brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. These results provide the first demonstration that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model.

Mindin is a critical mediator of ischemic brain injury in an experimental stroke model.

BACKGROUND: Stroke is the second leading cause of death among adults worldwide. Mindin is an ECM protein that plays important roles in regulating inflammation, angiogenesis and neuronal outgrowth. The role of mindin in the context of brain ischemia has not been examined. METHODS AND RESULTS: Transient occlusion of the middle cerebral artery was performed on mindin knockout (KO) mice, mice that carried a neuron-specific constitutively active mindin transgene (TG) and the appropriate controls. The outcome of the ischemia was evaluated by examination of the infarct and edema volumes and by neurological score assessments. The brains were collected 24 h or 3 days following the induced stroke. Compared with the control mice, the mindin KO mice exhibited lower infarct volumes and better outcomes in the neurological tests. Mindin-deficient mice exhibited low expression levels of stroke-induced inflammatory mediators, an attenuated recruitment of inflammatory cells, and inhibited activation of NF-κB. The neuronal apoptosis levels were also lower in the brains of the mindin KO mice than in those of the control mice. The mice that expressed a neuron-specific, constitutively active mindin transgene exhibited effects following the cerebral ischemic injury that were the opposite of those that were observed in the mindin KO mice. Moreover, Akt signaling activation was elevated in the ischemic brains of mindin KO mice. CONCLUSIONS: Mindin KO mice exhibited minor infarctions, an attenuated inflammatory response and low levels of neuronal apoptosis following an ischemic insult. These data demonstrate that mindin is a critical mediator of ischemic brain injury in an experimental stroke model. Akt signaling most likely mediates the biological function of mindin in this model of cerebral ischemia.

Association of estrogen receptor alpha gene polymorphisms with bone mineral density: a meta-analysis.

BACKGROUND: A number of studies have examined the association between estrogen receptor alpha (ESR-α) gene polymorphisms and bone mineral density (BMD), but previous studies of ESR-α gene XbaI (rs9340799) and PvuII (rs2234693) polymorphisms have been hampered by small sample size, regional restrictions and inconclusive results. Thus a meta-analysis is needed to assess their pooled effects. METHODS: This study reviewed all published articles indexed in Pubmed using the keywords in the title or abstract. All data were extracted independently by two reviewers using a standard form, the studies were meta-analyzed and minor discrepancies were resolved by authors' discussion. RESULTS: Twenty seven eligible studies involving 8467 women and 2032 men were identified. The XbaI and PvuII polymorphisms were significantly associated with BMD of the lumbar spine. XX and PP homozygotes had a protective effect in comparison with carriers of the x and p alleles, the effects were more significant in premenopausal women or Western women. At the femoral neck, the results were different. XX served as a protective factor in postmenopausal women, Western women, Western postmenopausal women, and men, while PP was likely to serve as a risk factor in Eastern women, Eastern postmenopausal women, and men. CONCLUSIONS: The XbaI polymorphism is correlated to BMD at diverse skeletal sites. PP had a protective role for the lumbar spine but might be a risk factor for the femoral neck.

SHPS-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress.

Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), also known as Signal-regulatory protein alpha (SIRPα) or SIRPA is a transmembrane protein that is predominantly expressed in neurons, dendritic cells, and macrophages. This study was conducted to investigate the role of SHPS-1 in the oxidative stress and brain damage induced by acute focal cerebral ischemia. Wild-type (WT) and SHPS-1 mutant (MT) mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion. SHPS-1 MT mice had significantly reduced infarct volumes and improved neurological function after brain ischemia. In addition, neural injury and oxidative stress were inhibited in SHPS-1 MT mice. The mRNA and protein levels of the antioxidant genes nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 were up-regulated in SHPS-1 MT mice. The SHPS-1 mutation suppressed the phosphorylation of SHP-1 and SHP-2 and increased the phosphorylation of Akt and GSK3ß. These results provide the first demonstration that SHPS-1 plays an important role in the oxidative stress and brain injury induced by acute cerebral ischemia. The activation of Akt signaling and the up-regulation of Nrf2 and heme oxygenase 1 likely account for the protective effects that were observed in the SHPS-1 MT mice.

1-[2,2-Bis(1,3-benzimidazol-1-ylmeth-yl)-3-bromo-prop-yl]-1,3-benzimidazole.

The title compound, C(26)H(23)BrN(6), has been synthesized as a potential ligand for the construction of metal-organic frameworks. The three benzimidazolyl groups present three potential coordination nodes. The dihedral angles between the benzimidazole ring systems are 74.03 (10), 66.49 (9) and 74.09 (9)°. The structure contains large voids, which contain highly disordered solvent mol-ecules that may be CH(3)CH(2)OH. Since the solvent mol-ecules could not be located, the PLATON/SQUEEZE procedure [Spek (2009 ▶). Acta Cryst. D65, 148-155] was used.

1,3,5,7-Tetra-bromo-adamantane.

In the pyramidal-shaped mol-ecule of the title compound, C(10)H(12)Br(4), the four terminal Br-C bond distances are nearly identical, ranging from 1.964 (4) to 1.974 (4) Å. The Br⋯Br distance of 3.6553 (7) Šindicates van der Waals contacts between mol-ecules in the crystal structure.

[Treatment of critically ill influenza A H1N1 patients in plateau region].

OBJECTIVE: To discuss the strategy of treatment of critically ill influenza A H1N1 patients in plateau region. METHODS: Four seriously ill and 4 critically ill patients suffering from influenza A H1N1 were admitted to the intensive care unit during October 10th through December 19th 2009. They were treated with antivirus drug, antibiotics, corticosteroid, measures to enhance immune function, fluid and electrolyte supplementation, symptomatic treatment, and mechanical ventilation. With their clinical data the distinguishing features in the treatment of these patients were analyzed. RESULTS: Oseltamivir as an antivirus drug, and moxifloxacin together with ceftriaxone or cefoperazone were given to all the patients. Fluid replacement was controlled to avoid over hydration. Corticosteroid was administered to 3 seriously ill patients and 3 critically ill patients. Methylprednisolone was given to 1 critically ill patient. gamma-globulin was given to 7 patients. Four patients underwent atraumatic mechanical ventilation with bi-level positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) with good result. Owing to deterioration in respiratory function, traumatic mechanical ventilation was instituted in a critically ill patient, primarily with synchronized intermittent mandatory ventilation (SIMV)+pressure support ventilation (PSV)+high positive end expiratory pressure (PEEP). The condition of the patient was improved, and ventilation modality was changed to spontaneous respiration+PSV+low PEEP before weaning. Finally the patient was weaned from respirator successfully. All the 8 patients survived and discharged from the hospital. CONCLUSION: Short term, full dosage of corticosteroid should be given to seriously ill and critically ill influenza A H1N1 patients according to specification, and atraumatic mechanical ventilation should be installed early in the treatment.