NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

Nuclear receptor coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in a C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue-specific contributions of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich Sv129/J strain. Increased body iron content protects these mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to that of wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Reconstitution of erythropoiesis with normalization of red blood count and hemoglobin concentration occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, erythropoietin administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematologic phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.     

Recurrent pre‐existing and acquired DNA copy number alterations,including focal TERT gains,in neuroblastoma central nervous system metastases

Stage 4 neuroblastomas have a high rate of local and metastatic relapse and associated disease mortality. The central nervous system (CNS) is currently one of the most common isolated relapse sites, yet the genomic alterations that contribute to these metastases are unknown. This study sought to identify recurrent DNA copy number alterations (CNAs) and target genes relating to neuroblastoma CNS metastases by studying 19 pre‐CNS primary tumors and 27 CNS metastases, including 12 matched pairs. SNP microarray analyses revealed that MYCN amplified (MYCNA) tumors had recurrent CNAs different from non‐MYCNA cohorts. Several CNAs known to be prevalent among primary neuroblastomas occurred more frequently in CNS metastases, including 4p?, 7q+, 12q+, and 19q? in non‐MYCNA metastases, and 9p? and 14q? irrespective of MYCNA status. In addition, novel CNS metastases‐related CNAs included 18q22.1 gains in non‐MYCNA pre‐CNS primaries and 5p15.33 gains and 15q26.1→tel losses in non‐MYCNA CNS metastases. Based on minimal common regions, gene expression, and biological properties, TERT (5p), NR2F2 (15q), ALDH1A3 (15q), CDKN2A (9p), and possibly CDH7 and CDH19 (18q) were candidate genes associated with the CNS metastatic process. Notably, the 5p15 minimal common region contained only TERT, and non‐MYCNA CNS metastases with focal 5p15 gains had increased TERT expression, similar to MYCNA tumors. These findings suggest that a specific genomic lesion (18q22.1 gain) predisposes to CNS metastases and that distinct lesions are recurrently acquired during metastatic progression. Among the acquired lesions, increased TERT copy number and expression appears likely to function in lieu of MYCNA to promote CNS metastasis. © 2013 Wiley Periodicals, Inc.     

高血压脑出血个体化手术治疗方案的探讨

目的评价中小骨窗开颅术,去大骨瓣减压术及锥颅血肿抽吸治疗高血压脑出血的疗效。方法通过对37例去大骨瓣减压开颅和68例早期显微镜下斜切口中小骨窗开颅术以及42例锥颅血肿抽吸治疗高血压脑出血的观察比较各组死亡率。结果发现去大骨瓣组死亡9例,死亡率为24.3%,植物生存4例,中小骨窗组死亡11例,死亡率为16.4%。锥颅组死亡22例,死亡率为52.1%。中小骨窗组与去大骨瓣组在血肿清除程度、死亡率和早期预后等方面相差无显著差异,而与锥颅组差异明显。结论显微镜下超早期中小骨窗开颅手术能满足在直视下清除血肿的需要,又有手术时间短,创伤小,术中出血少等优点。是当前手术治疗高血压性脑出血的有效选择。     

脑脊液IFN-γ IL-4在结核性脑膜炎病程中的动态变化

目的应用间接酶联免疫吸附试验(enzyme-linked immunol sorbance assay,ELISA)检测脑脊液中炎症因子IFN-γ、IL-4的动态变化,探讨其在诊断结核性脑膜炎(结脑)中的意义及与预后的关系。方法测定发病2周内结脑组及对照组脑脊液中IFN-γ、IL-4含量及结脑组经抗结核治疗8周后脑脊液IFN-γ、IL-4含量。结果结脑组早期脑脊液IFN-γ、IL-4含量较对照组明显升高,经过抗结核治疗8周后47例明显下降,3例无下降者均为重症患者,2例合并脑梗死,1例合并脊髓损害肠梗阻。结论急性期脑脊液中IFN-γ、IL-4含量升高有助于结脑的诊断,其动态变化有助于判断结脑预后。     

Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: Role of autophagy

The present study aimed to test the hypothesis that berberine, a plant‐derived anti‐oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague‐Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC‐3B, Beclin‐1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high‐dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post‐MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC‐3B II and Beclin‐1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho‐Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho‐Akt signalling pathways.