Recurrent chronic subdural hemorrhage due to cervical spinal CSF leak in a young adult: Report of a case

SummaryNontraumatic intracranial subdural hemorrhage may result from disorders at remote anatomic sites. Here, we report a young adult who suffered from bilateral subdural hematoma without antecedent head injury. The subdural hematoma did not resolve after surgical drainage. The symptom of postural headache prompted a contrast-enhanced magnetic resonance imaging (MRI) examination of the brain, which revealed signs indicative of intracranial hypotension. Subsequently, MRI of the spine demonstrated leakage of cerebrospinal fluid (CSF) in the upper cervical spine region. The patient recovered after conservative treatment. A review of the patient’s medical history revealed that the patient had chiropractic therapy on his neck 2 months prior to admission. Intracranial hypotension due to spinal CSF leak is a rare cause of subdural hemorrhage, yet it should be considered in the absence of head trauma

The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: An In Vitro and In Vivo Comparison Study with Herceptin

HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer

Metabolic syndrome in a Taiwanese metropolitan adult population

<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (MS) is a combination of medical disorders that increase one's risk for cardiovascular disease and diabetes. Little information exists on the prevalence of MS in a general adult population in Taiwan.</p> <p>Methods</p> <p>We did a cross-sectional survey in a representative sample of 2,359 Chinese adults aged 40 years and over who lived in a metropolitan city, Taiwan in 2004–05. MS was defined by Adult Treatment Panel III criteria modified for Asians.</p> <p>Results</p> <p>The prevalence of MetS was 35.32% and 43.23% in men aged 40–64 years and 65 years and over, respectively, and 24.19% and 51.82% in women aged 40–64 years and 65 years and over. Older age, postmenopausal status, higher body mass index, current smoking, low education attainment, low household income, no alcohol consumption, lower level of occupation physical activity, and a family history of diabetes were associated with increased odds of MetS.</p> <p>Conclusion</p> <p>MetS was present in more than 30% of the Taiwan adult population aged 40 years and over in a metropolitan area; there were substantial variations by age and body mass index groups.</p

Sex difference in the association of metabolic syndrome with high sensitivity C-reactive protein in a Taiwanese population

<p>Abstract</p> <p>Background</p> <p>Although sex differences have been reported for associations between components of metabolic syndrome and inflammation, the question of whether there is an effect modification by sex in the association between inflammation and metabolic syndrome has not been investigated in detail. Therefore, the aim of this study was to compare associations of high sensitivity C-creative protein (hs-CRP) with metabolic syndrome and its components between men and women.</p> <p>Methods</p> <p>A total of 1,305 subjects aged 40 years and over were recruited in 2004 in a metropolitan city in Taiwan. The biochemical indices, such as hs-CRP, fasting glucose levels, lipid profiles, urinary albumin, urinary creatinine and anthropometric indices, were measured. Metabolic syndrome was defined using the American Heart Association and the National Heart, lung and Blood Institute (AHA/NHLBI) definition. The relationship between metabolic syndrome and hs-CRP was examined using multivariate logistic regression analysis.</p> <p>Results</p> <p>After adjustment for age and lifestyle factors including smoking, and alcohol intake, elevated concentrations of hs-CRP showed a stronger association with metabolic syndrome in women (odds ratio comparing tertile extremes 4.80 [95% CI: 3.31-6.97]) than in men (2.30 [1.65-3.21]). The p value for the sex interaction was 0.002. All components were more strongly associated with metabolic syndrome in women than in men, and all sex interactions were significant except for hypertension.</p> <p>Conclusions</p> <p>Our data suggest that inflammatory processes may be of particular importance in the pathogenesis of metabolic syndrome in women.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Increase of Adenosine A1 Receptor Gene Expression in Cerebral Ischemia of Wistar Rats

In an attempt to know the role of adenosine A1 receptor in cerebral ischemia, the present study employed the ligation of bilateral carotid arteries to induce ischemia in Wistar rats. Changes of gene expression of adenosine A1 receptor in cerebral cortex of ischemic rats were compared with normal sham control and reperfusion group that received regular blood flow after a transient ischemia. The mRNA level of adenosine A1 receptor in cerebral cortex was markedly raised by this artificial ischemia. Also, reperfusion reversed this elevation to a level near the control. This change was also observed at the protein level using Western blot analysis of adenosine A1 receptor. The raised protein level of adenosine A1 receptor by ischemia was reversed to normal level after reperfusion. These data suggest that the gene expression of adenosine A1 receptor was increased by ischemia probably due to the compensative response of brain. The raised adenosine A1 receptor may play a protective role in these damaged tissues

Mediation of Beta-Endorphin by Ginsenoside Rh2 to Lower Plasma Glucose in Streptozotocin-Induced Diabetic Rats

We investigated the plasma glucose-lowering mechanism(s) of Rh2, a ginsenoside derived from Panax ginseng, in rats with streptozotocin- induced diabetes (STZ-diabetic rats). After intravenous injection over 120 min into fasting STZ-diabetic rats, Rh2 decreased plasma glucose in a dose-dependent manner. In parallel to the lowering of plasma glucose, an increase of plasma beta-endorphin-like immunoreactivity was observed. In addition, naloxone and naloxonazine at doses sufficient to block opioid mu -receptors inhibited the plasma glucose-lowering action of Rh2 in genetically wild-type, diabetic mice. In contrast, Rh2 failed to lower plasma glucose in opioid mu-receptor knockout diabetic mice. An increase in gene expression at both the mRNA and protein levels of glucose transporter subtype 4 (GLUT 4) was observed in soleus muscle obtained from STZ-diabetic rats treated with Rh2 three times daily for one day; this increase in expression was absent when opioid mu-receptors were blocked. In conclusion, our results suggest that ginsenoside Rh2 may lower plasma glucose in STZ-diabetic rats based on an increase in beta-endorphin secretion that activates opioid mu-receptors thereby resulting in an increased expression of GLUT 4

Angiopoietin-Like Protein 1 Decreases Blood Brain Barrier Damage and Edema Following Focal Cerebral Ischemia in Mice

Angiopoietin-like protein (Angptl) 1, a member of the angiopoietin- related protein family, modulates angiogenesis but little else is known of its physiological role. We found that angptl1 was upregulated at the 7th day after focal cerebral ischemia in normal mice. In order to understand the role of angptl1 in cerebral infarction, we induced focal cerebral ischemia in normal and glial fibrillary acidic protein promoter-angptl1 transgenic mice. In the transgenic mice without ischemia, overexpression of angptl1 in the whole brain led to a decrease in cortical microvascular density. Following focal cerebral ischemia, edema, but not infarct size, was less in transgenic mice relative to wild type littermates. This effect might be due to a reduction in the blood brain barrier breakdown, as confirmed by a decrease in Evans Blue leakage in the early post-ischemic phase. We conclude that angaptl1 may have a beneficial role in the preservation of vascular integrity following focal cerebral ischemia

Angiopoietin-Like Protein 1 Expression Is Related to Intermuscular Connective Tissue and Cartilage Development

Angptl1, a member of the angiopoietin-related protein family , is known to regulate angiogenesis, but little is known of its potential role in other processes. To identify the expression pattern and possible role of angptl1 during embryogenesis, we used gene targeting to generate angptl1- deficient, nLacZ knockin mice. Staining for beta- galactosidase from embryonic day 9.5 to 6 months of age revealed that angptl1 was initially expressed in the paraxial mesoderm. Expression then shifted to intermuscular connective tissue (fascial plane), joint capsules, and perichondrium (laryngo-trachea, ribs, and long bones), but not the muscles . The vasculature, central and peripheral nervous systems, digestive, respiratory, and other major organ systems did not show any angptl1 expression. This expression pattern suggests that angptl1 is related to development of the connective tissue and cartilage. Lack of phenotype in mutant mice may be due to a functional redundancy from other related factors

Studies of Vascular Related Genes in Rodent Stroke Model

在腦中風時，腦部組織缺血，腦血流中血紅素帶氧量降低。由於腦神經氧氣供應不足，因此腦血管產生立即反應，包括血管擴張、腦血流量增加等現象，同時腦部即誘發一連串基因或蛋白質的變化，其中許多血管相關基因會相對增加，而一些離子閥、輸送相關基因則可能降低。目前一些實驗室已成功藉調控某些血管生成蛋白的量，使中風模式後老鼠腦壞死範圍縮小。然而由於血管作用蛋白很多，彼此間又會相互作用，因此了解個別的、各種新的相關蛋白的作用為相當重要的課題。 血管生成素相似蛋白1(Angptl1)，為新近發現血管生成素相似蛋白質族中之一員 (Kim, et al., 1999b)，可調控血管增生，目前對其於生理上所扮演的角色，我們所知仍不多。我們發現在正常老鼠腦缺血後第七天，angptl1的表現量有增加的現象。 為了瞭解angptl1於腦中風所扮演的角色，我們在膠質原纖維酸性蛋白(GFAP)啟動子-angptl1基因轉殖小鼠及正常小鼠上，分別引發局部腦缺血。在未引發缺血之基因轉殖鼠中，angptl1大量於腦部表現，使得大腦皮層微小血管密度有上升之情形。雖然基因轉殖鼠及原生型小鼠在發生局部腦缺血後，其中風範圍大小相同，基因轉殖鼠腦水腫的程度則較同一胎原生型之小鼠為小。我們認為這可能是因為基因轉殖鼠的血腦障壁被破壞程度較原生型小鼠小，藉由中風後早期進行伊文斯藍滲漏實驗，我們證明基因轉殖鼠滲漏的程度較為減少。所以我們相信在局部腦缺血後，angptl1具有保護並維持血管完整性之功用。 Angptl1在胚胎發育或個體血管生成過程中所可能扮演的角色，目前我們所知的仍舊很少。為確定angptl1在胚胎生成過程中所扮演的角色以及表現的部位，我們利用基因標靶以生殖出缺乏angptl1但同時帶有nLacZ品系之小鼠。取樣自E9.5天至六個月大的小鼠，進行&szlig;-乳糖水解酶之染色後發現，angptl1最初會在旁軸的中胚層中表現。之後會轉至肌間質之結締組織(筋膜)、關節囊及軟骨膜(喉頭-氣管，肋骨及長骨)等處表現，但肌肉則無。血管系統、中央及週邊神經系統、消化、呼吸及其他主要器官系統中，並沒有任何angptl1之表現。根據所表現的位置可推測angptl1與結締組織及軟骨的發育有關。突變型小鼠沒有明顯的表現型，有可能是因為其功能仍受許多相關的因子之影響。 Adenosine為一血管擴張、新生物質，既往文獻有提到adenosine系統在腦缺血之生理變化佔有重要的角色。為了解adenosine A1受體於腦缺血模式中所扮演的角色，我們以Wistar大鼠作為實驗動物，阻斷其兩側頸動脈與中大腦動脈的血流，造成腦缺血現象。腦缺血的大鼠中，其大腦皮層內的adenosine A1受體之基因表現量，與經過sham作為控制組，以及在暫時缺血後恢復原先的血流的大鼠相比之下，腦缺血的大鼠，其大腦皮層的adenosine A1受體於核醣核酸（RNA）表現量，有明顯上升之趨勢；而經過暫時缺血又再灌流恢復血流的大鼠，adenosine A1受體於核醣核酸中的表現量與控制組的大鼠幾乎相同，並沒有明顯之提升。另外腦缺血後大鼠其adenosine A1受體蛋白質的表現，結果幾乎與RNA表現相同。由這些實驗數據，我們推測因缺血後，腦內會有補償反應的發生，導致adenosine A1受體的基因表現量增加，而adenosine A1受體的增加，推想是受傷的組織中產生出來之一種保護性角色。Angiopoietin-like protein (Angptl) 1, a member of the angiopoietin-related protein family, modulates angiogenesis but little else is known of its physiological role. We found that angptl1 was upregulated at the 7th day after focal cerebral ischemia in normal mice. In order to understand the role of angptl1 in cerebral infarction, we induced focal cerebral ischemia in normal and glial fibrillary acidic protein promoter-angptl1 transgenic mice. In the transgenic mice without ischemia, overexpression of angptl1 in the whole brain led to a decrease in cortical microvascular density. Following focal cerebral ischemia, edema, but not infarct size, was less in transgenic mice relative to wild type littermates. This effect might be due to a reduction in the blood brain barrier breakdown, as confirmed by a decrease in Evans Blue leakage in the early post-ischemic phase. We conclude that angptl1 may have a beneficial role in the preservation of vascular integrity following focal cerebral ischemia. Little is known of angptl1’s potential role in other processes. To identify the expression pattern and possible role of angptl1 during embryogenesis, we used gene targeting to generate angptl1 deficient, nLacZ knock-in mice. Staining for &szlig;-galactosidase from embryonic day 9.5 to 6 months of age revealed that angptl1 was initially expressed in the paraxial mesoderm. Expression then shifted to intermuscular connective tissue (fascial plane), joint capsules and perichondrium (laryngo-trachea, ribs and long bones) but not the muscles. The vasculature, central and peripheral nervous systems, digestive, respiratory and other major organ systems did not show any angptl1 expression. This expression pattern suggests that angptl1 is related to development of the connective tissue and cartilage. Lack of phenotype in mutant mice may be due to a functional redundancy from other related factors. In an attempt to know the role of adenosine A1 receptor in cerebral ischemia, the present study employed the ligation of bilateral carotid arteries to induce ischemia in Wistar rats. Changes of gene expression of adenosine A1 receptor in cerebral cortex of ischemic rats were compared with normal sham control and reperfusion group that received regular blood flow after a transient ischemia. The mRNA level of adenosine A1 receptor in cerebral cortex was markedly raised by this artificial ischemia. Also, reperfusion reversed this elevation to a level near the control. This change was also observed at the protein level using Western blot analysis of adenosine A1 receptor. The raised protein level of adenosine A1 receptor by ischemia was reversed to normal level after reperfusion. These data suggest that the gene expression of adenosine A1 receptor was increased by ischemia probably due to the compensative response of brain. The raised adenosine A1 receptor may play a protective role in these damaged tissues.縮寫表……………………………………………………………………6 附圖目錄…………………………………………………………………7 中文摘要…………………………………………………………………9 英文摘要………………………………………………………………11 齧齒類腦缺血性中風模式進行腦部血管相關基因之研究…………13 第一章 總論……………………………………………………………13 壹、腦中風之臨床概況………………………………………………13 一、腦中風之概述……………………………………………………13 二、腦中風之致病機轉………………………………………………14 三、腦中風之治療現況………………………………………………14 貳、腦中風之動物實驗模式簡介……………………………………15 一、中風之動物模式概論……………………………………………15 二、頸部導入縫線中大腦動脈栓塞模式……………………………16 三、中大腦動脈栓塞模式導出之腦部病變…………………………16 四、小鼠頸部塞線中大腦動脈栓塞模式……………………………17 參、中風後基因變化與血管新生的情形……………………………18 一、腦部缺血後之基因變化…………………………………………18 二、腦部缺血後之血管新生情形……………………………………18 第二章 血管生成素相似蛋白1（Angiopoietin-related protein 1）在腦中風後表現量之變化，與在發育時，中風時可能代表意義之研究………20 壹、血管生成素相似蛋白1概論………………………………………20 貳、假說一：血管生成素相似蛋白1對腦血管有減少傷害的作用…21 參、假說二：血管生成素相似蛋白1會影響胚胎之血管發育，且其表現位置可以反映其影響血管成熟功能的特性………………………21 肆、實驗材料與方法…………………………………………………21 一、取得含有全長小鼠Angptl1 cDNA之質體………………………21 二、篩選含有Angptl1 genomic DNA片段的噬菌體菌落……………22 1.探針的製備…………………………………………………………22 2.篩選含angptl1 genomic DNA的噬菌體菌落………………………22 三、利用電腦軟體及資料庫分析Angptl1基因………………………22 四、RNA的純化…………………………………………………………23 五、北方墨點法(Northern blot) …………………………………23 六、反轉錄聚合酶鏈反應(RT-PCR) …………………………………23 七、Angptl1融合蛋白質的表現及純化………………………………24 1.Angptl1融合蛋白質的表現…………………………………………24 2.質體DNA的轉染(transfection) …………………………………24 八、西方墨點法(Western Blot) ……………………………………25 九、免疫螢光分析法(Immunofluorescence analysis) …………25 十、GFAP-angptl1基因轉殖鼠的衍生及品系鑑定…………………25 十一、原位雜交法……………………………………………………26 十二、微血管密度測定………………………………………………27 十三、小鼠缺血性腦中風模式………………………………………27 十四、神經學測定……………………………………………………28 十五、中風範圍測定…………………………………………………28 十六、Angptl1基因剔除小鼠(knockout mice)產製………………28 1.剔除載體之設計與建構……………………………………………28 2.基因剔除載體轉殖至胚胎幹細胞(Embryonic Stem Cell) ……29 3.PCR篩選與南方墨點法………………………………………………29 十七、小鼠基因組鑑定(genome typing) …………………………30 十八、生化分析………………………………………………………30 十九、旋轉滾輪測試…………………………………………………30 二十、以小鼠胚胎及成鼠進行β-半乳糖苷酶染色…………………30 二十一、骨骼分析及血管攝影………………………………………31 二十二、組織病理分析………………………………………………31 二十三、腦及肌肉之血管增生評定…………………………………31 伍、第一部分實驗結果………………………………………………32 一、原生型FVB小鼠MCAO阻塞後Angptl1表現量的變化……………32 二、受GFAP調控之angptl1基因轉殖鼠之表現型及生殖能力………32 三、Angptl1基因轉殖鼠之微血管密度………………………………33 四、以2,3,5-氯化三苯基四唑染色…………………………………33 五、血腦障壁破壞程度評估…………………………………………33 陸、第二部分實驗結果………………………………………………34 一、原生型成鼠中各器官Angptl1之表現量…………………………34 二、Angptl1基因剔除同時帶有nLacZ基因品系小鼠之製造………34 三、缺乏Angptl1基因小鼠具有正常之表現型及生殖能力…………35 四、結締組織及軟骨中Angptl1表現的組織部位及時間點…………35 五、組織分析缺乏Angptl1基因同時帶有nLacZ突變型小鼠並無異常外觀……………………………………………………………………36 六、Angptl1基因剔除同時帶有nLacZ基因品系小鼠於血管發育上並無異常…………………………………………………………………36 七、Angptl1基因剔除同時帶有nLacZ基因品系小鼠並無早期關節退化跡象…………………………………………………………………36 柒、討論………………………………………………………………37 一、Angptl1基因在腦中風後呈現向上調控的趨勢…………………37 二、GFAP啟動子導引Angptl1基因在腦部表現增加，而此蛋白之過度表現對這些基因轉殖鼠沒有可見之生命威脅………………………38 三、GFAP啟動子導引Angptl1基因轉殖鼠的大腦皮層微血管只有稍微減少的現象……………………………………………………………38 四、GFAP啟動子導引Angptl1基因轉殖鼠在中風後腦水腫情形較野生型小鼠少，其原因可能導自於angptl1對微血管內皮細胞的保護功能………………………………………………………………………39 五、Angptl1基因功能之文獻回顧……………………………………40 六、Angptl1基因在胚胎時期表現部位分析…………………………41 七、成鼠Angptl1基因表現部位分析，符合其與肌肉間質結締組織、關節軟骨發育之相關性………………………………………………42 八、成鼠Angptl1基因剔除並不顯示出微血管或軀體大血管之發育障礙………………………………………………………………………43 第三章 腺甘酸（Adenosine）A1受體在腦中風初期所扮演角色的分析………………………………………………………………………45 壹、細胞間腺甘酸（Adenosine）的形成……………………………45 貳、腺甘酸受器………………………………………………………45 參、A1腺甘酸受器的生理作用………………………………………46 肆、腦缺血時A1腺甘酸受器的生理變化……………………………46 伍、材料與方法………………………………………………………47 陸、實驗結果與討論…………………………………………………48 第四章 展望…………………………………………………………50 壹、血管生成素相似蛋白1在臨床上的重要性………………………50 一、血管生成素相似蛋白1在血管發育上的重要性…………………50 二、血管生成素相似蛋白1在中風上的重要性………………………51 三、血管生成素相似蛋白1在腫瘤治療上的重要性…………………52 貳、分析中風後基因變化以找出重要的治療標的－腺苷酸治療缺血性中風…………………………………………………………………53 參、人類血管生成素相似蛋白1與腫瘤相關性實驗方法與設計……53 一、Bromodeoxyuridin (BrdU) 細胞增生分析……………………53 二、細胞移動分析……………………………………………………54 三、細胞侵犯分析……………………………………………………54 四、Soft agar colony formation assay…………………………54 五、腦部腫瘤種植……………………………………………………54 六、基因剔除小鼠腫瘤種植實驗……………………………………55 七、腫瘤微血管密度分析……………………………………………55 肆、初步結果…………………………………………………………55 伍、結論………………………………………………………………56 論文英文簡述…………………………………………………………57 圖表備註………………………………………………………………81 參考資料………………………………………………………………113 附錄……………………………………………………………………12