Islet amyloid polypeptide in the islets of Langerhans: friend or foe?

Islet amyloid polypeptide (IAPP), or amylin, was originally discovered as the constituent peptide in amyloid occurring in human insulinomas and in pancreatic islets in human subjects with Type II (non-insulin-dependent) diabetes mellitus. Its normal expression in beta cells and its co-secretion with insulin in response to nutrient stimuli, suggest a metabolic function for the peptide. Specifically, IAPP has most frequently been shown to inhibit insulin secretion, implying that IAPP has a role in the regulation of islet hormone homeostasis. The physiological significance of IAPP in islets has been difficult to assess; very high IAPP concentrations are required to alter insulin secretion. Moreover, until recently, IAPP receptors have not been characterised at the molecular level, thus leaving the actual target cells for IAPP unidentified. Furthermore, in experimental diabetes in rodents, the ratio of IAPP expression to that of insulin invariably is increased. In view of the pleiotropic effects attributed to IAPP, such regulation could be both adverse and beneficial in diabetes. Metabolic characterisation of mice carrying a null mutation in the IAPP gene or which overexpress IAPP in beta cells have recently confirmed that IAPP is a physiological inhibitor of insulin secretion. Based on experiments in which IAPP-deficient mice develop a more severe form of alloxan-induced diabetes, we argue that the action of IAPP in the islets normally is beneficial for beta-cell function and survival; thus, the established up regulation of IAPP expression compared with that of insulin in experimental rodent diabetes could serve to protect islets under metabolically challenging circumstances. [Diabetologia (2000) 43: 687–695]     

两种恢复方式对士兵冲刺间歇训练效果的影响

 目的 探讨冲刺间歇训练时两种恢复方式(积极性恢复 vs. 消极性恢复)对士兵运动能力和训练效果的影响。方法 选取18名男性武警士兵完成6组冲刺间歇训练(30 s Wingate全力蹬车试验),间歇期(4 min)分别进行消极性恢复(即在功率自行车上休息)和积极性恢复(以1.1 W/kg负荷继续蹬车),每次Wingate试验时(不包括间歇期)记录峰值功率(PP)、平均功率(MP)、疲劳指数(FI)、总做功(TW)和心率(HR)等参数。结果 与消极性恢复比较,积极性恢复PP在第2次Wingate试验时降低(P<0.05),MP和HR在第4~6次Wingate试验时升高,差异均有统计学意义(P<0.05),FI和TW差异无统计学意义(P>0.05)。结论 积极性恢复可提高冲刺间歇训练后期的训练效果, 士兵应根据训练方案选择合理的恢复方式。     

滋养层细胞与原代白血病细胞共培养体系的建立及其意义

目的:建立一套体外培养前B急性淋巴细胞白血病(ALL)原代细胞的方法,并尝试进行难治性白血病克隆的鉴定。方法:采用来源于骨髓的基质细胞HS-5作为滋养层细胞与原代白血病细胞进行双相培养,并通过药敏和凋亡检测进行双相培养体系生物动力学评估。结果:双相滋养层培养体系能够耐受细胞毒药物的毒性;8例前B急淋白血病原代细胞标本在基质滋养层支持下离体72 h存活率20.4%~68.3%不等,与无滋养层支持或基质细胞上清液支持的标本相比存活率有显著性提高;其中1例标本的体外生长与有否滋养层支持无关,怀疑为难治性白血病克隆。结论:骨髓基质细胞来源的滋养层具有一定的体外支持白血病细胞存活的能力,但存在个体差异,与肿瘤细胞本身生物学特征有关;利用双相培养体系可以在体外早期初步鉴别出难治性白血病克隆并早期制定干预措施。     

Transthyretin Is Dysregulated in Preeclampsia,and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model

Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.Preeclampsia occurs in 5% to 8% of pregnancies worldwide and is a major cause of fetal and maternal morbidity and mortality.^1–3 It is a heterogeneous disease with varied presentations from mild self-limited hypertension and proteinuria to severe forms with significant end-organ dysfunction and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).³ Although the cause of preeclampsia and its appropriate treatment remain elusive, this syndrome has been proposed to reflect at least two stages of complications during pregnancy. These begin with preclinical manifestations at the maternal-fetal interface, followed by systemic clinical symptoms.^1,2 Hypertension, proteinuria, and edema, with a variable degree of fetal growth restriction, are the cardinal features of preeclampsia.³ Because the placenta is the nutritional and immunological gateway to normal fetal development and pregnancy outcome, placenta-related events are believed to be central to the pathogenesis of this disease. Evidence exists for the release of disease-initiating molecules into maternal circulation that triggers the clinical symptoms.^1,4 Placental and systemic anomalies reflected by circulating placental debris, inflammation, impaired remodeling of spiral arteries, placental hypoxia/ischemia, excess production of anti-angiogenic factors [soluble fms-like tyrosine kinase-1 (sFlt-1)], and soluble endoglin (sEng), and angiotensin receptor autoantibodies have all emerged as contributors to the pathophysiological characteristics of preeclampsia.^2,4–14Preeclampsia has remained enigmatic because of lack of well-defined etiology and animal models. Although normal mice do not develop preeclampsia spontaneously, mouse models have been judged to be particularly useful to uterine diseases and pregnancy complications because many similarities in female reproduction and placentation have been identified between the two species.¹⁵ Moreover, their tractable genetics provide an effective way to probe mechanisms more deeply than many other species.^15–17 We recently showed that sera from preeclamptic women could function as a source of novel causative factors that induced hypertension, proteinuria, and kidney pathological characteristics, as well as intrauterine growth restriction (IUGR), in IL-10^−/− mice in a pregnancy-specific manner.¹⁸ IL-10 functions as a potent vascular and anti-inflammatory cytokine and has been shown to be present at significantly reduced levels in preeclampsia placental tissue.^19,20 Preeclampsia serum (PES) was found to disrupt endovascular cross talk between trophoblasts and endothelial cells and to induce placental hypoxia and excess production of sFlt-1 and sEng,¹⁸ soluble factors known to precipitate maternal symptoms.^21,22 These results from our serum-based humanized mouse model suggest that the pathophysiological characteristics of preeclampsia are more complex than previously thought and are likely to involve interactions and dysregulation of multiple factors. By using serum proteomic screening by surface-enhanced laser-desorption ionization-time-of-flight (SELDI-TOF), our results suggest that PES contains a reduced abundance of transthyretin, a plasma transport protein for the thyroid hormone, thyroxine, and retinol-binding protein.²³ More important, transthyretin has been widely studied for its role in amyloid diseases associated with protein misfolding and aggregation, resulting in deposits of toxic, fibrillar aggregates in specific organs.^24–26 Dysregulated or reduced transthyretin has also been implicated in Alzheimer disease, and overexpression of a wild-type human transthyretin transgene has been shown to ameliorate the disease in the transgenic murine model of human Alzheimer disease.^27,28 Transthyretin in its native form assumes a homotetrameric quaternary configuration (approximately 14 kDa per monomer). Post-translational modifications of the monomer result in detection of several isoforms.²⁹ Circulating transthyretin is also a validated marker of malnutrition and has a putative role in oocyte maturation and inflammation.^30–32 Although the presence of transthyretin during implantation in mice and in the placenta and trophoblasts in humans has been reported,^33,34 its functional role in normal pregnancy or adverse pregnancy outcomes has not been recognized. We hypothesize that transthyretin in preeclampsia is structurally and functionally dysregulated and contributes to the onset of this serious pregnancy complication. Herein, we present complementary in vitro and in vivo approaches, which show that endogenously altered transthyretin is a preeclampsia-causing agent and that native transthyretin has the ability to block the onset of preeclampsia-like features.     

不同切碎长度和发酵方式对全株饲用谷子青贮质量的影响

本研究旨在探索不同切碎长度和发酵方式对全株饲用青贮谷子质量的影响。采用2×3双因子试验设计,切割长度分别为1.5 cm、2.5 cm和3.5 cm,发酵方式分为复合菌剂发酵和乳酸菌发酵两个类型,每处理3个重复。常温发酵40 d后取样,进行感官评定,分析基础养分,测定挥发性成分。结果表明,随着切碎长度增加,气味评分和总分总体呈降低趋势,中性洗涤纤维(NDF)和酸性洗涤纤维(ADF)含量呈增加趋势,丁酸含量显著增加;相比乳酸菌发酵组,复合菌剂发酵组整体气味评分和乳酸含量较高,pH值和NDF、ADF含量较低。综上,不同切碎长度和发酵方式对于全株饲用谷子青贮质量均有显著影响。降低切碎长度和使用复合菌剂发酵均有助于促进纤维分解,减少丁酸产量,改善青贮感官评分。     

下颌骨前突患者下颌管走行及临床价值探讨

目的：：运用锥形束CT(cone-beam CT,CBCT)分析正常人群和下颌骨前突患者下颌神经管轨迹,为临床手术方案的制订和操作时避开重要神经血管提供帮助。方法：选取28例骨性Ⅲ类下颌骨前突患者（男10例,女18例）、20例正常对照组患者（男12例,女8例）,使用CBCT拍摄下颌管影像,从下颌孔至第一磨牙区分为5个平面,在每个层面分别测量下颌管内外径、下颌骨厚度、下颌管至颊舌侧骨皮质及下颌骨下缘的距离。采用SPSS 17.0软件包对测量结果进行统计学分析。结果：下颌骨前突患者自下颌支到下颌角前部逐渐增厚,继续至下颌第一磨牙区逐渐变薄。下颌神经管的内外径自下颌支到下颌体部逐渐变细。颊侧骨皮质厚度自下颌支区域逐渐增厚,到下颌体部继续变薄。下颌骨前突患者与对照组患者下颌管的对比分析显示,骨髓腔宽度与下颌支厚度有显著差异,且具有显著相关性。结论：CBCT能够精确显示下颌神经管的走行及与周边结构的关系,下颌骨前突患者与对照组患者下颌支厚度的差异主要由颊侧骨髓腔宽度造成。     

染料木素通过TIPE 2负性调控Akt活性促进脂多糖活化的巨噬细胞凋亡

目的探究染料木素(genistein,GEN)对脂多糖(lipopolysaccharide,LPS)活化的RAW264.7细胞凋亡的影响及其可能的药理学作用机制。方法GEN预孵育RAW264.7细胞或慢病毒介导的肿瘤坏死因子α诱导蛋白8样分子2(tumor necrosis factor-α-induced protein 8-like 2,TIPE 2)过表达细胞2 h,再与LPS共孵育24 h,采用CCK 8试剂盒检测细胞活力,Annexin V-FITC/PI试剂盒检测细胞凋亡水平,qRT-PCR检测TNF-α、IL-6、caspase-8、caspase-3和TIPE 2 mRNA,Western blot检测iNOS、COX-2、caspase-8、caspase-3、TIPE 2、Akt和p-Akt蛋白表达。结果LPS促进RAW264.7细胞TNF-α、IL-6、iNOS、COX-2合成;GEN抑制LPS活化的RAW264.7细胞活力,凋亡细胞增多,并上调caspase-8、caspase-3、TIPE 2 mRNA及蛋白表达;TIPE 2过表达上调活化RAW264.7细胞caspase-8、caspase-3 mRNA及蛋白表达,减少Akt磷酸化,且与GEN具有协同作用。结论GEN可能通过上调TIPE 2抑制Akt活性,激活外源性凋亡途径,促进LPS活化的RAW264.7细胞凋亡。     

舒芬太尼用于高龄患者全麻诱导气管插管的临床研究

目的：观察舒芬太尼用于高龄患者全麻诱导气管插管的临床效果。方法选择ASAⅡ～Ⅲ级,需在气管插管全身麻醉下行四肢手术的高龄（年龄≥80岁）患者45例,随机分三组：舒芬太尼0.15μg/kg 组（ S1组）、舒芬太尼0.25μg/kg组（S2组）及芬太尼2μg/kg组（F组）,每组15例。所有患者均分别记录基础值（T0）、插管前1 min（T1）、插管后1 min（T2）和插管后5 min（T3）的收缩压（SP）、舒张压（DP）和心率（HR）,并计算各时间点 SP 与 HR 的乘积（ RPP）;记录不良反应的发生及药物使用情况。结果三组T1时间点BP和T3时间点SP、S2组T2时间点SP和F组T3时间点DP均显著低于同组T0时间点（P均<0.01）,F组T2时间点DP显著高于同组T0时间点（P<0.05）和S2组同时间点（ P<0.05）,S1组和S2组T1时间点SP、S2组T2时间点BP均显著低于F组同时间点（ P<0.01或0.05）。S1组和F组T2时间点HR均显著大于同组T0时间点（ P均<0.01）和S2组同时间点（ P<0.05）。三组T1、T3时间点RPP均显著小于同组T0时间点（ P<0.01或0.05）。F组T2时间点RPP显著大于同组T0时间点（ P<0.05）和S2组同时间点（P<0.05）。S2组声带活动发生率、丙泊酚和瑞芬太尼使用率小于S1组,罗库溴铵、新福林使用率均显著小于S1组和F组（P<0.05）。结论舒芬太尼0.25μg/kg用于高龄患者全麻诱导,不仅能抑制插管反应,减少不良反应,而且能保持插管前后心血管功能稳定和心肌氧供需平稳,安全可行。     

透明质酸钠治疗颞下颌关节紊乱病的定量系统评价

目的:系统评价颞下颌关节腔内注射透明质酸钠治疗颞下颌关节紊乱病的有效性和安全性。方法:计算机检索Pubmed数据库、Cochrane临床试验注册中心、EMBASE数据库和中国生物医学文献数据库等,检索时间截至2013年12月。收集关节腔内注射透明质酸钠治疗颞下颌关节紊乱病的随机对照试验,由2名研究者独立进行文献质量评价和资料提取,运用Revman 5.0进行Meta分析。结果:共纳入19个随机对照试验,1422例患者。Meta分析结果显示与阴性对照相比,透明质酸钠改善颞下颌关节紊乱病患者短期及长期的最大张口度和临床总体评价差异有统计学意义(P<0.05);但在疼痛缓解和不良反应方面两组差异无统计学意义(P>0.05)。与糖皮质激素组相比,透明质酸钠能够改善颞下颌关节紊乱病患者临床总体评价和短期最大开口度(P<0.05);但在疼痛缓解、改善长期最大张口度及注射后不良反应方面,两组差异无统计学意义。结论:颞下颌关节腔内注射透明质酸钠治疗颞下颌关节紊乱病具有一定的有效性和安全性,但尚需更多高质量的临床随机对照试验支持。     

高渗羟乙基淀粉(200/0.5)氯化钠注射液用于择期颅脑手术麻醉效果探讨

目的 探讨高渗羟乙基淀粉(200/0.5)氯化钠注射液用于择期颅脑手术麻醉对患者血流动力学、电解质酸碱平衡及降低颅内压效果的影响.方法 选取行择期胶质瘤切除手术患者120例,以随机抽样方法分为对照组(60例)和高渗组(60例);分别给予常规羟乙基淀粉和高渗羟乙基淀粉(200/0.5)静脉输注,比较两组患者不同时间点心率(HR),平均动脉压(MAP),中心静脉压(CVP),Na+、K+、Ca2+、pH及颅内压(ICP)等指标水平.结果 两组患者T2、T3及T4时间点HR和CVP指标均较T0时间点明显提高,差异有统计学意义(P＜0.05);两组患者T3和T4时间点MAP指标均较T0时间点显著降低,差异有统计学意义(P＜0.05);而高渗组患者T4时间点HR和MAP指标水平均明显优于对照组,差异有统计学意义(P＜0.05);两组患者T1、T2、T3及T4时间点Na+和K+指标水平与T0时间点比较差异有统计学意义(P＜0.05);两组患者T2、T3及T4时间点ICP水平较T0时间点均显著降低,差异有统计学意义(P＜0.05);高渗组患者T4时间点ICP水平显著低于对照组,差异有统计学意义(P＜0.05).结论 高渗羟乙基淀粉(200/0.5)氯化钠注射液用于行颅脑外科手术治疗患者可有效稳定血流动力学,纠正电解质酸碱平衡平衡紊乱,并抑制颅内压升高.