Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis

BackgroundCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR.MethodsThis multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport.ResultsIn the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was ?3.0 mV (?6.6; 0.6) at day 15, ?4.1 mV (?7.8; ?0.4, p = .04) at day 26 (end of treatment) and ? 3.7 mV (?8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile.ConclusionsIn F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.     

Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock

OBJECTIVE:

Intravenous infusion of crystalloid solutions is a cornerstone of the treatment of hemorrhagic shock. However, crystalloid solutions can have variable metabolic acid-base effects, perpetuating or even aggravating shock-induced metabolic acidosis. The aim of this study was to compare, in a controlled volume–driven porcine model of hemorrhagic shock, the effects of three different crystalloid solutions on the hemodynamics and acid-base balance.

METHODS:

Controlled hemorrhagic shock (40% of the total blood volume was removed) was induced in 18 animals, which were then treated with normal saline (0.9% NaCl), Lactated Ringer''s Solution or Plasma-Lyte pH 7.4, in a blinded fashion (n = 6 for each group). Using a predefined protocol, the animals received three times the volume of blood removed.

RESULTS:

The three different crystalloid infusions were equally capable of reversing the hemorrhage-induced low cardiac output and anuria. The Lactated Ringer''s Solution and Plasma-Lyte pH 7.4 infusions resulted in an increased standard base excess and a decreased serum chloride level, whereas treatment with normal saline resulted in a decreased standard base excess and an increased serum chloride level. The Plasma-Lyte pH 7.4 infusions did not change the level of the unmeasured anions.

CONCLUSION:

Although the three tested crystalloid solutions were equally able to attenuate the hemodynamic and tissue perfusion disturbances, only the normal saline induced hyperchloremia and metabolic acidosis.     

Behavioral deficits and cellular damage following developmental ethanol exposure in rats are attenuated by CP-101,606, an NMDAR antagonist with unique NR2B specificity

NMDAR-mediated excitotoxicity has been implicated in some of the impairments following fetal ethanol exposure. Previous studies suggest that both neuronal cell death and some of the behavioral deficits can be reduced by NMDAR antagonism during withdrawal, including antagonism of a subpopulation of receptors containing NR2B subunits. To further investigate NR2B involvement, we selected a compound, CP-101,606 (CP) which binds selectively to NR2B/2B stoichiometries, for both in vitro and in vivo analyses. For the in vitro study, hippocampal explants were exposed to ethanol for 10 days and then 24 h following removal of ethanol, cellular damage was quantified via propidium iodide fluorescence. In vitro ethanol withdrawal-associated neurotoxicity was prevented by CP (10 and 25 nM). In vivo ethanol exposure was administered on PNDs 1-7 with CP administered 21 h following cessation. Activity (PNDs 20-21), motor skills (PNDs 31-33), and maze navigation (PNDs 43-44) were all susceptible to ethanol insult; treatment with CP (15 mg/kg) rescued these deficits. Our findings show that CP-101,606, a drug that blocks the NR2B/2B receptor, can reduce some of the damaging effects of “3rd trimester” alcohol exposure in our rodent model. Further work is clearly warranted on the neuroprotective potential of this drug in the developing brain.     

Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A

Earlier investigations in our lab indicated an anti-adrenergic effect induced by activation of p21-activated kinase (Pak-1) and protein phosphatase 2A (PP2A). Our objective was to test the hypothesis that Pak-1/PP2A is a signaling cascade controlling stress-induced cardiac growth. We determined the effects of ablation of the Pak-1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. Wild-type (WT) and Pak-1-knockout (Pak-1-KO) mice were randomized into six groups to receive either ISO, saline (CTRL), or ISO and FR180204, a selective inhibitor of Erk1/2. Echocardiography revealed that hearts of the Pak-1-KO/ISO group had increased LV fractional shortening, reduced LV chamber volume in diastole and systole, increased cardiac hypertrophy, and enhanced transmitral early filling deceleration time, compared to all other groups. The changes were associated with an increase in relative Erk1/2 activation in Pak-1-KO/ISO mice versus all other groups. ISO-induced cardiac hypertrophy and Erk1/2 activation in Pak-1-KO/ISO were attenuated when the selective Erk1/2 inhibitor FR180204 was administered. Immunoprecipitation showed an association between Pak-1, PP2A, and Erk1/2. Cardiac myocytes infected with an adenoviral vector expressing constitutively active Pak-1 showed a repression of Erk1/2 activation. p38 MAPK phosphorylation was decreased in Pak-1-KO/ISO and Pak-1-KO/CTRL mice compared to WT. Levels of phosphorylated PP2A were increased in ISO-treated Pak-1-KO mice, indicating reduced phosphatase activity. Maximum Ca²⁺-activated tension in detergent-extracted bundles of papillary fibers from ISO-treated Pak-1-KO mice was higher than in all other groups. Analysis of cTnI phosphorylation indicated that compared to WT, ISO-induced phosphorylation of cTnI was blunted in Pak-1-KO mice. Active Pak-1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A.     

辽宁汉族指长及指长比特点

目的 探讨辽宁汉族指长比的特点。 方法 在知情同意情况下随机整群选取20~22岁健康辽宁汉族728人（男270,女458）,排除手指有畸形、损伤和有内分泌及代谢病者,其母孕期间均未服用激素类药物,直接测量法测量其指长, SPSS140软件包对数据进行分析。 结果 辽宁汉族指长均呈现：3D＞4D＞2D＞5D,女性2D>男性（P<0.001）、男性4D>女性（P<0.001）;辽宁汉族指长比具有3D:5D＞4D:5D＞2D:5D＞3D:4D＞2D:4D＞2D:3D趋势;辽宁汉族指长比存在性别、侧别差异,以2D:4D较为明显;辽宁汉族指长比大于宁夏汉族、回族指长比,与其他国家群体之间也存在差异。 结论 辽宁汉族指长比具有性别、侧别差异性,其中以2D：4D最为显著;指长比可能还存在民族、地区及人种的差异。     

浅论中西医的区别及"中医西化"的危害性

"中医西化"是个值得关注的老话题.中医与西医,在理论依据、诊断手段、治疗法则及药物性质等方面都存在着不同之处.中医西化会产生五大危害性一是扼制了对中医玄妙的探究,二是妨碍了中药优势的发挥,三是阻滞了中医技巧的进步,四是影响了中药的治疗效果,五是影响了中医人才的培养.因此应扼制"中医西化"趋势,发挥中医独特的功能,不能将两者生搬硬套地揉和在一起.     

干化学和湿化学方法测定尿蛋白结果的比较

目的探讨干化学与湿化学不同方法测定尿蛋白（UPRO）的差异。方法选用强生干化学仪器的干化学法和日立7170A仪器连苯三酚红显色湿化学法测定尿蛋白,同时检测53份标本,进行相关性比较,结果采用t检验、相对偏差、回归分析．进行统计分析。结果湿化学结果与干化学结果相比明显偏低：低值、中值和高值分别偏低22．8％、39．7％和26．2％。t值分别为3．452、6．352、6．956,P〈0．01,差别有极显著意义。其回归曲线：y=0．7936x-64．224,对b（总体斜率）与a（总体截距）的检验,tb=5．397、8．502、5．741、5．520,ta=2．502、1．944、1．259、0．818;两种方法学测定UPRO结果的系统误差属临床不可接受水平。结论两种方法的测试结果有显著性差异,有条件的实验室应使用千化学方法定量检测尿蛋白。     

有效利用医保政策积极推进药品零差率改革

结合工作实践,从引入医保、紧贴医保、调整社区医疗卫生机构等3方面,总结了天津市南开区卫生局在推行、落实及执行药品差价改革中的措施。并指出,在推进药品差价改革中,社区医院义不容辞;医保资金是健全补偿机制的重要方面;调整好结构是推进药品差价改革的主攻方向。     

鼻咽癌调强放疗国内外委员会推荐剂量差异性分析

目的 分析ICRU 83号报告与中国鼻咽癌临床分期工作委员会推荐的鼻咽癌调强放疗处方剂量要求的差异性。方法 回顾分析2010-2012年间治疗的84例鼻咽癌调强放疗计划的剂量体积直方图,分别记录原发灶计划大体肿瘤体积(PGTV_nx)和计划高危临床靶体积-1(PCTV₁)的体积和百分x体积接受的剂量(D_x),计算上述读取内容的平均值、标准差、中位数、最小值、最大值、变异系数,以及PTVnx和PCTV₁的均匀性指数及D₉₅和D₅₀之间偏差。分组结果比较采用成组t检验。结果 PGTV_nx和PCTV₁的均匀性指数分别为0.118±0.045和0.272±0.037,PGTV_nx靶区体积越大,T分期越晚,HI越差。PGTV_nx和PCTV₁的D₉₅均<;D₅₀,平均偏差分别为－5.15%和－10.97%;实际差值分别为(382±180) cGy (P=0.000)和(41±140) cGy (P=0.000)。结论D₅₀作为ICRU 83号报告推荐的计划靶体积处方剂量,结合D₉₈和D₂能更准确评估调强放疗计划。如果用D₅₀替代D₉₅作为处方剂量,则PGTV_nx和PCTV₁需分别增加5%和11%剂量才能达到相似的预期肿瘤局部控制率。