BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.

背景与目标： ：结构-活性关系（SAR）研究主要在N1-芳基磺酰基-N2- [1-（1-（萘基）乙基]-反式-1,2-二氨基环己烷的N1位置进行，钙敏感受体（CaSR）。该系列中活性最高的化合物是4-（三氟甲氧基）苯磺酰基衍生物7e，在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯（[3H] IP）积累方面，其IC50为5.4 /-0.5 microM。表达CaSR的卵巢（CHO）细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍（7m，IC50 = 0.9 /-0.2 microM）。在合成的羧酰胺中，活性最高的化合物之一是4-氯苯基羧酰胺（1S，2S，1'R）-7n（Calhex 231，IC50 = 0.33 /-0.02 microM）。 （1S，2S，1'R）-7n的绝对构型是由化合物7d的一种非对映异构体的X射线晶体学研究得出的。 （1S，2S，1'R）异构体的立体化学偏好可以根据CaSR钙解结合口袋的三维模型来合理化。除去C-1'甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e，7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS:There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS:These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.

背景与目标： 背景与目的：我们检验了钙敏感受体（CASR）中的单核苷酸多态性（SNP）改变对拟钙剂西那卡塞的反应的假说。
设计，地点，参与者和测量：我们在Cinacalcet HCl降低心血管事件治疗评估（EVOLVE）试验中分析了DNA样品，该试验是在常规护理的背景下将cinacalcet与安慰剂进行比较的随机试验。在3883名随机分组的患者中，有1919名（49％）同意收集DNA，并对来自1852名参与者的样本进行了18种CASR多态性的基因分型。欧洲血统（EA； n = 1067）和非洲血统（AfAn； n = 405）分别进行了评估。测试了CASR中的SNP与基线时矿物质代谢的生化指标，从基线到20周的变化百分数以及临床骨折风险为因变量的相关性。
结果：在EA组中，CASR单核苷酸多态性与基线血清甲状旁腺激素和骨碱性磷酸酶升高之间存在适度的相关性，主要与次要等位基因相关（均P≤0.03），而在AfAn样品中则没有。相反，基线血清钙和FGF23降低与CASR SNPs（P = 0.04）之间存在适度的联系，主要与AfAn中的次要等位基因有关，而与EA样品中无关。在EA人群中，两个SNP的次要等位基因与甲状旁腺激素从基线降低到20周的百分比降低有关（P <0.04），而西那卡塞不变。在EA和AfAn中，相同的SNP（rs9740）与西那卡塞治疗引起的钙降低有关（EA和AfAnP≤0.03）。高连锁不平衡中的三个SNP与EA样品中的西那卡塞特治疗减弱的临床骨折风险较高相关（P <0.04）。
结论：这些适度的关联性如果得到验证，则可以解释EA和AfAn人群中CKD矿物骨骼疾病的差异，以及对拟钙剂的不同生化反应。

BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  

背景与目标： 背景：心脏衰竭，高血压，年龄，糖尿病，中风[加倍]（CHADS（2））评分是对血栓栓塞患者进行风险分层的有用方案，但有关其对抗心律不齐药物（AAD）评估的有用性的信息很少） 治疗。
方法与结果：这项研究纳入459例阵发性房颤（AF）患者（309名男性，平均年龄66±12岁，平均随访50±35个月），并根据CHADS（2）评分分析了其预防性疗效。 （1）得分为0的组在1、6、12和24个月无房颤复发的生存率分别为89％，74％，63％和47％（n = 152）；得分1组（n = 158）为92％，68％，59％和48％；得分2组分别为86％，64％，56％和46％（n = 84）；得分3组（n = 43）分别为81％，65％，51％和35％； ≥4分组（n = 22）分别为68％，50％，36％和18％（P <0.05； 0分，1分或2分与≥4分组比较）。 （2）在0级评分组中，在12、36、60和90个月无进展为慢性房颤的生存率分别为95％，93％，91％和89％；得分1组分别为97％，91％，89％和88％；得分2组分别为96％，93％，88％和83％；分数3组的比例分别为91％，74％，67％和60％； ≥4分组分别为91％，82％，68％和55％（P <0.01； 0分，1分或2分与≥4分组比较）。 （3）在针对潜在混杂变量进行调整的多因素logistic回归分析中，CHADS（2）评分与房颤复发相关（几率[OR] 1.45、95％置信区间[CI] 1.16-1.81，P <0.001）和进展到AAD治疗期间的慢性房颤（OR 1.64，95％CI 1.04-2.69，P <0.001）。
结论：使用节律控制策略时，CHADS（2）评分是预测阵发性房颤患者AAD治疗结果的有用方案。

BACKGROUND & AIMS: BACKGROUND & AIMS:Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. METHODS:Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. RESULTS:Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). CONCLUSIONS:NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.

背景与目标： 背景与目的：某些慢性乙型肝炎病毒（HBV）感染患者会发展为肝细胞癌（HCC）。然而，尚不清楚核苷酸（t）ide类似物（NA）治疗对肝癌进展的长期影响。
方法：因此，我们使用倾向分析将接受NA治疗的慢性乙型肝炎患者与未接受NA治疗的慢性乙型肝炎患者进行比较。
结果：在1998年至2008年之间的785例连续HBV携带者中，通过资格标准和倾向评分匹配选择了接受NA治疗的117例患者和未接受NA治疗的117例患者。分析了与肝癌发展相关的因素。在随访期间，234例患者中有57例发生了HCC（24.4％）。由Cox比例风险模型确定的与HCC发生率显着相关的因素包括较高的年龄（风险比，4.36 [95％置信区间，1.33-14.29]，p = 0.015），NA治疗（0.28 [0.13-0.62]） ，p = 0.002），基础核心启动子（BCP）突变（12.74 [1.74-93.11]，p = 0.012），高HBV核心相关抗原（HBcrAg）（2.77 [1.07-7.17]，p = 0.036）和高γ-谷氨酰转肽酶水平（2.76 [1.49-5.12]，p = 0.001）。
结论：与未治疗的对照组相比，NA治疗降低了HCC的风险。血清HBcrAg和BCP突变的较高水平与肝癌进展相关，而与NA治疗无关。

BACKGROUND & AIMS: :This prospective study assesses the impact of fat and calcium intake on the risk of developing cancer in each large-bowel subsite. The study population is a cohort of Hawaii Japanese men who experience high rates of colon cancer, especially of the sigmoid segment. Total calcium intake is not related to the risk of colon cancer, and separation of calcium into dairy and nondairy sources does not alter the result. There is, however, a significant, monotonic increase in sigmoid colon cancer risk with decreasing total calcium intake. Similar trends are shown for both dairy and nondairy calcium. Dietary calcium is not consumed in large quantities among the Hawaii Japanese, partly because of their limited consumption of milk due to lactose intolerance. If calcium plays a protective role against sigmoid colon cancer, this effect is unlikely to be related to fat intake. Sigmoid colon cancer subjects had lower intakes of fat than other cohort men, and a statistical test for the interaction effect of total calcium and fat intake on colon cancer risk was statistically insignificant (P = 0.2).

背景与目标： ：这项前瞻性研究评估了每个大肠亚部位中脂肪和钙的摄入对罹患癌症风险的影响。该研究人群是夏威夷日本男性的队列，他们的结肠癌特别是乙状结肠癌的发生率很高。钙的总摄入量与结肠癌的风险无关，将钙分为乳品和非乳品来源也不会改变结果。但是，随着总钙摄入量的减少，乙状结肠癌的风险显着单调增加。乳品钙和非乳品钙也显示出相似的趋势。在夏威夷日本人中，饮食中的钙摄入量不大，部分原因是由于乳糖不耐症，牛奶摄入量有限。如果钙对乙状结肠癌起保护作用，则这种作用不太可能与脂肪摄入有关。乙状结肠癌受试者的脂肪摄入量低于其他队列男性，并且总钙和脂肪摄入对结肠癌风险的相互作用的统计学检验在统计学上无统计学意义（P = 0.2）。

BACKGROUND & AIMS: AIMS:We sought to evaluate bleeding complications and periprocedural outcomes of the radial approach (RA) as compared to the femoral approach (FA) during percutaneous coronary intervention (PCI) in "real-world" patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS:The study group consisted of 22,812 consecutive patients with STEMI treated with PCI and stent implantation between January 2014 and June 2015 in 151 tertiary invasive cardiology centres in Poland (the ORPKI Polish National Registry). Patients treated using the RA and FA were compared using a propensity score analysis to avoid possible selection bias. The analysis was carried out in an "as-treated" manner. The FA was used in 9,334 (40.9%) and the RA in 13,478 (59.1%) patients. After propensity score matching, a higher total amount of contrast (191.8±8.0 vs. 174.8±68.8 ml; p=0.001) and lower radiation doses (1,279.5±1,346.3 vs. 1,182.6±887 mGy; p=0.02) were reported in FA. More access-site-related bleeding complications after both angiography (0.17% vs. 0.02%; p=0.004) and PCI (0.23% vs. 0.09%; p=0.049) were reported in the FA group. Periprocedural death (1.94% vs. 0.93%; p=0.001) was more common after PCI performed with the FA. CONCLUSIONS:The radial approach was associated with a lower incidence of periprocedural death in STEMI patients as well as a significant reduction of bleeding complications at the access site.

背景与目标： 目的：我们试图评估“现实” ST段抬高型心肌梗死（STEMI）患者在经皮冠状动脉介入治疗（PCI）期间与股动脉入路（FA）相比，radial动脉入路（RA）的出血并发症和围手术期结局）。
方法与结果：该研究小组于2014年1月至2015年6月在波兰的151个三级侵入性心脏病学中心（ORPKI波兰国家注册中心）对22,812例连续的STEMI患者进行了PCI和支架植入治疗。使用倾向评分分析比较使用RA和FA治疗的患者，以避免可能的选择偏倚。该分析以“处理后”的方式进行。 FA用于9,334（40.9％），RA用于13,478（59.1％）患者。倾向得分匹配后，FA中的造影剂总量较高（191.8±8.0 vs. 174.8±68.8 ml； p = 0.001）和较低的放射剂量（1,279.5±1,346.3 vs.1,182.6±887 mGy； p = 0.02）。在FA组中，血管造影后（0.17％vs. 0.02％; p = 0.004）和PCI（0.23％vs. 0.09％; p = 0.049）出现更多的与出入部位相关的出血并发症。在FA进行PCI后，围手术期死亡（1.94％vs. 0.93％; p = 0.001）更为常见。
结论：radial动脉入路与STEMI患者围手术期死亡的发生率较低，以及进入部位出血并发症的发生率显着降低有关。

BACKGROUND & AIMS: :This laboratory has previously demonstrated that shortening of the cell body of a heterotrich ciliate, Blepharisma japonicum, could be induced as a step-down photophobic response. Here, we examined the structure and contractility of the myonemes in detergent-extracted cell models and in isolated cortical fragments. Ultrastructural observation showed that the myoneme was connected to the basal ends of the posterior kinetosomes and constructed a systematic network as a whole. Shortening of the cell model was induced by > 10(-4) M Ca(2+), while the rounded cell model did not re-elongate even when it was washed in a calcium-free solution either with or without addition of ATP. Fluffy fibrils, which were tentatively identified as aggregated bundles of the myonemes, were isolated with the kinetosomal complex and showed calcium-dependent and ATP-independent contraction. The minimum concentration of Ca(2+) required for inducing contraction was at the level of 10(-6) M. These results suggest that the cell body shortening in Blepharisma is caused by the Ca(2+)-dependent contraction of the myonemal network.

背景与目标： ：该实验室先前已证明杂多纤毛纤毛虫（Blepharisma japonicum）的细胞体缩短可以作为逐步降低的憎光反应而被诱导。在这里，我们检查了去污剂提取的细胞模型和分离的皮层碎片中的模因的结构和收缩性。超微结构观察表明，肌球蛋白与后运动体的基端相连，并构成了一个整体的系统网络。细胞模型的缩短是由> 10（-4）M Ca（2）引起的，而圆形细胞模型即使在无钙溶液中添加或不添加ATP洗涤也不会重新伸长。蓬松的原纤维被初步确定为肌源蛋白的聚集束，与运动体复合物分离并显示出钙依赖性和ATP依赖性收缩。诱导收缩所需的Ca（2）的最低浓度为10（-6）M。这些结果表明，血吸虫病中的细胞体缩短是由肌层网络的Ca（2）依赖性收缩引起的。

BACKGROUND & AIMS: AIMS:It is not known if successful catheter ablation for atrial fibrillation (AF) improves the patient's long-term cardiovascular outcomes. This study investigated the long-term outcomes and mortality of AF patients at high risk who received antiarrhythmic medication and catheter ablation. METHODS AND RESULTS:The propensity scores for AF were calculated for each patient and were used to assemble a cohort of 174 AF patients with ablation who were compared with an equal number of AF patients without ablation. Composite cardiovascular end points (major adverse cardiovascular event, MACE), including mortality and vascular events in the medically treated patients representing the control group (group 1), were compared with those in the ablation-treated patients (group 2). The rates of the total mortality (2.95% vs. 0.74% per year; P < 0.01), cardiovascular death (1.77% vs. 0% per year; P = 0.001), and ischaemic stroke/transient ischaemic attack (2.21% vs. 0.59% per year; P = 0.02) were higher in group 1 than group 2, respectively. A multivariate Cox regression analysis of the MACE scores showed that a higher CHA2DS2-VASc score [hazard ratio (HR) = 1.309 per increment of score, 95% confidence interval (CI) = 1.06-1.617; P = 0.01] and the performance of the ablation procedure (HR = 0.225, CI = 0.076-0.671; P = 0.007) were independent predictors of a MACE. In patients who received catheter ablation, recurrence of any atrial arrhythmia was a predictor of vascular events and total mortality (P < 0.05). CONCLUSION:In AF patients with CHA2DS2-VASc score ≥1, catheter ablation of AF reduced the risk of the total/cardiovascular mortality and total vascular events. Atrial fibrillation recurrence predicts long-term cardiovascular outcomes, as well as the CHA2DS2-VASc score.

背景与目标： 目的：尚不清楚成功的心房纤颤（AF）导管消融术能否改善患者的长期心血管结局。这项研究调查了接受抗心律不齐药物和导管消融治疗的高危房颤患者的长期预后和死亡率。
方法和结果：计算每位患者的房颤倾向评分，并用其汇总了174例房颤消融的房颤患者，与无消融的房颤患者进行比较。将复合心血管终点（主要不良心血管事件，MACE），包括代表对照组（第1组）的药物治疗患者的死亡率和血管事件，与消融治疗患者（第2组）进行了比较。总死亡率（每年2.95％比0.74％； P <0.01），心血管死亡（每年1.77％比0％； P = 0.001）和缺血性中风/短暂性脑缺血发作的发生率（2.21％比2％）。每年0.59％； P = 0.02）在第1组中分别高于第2组。 MACE分数的多变量Cox回归分析显示，CHA2DS2-VASc分数较高[危险比（HR）= 1.309 /分数递增，95％置信区间（CI）= 1.06-1.617； P = 0.01]和消融程序的执行情况（HR = 0.225，CI = 0.076-0.671； P = 0.007）是MACE的独立预测因子。在接受导管消融的患者中，任何心律失常的复发都是血管事件和总死亡率的预测指标（P <0.05）。
结论：在CHA2DS2-VASc评分≥1的房颤患者中，导管消融房颤可降低总/心血管死亡和总血管事件的风险。心房颤动的复发可预测长期的心血管结局，以及CHA2DS2-VASc评分。

BACKGROUND & AIMS: :Purinergic stimulation of human airway epithelia results in a prolonged increase in ciliary beat frequency that depends on calcium-mediated cAMP production [Lieb, T., Wijkstrom Frei, C., Frohock, J.I., Bookman, R.J. and Salathe, M. (2002) Prolonged increase in ciliary beat frequency after short-term purinergic stimulation in human airway epithelial cells. J. Physiol. (Lond.) 538, 633-646]. Here, fully differentiated human airway epithelial cells in culture are shown to express calcium-stimulated transmembrane adenylyl cyclase (tmAC) isoforms (types 1, 3, and 8) by reverse transcription polymerase chain reaction. Immunohistochemistry of tracheal sections and fully differentiated airway epithelial cell cultures revealed polarized expression of these tmACs, with types 1 and 8 localized to the apical membrane and thus at the position required for ciliary regulation. Real-time, ciliated-cell specific cAMP production by tmACs upon apical, purinergic stimulation with UTP was confirmed using fluorescent energy resonance transfer between fluorescently tagged PKA subunits.

背景与目标： ：对人气道上皮的脓毒症刺激导致纤毛搏动频率的延长增加，这取决于钙介导的cAMP的产生[Lieb，T.，Wijkstrom Frei，C.，Frohock，J.I.，Bookman，R.J.和Salathe，M.（2002）短期嘌呤能刺激人气道上皮细胞后，纤毛搏动频率延长。 J.生理学。 （Lond。）538，633-646]。在这里，在培养物中完全分化的人气道上皮细胞显示出通过逆转录聚合酶链反应表达钙刺激的跨膜腺苷酸环化酶（tmAC）同工型（1、3和8型）。气管切片和完全分化的气道上皮细胞培养物的免疫组织化学揭示了这些tmAC的极化表达，其中1型和8型位于心尖膜，因此位于睫状调节所需的位置。使用荧光标记的PKA亚基之间的荧光能量共振转移，可以确认tmAC在使用UTP进行根尖，嘌呤能刺激后实时产生纤毛细胞，并产生特定的cAMP。

BACKGROUND & AIMS: :The Ca2+-triggered luciferin-binding protein of Renilla reniformis (RLBP) is a non-covalent complex of apoprotein (apoRLBP) and coelenterazine (luciferin). The gene encoding apoRLBP with 552 nucleotides has been synthesized by assembly PCR methods with synthetic oligonucleotides, and the histidine-tagged apoRLBP expressed as a soluble form in the periplasmic space of Escherichia coli cells. The apoRLBP was purified by nickel chelate chromatography and the procedure yielded 18.2mg of recombinant apoRLBP from 80 ml of cultured cells with purity greater than 95%. The purified apoRLBP was converted to RLBP by incubation with coelenterazine in the presence of dithiothreitol and the purity of recombinant RLBP was estimated to be over 95% by comparison with the absorption spectral data of native RLBP. When RLBP mixed with Ca2+, coelenterazine was dissociated from RLBP and was utilized for the luminescence reaction of Renilla luciferase. Also semi-synthetic RLBPs with h-, e-, and Bis-coelenterazines were prepared and characterized.

背景与目标： 肾性肾病（RLBP）的Ca2触发的萤光素结合蛋白是载脂蛋白（apoRLBP）和腔肠素（萤光素）的非共价复合物。已经用合成的寡核苷酸通过组装PCR方法合成了具有552个核苷酸的编码apoRLBP的基因，并且组氨酸标记的apoRLBP在大肠杆菌细胞的周质空间中以可溶形式表达。通过镍螯合层析纯化apoRLBP，该程序从80ml培养的细胞中产生18.2mg重组apoRLBP，纯度大于95％。通过在二硫苏糖醇存在下与腔肠素一起孵育，将纯化的apoRLBP转化为RLBP，与天然RLBP的吸收光谱数据相比，重组RLBP的纯度估计超过95％。当RLBP与Ca2混合时，腔肠素与RLBP分离，并用于海肾荧光素酶的发光反应。还制备并表征了具有h-，e-和Bis-腔肠素的半合成RLBP。

BACKGROUND & AIMS: :By interrupting the integrity of the systemic and renal renin-angiotensin system, angiotensin-converting enzyme inhibitors have been shown, experimentally, to preferentially reduce postglomerular capillary arteriolar resistance, to reduce glomerular capillary pressure, and to increase the ultrafiltration coefficient. Under normal physiological conditions, angiotensin-converting enzyme inhibitors have little effect on glomerular filtration rate; however, they increase effective renal plasma flow at renal perfusion pressures within the normal autoregulatory range and renal vascular resistance is decreased. In contrast, calcium antagonists have been shown, experimentally, to preferentially reduce preglomerular capillary arteriolar resistance. Their effects on angiotensin II and postglomerular capillary arteriolar resistance (hence, glomerular capillary pressure and the ultrafiltration coefficient) are controversial. Under normal physiological conditions, calcium antagonists increase both glomerular filtration rate and effective renal plasma flow at renal perfusion pressures within the normal autoregulatory range and renal vascular resistance is decreased. In patients with essential hypertension, studies have demonstrated that angiotensin-converting enzyme inhibitors (as predicted) sustain glomerular filtration rate, increase effective renal plasma flow, and decrease renal vascular resistance. However, essential hypertensive patients with impaired glomerular filtration rate may demonstrate marked improvement in both glomerular filtration rate and effective renal plasma flow. Calcium antagonists (as predicted) may increase both glomerular filtration rate and effective renal plasma flow (at high renal perfusion pressures) and may decrease renal vascular resistance. Calcium antagonists may also improve both glomerular filtration rate and effective renal plasma flow in patients with impaired glomerular filtration rate. Long-term clinical trials comparing the renal effects of angiotensin-converting enzyme inhibitors with those of calcium antagonists in essential hypertensive patients have not been reported. It remains to be determined if the potentially different effects of these two classes of antihypertensive drugs on the renal microcirculation do or do not translate into different renal protective advantages to patients at risk for the development and/or progression of hypertensive nephrosclerosis.

背景与目标： 通过实验证明，通过破坏全身和肾脏的肾素-血管紧张素系统的完整性，血管紧张素转化酶抑制剂可优先降低肾小球毛细血管小动脉阻力，降低肾小球毛细血管压力，并增加超滤系数。在正常的生理条件下，血管紧张素转化酶抑制剂对肾小球滤过率的影响很小。但是，它们在正常自我调节范围内的肾脏灌注压力下会增加有效的肾脏血浆流量，并且肾血管阻力降低。相反，实验表明钙拮抗剂可优先降低肾小球前毛细血管的阻力。它们对血管紧张素II和肾小球后毛细血管小动脉阻力（因此，肾小球毛细血管压力和超滤系数）的影响是有争议的。在正常生理条件下，钙拮抗剂在正常自动调节范围内的肾脏灌注压力下会增加肾小球滤过率和有效肾血浆流量，并且肾血管阻力降低。在原发性高血压患者中，研究表明，血管紧张素转化酶抑制剂（如预期的那样）可维持肾小球滤过率，增加有效肾血浆流量并降低肾血管阻力。然而，肾小球滤过率受损的原发性高血压患者可能表现出肾小球滤过率和有效肾血浆流量的明显改善。钙拮抗剂（如预期的那样）可能会增加肾小球滤过率和有效的肾血浆流量（在高肾灌注压力下），并且可能会降低肾血管阻力。对于肾小球滤过率受损的患者，钙拮抗剂还可以改善肾小球滤过率和有效的肾血浆流量。尚未有长期临床试验比较血管紧张素转化酶抑制剂与钙拮抗剂在基本高血压患者中的肾脏作用。这两类降压药对肾脏微循环的潜在不同作用是否会转化为对患有高血压肾硬化发展和/或进展风险的患者的不同肾脏保护优势，尚待确定。

BACKGROUND & AIMS: In cultured rat pituitary gonadotrophs, GnRH-induced oscillations in cytosolic calcium concentration ([Ca2+]i) are associated with periodic membrane hyperpolarization. The hyperpolarizing waves are secondary to the activation of apamin-sensitive Ca2+-activated K+ channels that account for a single class of 125I-apamin binding sites present in these cells. In a substantial fraction of gonadotrophs, however, we observed a Ca2+-controlled oscillatory current that was resistant to apamin, even at concentrations five orders of magnitude higher than the dissociation constant (Kd) observed in the binding experiments. With the K+ in the pipette, the apamin-resistant current showed a reversal potential of -42 mV, nearly 40 mV more positive than that of the apamin-sensitive current. With Cs+ in place of K+ in the pipette solution, both the size of the apamin-insensitive current and its reversal potential remained unchanged. Ion substitution studies further revealed that the reversal potential was independent of Cl-. In contrast, an 11 mV hyperpolarizing shift in the reversal potential occurred when extracellular Na+ was reduced to 80 mM. In cells expressing apamin-resistant conductances, addition of apamin evoked a marked increase in the duration of the action potentials and reduction in the frequency of spontaneous spiking. In the presence of GnRH, gonadotrophs exhibit the typical burst pattern of electrical activity. Further exposure of the cells to apamin depolarized the membrane from a silent phase bursting level of about -80 mV to a new level of about -40 mV. These observations indicate that, in addition to apamin-sensitive current, a subpopulation of pituitary gonadotrophs also expresses a cationic component of the Ca2+-activated membrane conductance that has the potential to remodulate spontaneous and agonist-induced electrical activity.

背景与目标： 在培养的大鼠垂体促性腺激素中，GnRH诱导的胞浆钙浓度（[Ca2] i）振荡与周期性膜超极化有关。超极化波是对罂粟碱敏感的Ca2激活的K通道的激活的继发子，这些通道解释了这些细胞中存在的一类125I-apapamin结合位点。然而，在相当一部分的促性腺激素中，即使在比结合实验中观察到的解离常数（Kd）高5个数量级的浓度下，我们也观察到了对apamin有抗性的Ca2控制的振荡电流。当移液器中的K值时，抗木瓜蛋白酶的电流显示出-42 mV的反向电位，比对木瓜蛋白酶敏感的电流的正电位高近40 mV。在移液器中用Cs代替K时，对罂粟碱不敏感电流的大小及其逆转电位均保持不变。离子取代研究进一步表明，逆转电位独立于Cl-。相反，当细胞外Na降至80 mM时，逆转电位发生11 mV超极化变化。在表达抗谷氨酰胺的电导的细胞中，添加谷氨酰胺可引起动作电位持续时间的显着增加和自发加标频率的降低。在存在GnRH的情况下，促性腺激素表现出典型的电活动猝发模式。将细胞进一步暴露于罂粟碱可使膜从约-80 mV的无声相爆发水平去极化至约-40 mV的新水平。这些观察结果表明，除了对罂粟碱敏感的电流外，垂体促性腺激素亚群还表达了Ca2激活的膜电导的阳离子成分，该成分可能会重新调节自发和激动剂诱导的电活动。

BACKGROUND & AIMS: Histochemical, immunohistochemical, and biochemical evidence is reported showing that the ink gland of the cuttlefish Sepia officinalis contains a calcium-dependent isoform of nitric oxide synthase as well as an NMDA R1 receptor subunit localized for the most part in the immature inner cells of the epithelial layer of the gland. These results may be taken to implicate a hitherto unrecognized regulatory role of the glutamate-nitric oxide pathway in the maturation and metabolic activity of melanin-producing cells in the cephalopod defense system.

背景与目标： 据组织化学，免疫组化和生物化学证据显示，墨鱼乌贼墨the的墨腺含有一氧化氮合酶的钙依赖性同种型，以及大部分位于上皮未成熟内细胞中的NMDA R1受体亚基。腺体层。这些结果可能暗示了迄今为止尚未认识到的谷氨酸一氧化氮途径在头足防御系统中黑色素生成细胞的成熟和代谢活性中的作用。

BACKGROUND & AIMS: :Bacteremia is a life-threatening condition that is associated with substantial healthcare costs. Escherichia coli and Klebsiella pneumoniae are the leading causes of community-onset gram-negative bacteremia. However, a comprehensive comparison between these pathogens involved in bacteremia episodes has yet to be reported.In this retrospective cohort study, adults with community-onset monomicrobial bacteremia caused by E coli or K pneumoniae were recruited in the emergency department of a medical center during a 6-year period, and the clinical variables were collected retrospectively from medical records. The complicated abscess occurrence was determined through imaging studies, according to the opinion of an infectious disease consultant. According to the independent predictors of 28-day mortality identified through multivariate regression analyses, patients in the E coli group were propensity score matched (PSM) in a 1:1 ratio to those in the K pneumoniae group.A total of 274 and 823 adults with K pneumoniae and E coli bacteremia were included in the present study. The K pneumoniae group had more patients with fatal comorbidities (McCabe classification), critical illness (Pitt bacteremia score ≥ 4) at bacteremia onset, and initial syndrome (e.g., severe sepsis and septic shock) as well as a higher crude mortality rate than did the E coli group. After appropriate matching, no significant differences were observed in the critical illness at bacteremia onset, initial syndrome, major comorbidities, and comorbidity severity of the 2 groups (E coli, n = 242; K pneumoniae, n = 242). Furthermore, despite similar 14- and 28-day crude mortality rates between the 2 PSM groups, more frequent abscess occurrences and a longer length of hospitalization were observed in the K pneumoniae group than in the E coli group.Conclusively, numerous clinical features at initial presentations varied between the E coli and K pneumoniae groups. Despite conducting a PSM analysis to control the differences in the baseline characteristics, a longer length of hospitalization and more frequent abscess occurrences were observed in the K pneumoniae group than in the E coli group.

背景与目标： 细菌血症是一种威胁生命的疾病，与大量医疗费用相关。大肠杆菌和肺炎克雷伯菌是引起社区发作的革兰氏阴性菌血症的主要原因。然而，尚未有关于这些与菌血症发作有关的病原体的全面比较的报道。在这项回顾性队列研究中，在大流行期间，在医疗中心的急诊室招募了患有由大肠杆菌或肺炎克雷伯菌引起的社区性传染性单菌菌血症的成年人。为期6年，并从病历中回顾性收集临床变量。根据传染病顾问的意见，通过影像学检查确定了复杂的脓肿的发生。根据多元回归分析确定的28天死亡率的独立预测因子，大肠杆菌组患者与肺炎克雷伯氏菌组患者的倾向得分匹配（PSM）为1：1，共有274和823名成人肺炎克雷伯氏菌和大肠杆菌菌血症包括在本研究中。肺炎克雷伯氏菌组的致命合并症（McCabe分类），危重病（Pitt菌血症评分≥4），菌血症发作和初始综合征（例如严重的败血症和败血性休克）以及较高的粗死亡率的患者更多。大肠埃希氏菌群。经过适当的匹配后，两组的菌血症发病率，初始综合征，主要合并症和合并症严重程度在危重疾病中均未观察到显着差异（大肠杆菌，n = 242；肺炎克雷伯菌，n = 242）。此外，尽管2个PSM组之间的14天和28天的粗死亡率相似，但肺炎克雷伯氏菌组的脓肿发生率和住院时间更长，而E.coli组则更为明显。大肠杆菌和肺炎克雷伯氏菌组之间的表现有所不同。尽管进行了PSM分析以控制基线特征的差异，但肺炎克雷伯氏菌组的住院时间却比大肠杆菌组更长，而且脓肿的发生频率更高。

BACKGROUND & AIMS: :Calcium oxalate monohydrate (COM) stones are often resistant to breakage using shock wave (SW) lithotripsy. It would be useful to identify by computed tomography (CT) those COM stones that are susceptible to SW's. For this study, 47 COM stones (4-10 mm in diameter) were scanned with micro CT to verify composition and also for assessment of heterogeneity (presence of pronounced lobulation, voids, or apatite inclusions) by blinded observers. Stones were then placed in water and scanned using 64-channel helical CT. As with micro CT, heterogeneity was assessed by blinded observers, using high-bone viewing windows. Then stones were broken in a lithotripter (Dornier Doli-50) over 2 mm mesh, and SW's counted. Results showed that classification of stones using micro CT was highly repeatable among observers (kappa = 0.81), and also predictive of stone fragility. Stones graded as homogeneous required 1,874 +/- 821 SW/g for comminution, while stones with visible structure required half as many SW/g, 912 +/- 678. Similarly, when stones were graded by appearance on helical CT, classification was repeatable (kappa = 0.40), and homogeneous stones required more SW's for comminution than did heterogeneous stones (1,702 +/- 993 SW/g, compared to 907 +/- 773). Stone fragility normalized to stone size did not correlate with Hounsfield units (P = 0.85). In conclusion, COM stones of homogeneous structure require almost twice as many SW's to comminute than stones of similar mineral composition that exhibit internal structural features that are visible by CT. This suggests that stone fragility in patients could be predicted using pre-treatment CT imaging. The findings also show that Hounsfield unit values of COM stones did not correlate with stone fragility. Thus, it is stone morphology, rather than X-ray attenuation, which correlates with fragility to SW's in this common stone type.

背景与目标： ：一水草酸钙（COM）结石通常可抵抗冲击波（SW）碎石术的破坏。通过计算机断层扫描（CT）识别那些易受SW影响的COM结石将是有用的。在本研究中，由盲人观察者用微型CT扫描了47颗COM结石（直径4-10毫米），以验证成分，并评估异质性（存在明显的叶状体，空隙或磷灰石夹杂物）。然后将石头放入水中，并使用64通道螺旋CT进行扫描。与微型CT一样，使用高骨观察窗由不知情的观察者评估异质性。然后用碎石机（Dornier Doli-50）在2毫米的筛网上将石头打碎，并计算SW的数量。结果表明，使用显微CT对结石进行分类在观察者中具有很高的可重复性（kappa = 0.81），并且可以预测结石的脆性。分级为均质的宝石需要粉碎1,874 /-821 SW / g，而具有可见结构的宝石则需要SW / g的一半，即912 /-678。类似地，当按螺旋CT的外观对宝石进行分级时，分类是可重复的（kappa = 0.40），并且均质的石头比不均质的石头需要更多的SW（1,702 /-993 SW / g，而907 /-773）。归结为石材尺寸的石材易碎性与Hounsfield单位不相关（P = 0.85）。综上所述，均匀结构的COM碎石所需的SW几乎是矿物成分相似，具有CT可见的内部结构特征的SW的两倍。这表明可以使用治疗前的CT成像预测患者的结石脆性。研究结果还表明，COM结石的Hounsfield单位值与结石的脆性无关。因此，这是石头的形态，而不是X射线衰减，这与这种普通石头类型中SW的脆性有关。