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。

BACKGROUND & AIMS: :A series of pyrrolopyridinone derivatives as specific inhibitors towards the cell division cycle 7 (Cdc7) was taken into account, and the efficacy of these compounds was analyzed by QSAR and docking approaches to gain deeper insights into the interaction mechanism and ligands selectivity for Cdc7. By regression analysis the prediction models based on Grid score and Zou-GB/SA score were found, respectively with good quality of fits (r(2)=0.748, 0.951; r(cv)(2)=0.712, 0.839). The accuracy of the models was validated by test set and the deviation of the predicted values in validation set using Zou-GB/SA score was smaller than that using Grid score, suggesting that the model based on Zou-GB/SA score provides a more effective method for predicting potencies of Cdc7 inhibitors.

背景与目标： ：考虑到一系列吡咯并吡啶酮衍生物作为对细胞分裂周期7​​（Cdc7）的特异性抑制剂，并通过QSAR和对接方法分析了这些化合物的功效，以更深入地了解Cdc7的相互作用机理和配体选择性。通过回归分析，发现基于Grid得分和Zou-GB / SA得分的预测模型分别具有良好的拟合质量（r（2）= 0.748，0.951; r（cv）（2）= 0.712，0.839）。通过测试集验证了模型的准确性，使用Zou-GB / SA得分的验证集中预测值的偏差小于使用Grid得分的预测值的偏差，这表明基于Zou-GB / SA得分的模型提供了更大的准确性。预测Cdc7抑制剂效力的有效方法。

BACKGROUND & AIMS: BACKGROUND:Distance based unsupervised clustering of gene expression data is commonly used to identify heterogeneity in biologic samples. However, high noise levels in gene expression data and relatively high correlation between genes are often encountered, so traditional distances such as Euclidean distance may not be effective at discriminating the biological differences between samples. An alternative method to examine disease phenotypes is to use pre-defined biological pathways. These pathways have been shown to be perturbed in different ways in different subjects who have similar clinical features. We hypothesize that differences in the expressions of genes in a given pathway are more predictive of differences in biological differences compared to standard approaches and if integrated into clustering analysis will enhance the robustness and accuracy of the clustering method. To examine this hypothesis, we developed a novel computational method to assess the biological differences between samples using gene expression data by assuming that ontologically defined biological pathways in biologically similar samples have similar behavior. RESULTS:Pre-defined biological pathways were downloaded and genes in each pathway were used to cluster samples using the Gaussian mixture model. The clustering results across different pathways were then summarized to calculate the pathway-based distance score between samples. This method was applied to both simulated and real data sets and compared to the traditional Euclidean distance and another pathway-based clustering method, Pathifier. The results show that the pathway-based distance score performs significantly better than the Euclidean distance, especially when the heterogeneity is low and genes in the same pathways are correlated. Compared to Pathifier, we demonstrated that our approach achieves higher accuracy and robustness for small pathways. When the pathway size is large, by downsampling the pathways into smaller pathways, our approach was able to achieve comparable performance. CONCLUSIONS:We have developed a novel distance score that represents the biological differences between samples using gene expression data and pre-defined biological pathway information. Application of this distance score results in more accurate, robust, and biologically meaningful clustering results in both simulated data and real data when compared to traditional methods. It also has comparable or better performance compared to Pathifier.

背景与目标： 背景：基于距离的基因表达数据无监督聚类通常用于鉴定生物样品中的异质性。但是，经常会遇到基因表达数据中的高噪声水平以及基因之间相对较高的相关性，因此传统距离（例如欧几里得距离）可能无法有效区分样品之间的生物学差异。检查疾病表型的另一种方法是使用预定义的生物学途径。在具有相似临床特征的不同受试者中，这些途径已显示出受到不同方式的干扰。我们假设与标准方法相比，给定途径中基因表达的差异更能预测生物学差异的差异，并且如果将其整合到聚类分析中，则将增强聚类方法的鲁棒性和准确性。为了检验这一假设，我们通过假设生物学上相似的样本中的本体论定义的生物学途径具有相似的行为，开发了一种新的计算方法来使用基因表达数据评估样本之间的生物学差异。
结果：下载了预定的生物学途径，并使用高斯混合模型将每个途径中的基因用于对样品进行聚类。然后汇总跨不同途径的聚类结果，以计算样品之间基于途径的距离得分。将该方法应用于模拟和真实数据集，并与传统的欧几里得距离和另一种基于路径的聚类方法Pathifier进行了比较。结果表明，基于路径的距离得分表现明显优于欧几里得距离，尤其是当异质性较低且相同路径中的基因相互关联时。与Pathifier相比，我们证明了我们的方法可为小路径实现更高的准确性和鲁棒性。当路径较大时，通过将路径下采样为较小的路径，我们的方法能够实现可比的性能。
结论：我们已经开发了一种新颖的距离评分，该评分使用基因表达数据和预定义的生物途径信息来代表样品之间的生物学差异。与传统方法相比，此距离得分的应用可在模拟数据和真实数据中产生更准确，可靠且具有生物学意义的聚类结果。与Pathifier相比，它还具有可比或更好的性能。

BACKGROUND & AIMS: AIMS:To reduce sudden cardiac death, implantable cardioverter-defibrillators (ICDs) are indicated in patients with ischaemic and non-ischaemic dilated cardiomyopathy and a left ventricular ejection fraction (LVEF) ≤35%. Current guidelines do not recommend device therapy in patients with a life expectancy <1 year since benefit in these patients is low. In this study, we evaluated the incidence and predictors of early mortality (<1 year after implantation) in a consecutive primary prevention population. METHODS AND RESULTS:Analysis was performed on a prediction and validation cohort. The primary endpoint was all-cause mortality at 1 year. The prediction cohort comprised 861 prophylactic ICD recipients with ischaemic cardiomyopathy or dilated cardiomyopathy from the Academic Medical Center (Amsterdam) and Thorax Center Twente (Enschede). Detailed clinical data were collected. After multivariate analysis, a risk score was developed based on age ≥75 years, LVEF ≤ 20%, history of atrial fibrillation, and estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m(2). Using these predictors, a low (≤1 factor), intermediate (2 factors), and high (≥3 factors) risk group could be identified with 1-year mortality of, respectively, 3.4, 10.9, and 38.9% (P< 0.01). Afterwards, the risk score was validated in 706 primary prevention patients from the Erasmus Medical Center (Rotterdam). One-year mortality was, respectively, 2.5, 13.2, and 46.3% (all P< 0.01). CONCLUSION:A simple risk score based on age, LVEF, eGFR, and atrial fibrillation can identify patients at low, intermediate, and high risk for early mortality after ICD implantation. This may be helpful in the risk assessment of ICD candidates.

背景与目标： 目的：为了减少心脏猝死，在缺血性和非缺血性扩张型心肌病且左心室射血分数（LVEF）≤35％的患者中，建议使用植入式心脏复律除颤器（ICD）。目前的指南不建议对预期寿命<1年的患者进行器械治疗，因为这些患者的获益很低。在这项研究中，我们评估了连续的一级预防人群的发生率和早期死亡率（植入后<1年）的预测指标。
方法和结果：对预测和验证队列进行了分析。主要终点是1年时的全因死亡率。该预测队列包括来自学术医学中心（阿姆斯特丹）和特温特胸腔中心（恩斯赫德）的861名患有缺血性心肌病或扩张型心肌病的预防性ICD接受者。收集详细的临床数据。经过多变量分析后，根据年龄≥75岁，LVEF≤20％，房颤病史和估计的肾小球滤过率（eGFR）≤30mL / min / 1.73 m（2）得出风险评分。使用这些预测因子，可以确定低（≤1因子），中（2因子）和高（≥3因子）风险组，其一年死亡率分别为3.4％，10.9％和38.9％（P <0.01）。 ）。之后，在伊拉斯姆斯医学中心（鹿特丹）的706名一级预防患者中验证了风险评分。一年死亡率分别为2.5％，13.2％和46.3％（所有P <0.01）。
结论：基于年龄，LVEF，eGFR和心房颤动的简单风险评分可以确定ICD植入后早期死亡的低，中和高风险患者。这可能有助于ICD候选人的风险评估。

BACKGROUND & AIMS: :Hydrogel polymers have many applications in regenerative medicine. The aim of this study in dogs was to investigate bone regeneration in dehiscence-type peri-implant defects created surgically and treated with (i) biphasic calcium phosphate (BCP) granules alone; (ii) a composite putty hydroxypropyl methylcellulose (HPMC)/BCP (MBCP/putty); and (iii) a polymer crosslinked membrane of silanized-HPMC (Si-HPMC/BCP) compared with empty controls. At 3 months, new bone formation was significantly more important in defects filled with HPMC/BCP or Si-HPMC/BCP compared with spontaneous healing in control (P = 0.032 and P = 0.046 respectively) and more substantial compared with BCP alone. Furthermore, new bone formation in direct contact with the implant surface was observed in all three groups treated with BCP. The addition of HPMC to the BCP granules may have enhanced the initial stability of the material within the blood clot in these large and complex osseous defects. The Si-HPMC hydrogel may also act as an occlusive membrane covering the BCP, which could improve the stability of the granules in the defect area. However, the crosslinking time of the Si-HPMC is too long for easy handling and the mechanical properties remain to be improved. The composite MBCP/putty appears to be a valuable bone-graft material in complex defects in periodontology and implantology. These encouraging results should now be confirmed in clinical studies.

背景与目标： ：水凝胶聚合物在再生医学中有许多应用。在狗中进行这项研究的目的是研究通过外科手术造成的裂开型植入物周围缺损中的骨再生，其中： （ii）复合腻子羟丙基甲基纤维素（HPMC）/ BCP（MBCP / putty）； （iii）与空白对照相比，硅烷化的HPMC的聚合物交联膜（Si-HPMC / BCP）。在3个月时，与对照组的自发愈合相比，在充满HPMC / BCP或Si-HPMC / BCP的缺损中，新骨的形成更为重要（分别为P = 0.032和P = 0.046），并且与单独的BCP相比，新骨的形成更为重要。此外，在用BCP治疗的所有三组中均观察到与植入物表面直接接触的新骨形成。在这些大而复杂的骨缺损中，向BCP颗粒中添加HPMC可能会增强血凝块中材料的初始稳定性。 Si-HPMC水凝胶还可以充当覆盖BCP的闭塞膜，从而可以改善缺陷区域中颗粒的稳定性。然而，Si-HPMC的交联时间太长，难以处理，并且机械性能仍有待提高。 MBCP / putty复合材料似乎是牙周病学和植入术中复杂缺陷的有价值的骨移植材料。这些令人鼓舞的结果现在应该在临床研究中得到证实。