BACKGROUND & AIMS: :Although mean efficacy of multivalent pneumococcus vaccines has been intensively studied, variance in vaccine efficacy (VE) has been overlooked. Different net individual protection across settings can be driven by environmental conditions, local serotype and clonal composition, as well as by socio-demographic and genetic host factors. Understanding efficacy variation has implications for population-level effectiveness and other eco-evolutionary feedbacks. Here I show that realized VE can vary across epidemiological settings, by applying a multi-site-one-model approach to data post-vaccination. I analyse serotype prevalence dynamics following PCV7, in asymptomatic carriage in children attending day care in Portugal, Norway, France, Greece, Hungary and Hong-Kong. Model fitting to each dataset provides site-specific estimates for vaccine efficacy against acquisition, and pneumococcal transmission parameters. According to this model, variable serotype replacement across sites can be explained through variable PCV7 efficacy, ranging from 40% in Norway to 10% in Hong-Kong. While the details of how this effect is achieved remain to be determined, here I report three factors negatively associated with the VE readout, including initial prevalence of serotype 19F, daily mean temperature, and the Gini index. The study warrants more attention on local modulators of vaccine performance and calls for predictive frameworks within and across populations.

背景与目标： : 尽管已经深入研究了多价肺炎球菌疫苗的平均效力，但疫苗效力 (VE) 的差异却被忽略了。环境条件，当地血清型和克隆组成以及社会人口统计学和遗传宿主因素可以驱动不同环境的净个体保护。了解功效变化会对人口水平的有效性和其他生态进化反馈产生影响。在这里，我表明，通过将多站点一模型的方法应用于疫苗接种后的数据，实现的VE可以在流行病学设置中有所不同。我分析了PCV7之后在葡萄牙，挪威，法国，希腊，匈牙利和香港的日托儿童中无症状携带的血清型患病率动态。对每个数据集的模型拟合提供了针对采集的疫苗功效和肺炎球菌传播参数的特定站点估计。根据该模型，可以通过从挪威的40% 到香港的10% 的可变PCV7功效来解释跨位点的可变血清型替代。尽管如何实现这种效果的细节仍有待确定，但在这里我报告了与VE读数负相关的三个因素，包括血清型19F的初始患病率，每日平均温度和基尼指数。该研究需要更多地关注疫苗性能的局部调节剂，并呼吁在人群内部和人群之间建立预测框架。

BACKGROUND & AIMS: :In a neoadjuvant setting, three parameters for Ki-67 could be obtained: pre-treatment Ki-67, post-treatment Ki-67 and Ki-67 change between pre- and post-treatments. It is uncertain which of the three parameters has the greatest prognostic significance, and whether this parameter has significance in each subtype of breast cancer. A total of 385 patients who received neoadjuvant anthracycline followed by taxane chemotherapy and subsequent surgery for breast cancer were analyzed retrospectively. By immunohistochemistry (IHC), patients were divided into four subtypes (Luminal A, Luminal B, Triple negative, and HER2). Ki-67 was examined by IHC in pre-treatment core needle samples and post-treatment surgical excision specimens. The relapse-free survival (RFS) rate was compared among each subtype. The median follow-up period was 56 months. The rate of pathological complete response was higher for HER2 (34.8 %) and Triple negative (24.3 %) subtypes than for Luminal B (8.3 %) and Luminal A (3.8 %) subtypes (p < 0.0001). A reduction in Ki-67 was observed in 58.5, 83.4, 70.2, and 74.2 % of patients in the Luminal A, Luminal B, Triple negative, and HER2 subtypes, respectively. Ki-67 change between pre- and post-treatments was an independent prognostic factor, but pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis. The RFS was significantly different between patients whose Ki-67 was reduced and those not reduced for Luminal B (81.4 vs. 50.0 %, p = 0.006), Triple negative (74.8 vs. 43.5 %, p = 0.006) and HER2 (82.7 vs. 59.0 %, p = 0.009). However, for Luminal A, the difference in RFS was not associated with changes of Ki-67 (78.8 vs. 75.3 %, p = 0.193). Ki-67 change between pre- and post-neoadjuvant chemotherapy is an independent prognostic factor in patients of Luminal B, Triple negative, and HER2 subtypes. Pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis.

背景与目标： : 在新佐剂环境中，可以获得三个Ki-67参数: 治疗前Ki-67，治疗后Ki-67以及治疗前和治疗后之间的Ki-67变化。不确定这三个参数中哪个具有最大的预后意义，以及该参数在每种乳腺癌亚型中是否具有意义。回顾性分析了总共385例接受新辅助蒽环类药物后进行紫杉烷化疗和随后进行乳腺癌手术的患者。通过免疫组织化学 (IHC) 将患者分为四种亚型 (Luminal A，Luminal B，三重阴性和HER2)。用IHC检查治疗前的芯针样品和治疗后的手术切除标本中的Ki-67。比较每种亚型之间的无复发生存率 (RFS)。中位随访期为56个月。HER2 (34.8%) 和三阴性 (24.3%) 亚型的病理完全缓解率高于管腔B (8.3%) 和管腔A (3.8%) 亚型 (p <0.0001)。在腔A，腔B，三阴性和HER2亚型中分别观察到58.5，83.4，70.2和74.2% 患者的Ki-67降低。在多变量分析中，治疗前后的Ki-67变化是独立的预后因素，但治疗前Ki-67和治疗后Ki-67不是独立的预后因素。Luminal B (81.4 vs. 50.0%，p = 0.006)，三阴性 (74.8 vs. 43.5%，p = 0.006) 和HER2 (82.7 vs. 59.0%，p = 0.009) 的Ki-67降低和未降低的患者之间的RFS显着不同。然而，对于Luminal A，RFS的差异与Ki-67的变化无关 (78.8 vs. 75.3%，p = 0.193)。新辅助化疗前后的Ki-67变化是Luminal B，三阴性和HER2亚型患者的独立预后因素。在多变量分析中，治疗前Ki-67和治疗后Ki-67不是独立的预后因素。

BACKGROUND & AIMS: Presented is the first reported case of an anaphylactoid reaction following Norplant contraceptive implant insertion. The 19-year-old UK woman denied any history of allergic reaction to local anesthesia. After subcutaneous infiltration with 50 mg of 1% lidocaine (without adrenalin), 6 Norplant capsules were inserted through use of the standard insertion technique. Shortly after completion of the procedure, the patient collapsed and had 2 short convulsions. Her blood pressure dropped to 80/40 mm Hg and her radial pulse was 60 beats/minute and thready. Recovery was rapid following administration of intramuscular adrenalin and intravenous hydrocortisone. The woman later recalled a similar episode during a visit to her dentist. An estimated 3 in every 100,000 patients receiving lignocaine hydrochloride have an episode of anaphylaxis in the hospital. In type I hypersensitivity reactions, there is often a history of previous exposure to the allergen, as occurred in this patient. Those undertaking Norplant insertion and removal should be aware of the potential for serious allergic reactions and have access to resuscitative equipment.

背景与目标： 提出了第一例报道的Norplant避孕植入物插入后发生类过敏反应的病例。这位19岁的英国妇女否认对局部麻醉有任何过敏反应史。在皮下浸润50 mg 1% 利多卡因 (不含肾上腺素) 后，通过使用标准插入技术插入6个Norplant胶囊。手术完成后不久，患者晕倒并出现2次短暂抽搐。她的血压下降到80/40毫米汞柱，她的桡动脉脉搏是60次/分钟和微弱的。肌肉注射肾上腺素和静脉注射氢化可的松后恢复迅速。这位女士后来在去看牙医时回忆起类似的情节。每100,000名接受盐酸利诺卡因的患者中估计有3名在医院发生过敏反应。在I型超敏反应中，通常有先前暴露于过敏原的病史，如在该患者中发生的。那些进行Norplant插入和移除的人应该意识到严重过敏反应的可能性，并可以使用复苏设备。

BACKGROUND & AIMS: :Old and frail patients with advance breast malignancy require mastectomy which often results in large defects requiring soft tissue cover. We present three cases of large fasciocutaneous perforator based V-Y advancement flaps for reconstruction of large post-mastectomy wounds in older patients with large tumours. This technique reduces the morbidity of patients who have severe co-existing morbidity factor in addition to the advance breast disease.

背景与目标： : 患有晚期乳腺恶性肿瘤的年老体弱患者需要进行乳房切除术，这通常会导致大量缺损，需要软组织覆盖。我们介绍了3例基于大型筋膜皮肤穿孔器的v-y推进皮瓣，用于重建患有大肿瘤的老年患者的大型乳房切除术后伤口。除了晚期乳腺疾病外，该技术还可以降低具有严重并存发病率因素的患者的发病率。

BACKGROUND & AIMS: :The existence of a chest wall "steal" of blood away from the myocardium through patent internal mammary artery branches has been hypothesized as a cause of recurrent angina pectoris after coronary artery bypass grafting. Although some authors believe that such a steal is physiologically impossible because coronary flow occurs in diastole and chest wall flow in systole, we recently documented ischemia in the left anterior descending coronary artery distribution before embolization of a large left internal mammary artery first intercostal branch that had been left intact at the time of operation. After embolization of the branch, clinical and objective evidence of ischemia resolved.

背景与目标： : 假设存在胸壁通过未闭的乳内动脉分支从心肌 “窃取” 血液，这是冠状动脉旁路移植术后再发心绞痛的原因。尽管一些作者认为这种偷窃在生理上是不可能的，因为冠状动脉血流发生在舒张期，胸壁血流发生在收缩期，但我们最近记录了左前降支在栓塞大的左乳内动脉第一肋间分支之前的缺血。在手术时保持完整。分支栓塞后，缺血的临床和客观证据得以解决。

BACKGROUND & AIMS: :Recent findings demonstrate that multiple mRNAs are co-regulated by one or more sequence-specific RNA-binding proteins that orchestrate their splicing, export, stability, localization and translation. These and other observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinately regulated during cell growth and differentiation as post-transcriptional RNA operons or regulons, through a ribonucleoprotein-driven mechanism. Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.

背景与目标： : 最近的发现表明，多种mrna由一种或多种序列特异性RNA结合蛋白共同调控，这些蛋白协调了它们的剪接，输出，稳定性，定位和翻译。这些和其他观察结果产生了一个模型，在该模型中，编码功能相关蛋白的mrna在细胞生长和分化过程中通过核糖核蛋白驱动的机制作为转录后RNA操纵子或调控子被协同调控。在这里，我描述了最近发现的几个在发芽的酵母，果蝇和哺乳动物细胞中的RNA操纵子的例子，以及它们在免疫反应，氧化代谢，应激反应，昼夜节律和疾病等过程中的潜在重要性。最后，我考虑了这些组合转录后基因表达网络的进化和重新布线。

BACKGROUND & AIMS: :The aim of this study was to investigate the effects of the application of gaseous ozone and Nd:YAG laser on glass-fibre post bond strength. Forty-two madibular premolar roots were cut, endodontically instrumented and irrigated with 2.5% NaOCl. Post spaces were prepared and roots were divided into three groups (n = 14). The antimicrobial pretreatment was conducted as follows: gaseous ozone, Nd:YAG laser and control (no additional disinfection methods). Scanning electron microscope analysis was made for each group (n = 2). A resin cement was used for luting the posts. For push-out test, each root was cut horizontally (two cervical, two middle and two apical). Statistical analyses were performed with one-way anova (α = 0.05). Fracture types were observed. There was no statistically significant difference between the groups (P > 0.05). There were statistically significant differences in cervical and apical segments of laser and control groups (P < 0.05). The disinfection of the post spaces with Nd:YAG laser and ozone had no adverse effects on bond strength of glass-fibre post.

背景与目标： : 这项研究的目的是研究气态臭氧和Nd:YAG激光对玻璃纤维后粘结强度的影响。切开42个颌前磨牙根，进行牙髓器械治疗并用2.5% NaOCl冲洗。准备了柱子空间，将根分为三组 (n = 14)。抗菌预处理如下: 气态臭氧，Nd:YAG激光和对照 (无其他消毒方法)。对每组进行扫描电子显微镜分析 (n = 2)。使用树脂水泥来润滑柱子。对于推出测试，将每个根部水平切割 (两个子宫颈，两个中间和两个顶端)。用单因素方差分析 (α = 0.05) 进行统计分析。观察到骨折类型。各组间差异无统计学意义 (P> 0.05)。激光组和对照组的宫颈和根尖节段差异有统计学意义 (P <0.05)。Nd:YAG激光和臭氧对桩间隙的消毒对玻璃纤维桩的粘结强度没有不利影响。

BACKGROUND & AIMS: :Cancer is one of the major causes of mortality in organ transplant patients receiving immunosuppressive regimen based on Cyclosporin A (CsA). Organ transplantation and chronic immunosuppression are typically associated with skin cancers (both squamous cell carcinoma and melanoma) and renal cell carcinoma (RCC). Recent studies have shown that in addition to its immunosuppressive effects, accounted for by the inhibition of calcineurin and the modulation of the transcriptional programme of lymphocytes, CsA also directly stimulates the growth and aggressive behaviour of various cancer cells. Using renal carcinogenesis as an example, we discuss the current evidence for a role of cellular proteostasis, i.e. the regulation of the production, maturation and turnover of proteins in eukaryotic cells, in tumorigenesis arising under conditions of chronic immunosuppression. We present the recent studies showing that CsA induces the unfolded protein response (UPR) in normal and transformed kidney cells. We examine how the UPR might be important, considering in particular the genomic analyses showing the existence of a correlation between the levels of expression of the actors of the UPR, the chaperones of the endoplasmic reticulum (ER) and the aggressiveness of renal carcinoma. The UPR may offer a possible explanation for how immunosuppressive regimens based on CsA promote renal carcinogenesis. We discuss the opportunities offered by this biological knowledge in terms of screening, diagnosis and treatment of post-transplant cancers, and propose possible future translational studies examining the role of tumour proteostasis and the UPR in this context.

背景与目标： : 癌症是接受基于环孢菌素A (CsA) 的免疫抑制方案的器官移植患者死亡的主要原因之一。器官移植和慢性免疫抑制通常与皮肤癌 (鳞状细胞癌和黑色素瘤) 和肾细胞癌 (RCC) 相关。最近的研究表明，除了其免疫抑制作用 (通过抑制钙调神经磷酸酶和调节淋巴细胞的转录程序) 外，CsA还直接刺激各种癌细胞的生长和攻击行为。以肾癌发生为例，我们讨论了细胞蛋白质平衡作用的当前证据，即在慢性免疫抑制条件下发生的肿瘤发生中，真核细胞中蛋白质的产生，成熟和更新的调节。我们介绍了最近的研究，表明CsA在正常和转化的肾细胞中诱导未折叠蛋白反应 (UPR)。我们研究了UPR可能是如何重要的，特别是考虑到基因组分析，这些分析显示UPR参与者的表达水平，内质网 (ER) 的伴侣与肾癌的侵袭性之间存在相关性。UPR可能为基于CsA的免疫抑制方案如何促进肾癌发生提供了可能的解释。我们讨论了这种生物学知识在移植后癌症的筛查，诊断和治疗方面提供的机会，并提出了可能的未来转化研究，以检查肿瘤蛋白质平衡和UPR在这种情况下的作用。

BACKGROUND & AIMS: :Deinococcus radiodurans is inherently resistant to both ionizing radiation and desiccation. Fifteen months of desiccation was found to be the LD50 dose for D. radiodurans. Desiccated cells of D. radiodurans entered 6h of growth arrest during post-desiccation recovery (PDR). Proteome dynamics during PDR were mapped by resolving cellular proteins by 2-dimensional gel electrophoresis coupled with mass spectrometry. At least 41 proteins, represented by 51 spots on proteome profiles, were differentially expressed throughout PDR. High upregulation in expression was observed for DNA repair proteins involved in single strand annealing (DdrA and DdrB), nucleotide excision repair (UvrA and UvrB), homologous recombination (RecA) and other vital proteins that contribute to DNA replication, recombination and repair (Ssb, GyrA and GyrB). Expression of CRP/FNR family transcriptional regulator (Crp) remained high throughout PDR. Other pathways such as cellular detoxification, protein homeostasis and metabolism displayed both, moderately induced and repressed proteins. Functional relevance of proteomic modulations to surviving desiccation stress is discussed in detail. Comparison of our data with the published literature revealed convergence of radiation and desiccation stress responses of D. radiodurans. This is the first report that substantiates the hypothesis that the radiation stress resistance of D. radiodurans is incidental to its desiccation stress resistance.

背景与目标： : 放射性球菌对电离辐射和干燥具有固有的抵抗力。发现15个月的干燥是D. radiodurans的LD50剂量。在干燥后恢复 (PDR) 期间，放射性D. radiodurans的干燥细胞进入6小时的生长停滞。PDR期间的蛋白质组动力学通过二维凝胶电泳结合质谱解析细胞蛋白来定位。在整个PDR中，至少有41种蛋白质 (由蛋白质组谱上的51个斑点表示) 差异表达。观察到参与单链退火 (DdrA和DdrB)，核苷酸切除修复 (UvrA和UvrB)，同源重组 (reea) 和其他有助于DNA复制，重组和修复的重要蛋白的DNA修复蛋白的表达高度上调 (Ssb，GyrA和GyrB)。在整个PDR中，CRP/FNR家族转录调节因子 (Crp) 的表达仍然很高。其他途径，例如细胞解毒，蛋白质稳态和代谢，同时显示出中度诱导和抑制的蛋白质。详细讨论了蛋白质组学调节与存活的干燥胁迫的功能相关性。将我们的数据与已发表的文献进行比较，发现D. radiodurans的辐射和干燥应力响应会收敛。这是第一份证实以下假设的报告: D. radiodurans的辐射应力性与其干燥应力性有关。

BACKGROUND & AIMS: BACKGROUND:Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. PATIENTS AND METHODS:Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. RESULTS:Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. CONCLUSION:Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy.

背景与目标：

BACKGROUND & AIMS: PURPOSE:Our laboratory recently demonstrated that post-exercise blood flow restriction attenuated muscle hypertrophy only in females, which we hypothesized may be due to alterations in post-exercise blood flow. The aim of this study is to test our previous hypothesis that sex differences in blood flow would exist when employing the same protocol. METHODS:Twenty-two untrained individuals (12 females; 10 males) performed two exercise sessions, each involving one set of elbow flexion exercise to volitional failure on the right arm. The experimental condition had blood flow restriction applied for a 3 min post-exercise period, whereas the control condition did not. Blood flow was measured using an ultrasound at the brachial artery and was taken 1 and 4 min post-exercise. This corresponded to 1 min post inflation and 1 min post deflation in the experimental condition. RESULTS:There were no differences in the alterations in blood flow between the control and experimental conditions when examined across sex. Increases in blood flow [mean (standard deviation)] were as follows: males 1 min [control 764 (577) %; experimental 113 (108) %], males 4 min [control 346 (313) %; experimental 449 (371) %], females 1 min [control 558 (367) %; experimental 87 (105) %], and females 4 min [control 191 (183) %; experimental 328 (223) %]. CONCLUSION:It does not appear that the sex-specific attenuation of muscle hypertrophy we observed previously can be attributed to different alterations in post-exercise blood flow. Future studies may wish to replicate our previous training study, or examine alternative mechanisms which may be sex specific.

背景与目标：

BACKGROUND & AIMS: :We have previously demonstrated that gonadectomy either prior to (early) or after (late) puberty elevated ethanol consumption in males to levels similar to intact adult females-effects that were attenuated by testosterone replacement. To assess whether alterations in the aversive effects of ethanol might contribute to gonadectomy-associated increases in ethanol intake in males, the present study examined the impact of gonadectomy on conditioned taste aversions (CTA) to ethanol in male and female Sprague-Dawley rats. Animals were gonadectomized, received sham surgery (SH) or non-manipulated (NM) on postnatal (P) day 23 (early) or 67 (late) and tested for CTA to ethanol in adulthood. Water-deprived rats were given 1 hr access every-other-day to 10% sucrose followed by an injection of ethanol (0, 1g/kg) for 5 test sessions. Test data were analyzed to determine the first day significant aversions emerged in each ethanol group (i.e., sucrose intakes significantly less than their saline-injected counterparts). Early gonadectomized males acquired the CTA more rapidly than did early SH and NM males (day 1 vs 3 and 4 respectively), whereas a gonadectomy-associated enhancement in ethanol CTA was not evident in late males. Among females, gonadectomy had little impact on ethanol-induced CTA, with females in all groups showing an aversion by the first or second day, regardless of surgery age. These data suggest that previously observed elevations in ethanol intake induced by either pre- or post-pubertal gonadectomy in males are not related simply to gonadectomy-induced alterations in the aversive effects of ethanol indexed via CTA.

背景与目标： : 我们以前已经证明，在青春期 (早期) 或青春期 (晚期) 之前进行性腺切除术会将男性的乙醇消耗量提高到与完整的成年女性相似的水平-睾丸激素替代作用会减弱。为了评估乙醇的厌恶作用的改变是否可能导致男性性腺切除术相关的乙醇摄入量增加，本研究检查了性腺切除术对雄性和雌性Sprague-Dawley大鼠对乙醇的条件性味厌恶 (CTA) 的影响。在出生后第23天 (早期) 或第67天 (晚期) 对动物进行性腺切除，接受假手术 (SH) 或非操纵 (NM)，并在成年后测试CTA至乙醇。每隔一天给缺水的大鼠1小时10% 蔗糖，然后注射乙醇 (0,1 g/kg) 进行5次测试。分析测试数据以确定每个乙醇组中出现的第一天明显厌恶 (即，蔗糖摄入量明显少于注射盐水的对应物)。早期性腺切除的男性获得CTA的速度比早期SH和NM的男性更快 (分别为第1天和第3天和第4天)，而在晚期男性中，性腺切除术相关的乙醇CTA增强并不明显。在女性中，性腺切除术对乙醇诱导的CTA几乎没有影响，无论手术年龄如何，所有组的女性在第一天或第二天都表现出厌恶情绪。这些数据表明，先前观察到的男性青春期前或青春期后性腺切除术引起的乙醇摄入量升高与性腺切除术引起的通过CTA索引的乙醇厌恶作用的改变无关。

BACKGROUND & AIMS: BACKGROUND:A possible negative role of pre-operative use of antitumour necrosis factor-alpha (anti-TNF-α) agents on post-operative outcomes in Crohn's disease (CD) patients is still debated. AIM:To examine the impact of pre-operative anti-TNF-α agents on post-operative outcomes 30 and 60 days after CD surgery in a nationwide Danish cohort. Outcomes were death, reoperation, anastomosis leakage, intra-abdominal abscess and bacteraemia. METHODS:We identified all patients having surgical procedures from 1 January 2000 to 31 December 2010 (n = 2293). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery (exposed) or not (unexposed). Outcomes were obtained from nationwide registries and a bacteraemia registry. Sub-analyses were performed for bacteraemia and for impact of pre-operative timing of anti-TNF-α agents. RESULTS:Among surgical procedures for CD, 214 were exposed and 2079 were not. We found no increased relative risks of death or abscess drainage 30 or 60 days after follow-up. Among exposed, 7.5% had a reoperation within 30 days vs. 8.6% among unexposed, adjusted odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.52-1.63. Among exposed, 3.8% had an anastomosis leakage within 30 days after surgery vs. 2.8% among unexposed, adjusted OR = 1.33, 95% CI: 0.59-3.02. No further cases of anastomosis leakages appeared within 60 days. Sub-analyses indicated no increased risk of bacteraemia after 30 days and no increased risks when anti-TNF-α agents were given ≤14 days before surgery. CONCLUSION:We found no significantly increased relative risks of post-operative complications after use of anti-TNF-α agents either 12 weeks or ≤14 days before surgery for Crohn's disease.

背景与目标：

BACKGROUND & AIMS: :The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

背景与目标： : 发作期后不动综合症之后，动物和男性的伤害性阈值显着增加。在这种有趣的发作期后行为反应中，已经提出了内源性阿片肽介导的机制以及胆碱能介导的抗伤害感受过程。然而，考虑到许多血清素能下降途径与抗伤害感受反应有关，因此本工作的目的是研究5-HT(2)-血清素能受体亚家族在发作期抗伤害感受中的参与。每组7或8只Wistar大鼠通过甩尾试验测量镇痛效果。抽搐后，至少在发作后的120分钟内，甩尾潜伏期 (TFL) 具有统计学上的显着增加。雄性Wistar大鼠接受立体定向手术，以在菱形脑中引入引导套管，以瞄准中缝大核 (NRM) 或千兆体复合体。在独立的动物组中，这些核通过单侧微量注射ibotenic酸 (1.0 microg/0.2 microL) 被神经化学损伤。NRM或网状核巨囊细胞/旁囊细胞复合物的神经元损伤降低了发作后的镇痛作用。同样，在其他独立组中，在研究的所有发作期后，与对照组相比，将利坦色林 (5.0 microg/0.2 microL) 或生理盐水集中施用到每个研究的网状形成核中，引起抓住动物的TFL在统计学上显着降低。这些结果表明，脑桥和延髓网状核的5-羟色胺输入连接的神经元可能参与了发作期后的镇痛。

BACKGROUND & AIMS: :Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.

背景与目标： : 与以前的报道一致，高浓度 (5 microM) 的鞘氨醇具有心脏毒性，这可以通过在离体大鼠心脏中响应缺血/再灌注而增加的梗塞面积来证明。5微米的1-磷酸鞘氨醇 (S1P) 具有心脏保护作用。然而，在生理浓度 (0.4微米) 下，鞘氨醇以及S1P在缺血40分钟前灌注 (预处理) 或在缺血后再灌注培养基中加入 (后处理) 时均有效保护心脏免受缺血/再灌注损伤。在预处理前和后处理中，鞘氨醇和S1P的保护作用是通过再灌注期间左心室发展压力的> 75% 恢复以及梗塞面积从危险区域的45% 减少到小于8% 来证明的。当将S1P(1and3) g蛋白偶联受体拮抗剂VPC23019与S1P一起添加到预处理或后处理培养基中时，它完全阻断了S1P-induced保护。但是，VPC 23019不影响0.4 microM鞘氨醇对预处理或后处理心脏的能力。预处理研究表明，用GF109203X抑制蛋白激酶C可阻断S1P的预处理。然而，GF109203X不影响0.4 microM鞘氨醇的预处理。同样，与PI3激酶抑制剂wortmanin共同治疗可阻断S1P的预处理，但不能阻断鞘氨醇的预处理。相比之下，KT5823抑制蛋白激酶G对S1P预处理没有影响，但完全消除了鞘氨醇的预处理。此外，蛋白激酶A抑制肽14-22酰胺可阻断鞘氨醇而不是S1P的预处理。这些数据首次揭示了鞘氨醇在生理浓度下没有毒性，而是一种有效的心脏保护剂，利用与S1P完全不同的机制; 一种独立于g蛋白偶联受体并利用环状核苷酸依赖性途径的药物。