BACKGROUND & AIMS: :Brucella melitensis Rev.1 is the live attenuated Elberg-originated vaccine strain of the facultative intracellular Brucella species, and is widely used to control brucellosis in small ruminants. However, Rev.1 may cause abortions in small ruminants that have been vaccinated during the last trimester of gestation, it is pathogenic to humans, and it induces antibodies directed at the O-polysaccharide (O-PS) of the smooth lipopolysaccharide, thus making it difficult to distinguish between vaccinated and infected animals. Rough Brucella strains, which lack O-PS and are considered less pathogenic, have been introduced to address these drawbacks; however, as Rev.1 confers a much better immunity than the rough mutants, it is still considered the reference vaccine for the prophylaxis of brucellosis in small ruminants. Therefore, developing an improved vaccine strain, which lacks the Rev.1 drawbacks, is a highly evaluated task, which requires a better understanding of the molecular mechanisms underlying the virulence attenuation of Rev.1 smooth strains and of natural Rev.1 rough strains, which are currently only partly understood. As the acidification of the Brucella-containing vacuole during the initial stages of infection is crucial for their survival, identifying the genes that contribute to their survival in an acidic environment versus a normal environment will greatly assist our understanding of the molecular pathogenic mechanisms and the attenuated virulence of the Rev.1 strain. Here, we compared the transcriptomes of the smooth and natural rough Rev.1 strains, each grown under either normal or acidic conditions. We found 12 key genes that are significantly downregulated in the Rev.1 rough strains under normal pH, as compared with Rev.1 smooth strains, and six highly important genes that are significantly upregulated in the smooth strains under acidic conditions, as compared with Rev.1 rough strains. All 18 differentially expressed genes are associated with bacterial virulence and survival and may explain the attenuated virulence of the rough Rev.1 strains versus smooth Rev.1 strains, thus providing new insights into the virulence attenuation mechanisms of Brucella. These highly important candidate genes may facilitate the design of new and improved brucellosis vaccines.

背景与目标： : 布鲁氏菌melitensis Rev.1是兼性细胞内布鲁氏菌物种的Elberg减毒活疫苗株，广泛用于控制小反刍动物的布鲁氏菌病。但是，Rev.1可能会导致在妊娠的最后三个月接种过疫苗的小反刍动物流产，它对人类具有致病性，并且会诱导针对光滑脂多糖的O-多糖 (o-ps) 的抗体，因此很难区分接种疫苗的动物和感染的动物。为了解决这些缺点，引入了缺乏o-ps且被认为致病性较低的粗布鲁氏菌菌株; 但是，由于Rev.1赋予比粗突变体更好的免疫力，因此仍被认为是预防小反刍动物布鲁氏菌病的参考疫苗。因此，开发一种缺乏Rev.1缺点的改进的疫苗株是一项高度评价的任务，这需要更好地理解Rev.1平滑株和天然Rev.1粗糙株毒力衰减的分子机制，目前仅部分了解。由于在感染的初始阶段，含布鲁氏菌的液泡的酸化对其生存至关重要，因此确定有助于其在酸性环境与正常环境中生存的基因将极大地帮助我们理解分子致病机制和Rev.1菌株的减毒毒力。在这里，我们比较了在正常或酸性条件下生长的光滑和自然粗糙Rev.1菌株的转录组。与Rev.1平滑菌株相比，我们发现了在正常pH下的Rev.1粗糙菌株中明显下调的12个关键基因，以及与Rev.1粗糙菌株相比，在酸性条件下光滑菌株中明显上调的6个高度重要基因。所有18个差异表达的基因都与细菌的毒力和存活有关，并且可以解释粗糙的Rev.1菌株与光滑的Rev.1菌株的毒力减弱，从而为布鲁氏菌的毒力减弱机制提供了新的见解。这些高度重要的候选基因可能有助于设计新的和改进的布鲁氏菌病疫苗。

BACKGROUND & AIMS: BACKGROUND:The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups. METHODS:Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment. RESULTS:The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of < 0.05 were consistently observed across studies only for baseline anti-cyclic citrullinated peptide antibody (ACPA) status for American College of Rheumatology 20% response, but not American College of Rheumatology 50% or 70% response. Adverse events and worsening laboratory parameters occurred more frequently in sarilumab-treated vs. placebo-treated patients and were more frequent in the small number of patients ≥ 65 years (n = 289) vs. patients < 65 years (n = 1819). Serious infections occurred in six patients aged ≥ 65 years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥ 65 years regardless of treatment. CONCLUSIONS:Apart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA. TRIAL REGISTRATION:ClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015.

背景与目标：

BACKGROUND & AIMS: :Titanium implants are the standard therapeutic option when restoring missing teeth and reconstructing fractured and/or diseased bone. However, in the 30 years since the advent of micro-rough surfaces, titanium's ability to integrate with bone has not improved significantly. We developed a method to create a unique titanium surface with distinct roughness features at meso-, micro-, and nano-scales. We sought to determine the biological ability of the surface and optimize it for better osseointegration. Commercially pure titanium was acid-etched with sulfuric acid at different temperatures (120, 130, 140, and 150 °C). Although only the typical micro-scale compartmental structure was formed during acid-etching at 120 and 130 °C, meso-scale spikes (20-50 μm wide) and nano-scale polymorphic structures as well as micro-scale compartmental structures formed exclusively at 140 and 150 °C. The average surface roughness (Ra) of the three-scale rough surface was 6-12 times greater than that with micro-roughness only, and did not compromise the initial attachment and spreading of osteoblasts despite its considerably increased surface roughness. The new surface promoted osteoblast differentiation and in vivo osseointegration significantly; regression analysis between osteoconductivity and surface variables revealed these effects were highly correlated with the size and density of meso-scale spikes. The overall strength of osseointegration was the greatest when the acid-etching was performed at 140 °C. Thus, we demonstrated that our meso-, micro-, and nano-scale rough titanium surface generates substantially increased osteoconductive and osseointegrative ability over the well-established micro-rough titanium surface. This novel surface is expected to be utilized in dental and various types of orthopedic surgical implants, as well as titanium-based bone engineering scaffolds.

背景与目标： : 钛植入物是修复缺失牙齿和重建骨折和/或患病骨时的标准治疗选择。但是，自微粗糙表面出现以来的30年中，钛与骨骼整合的能力并未显着提高。我们开发了一种方法来创建独特的钛表面，该钛表面在细观，微观和纳米级具有明显的粗糙度特征。我们试图确定表面的生物学能力，并对其进行优化以实现更好的骨整合。商业纯钛在不同温度 (120、130、140和150 °C) 下用硫酸酸蚀。尽管在120和130 °C的酸蚀刻期间仅形成典型的微尺度隔室结构，但仅在140和150 °C形成的中尺度尖峰 (20-50μm宽) 和纳米级多晶型结构以及微尺度隔室结构。三尺度粗糙表面的平均表面粗糙度 (Ra) 是仅具有微粗糙度的表面粗糙度的6-12倍，尽管其表面粗糙度显着增加，但并未损害成骨细胞的初始附着和扩散。新表面显着促进了成骨细胞的分化和体内骨整合; 骨传导性和表面变量之间的回归分析表明，这些作用与中尺度尖峰的大小和密度高度相关。当在140 °C下进行酸蚀刻时，骨整合的整体强度最大。因此，我们证明了我们的中，微米和纳米级的粗糙钛表面在成熟的微粗糙钛表面上产生了显着增强的骨传导性和骨整合能力。这种新颖的表面有望用于牙科和各种类型的骨科手术植入物以及基于钛的骨工程支架。

BACKGROUND & AIMS: PURPOSE:Although high-level evidence supports moderately hypofractionated radiation therapy for definitive prostate treatment, there is less evidence for its use in the postprostatectomy setting. We externally validated a contemporary nomogram predicting biochemical failure (BF) after salvage radiation therapy (SRT) and report long-term disease control outcomes for hypofractionated SRT to the prostate bed. METHODS AND MATERIALS:A retrospective review was performed for 112 patients treated with hypofractionated SRT (52.5 Gy in 20 fractions using 3-dimensional conformal radiation therapy) for pT2-4R0-1N0/XM0 prostate adenocarcinoma, with postoperative prostate-specific antigen (PSA) greater than 0.1 ng/mL or rising. Freedom from BF (FFBF), distant metastasis, cancer-specific mortality, and overall survival were analyzed from commencement of radiation therapy. Cox regression was performed on FFBF to account for covariates. BF was defined as a PSA ≥0.4 ng/mL and rising after SRT. Early SRT was defined as SRT commencing at a pre-SRT PSA of ≤0.2 ng/mL. RESULTS:Median follow-up was 10.0 years (interquartile range, 9.3-10.7 years), median pre-SRT PSA was 0.4 ng/mL, and androgen deprivation therapy was used in 14% of patients. The 5/10-year FFBF, distant metastasis, cancer-specific mortality, and overall survival were 68%/51%, 7%/16%, 5%/11%, and 90%/75%, respectively. FFBF for early SRT compared with late SRT was 81% versus 66% at 5 years and 68% versus 49% at 10 years. On multivariable analysis, pre-SRT PSA, International Society of Urologic Pathology grade group, seminal vesicle invasion, and androgen deprivation therapy use were associated with FFBF. The nomogram c-index was 0.67, and it overestimated FFBF by 10% and 15% at 5 and 10 years, respectively, with confidence intervals overlapping the line of unity. CONCLUSIONS:Hypofractionated SRT provides long-term disease control outcomes comparable to conventionally fractionated radiation therapy. Early SRT provides improved disease control, with two-thirds of patients with pre-SRT PSA of ≤0.2 ng/mL free of BF at 10 years. We performed the first external validation of the Tendulkar salvage nomogram, which showed a robust model performance.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency. METHODS:We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI <100 or 150 points; CDAI <150 points plus decrease by 70 or 100 points; CDAI <150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200-299 or > or =300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (<40 or > or =40 yr), gender and duration of disease (<2 or > or =2 yr) were performed to determine predictors of response when applied to these CDAI definitions. RESULTS:Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI > or =70 points for the last two consecutive visits or decrease in baseline CDAI > or =100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI > or =100 points had some advantages over a decrease CDAI > or =70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors. CONCLUSION:Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by > or =70 points for the last two consecutive visits or a decrease in baseline CDAI by > or =100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications.

背景与目标：

BACKGROUND & AIMS: :The distributed point source method is commonly used to predict the complex acoustic field emitted by ultrasonic transducers. In this paper, it is presented as an alternative to conventional approaches often used when solving rough surface scattering problems. Surface shadowing and multiple scattering effects are inherently included in the mesh-free semi-analytical simulation method through matrix manipulation making it very efficient and simple to implement. Results are presented which illustrate the improvement in accuracy gained over the Kirchhoff approximation and the decrease in computational load over the finite element method, culminating in greater than an order of magnitude decrease in required simulation time. The method is applied to the practical problem of online wall thickness monitoring within corrosive environments, illustrating the variability in reflected pulse shape that could be expected from rough surfaces with similar statistics. Three commonly implemented time-of-flight algorithms are used to analyze a large number of simulated signals from which it is concluded that those based on first arrival time are more stable under increasing roughness conditions than those which are based on reflected pulse shape.

背景与目标： : 分布式点源方法通常用于预测超声换能器发出的复杂声场。在本文中，它是解决粗糙表面散射问题时经常使用的常规方法的替代方法。无网格半解析模拟方法通过矩阵操纵固有地包含表面阴影和多重散射效应，使其非常有效且易于实现。给出的结果说明了在Kirchhoff近似下获得的精度提高以及在有限元方法上的计算负荷减少，最终所需的仿真时间减少了一个数量级以上。该方法适用于腐蚀环境中在线壁厚监测的实际问题，说明了反射脉冲形状的可变性，这可能是由具有相似统计数据的粗糙表面所期望的。使用三种常用的飞行时间算法来分析大量的模拟信号，从中得出的结论是，在粗糙度增加的条件下，基于首次到达时间的模拟信号比基于反射脉冲形状的模拟信号更稳定。

BACKGROUND & AIMS: :High salt intake is a well-recognized risk factor for osteoporosis because it induces calciuria, but the effects of salt on calcium metabolism and the potential impact on bone health in postmenopausal women have not been fully characterized. This study investigated adaptive mechanisms in response to changes in salt and calcium intake in postmenopausal women. Eleven women completed a randomized cross-over trial consisting of four successive 5-wk periods of controlled dietary intervention, each separated by a minimum 4-wk washout. Moderately low and high calcium (518 versus 1284 mg) and salt (3.9 versus 11.2 g) diets, reflecting lower and upper intakes in postmenopausal women consuming a Western-style diet, were provided. Stable isotope labeling techniques were used to measure calcium absorption and excretion, compartmental modeling was undertaken to estimate bone calcium balance, and biomarkers of bone formation and resorption were measured in blood and urine. Moderately high salt intake (11.2 g/d) elicited a significant increase in urinary calcium excretion (p = 0.0008) and significantly affected bone calcium balance with the high calcium diet (p = 0.024). Efficiency of calcium absorption was higher after a period of moderately low calcium intake (p < 0.05) but was unaffected by salt intake. Salt was responsible for a significant change in bone calcium balance, from positive to negative, when consumed as part of a high calcium diet, but with a low calcium intake, the bone calcium balance was negative on both high and low salt diets.

背景与目标： : 高盐摄入量是骨质疏松症的公认危险因素，因为它会诱发钙尿症，但盐对钙代谢的影响以及对绝经后妇女骨骼健康的潜在影响尚未完全表征。这项研究调查了绝经后妇女对盐和钙摄入量变化的适应性机制。11名妇女完成了一项随机交叉试验，该试验包括四个连续5周的受控饮食干预期，每个间隔最少4周。提供了中度低钙和高钙 (518对1284 mg) 和盐 (3.9对11.2g) 饮食，反映了食用西式饮食的绝经后妇女的较低和较高摄入量。使用稳定的同位素标记技术来测量钙的吸收和排泄，进行隔室建模以估计骨钙平衡，并在血液和尿液中测量骨形成和吸收的生物标志物。适度高盐摄入 (11.2g/d) 引起尿钙排泄显着增加 (p = 0.0008)，并显着影响高钙饮食的骨钙平衡 (p = 0.024)。在适度低钙摄入一段时间后，钙吸收效率较高 (p <0.05)，但不受盐摄入的影响。当作为高钙饮食的一部分食用时，盐是导致骨钙平衡从正变为负的显着变化的原因，但是在钙摄入量低的情况下，高盐和低盐饮食的骨钙平衡均为负。

BACKGROUND & AIMS: OBJECTIVES:For a moderately dilated ascending aorta (diameter 35-54 mm), current guidelines recommend continuous annual or semi-annual examinations with computed tomography or magnetic resonance imaging. However, few data have shown the yield and benefit of such a protocol. This study aimed to investigate the fate of a moderately dilated ascending aorta and thereby determine the adequate imaging interval. METHODS:In our institutional database, we identified adult patients having an ascending aortic diameter ≥40 mm in contrast-enhanced computed tomography and follow-up imaging(s) after ≥1 year. Of the 509 patients (mean age 67.2 ± 10.4 years) enrolled in the study, the maximal diameter of the ascending aorta was compared between the first and last images. Also, their medical records were reviewed to investigate the associated illness and clinical events. RESULTS:The mean growth rate of the patients with a 40-44 mm ( n  = 321), 45-49 mm ( n  = 142) and ≥50 mm ( n  = 46) ascending aorta was 0.3 ± 0.5, 0.3 ± 0.5 and 0.7 ± 0.9 mm/year, respectively. During the mean interval of 4.3 ± 2.4 years, significant progression (diameter increase by ≥5 mm) occurred in 3.4, 5.6 and 21.7%, respectively. The 3- to 5-year rates of freedom from significant progression were 99.1%-96.5% (40-44 mm) and 97.8%-96.4% (45-49 mm). In multivariate analysis, initial ascending aortic diameter ≥45 mm and aortic valve regurgitation were significantly associated with significant progression. Acute type A aortic dissection occurred in 5 patients (1%), before the maximal diameter of the ascending aorta reached 55 mm or significant progression was observed. CONCLUSIONS:For a moderately dilated ascending aorta not exceeding 45 mm in maximal diameter and stable in the first annual follow-up image, a 3- to 4-year interval would be reasonable before subsequent imaging. More frequent imaging may be warranted in patients with aortic valve insufficiency or with an aortic diameter ≥45 mm.

背景与目标：

BACKGROUND & AIMS: :In order to identify the ATP transporter in rat liver rough endoplasmic reticulum (RER), a photoreactive azido derivative of ATP, 3'-O-(p-azidobenzoyl)-ATP (AB-ATP), was synthesized by the reaction of ATP with N-hydroxysuccinimido 4-azidobenzoate (NHS-AB). The activity of the ATP transporter was determined by measuring the influx of [8-14C]ATP. The ATP transport had an apparent Km value of 6.5 microM and a Vmax of 1 nmol min-1 (mg of protein)-1. The transport of ATP was specifically inhibited by AB-ATP and 4, 4'-diisothiocyanatostilbene-2', 2'-disulfonic acid (DIDS). Under a dim light, AB-ATP was a competitive inhibitor of the ATP transport with Ki value of 0.19 microM, which indicates that AB-ATP has a high affinity for the ATP transporter, so it can be utilized as a photoaffinity probe for the identification of the ATP transporter in rat liver RER. An SDS--PAGE analysis of RER vesicles photolabeled with [gamma-32P]AB-ATP indicates the presence of a 56-kDa protein. The 56-kDa protein was completely protected from photoaffinity labeling by 10 microM ATP but not by 30 microM GTP. The specific labeling of the 56-kDa protein was sensitive to the anion transport inhibitor DIDS. In order to confirm whether the apparent uptake of ATP was due to the 56-kDa protein, the ATP transporter was partially purified through two successive ion-exchange chromatography steps (DEAE and Mono-S). The fraction showing the high activity of the ATP transporter also contained the 56-kDa protein photolabeled with [gamma-32P]AB-ATP. On the basis of the photoaffinity labeling and reconstitution experiment, we conclude that the 56-kDa protein represents the ATP transporter in rat liver RER.

背景与目标： : 为了鉴定大鼠肝脏粗内质网 (RER) 中的ATP转运蛋白，ATP的光反应性叠氮基衍生物，3 '-O-(对叠氮基苯甲酰基)-ATP (AB-ATP)，通过ATP与N-羟基琥珀酰亚胺4-叠氮基苯甲酸酯 (NHS-AB) 反应合成。ATP转运蛋白的活性通过测量 [8-14C]ATP的流入来确定。ATP转运的表观Km值为6.5微米，Vmax为1 nmol min-1 (毫克蛋白质)-1。ATP的转运被AB-ATP和4特异性抑制，4 '-diisothiocyanatostilbene-2'，2 '-二磺酸 (DIDS)。在暗光下，AB-ATP是ATP转运的竞争性抑制剂，Ki值为0.19 microM，这表明AB-ATP对ATP转运蛋白具有高亲和力，因此，它可以用作鉴定大鼠肝脏RER中ATP转运蛋白的光亲和探针。用 [gamma-32P]AB-ATP光标记的RER囊泡的SDS--PAGE分析表明存在56 kDa蛋白。10微米ATP完全保护56 kDa蛋白免受光亲和标记但不是通过30 microM GTP。56 kDa蛋白的特异性标记对阴离子转运抑制剂DIDS敏感。为了确认ATP的表观摄取是否由于56 kDa蛋白，ATP转运蛋白通过两个连续的离子交换色谱步骤 (DEAE和Mono-S) 部分纯化。显示ATP转运蛋白高活性的部分还含有用 [gamma-32P]AB-ATP光标记的56 kDa蛋白。在光亲和标记和重构实验的基础上，我们得出结论，56 kDa蛋白代表大鼠肝脏RER中的ATP转运蛋白。

BACKGROUND & AIMS: INTRODUCTION:Chemotherapy-induced nausea and vomiting (CINV) can be a serious and debilitating adverse effect that is highly feared by cancer patients. For patients receiving moderately emetogenic chemotherapy regimens at our institution in the ambulatory infusion center, palonosetron was selected as the preferred serotonin (5-HT3) antagonist for CINV prophylaxis per the 2016 NCCN Guidelines, when a neurokinin1 antagonist was not included in the prophylactic regimen. The purpose of this study was to evaluate the efficacy of dexamethasone and palonosetron versus granisetron for the prevention of CINV in patients receiving moderately emetogenic chemotherapy regimens. METHODS:This study is an Institutional Review Board-approved, single-center retrospective review of electronic health records including patients who received moderately emetogenic chemotherapy regimens with CINV prophylaxis with dexamethasone and either palonosetron or granisetron. RESULTS:A total of 268 eligible patients were included in the study. Eighty-eight patients received palonosetron and 180 patients received granisetron as their 5-HT3 receptor antagonist between October 31, 2014 and October 31, 2016. There were no statistically significant differences between the two antiemetic groups for the primary outcome of presence of any change in day 1 intravenous prophylactic antiemetics. Nine (10.23%) palonosetron patients and 15 (8.33%) granisetron patients required a change in their day 1 intravenous prophylactic antiemetics (P = 0.610). CONCLUSIONS:Despite palonosetron's better efficacy, longer half-life, and higher binding affinity, the results of this retrospective review demonstrates that the choice of serotonin antagonist, palonosetron or granisetron, did not result in a change in day 1 intravenous prophylactic antiemetics or antiemetic outpatient medications for patients undergoing moderately emetogenic chemotherapy regimens.

背景与目标：

BACKGROUND & AIMS: :Influence of fluoride on exocrine pancreas cells was examined morphologically with traditional and prolonged osmium fixation techniques for electron microscopy in the enamel fluorosis model rats injected subcutaneously twice a day with 20 mg/kg body weight of sodium fluoride. Although the rough endoplasmic reticulum (rER) of exocrine pancreas cells in control rats was laminated and oriented parallel to the circumference of the nucleus, the rER of the cells in NaF-treated rats was dilated, disrupted the laminated arrangement, and changed to the globular-shape rER. Many intracisternal granules were formed in these globular-shape rER of the cells exposed to fluoride. Lots of autophagosomes were also seen in the exocrine cells with NaF treatment. The autophagosomes were limited with a double or multiple membranes, and contained cytoplasmic organelles and/or the intracisternal granules. The outer and inner leaflets of double membranes of the autophagosomes were usually separated by a distinct electron-lucent area. In prolonged osmium fixation, the area between the double membranes of the autophagosome was filled with osmiun reaction deposits. Many autophagosomes were encircled with the single or multiple osmiophilic layers. In some cases, the osmium positive saccules also surrounded the free surface of the globular-shape rER containing intracisternal granules. These findings indicate that fluoride disrupts the export of zymogens from the rER, resulting in formation of intracisternal granules and autophagosomes, and that the osmiophilic saccules participate in sequestration of cytoplasmic organelles in forming autophagosomes.

背景与目标： : 在牙釉质氟中毒模型大鼠中，每天两次皮下注射20 mg/kg体重的氟化钠，用传统和延长的固定技术进行电子显微镜检查了氟化物对外分泌胰腺细胞的影响。尽管对照大鼠外分泌胰腺细胞的粗面内质网 (rER) 被层压并平行于细胞核的圆周取向，但NaF处理的大鼠细胞的rER却被扩张，破坏了层压排列，并变为球状rER。在这些暴露于氟化物的细胞的球状rER中形成了许多脑内颗粒。在NaF处理的外分泌细胞中也发现了许多自噬体。自噬体被双层或多层膜限制，并包含细胞质细胞器和/或脑内颗粒。自噬体的双层膜的外部和内部小叶通常被一个明显的电子透明区域隔开。在长时间的固定中，自噬体的双层膜之间的区域充满了osmiun反应沉积物。许多自噬体被单个或多个亲渗层包围。在某些情况下，阳性球囊也包围了球状rER的自由表面，该rER含有脑内颗粒。这些发现表明，氟化物破坏了rER中酶原的输出，导致了胞内颗粒和自噬体的形成，并且嗜渗性囊虫参与了细胞质细胞器的隔离，形成了自噬体。

BACKGROUND & AIMS: BACKGROUND:During incremental exercise, heart rate variability (HRV) has been shown to display distinct stabilization and inflection points, which have been used to indirectly detect the ventilatory threshold (VT). METHODS:Ten moderately trained males (26·5 ± 5·9 years: VO2peak 48·7 ± 4·1 ml min-1  kg-1 ) performed an incremental test on a cycle ergometer until volitional exhaustion with both R-R intervals and respiratory indices recorded. HRV was quantified using both nonlinear (Poincare plot; short-term variability SD1) and spectral analysis of the R-R intervals (high-frequency component; HFp). The VT was identified using the V-slope method. The relationship between HRV parameters and the VT was assessed using both a paired t-test and Pearson's product correlation. In addition, Bland and Altman plots were used to quantify the mean difference along with a 95% confidence interval. RESULTS:When expressed as the corresponding heart rate values, both the SD1 and the HFp stabilization points revealed a strong (r = 0·86 and 0·087, respectively) correlation with the VT. However, only for SD1 this relationship was different to the VT (t-test). The Bland-Altman plots supported these findings showing wide limits of agreement present for SD1 and the VT whilst the relationship between HFp and the VT revealed narrower limits. CONCLUSION:There does not appear to be a relationship present between the VT and the SD1 stabilization point in moderately trained healthy males, whereas the HFp stabilization point revealed a strong relationship with the VT when expressed as heart rate.

背景与目标：

BACKGROUND & AIMS: :Delayed vomiting is a potentially significant adverse effect of chemotherapy used to treat childhood cancer, but little is known about the experience of delayed vomiting in children and adolescents. An exploratory study was conducted to determine the pattern of delayed vomiting in children and adolescents with cancer after highly emetic chemotherapy and to identify possible risk factors. In a sample of 82 children and adolescents who completed 117 cycles of highly emetic chemotherapy, the overall prevalence of delayed vomiting was 32%. The frequency of delayed vomiting was highest on delayed day 2, with 21% of participants experiencing vomiting. By delayed day 7, only 9% of participants still reported vomiting. The severity of vomiting was moderate to severe in 11% to 12% of subjects. Age and gender had no significant effect on delayed vomiting. The emetic potential of the agent, incomplete protection from acute vomiting, and treatment regimens that lasted 6 or more days significantly affected delayed vomiting. In addition, a history of motion sickness, lack of acute control, and 6 or more days of chemotherapy were predictive of delayed vomiting.

背景与目标： : 延迟呕吐是用于治疗儿童癌症的化学疗法的潜在重大不良反应，但对儿童和青少年延迟呕吐的经验知之甚少。进行了一项探索性研究，以确定高度催吐化疗后儿童和青少年癌症患者延迟呕吐的模式，并确定可能的危险因素。在完成117周期高催吐化疗的82名儿童和青少年样本中，延迟呕吐的总体患病率为32%。延迟呕吐的频率在延迟第2天最高，有21% 的参与者出现呕吐。延迟第7天，只有9% 的参与者仍报告呕吐。11% 至12% 的受试者呕吐的严重程度为中度至重度。年龄和性别对延迟呕吐无明显影响。药物的催吐潜力，对急性呕吐的不完全保护以及持续6天或更长时间的治疗方案显着影响了延迟呕吐。此外，有晕车史，缺乏急性控制以及6天或更长时间的化疗可预测呕吐延迟。

BACKGROUND & AIMS: BACKGROUND:Patients with moderately-to-severely active ulcerative colitis (UC) are unlikely to continue anti-TNF therapy in the absence of early therapeutic response. AIM:To assess week 52 efficacy, safety and benefit/risk balance of adalimumab treatment in patients with moderately-to-severely active UC failing conventional therapy who achieved clinical response at week 8 in the 52-week ULTRA 2 trial. METHODS:Patients randomised to adalimumab (160/80 mg, week 0/2; 40 mg, every other week thereafter) in ULTRA 2 who achieved clinical response at week 8 per partial Mayo score (Mayo score without endoscopy subscore) were assessed for week 52 clinical remission, clinical response, mucosal healing, steroid-free remission and steroid discontinuation rates, overall and by prior anti-TNF use. Benefit/risk balance for the overall ITT population (regardless of week 8 responder status) was assessed using 'net efficacy adjusted for risk' (NEAR) odds ratios. Safety was assessed using adverse event rates. RESULTS:Of 248 adalimumab-treated patients, 123 (49.6%) achieved clinical response at week 8. Of these, 30.9%, 49.6%, and 43.1% achieved clinical remission, clinical response, and mucosal healing, respectively, at week 52. Of the week 8 responders using corticosteroids at baseline (N = 90), 21.1% achieved steroid-free remission and 37.8% were steroid-free at week 52. NEAR odds ratios indicated a positive benefit/risk balance for achievement of week 8 and week 52 response or remission without serious adverse events or serious infections. No safety concerns were identified. CONCLUSIONS:Adalimumab treatment was associated with a positive benefit/risk balance in the overall population of patients with moderately-to-severely active ulcerative colitis in ULTRA 2; early response was predictive of a positive outcome at 1 year (NCT00408629).

背景与目标：

BACKGROUND & AIMS: PURPOSE:To determine the vascularity of moderately and poorly differentiated hepatocellular carcinoma (mHCC and pHCC, respectively) as observed on and depicted by computed tomography during hepatic angiography and to perform pathological correlation. MATERIALS AND METHODS:Eighty-seven consecutive patients with 89 hepatocellular carcinomas (61 mHCCs and 28 pHCCs) were surgically resected in our hospital. The degree of contrast enhancement on computed tomography during hepatic angiography of the tumors was classified into high attenuation (H), isoattenuation (I), and low attenuation (L). We also examined hepatocellular carcinomas measuring less than 4 cm in diameter. Pathologically, the number of unpaired arteries in the tumors was determined (x200 magnification). RESULTS:The number of mHCC and pHCC in each degree of enhancement (H/I/L) was 59:1:1 and 19:6:3, respectively. The number of mHCC and pHCC measuring less than 4 cm without portal invasion was 48 and 15, respectively; the number of these tumors in each degree of enhancement (H/I/L) was 47:1:0 and 11:3:1, respectively. The mean number of unpaired arteries was 8.9 +/- 4.4 in mHCC and 5.2 +/- 4.3 in pHCC, respectively. All results were statistically significant (P < 0.01). CONCLUSIONS:Our results indicated that the arterial blood supply of pHCC was lower than that of mHCC.

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