BACKGROUND & AIMS: :In this study, the contribution of the CD5+ B cell to the preferential expression of VH 7183 and Q52 observed early in development was determined. CD5+ and CD5- B cells from BALB/c mice were isolated by fluorescence-activated cell sorter and the expression of particular VH gene families was determined directly by in situ hybridization. The results indicate that CD5+ B cells obtained from both adult and neonatal animals express Q52 at increased levels compared with CD5- B cells. Preferential expression of VH 7183 was observed only in the neonatal CD5- B cell subset. Thus, the increased expression of VH 7183 early in development is caused by the CD5- subset whereas increased Q52 expression is caused by the CD5+ subset. These results indicate that the fetal/neonatal conventional B cell is distinct from conventional adult B cells in terms of Ig gene repertoire expression.

背景与目标： : 在这项研究中，确定了CD5 b细胞对发育早期观察到的VH 7183和Q52的优先表达的贡献。通过荧光激活细胞分选仪分离BALB/c小鼠的CD5和CD5-b细胞，并通过原位杂交直接确定特定VH基因家族的表达。结果表明，与CD5-b细胞相比，从成年动物和新生动物获得的CD5 b细胞表达Q52的水平更高。仅在新生儿cd5-b细胞亚群中观察到VH 7183的优先表达。因此，VH 7183在发育早期的表达增加是由CD5-子集引起的，而Q52表达增加是由CD5 + 子集引起的。这些结果表明，就Ig基因库表达而言，胎儿/新生儿常规b细胞与常规成人b细胞不同。

BACKGROUND & AIMS: Magnetic resonance has assumed a preeminent role in the imaging evaluation of the spine. Owing to its multiplanar capability and superior soft tissue contrast, magnetic resonance imaging is the procedure of choice for a host of spinal disorders including degenerative disc disease, tumor evaluation, trauma, and spinal deformities. It represents the most accurate means of distinguishing between recurrent disc herniation and epidural fibrosis, and it excels at the assessment of many postoperative abnormalities such as infection, adjacent segment disc degeneration, and arachnoiditis. Magnetic resonance imaging is also helpful in the evaluation of numerous diagnostic challenges that are less well resolved by other means. This includes the distinction between disc herniation and epidural hematoma, synovial cyst from nonspecific fibrous thickening of a facet capsule, and the evaluation of numerous other soft tissue abnormalities. Computed tomography, computed tomography myelography, and scintigraphy continue to be useful for numerous specific disorders and in those patients with metal hardware or contraindications to magnetic resonance scanning. Overall, however, magnetic resonance is the imaging procedure preferred for many spinal disorders. This article is the first installment of a 3-part series discussing the role of magnetic resonance imaging of spinal disorders. Section 1 will describe the varying imaging modalities available and their relative advantages and disadvantages. A consideration of magnetic resonance imaging techniques will follow, followed by a discussion of the imaging manifestations of early degenerative disc disease. Section 2 will be devoted to an in depth discussion of specific pathologic processes encountered in patients with degenerative disc disease. Section 3 will end the series with a consideration of postoperative imaging followed by a discussion of spinal deformities, trauma, and neoplasms.

背景与目标： 磁共振在脊柱的成像评估中发挥了重要作用。由于其多平面能力和出色的软组织对比度，磁共振成像是许多脊柱疾病 (包括退行性椎间盘疾病，肿瘤评估，创伤和脊柱畸形) 的首选方法。它代表了区分复发性椎间盘突出症和硬膜外纤维化的最准确方法，并且擅长评估许多术后异常，例如感染，相邻节段椎间盘退变和蛛网膜炎。磁共振成像也有助于评估许多诊断难题，而其他方法无法很好地解决这些难题。这包括椎间盘突出症和硬膜外血肿之间的区别，关节突囊的非特异性纤维增厚引起的滑膜囊肿，以及对许多其他软组织异常的评估。计算机断层扫描，计算机断层扫描脊髓造影和闪烁显像对于许多特定疾病以及那些具有金属硬件或磁共振扫描禁忌症的患者仍然有用。然而，总的来说，磁共振是许多脊柱疾病首选的成像程序。本文是由3部分组成的系列文章的第一部分，讨论了脊柱疾病的磁共振成像的作用。第1节将描述可用的各种成像方式及其相对的优缺点。随后将考虑磁共振成像技术，然后讨论早期退行性椎间盘疾病的成像表现。第2节将致力于深入讨论退行性椎间盘疾病患者遇到的特定病理过程。第3节将在系列结束时考虑术后影像学，然后讨论脊柱畸形，创伤和肿瘤。

BACKGROUND & AIMS: The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25-35 years were compared with 41 elderly women age 65-83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12-30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

背景与目标： 随着年龄的增长，肠道钙吸收减少的确切机制尚不清楚。血清1,25-二羟基维生素d (1,25(OH)2D) 随着年龄的增长而降低或肠道维生素d受体 (VDR) 蛋白浓度降低是可能的原因。这项研究的目的是检查年龄对这些因素的影响。将59名年龄在25-35岁之间的年轻女性与41名年龄在65-83岁之间的老年女性进行了比较，这些女性接受了VDR，使用20 mg和100 mg钙载体的钙吸收以及钙促激素的测量。与年轻女性相比，老年女性两种测试对钙的吸收均较低 (p <0.05)。血清1,25(OH)2D和十二指肠VDR蛋白浓度在两个年龄组之间没有显着差异。血清1,25(OH)2D与青年 (r = 0.35，p <0.007) 和老年妇女 (r = 0.58，p <0.0001) 的20 mg钙吸收试验相关，与老年人的100 mg钙吸收相关 (r = 0.32; p <0.05)。VDR与年轻女性或老年女性的钙吸收无关，也与血清1,25(OH)2D和血清25-羟基维生素d无关。总而言之，钙吸收的减少不能用肠道VDR的减少来解释。血清1,25(OH)2D与两种钙吸收测试之间的相关性仅占钙吸收测试中年龄相关变化的12-30%。其他尚未了解的因素是钙吸收随年龄下降的原因。

BACKGROUND & AIMS: Pseudomonas putida U does not degrade D-glucose through the glycolytic pathway but requires (i) its oxidation to D-gluconic acid by a peripherally located constitutive glucose dehydrogenase (insensitive to osmotic shock), (ii) accumulation of D-gluconic acid in the extracellular medium, and (iii) the induction of a specific energy-dependent transport system responsible for the uptake of D-gluconic acid. This uptake system showed maximal rates of transport at 30 degrees C in 50 mM potassium phosphate buffer, pH 7.0. Under these conditions the K(m) calculated for D-gluconic acid was 6.7 microM. Furthermore, a different transport system, specific for the uptake of glucose, was also identified. It is active and shows maximal uptake rates at 35 degrees C in 50 mM potassium phosphate buffer, pH 6.0, with a K(m) value of 8.3 microM.

背景与目标： 恶臭假单胞菌U不会通过糖酵解途径降解D-葡萄糖，但需要 (i) 通过位于外周的组成型葡萄糖脱氢酶将其氧化为D-葡萄糖酸 (对渗透休克不敏感)，(ii) D-葡萄糖酸在细胞外培养基中的积累，(iii) 诱导负责吸收D-葡萄糖酸的特定能量依赖性转运系统。该吸收系统在50 mM磷酸钾缓冲液 (pH 7.0) 中显示了在30 ℃ 下的最大转运速率。在这些条件下，计算的D-葡萄糖酸的K(m) 为6.7微米。此外，还确定了特定于葡萄糖摄取的不同转运系统。它具有活性，并在50 mM磷酸钾缓冲液 (pH 6.0) 中的35摄氏度下显示出最大的吸收速率，K(m) 值为8.3微米。

BACKGROUND & AIMS: :Debt among Canadian university graduates is increasing, while money apportioned to federal and provincial needs-based student assistance programs has been decreasing since the 1990s. Dental students have had to absorb increased tuition fees at both the undergraduate and post-baccalaureate levels. Existing debt and high tuition fees may adversely influence a potential candidate"s decision to enroll in dental school. Likewise, debt incurred during the minimum 2 years of pre-dental education adds to the future debt load of dental graduates. It seems that few dental students can remain debt-free during their dental education, although data are lacking about the extent of debt among dental students and its impact on their career decisions. Government statistics focus primarily on tuition costs for baccalaureate-degree students. Tuition and clinic-related fees constitute a significant proportion of costs for dental students; moreover, university administrations perceive dentistry as an expensive curriculum. This first article of a 4-part series examines debt among dental students, both nationally and internationally.

背景与目标： : 自20世纪90年代以来，加拿大大学毕业生的债务正在增加，而分配给联邦和省级基于需求的学生援助计划的资金却在减少。牙科学生不得不在本科和学士学位后水平上吸收增加的学费。现有的债务和高昂的学费可能会对潜在候选人就读牙科学校的决定产生不利影响。同样，在至少2年的牙科前教育期间产生的债务增加了牙科毕业生未来的债务负担。尽管缺乏有关牙科学生的债务程度及其对职业决定的影响的数据，但似乎很少有牙科学生在牙科教育期间能够保持无债务状态。政府统计数据主要集中在学士学位学生的学费上。学费和诊所相关费用占牙科学生费用的很大一部分; 此外，大学管理部门认为牙科是一项昂贵的课程。由4部分组成的系列文章的第一篇文章研究了国内外牙科学生的债务。

BACKGROUND & AIMS: OBJECTIVE:The scholarly dissemination of innovative medical education practices helps broaden the reach of this type of work, allowing scholarship to have an impact beyond a single institution. There is little guidance in the literature for those seeking to publish program evaluation studies and innovation papers. This study aims to derive a set of evidence-based features of high-quality reports on innovations in emergency medicine (EM) education. METHODS:We conducted a scoping review and thematic analysis to determine quality markers for medical education innovation reports, with a focus on EM. A search of MEDLINE, EMBASE, ERIC, and Google Scholar was augmented by a hand search of relevant publication guidelines, guidelines for authors, and website submission portals from medical education and EM journals. Study investigators reviewed the selected articles, and a thematic analysis was conducted. RESULTS:Our search strategy identified 14 relevant articles from which 34 quality markers were extracted. These markers were grouped into seven important themes: goals and need for innovation, preparation, innovation development, innovation implementation, evaluation of innovation, evidence of reflective practice, and reporting and dissemination. In addition, multiple outlets for the publication of EM education innovations were identified and compiled. CONCLUSION:The publication and dissemination of innovations are critical for the EM education community and the training of health professionals. We anticipate that our list of innovation report quality markers will be used by EM education innovators to support the dissemination of novel educational practices.

背景与目标：

BACKGROUND & AIMS: :Recently, growing interest in vitamin D has emerged from findings that demonstrate a low vitamin D status in populations. Similarly, much interest has been shown in the role that anti-Müllerian hormone (AMH) plays in reproductive physiology. Considerable confusion as to whether vitamin D status is related to ovarian function can be found in the literature. Our retrospective study was performed from June 2014 to April 2015. Oocyte donors were recruited and stimulated under the antagonist protocol with gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation. In 851 stimulation cycles, we determined the association among serum total and bioavailable vitamin D levels, ovarian reserve and response to ovarian stimulation and the reproductive outcome in their recipients. We showed that vitamin D levels were unrelated to ovarian reserve or ovarian response after ovarian stimulation; in oocyte recipients, gestational outcome did not differ according to a donor's vitamin D serum status. No correlation was observed between serum AMH and vitamin D. Bioavailable vitamin D was not related to recipients' ongoing pregnancy rate. Highly prevalent vitamin D insufficiency neither impaired ovarian reserve nor response or oocyte quality in egg donors. No evidence was found for recommending the analysis of vitamin D status in oocyte donors.

背景与目标： : 最近，人们对维生素d的兴趣日益浓厚，这些发现表明人群中维生素d水平较低。同样，人们对抗苗勒激素 (AMH) 在生殖生理学中的作用也表现出了极大的兴趣。在文献中可以发现关于维生素d状态是否与卵巢功能有关的相当困惑。我们的回顾性研究是从2014年6月到2015年4月进行的。招募卵母细胞供体，并在拮抗剂方案下用促性腺激素释放激素 (GnRH) 激动剂刺激排卵。在851刺激周期中，我们确定了血清总维生素d和生物利用维生素d水平，卵巢储备和对卵巢刺激的反应以及接受者的生殖结果之间的关联。我们发现维生素d水平与卵巢储备或卵巢刺激后的卵巢反应无关; 在卵母细胞接受者中，根据供体的维生素d血清状态，妊娠结局没有差异。血清AMH与维生素d之间没有相关性。生物利用维生素d与接受者的持续怀孕率无关。非常普遍的维生素d不足不会损害卵子供体的卵巢储备，反应或卵母细胞质量。没有发现建议分析卵母细胞供体中维生素d状态的证据。

BACKGROUND & AIMS: :Differentiation-inducing factor-1 [1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one (DIF-1)] is an important regulator of cell differentiation and chemotaxis in the development of the cellular slime mold Dictyostelium discoideum However, the entire signaling pathways downstream of DIF-1 remain to be elucidated. To characterize DIF-1 and its potential receptor(s), we synthesized two fluorescent derivatives of DIF-1, boron-dipyrromethene (BODIPY)-conjugated DIF-1 (DIF-1-BODIPY) and nitrobenzoxadiazole (NBD)-conjugated DIF-1 (DIF-1-NBD), and investigated their biological activities and cellular localization. DIF-1-BODIPY (5 µM) and DIF-1 (2 nM) induced stalk cell differentiation in the DIF-deficient strain HM44 in the presence of cyclic adenosine monosphosphate (cAMP), whereas DIF-1-NBD (5 µM) hardly induced stalk cell differentiation under the same conditions. Microscopic analyses revealed that the biologically active derivative, DIF-1-BODIPY, was incorporated by stalk cells at late stages of differentiation and was localized to mitochondria. The mitochondrial uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), at 25-50 nM, and dinitrophenol (DNP), at 2.5-5 µM, induced partial stalk cell differentiation in HM44 in the presence of cAMP. DIF-1-BODIPY (1-2 µM) and DIF-1 (10 nM), as well as CCCP and DNP, suppressed chemotaxis in the wild-type strain Ax2 in shallow cAMP gradients. These results suggest that DIF-1-BODIPY and DIF-1 induce stalk cell differentiation and modulate chemotaxis, at least in part, by disturbing mitochondrial activity.

背景与目标： : 分化诱导因子-1 [1-(3,5-二氯-2,6-二羟基-4-甲氧基苯基) hexan-1-one (DIF-1)] 是细胞黏菌发育过程中细胞分化和趋化性的重要调节剂DIF-1下游的整个信号通路仍有待阐明。为了表征DIF-1及其潜在受体，我们合成了两种DIF-1的荧光衍生物，硼-二吡咯亚甲基 (BODIPY)-共轭DIF-1 (DIF-1-BODIPY) 和硝基苯并恶二唑 (NBD)-共轭DIF-1 (DIF-1-NBD)，并研究了它们的生物学活性和细胞定位。在环腺苷单球 (cAMP) 存在下，DIF-1-BODIPY (5  µ m) 和DIF-1 (2  nM) 诱导DIF缺陷菌株HM44的茎细胞分化，而DIF-1-NBD (5 µm µ m) 在相同条件下几乎不诱导茎细胞分化。显微分析显示，生物活性衍生物DIF-1-BODIPY在分化后期被茎细胞掺入，并定位于线粒体。线粒体解偶联羰基氰化物间氯苯基腙 (CCCP)，在cAMP. DIF-1-BODIPY (1-2  µ m) 和DIF-1 (10  nM) 以及CCCP和DNP的存在下，HM44在25-50  nM和2.5-5  µ m诱导茎秆细胞部分分化，在浅cAMP梯度中抑制野生型菌株Ax2的趋化性。这些结果表明，DIF-1-BODIPY和DIF-1至少部分地通过干扰线粒体活性来诱导茎细胞分化并调节趋化性。

BACKGROUND & AIMS: :Previously reported propellane derivative KNT-42 preferred the κ receptor and functioned as a message part in the message-address concept, but its affinity for the κ receptor was not high. To improve affinity, we synthesized five pentacyclic propellane derivatives designed for the purpose of fixing the conformation of KNT-42. The etheno- and ethano-bridged derivatives SYK-347 and SYK-393 exhibited high affinity and selectivity for the κ receptor, whereas the other derivatives did not. These results would be due to the different ranges of movement of the basic nitrogens and less basicity of the nitrogens due to the electron withdrawing effect of the introduced hydroxy or keto group. SYK-347 and SYK-393 preferring the κ receptor were expected to be useful for designing selective ligands for opioid receptor types, especially the κ receptor.

背景与目标： : 先前报道的推进烷衍生物KNT-42更喜欢 κ 受体，并在消息地址概念中充当消息部分，但其对 κ 受体的亲和力不高。为了提高亲和力，我们合成了五个五环推进烷衍生物，目的是固定KNT-42的构象。etheno和ethano桥接的衍生物SYK-347和SYK-393对 κ 受体表现出高亲和力和选择性，而其他衍生物则没有。这些结果是由于碱性氮的运动范围不同，而由于引入的羟基或酮基的吸电子效应，氮的碱度较低。优选 κ 受体的SYK-347和SYK-393被认为可用于设计阿片受体类型的选择性配体，尤其是 κ 受体。

BACKGROUND & AIMS: :Vitamin D hormone (1,25-dihydroxyvitamin D) is involved in innate immunity and induces host defense peptides in epithelial cells, suggesting its involvement in mucosal defense against infections. Chlamydia trachomatis is a major cause of bacterial sexually transmitted disease worldwide. We tested the hypothesis that the vitamin D endocrine system would attenuate chlamydial infection. Vitamin D receptor knock-out mice (VDR(-/-)) and wild-type mice (VDR(+/+)) were infected with 10(3) inclusion forming units of Chlamydia muridarum and cervical epithelial cells (HeLa cells) were infected with C. muridarum at multiplicity of infection 5:1 in the presence and absence of 1,25-dihydroxyvitamin D3. VDR(-/-) mice exhibited significantly higher bacterial loading than wild-type VDR(+/+) mice (P<0.01) and cleared the chlamydial infection in 39 days, compared with 18 days for VDR(+/+) mice. Monocytes and neutrophils were more numerous in the uterus and oviduct of VDR(-/-) mice than in VDR(+/+) mice (P<0.05) at d 45 after infection. Pre-treatment of HeLa cells with 10nM or 100nM 1,25-dihydroxyvitamin D3 decreased the infectivity of C. muridarum (P<0.001). Several differentially expressed protein spots were detected by proteomic analysis of chlamydial-infected HeLa cells pre-treated with 1,25-dihydroxyvitamin D3. Leukocyte elastase inhibitor (LEI), an anti-inflammatory protein, was up-regulated. Expression of LEI in the ovary and oviduct of infected VDR(+/+) mice was greater than that of infected VDR(-/-) mice. We conclude that the vitamin D endocrine system reduces the risk for prolonged chlamydial infections through regulation of several proteins and that LEI is involved in its anti-inflammatory activity.

背景与目标： : 维生素d激素 (1,25-二羟基维生素d) 参与先天免疫，并在上皮细胞中诱导宿主防御肽，表明其参与粘膜防御感染。沙眼衣原体是全球细菌性性传播疾病的主要原因。我们检验了维生素d内分泌系统会减轻衣原体感染的假设。维生素d受体敲除小鼠 (VDR(-/-)) 和野生型小鼠 (VDR (/)) 感染了10(3) 包涵体形成单位的衣原体和宫颈上皮细胞 (HeLa细胞) 感染多重性的C. muridarum 5:1在存在和不存在1的情况下，25-二羟基维生素d3。VDR(-/-) 小鼠表现出显著高于野生型VDR(+/+) 小鼠的细菌负荷 (P<0.01)，并且在39天内清除衣原体感染，而VDR(+/+) 小鼠为18天。在感染后第45天，VDR(-/-) 小鼠的子宫和输卵管中的单核细胞和中性粒细胞多于VDR (/+) 小鼠 (P<0.05)。用10nM或100nM 1,25-二羟基维生素D3预处理HeLa细胞会降低C. muridarum的感染性 (P<0.001)。通过用1,25-二羟基维生素d3预处理的衣原体感染的HeLa细胞的蛋白质组学分析，检测了几个差异表达的蛋白质斑点。抗炎蛋白白细胞弹性蛋白酶抑制剂 (LEI) 上调。感染的VDR (/) 小鼠的卵巢和输卵管中LEI的表达大于感染的VDR(-/-) 小鼠的表达。我们得出的结论是，维生素d内分泌系统通过调节多种蛋白质降低了长期衣原体感染的风险，并且LEI参与了其抗炎活性。

BACKGROUND & AIMS: :The neuropeptide calcitonin gene-related peptide (CGRP) plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Coadministration of rizatriptan, a 5-HT(1B/D) agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.

背景与目标： : 神经肽降钙素基因相关肽 (CGRP) 在偏头痛的病理生理中起关键作用。我们关注CGRP在畏光中的作用，这是一种常见的偏头痛症状。我们以前使用基于操作的测定法来显示CGRP致敏的转基因 (nestin/hRAMP1)，但不是对照，小鼠对脑室内CGRP注射表现出光厌恶。一个关键问题是转基因表型是否归因于CGRP受体在内源性或新型表达位点的过表达。我们认为，如果内源性受体位点足以引起光厌恶行为，那么当给予足够强的刺激时，野生型小鼠也应显示出表型。在这项研究中，我们报告了具有正常水平的内源性CGRP受体的小鼠在CGRP给药后表现出避免光的作用。这种表型需要两个因素的结合: 更高的光强度和测试室的习惯。对照测试证实，光厌恶取决于同时暴露于CGRP和光，不能用焦虑增加来完全解释。此外，CGRP仅在黑暗中而不是在光线中减少运动。利扎曲普坦是一种5-HT(1B/D) 激动剂抗偏头痛药物，可减轻外源性CGRP对光厌恶和运动的影响。这表明曲坦类药物可以通过不同于抑制CGRP释放的机制起作用。因此，我们证明内源性CGRP受体的激活足以引起小鼠的光厌恶，这可以通过通常用于治疗偏头痛的药物来调节。

BACKGROUND & AIMS: :Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework.

背景与目标： 迫切需要新的结核病治疗策略。有许多不同的评估抗结核药物活性的临床前模型，但尚不清楚哪种模型组合最能预测临床治疗效果。这项研究的目的是确定我们的体外时间杀伤动力学测定法作为评估抗结核药物活性的预测性临床前建模框架的资产的作用。在暴露于结核分枝杆菌北京基因型菌株的过程中，确定了六种抗结核药物的浓度和时间依赖性的分枝杆菌杀伤能力，并评估了耐药性。链霉素，利福平和异烟肼对快速生长的结核分枝杆菌最有效。异烟肼与利福平或高剂量乙胺丁醇是唯一的协同药物组合。在异烟肼中添加利福平或链霉素可防止异烟肼耐药性。体外排名显示，对于某些 (但不是所有) 抗结核药物，结核病患者的早期杀菌活性一致。时间杀伤动力学测定法提供了有关药物暴露早期抗结核药物的分枝杆菌杀伤动力学的重要信息。因此，该测定是临床前建模框架的有价值的组成部分。

BACKGROUND & AIMS: Context:Vitamin D deficiency patients have an increased cardiovascular (CV) morbidity and mortality. Carotid intima-media thickness (IMT) and carotid plaques are markers of subclinical atherosclerosis and predictors of CV events. Objective:To perform a meta-analysis of studies evaluating the impact of Vitamin D deficiency on common carotid artery IMT (CCA-IMT) and on the prevalence of carotid plaques. Data Sources:Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Results:Twenty-one studies (3,777 Vitamin D deficiency patients and 4,792 controls) with data on CCA-IMT and 6 studies (1,889 Vitamin D deficiency patients and 2,883 controls) on the prevalence of carotid plaques were included. Compared to controls, Vitamin D deficiency patients showed a significantly higher CCA-IMT (mean difference [MD]: 0.043 mm; 95%CI: 0.030, 0.056; P<0.001), and an increased prevalence of carotid plaques (Odds Ratio [OR]: 2.29, 95%CI: 1.03-5.11; P=0.043) with an attributable risk of 35.9%. When selecting studies specifically including patients with diabetes, the prevalence of carotid plaques in Vitamin D deficiency patients than in controls resulted higher (OR: 3.27; 95%CI: 1,62-6.62; P=0.001). A significant difference in CCA-IMT was confirmed when comparing patients with Vitamin D insufficiency to controls (MD: 0.011; 95%CI: 0.010-0.012, P<0.001). Sensitivity analyses substantially confirmed results and regression models showed that with the exception of LDL-cholesterol, HDL-cholesterol, triglycerides and the prevalence of hypercholesterolemia, all the other clinical and demographic co-variates significantly impacted on the difference in CCA-IMT between Vitamin D deficiency patients and controls. Conclusions:Both Vitamin D deficiency and Vitamin D insufficiency are associated with subclinical atherosclerosis, potentially suggesting an increased CV risk in these clinical settings.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS:One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS:Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

背景与目标：

BACKGROUND & AIMS: :Rat brain synaptosomal membranes that are depleted of endogenous excitatory amino acids cannot bind [(+)-5-methyl-10, 11-dihydro-5H-dibenzo(a,d]cyclohept-5,10-imine maleate] ([3H]MK-801). However, they do so upon the restoration of excitatory amino acid agonists such as L-glutamate. [3H]MK-801 provides a molecular probe which is specific for a binding site located within the ionophore of the N-methyl-D-aspartate-type excitatory amino acid receptor, [3H]MK-801 does not bind to non-N-methyl-D-aspartate excitatory amino acid receptors. Exploiting [3H]MK-801 binding as a quantitative measure of agonist activity with respect to ability of inducing the open channel conformation, the present study demonstrates that L-homocysteate is an agonist almost equivalent to L-glutamate in terms of efficacy (maximal N-methyl-D-aspartate response) as well as potency (EC50). The effect of L-homocysteate was dose-dependent, stereospecific (L-homocysteate greater than DL-homocysteate greater than D-homocysteate), suppressible by the N-methyl-D-aspartate-selective competitive antagonist (+/-)-3(2-carboxy-piperazine-4-yl)propyl-l-phosphonate, and potentiated by the N-methyl-D-aspartate-selective "allosteric" modulator glycine. The demonstrated inactivity of L-homocysteine (and virtually all naturally occurring, non-acidic amino acids) implies that the omega-sulphonic acid moiety is an acceptable substitute for the omega carboxyl group for activating the N-methyl-D-aspartate receptor. While the potency of L-homocysteate at N-methyl-D-aspartate receptors was by a factor of only 1.6 smaller than that of L-glutamate, the affinity of L-homocysteate for kainate-type excitatory amino acid receptors was approximately four-fold lower than that of L-glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： : 消耗内源性兴奋性氨基酸的大鼠脑突触体膜不能结合 [(+)-5-甲基-10,11-dihydro-5H-dibenzo(a，d]cyclohept-5，马来酸10-亚胺] ([3H]MK-801)。它们是在兴奋性氨基酸激动剂如L-谷氨酸恢复时这样做的。[3H]MK-801提供了一种分子探针，该探针对位于N-甲基-D-天冬氨酸型兴奋性氨基酸受体的离子载体内的结合位点具有特异性，[3H]MK-801不结合非N-甲基-D-天冬氨酸兴奋性氨基酸受体。利用 [3H]MK-801结合作为关于诱导开放通道构象能力的激动剂活性的定量测量，本研究表明，L-同型半胱氨酸在功效 (最大N-甲基-D-天冬氨酸反应) 和效力 (EC50) 方面几乎等同于L-谷氨酸。L-同型半胱氨酸的作用是剂量依赖性的，立体特异性 (L-高半胱氨酸大于DL-高半胱氨酸大于D-高半胱氨酸)，可被N-甲基-D-天冬氨酸选择性竞争性拮抗剂 (/-)-3(2-羧基哌嗪-4-基) 丙基-l-膦酸酯抑制，并由N-甲基-D-天冬氨酸选择性 “变构” 调节剂甘氨酸增强。已证明L-高半胱氨酸 (几乎所有天然存在的，非酸性氨基酸) 意味着 ω-磺酸部分是激活N-甲基-D-天冬氨酸受体的 ω 羧基的可接受替代品。而L-同型半胱氨酸在N-甲基-D-天冬氨酸受体上的效力仅比1.6小L-谷氨酸，L-同型半胱氨酸对红藻氨酸型兴奋性氨基酸受体的亲和力大约比L-谷氨酸低4倍。(摘要截短于250字)