BACKGROUND & AIMS: The kinetic properties of wild-type rat brain IIa sodium channels in excised macropatches were studied using step depolarizations and ramp depolarizations to imitate the slow settling-time of voltage in two-electrode voltage clamp. Ramp depolarizations longer than 1 ms produce an increasing suppression of peak sodium current (I[Na]). Two rates of inactivation can be seen in macroscopic sodium current records from excised patches following both step and ramp depolarizations. During slow ramp depolarizations, reduction in peak I[Na] is associated with selective loss of the fastest rate of test-pulse inactivation. This change can be interpreted as resulting from inactivation of a separate sub-population of 'fast mode' channels. The slow rate of test-pulse inactivation is relatively unaffected by changing ramp durations. These results are sufficient to explain the typically slow inactivation kinetics seen in two-electrode voltage clamp recordings of sodium channels in Xenopus oocytes. Thus, the kinetics of sodium channels expressed in Xenopus oocytes are not readily characterizable by two-electrode clamp because of the large membrane capacitance and resulting slow clamp settling time which artifactually selects for slow mode channels.

背景与目标： 使用逐步去极化和斜坡去极化来模拟在两电极电压钳中电压的缓慢建立时间，研究了切除的大斑块中野生型大鼠脑IIa钠通道的动力学特性。超过1 ms的斜坡去极化会产生对钠电流峰值（I [Na]）的越来越大的抑制。在阶跃和斜波去极化后，从切下的小片的宏观钠电流记录中可以看到两种失活速率。在缓慢的斜坡去极化期间，峰值I [Na]的降低与最快的测试脉冲失活速率的选择性损失有关。可以将这种变化解释为是由于“快速模式”通道的单独子群体未激活而导致的。测试脉冲失活的缓慢速率相对不受斜坡持续时间变化的影响。这些结果足以解释爪蟾卵母细胞中钠通道的两电极电压钳记录中典型的缓慢失活动力学。因此，非洲爪蟾卵母细胞中表达的钠通道的动力学不易通过两电极钳夹来表征，因为膜电容大且钳夹建立时间慢，这是人为地选择慢模式通道的原因。

BACKGROUND & AIMS: :The purpose of this study was to examine the acute effects of a caffeine-containing supplement on upper- and lower-body strength and muscular endurance as well as anaerobic capabilities. Thirty-seven resistance-trained men (mean +/- SD, age: 21 +/- 2 years) volunteered to participate in this study. On the first laboratory visit, the subjects performed 2 Wingate Anaerobic Tests (WAnTs) to determine peak power (PP) and mean power (MP), as well as tests for 1 repetition maximum (1RM), dynamic constant external resistance strength, and muscular endurance (TOTV; total volume of weight lifted during an endurance test with 80% of the 1RM) on the bilateral leg extension (LE) and free-weight bench press (BP) exercises. Following a minimum of 48 hours of rest, the subjects returned to the laboratory for the second testing session and were randomly assigned to 1 of 2 groups: a supplement group (SUPP; n = 17), which ingested a caffeine-containing supplement, or a placebo group (PLAC; n = 20), which ingested a cellulose placebo. One hour after ingesting either the caffeine-containing supplement or the placebo, the subjects performed 2 WAnTs and were tested for 1RM strength and muscular endurance on the LE and BP exercises. The results indicated that there was a significant (p < 0.05) increase in BP 1RM for the SUPP group, but not for the PLAC group. The caffeine-containing supplement had no effect, however, on LE 1RM, LE TOTV, BP TOTV, PP, and MP. Thus, the caffeine-containing supplement may be an effective supplement for increasing upper-body strength and, therefore, could be useful for competitive and recreational athletes who perform resistance training.

背景与目标： ：这项研究的目的是检查含咖啡因的补充剂对上，下半身的力量，肌肉耐力以及无氧能力的急性作用。三十七名经过抗性训练的男性（平均/-SD，年龄：21 /-2岁）自愿参加了这项研究。在第一次实验室访问中，受试者进行了2次Wingate无氧测试（WAnT），以确定峰值功率（PP）和平均功率（MP），以及1次重复最大值（1RM），动态恒定的外部阻力强度和肌肉的测试耐力（TOTV；在耐力测试中以1RM的80％进行测试时提升的总重量）在双腿伸展（LE）和自由重量卧推（BP）锻炼中。至少休息48小时后，受试者返回实验室进行第二次测试，并随机分为2组中的1组：补充组（SUPP; n = 17），摄入含咖啡因的补充剂，或服用纤维素安慰剂的安慰剂组（PLAC； n = 20）。摄入含咖啡因的补充剂或安慰剂一小时后，受试者进行了2次WAnT，并在LE和BP锻炼中测试了1RM强度和肌肉耐力。结果表明SUPP组的BP 1RM显着增加（p <0.05），而PLAC组则没有。但是，含咖啡因的补充剂对LE 1RM，LE TOTV，BP TOTV，PP和MP无作用。因此，含咖啡因的补充剂可能是增加上半身力量的有效补充剂，因此对进行阻力训练的竞技和休闲运动员有用。

BACKGROUND & AIMS: :Consonant identification was measured for a stationary and amplitude-modulated noise masker in four listeners with flat cochlear hearing loss, and four age-matched normal-hearing listeners. The masker modulation rate was systematically varied between 2 and 128 Hz. Masking release (MR), that is better identification performance in fluctuating, than in stationary noise, was highest in a masker fluctuating at 8-16 Hz in all normal-hearing listeners. In comparison, MR was only observed in two out of the four impaired listeners. In these listeners, MR was poorer than normal, and peaked at lower rates, that is 2 or 8 Hz. MR corresponded to increased reception of information for voicing, place, and manner between 2 and 64 Hz in all normal-hearing listeners. In impaired listeners, increased reception of information was mainly observed for manner, and mainly reduced for place, but these differences were not significant. For all phonetic features, MR was observed at lower masker fluctuation rates (< or =32 Hz) than in normal-hearing listeners. This study therefore shows that cochlear damage affects MR, both quantitatively and qualitatively.

背景与目标： ：在四个平直的人工耳聋听力下降的听众和四个年龄相匹配的正常听力的听众中，对平稳和调幅的噪声掩蔽器的辅音识别进行了测量。掩蔽调制率在2到128 Hz之间系统地变化。在所有正常听力的听众中，以8-16 Hz波动的掩蔽器中，掩蔽释放（MR）的波动性要好于平稳噪声，这在静态噪声中具有更好的识别性能。相比之下，只有四个受损听者中有两个观察到了MR。在这些听众中，MR比正常人差，并且以较低的频率（即2或8 Hz）达到峰值。 MR对应于在所有正常听力的收听者中2至64 Hz之间的声音，位置和方式信息接收的增加。在听力受损的听众中，主要是通过方式观察到了信息接收的增加，而对于场所则主要是观察到的减少，但是这些差异并不明显。对于所有的语音特征，与正常听力的听众相比，在较低的掩蔽者波动率（<或= 32 Hz）下观察到了MR。因此，这项研究表明，耳蜗损害在数量和质量上都影响MR。

BACKGROUND & AIMS: :Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of approximately 80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (<10%, 10% to 50%, >or=50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed.

背景与目标： ：通过免疫组织化学法构建组织微阵列（TMA）以有效表征乳腺中大量非侵袭性上皮病变的方法是一种有吸引力的研究方法，但也带来了技术挑战。我们报告进行的方法学研究，以优化从大型乳腺癌病例对照研究中收集的无创乳腺组织中构建TMA的方法。我们使用直径为2.0毫米针头的手动排列技术，从32位乳腺癌女性的标本中构建了TMA，这些标本包括以下目标：（1）28个末梢小叶单位（TDLU）； （2）28例原位导管癌，（3）23例浸润性癌。通过精心选择目标，我们通过TMA第30节实现了约80％的非侵入性目标的代表，并得到了持续的保护。 TDLU靶标的免疫组织化学染色显示，在30.8％的肾小管中，雌激素受体（ER）阳性染色，在50.0％中，孕激素受体（PR）染色阳性。为了建立一种有效的方法来评估TDLU中的染色结果，我们创建了一个分类评分系统，以估计含有阳性染色细胞的小管的百分比（<10％，10％至5​​0％，>或= 50％），并比较结果与那些通过肾小管计数获得的。两种方法之间的比较表明，ER染色的70.8％和PR染色的79.2％完全吻合，没有两类差异。单个区域中相同组织类型（TDLU或DCIS）的多个（多达4个）非侵入性靶标中的ER / PR表达水平显示出良好的相关性。这些数据表明，尽管精心选择了靶标，但生产无创性乳房结构的TMA是可行的，并且此类核心的免疫染色可允许对肿瘤周围组织进行有效的免疫组织化学表征。需要对该方法进行其他探索。

BACKGROUND & AIMS: :In 4 experiments, the authors investigated the reversal of spatial congruency effects when participants concurrently practiced incompatible mapping rules (J. G. Marble & R. W. Proctor, 2000). The authors observed an effect of an explicit spatially incompatible mapping rule on the way numerical information was associated with spatial responses. The authors also observed an effect of an incompatible numerical mapping rule (if smaller than 5, press right; if larger than 5, press left) on the Simon effect. This effect was observed only when both tasks used the same effectors. The results point to a shared spatial representation for explicit spatial information (locations) and implicit spatial information (numbers).

背景与目标： ：在4个实验中，作者研究了参与者同时练习不兼容的映射规则时空间一致性效果的逆转（J. G. Marble和R. W. Proctor，2000）。作者观察到明确的空间不兼容映射规则对数字信息与空间响应相关联的方式的影响。作者还观察到不兼容的数字映射规则（如果小于5，请按向右；如果大于5，请按向左）对西蒙效果的影响。仅当两个任务使用相同的效应器时，才观察到这种效果。结果指向用于显式空间信息（位置）和隐式空间信息（数字）的共享空间表示。

BACKGROUND & AIMS: :Extensive literatures have shown significant trend of progressive electrical changes according to the proliferative characteristics of breast epithelial cells. Physiologists also further postulated that malignant transformation resulted from sustained depolarization and a failure of the cell to repolarize after cell division, making the area where cancer develops relatively depolarized when compared to their non-dividing or resting counterparts. In this paper, we present a new approach, the Biofield Diagnostic System (BDS), which might have the potential to augment the process of diagnosing breast cancer. This technique was based on the efficacy of analysing skin surface electrical potentials for the differential diagnosis of breast abnormalities. We developed a female breast model, which was close to the actual, by considering the breast as a hemisphere in supine condition with various layers of unequal thickness. Isotropic homogeneous conductivity was assigned to each of these compartments and the volume conductor problem was solved using finite element method to determine the potential distribution developed due to a dipole source. Furthermore, four important parameters were identified and analysis of variance (ANOVA, Yates' method) was performed using design (n = number of parameters, 4). The effect and importance of these parameters were analysed. The Taguchi method was further used to optimise the parameters in order to ensure that the signal from the tumour is maximum as compared to the noise from other factors. The Taguchi method used proved that probes' source strength, tumour size and location of tumours have great effect on the surface potential field. For best results on the breast surface, while having the biggest possible tumour size, low amplitudes of current should be applied nearest to the breast surface.

背景与目标： ：大量文献显示，根据乳腺上皮细胞的增殖特性，进行性电变化的显着趋势。生理学家还进一步假设，恶性转化是由于持续的去极化和细胞分裂后细胞无法重新极化所致，因此与非分裂或静止状态的癌症相比，癌症发展的区域相对去极化了。在本文中，我们提出了一种新的方法，即Biofield Diagnostic System（BDS），它可能具有增强乳腺癌诊断过程的潜力。该技术基于分析皮肤表面电势以鉴别诊断乳房异常的功效。我们通过将乳房视作处于仰卧状态的半球，且各层厚度不相等，从而开发出了接近实际的女性乳房模型。各向同性的电导率分配给这些隔室中的每一个，并使用有限元方法解决了体积导体问题，以确定由偶极子源产生的电势分布。此外，确定了四个重要参数，并使用设计进行了方差分析（ANOVA，Yates方法）（n =参数数量4）。分析了这些参数的作用和重要性。 Taguchi方法进一步用于优化参数，以确保与其他因素产生的噪声相比，来自肿瘤的信号最大。使用的Taguchi方法证明了探针的源强度，肿瘤大小和肿瘤位置对表面电势场有很大的影响。为了在乳腺表面获得最佳效果，同时应尽可能增大肿瘤的大小，应在最靠近乳腺表面的地方施加较小的电流。

BACKGROUND & AIMS: OBJECTIVE:The purpose of our study was to evaluate the effects of 0.3-second high-resolution CT (HRCT) of the lung using partial reconstruction on cardiac motion artifacts and image noise. SUBJECTS AND METHODS:Thirty-seven pairs of 0.3-second (partial reconstruction) and 0.75-second (full reconstruction) HRCT images were obtained for the lower lung zone during full-inspiration breath-holding. Imaging parameters other than temporal resolution were identical for each patient. Two radiologists visually graded motion artifacts of the cardiac border, bronchi, pulmonary vessels, and fissure in the left lung on a 4-point scale (with 4 indicating no artifacts). The maximum width of motion along the left cardiac border and the area percentage of motion artifacts in the left lung were calculated. Image noise in the air and lung was also determined. Cardiac motion artifacts and image noises were compared between the two sets of CT images. RESULTS:Visual grades for the cardiac border (4 +/- 0), bronchi (3.8 +/- 0.7), pulmonary vessels (3.6 +/- 0.8), and fissure (3.9 +/- 0.5) were higher for 0.3-second images than for 0.75-second images (1.7 +/- 0.7, 2.0 +/- 1.0, 1.6 +/- 0.7, and 2.4 +/- 0.9, respectively) (p < 0.001). The maximum width of motion along the left cardiac border (0.1 +/- 0.5 mm) and the area percentage of motion artifacts in the left lung (6.7% +/- 18.4%) were smaller for 0.3-second images than for 0.75-second images (4.5 +/- 1.7 mm and 36.2% +/- 20.9%, respectively) (p < 0.001). Image noises in the air (38.0 +/- 9.2) and the lung (86.0 +/- 23.1) were greater for 0.3-second images than for 0.75-second images (35.6 +/- 9.6 and 76.0 +/- 20.3, respectively) (p < 0.01). CONCLUSION:Compared with 0.75-second HRCT using full reconstruction, 0.3-second HRCT using partial reconstruction substantially reduces cardiac motion artifacts in the lung at the expense of increasing image noise.

背景与目标： 目的：本研究的目的是通过部分重建对心脏运动伪影和图像噪声的效果，评估0.3秒高分辨率肺部CT（HRCT）的影响。
研究对象和方法：在全屏吸气时，获得了37对0.3秒（部分重建）和0.75秒（完全重建）的HRCT图像，用于下肺区。对于每个患者，除时间分辨率以外的成像参数均相同。两位放射科医生对心脏边界，支气管，肺血管和左肺裂的运动伪影进行了4分制的视觉分级（其中4表示无伪影）。计算沿左心脏边界的最大运动宽度和左肺中运动伪影的面积百分比。还确定了空气和肺中的图像噪声。比较两组CT图像之间的心脏运动伪影和图像噪声。
结果：0.3秒图像的心脏边界（4 /-0），支气管（3.8 /-0.7），肺血管（3.6 /-0.8）和裂痕（3.9 /-0.5）的视觉等级高于0.75秒图像（分别为1.7 /-0.7、2.0 /-1.0、1.6 /-0.7和2.4 /-0.9）（p <0.001）。对于0.3秒的图像，沿左心脏边界的最大运动宽度（0.1 /-0.5 mm）和左肺中的运动伪影的面积百分比（6.7％/-18.4％）小于0.75秒的图像（分别为4.5±1.7毫米和36.2％±20.9％（p <0.001）。对于0.3秒的图像，空气（38.0 /-9.2）和肺（86.0 /-23.1）的图像噪声大于0.75秒的图像噪声（分别为35.6 /-9.6和76.0 /-20.3）（p <0.01 ）。
结论：与使用完全重建的0.75秒HRCT相比，使用部分重建的0.3秒HRCT可以显着减少肺部的心脏运动伪影，但会增加图像噪声。

BACKGROUND & AIMS: Prostate-specific antigen (PSA), a glycoprotein initially thought to be produced only by the epithelial cells of the prostate, has recently been found in 30% of female breast tumours using immunofluorometry. Our aim was to localize PSA immunohistochemically in a selected group of 27 paraffin-embedded breast tissues. A scoring system was developed for the histological assessment of PSA positivity within the breast tissue. One pathologist (DH) scored, classified and graded all tumours. Site-specific PSA staining was noted in the histology slides. Intense staining was identified in apocrine metaplasia and within the lining ductal epithelium of cystically dilated ducts. The epithelium in lesions of sclerosing adenosis was also frequently positive for PSA staining. Hyperplastic ductal epithelium (especially of mild degree) occasionally stained positive, as did normal breast ducts. Better differentiated tumours showed PSA staining [e.g. mucinous carcinoma (colloid)]. If an infiltrating duct carcinoma showed staining for PSA, adjacent intraductal carcinoma was also noted to stain positively, if present.

背景与目标： 前列腺特异性抗原（PSA）是一种最初被认为仅由前列腺上皮细胞产生的糖蛋白，最近在30％的女性乳腺肿瘤中使用免疫荧光法发现了这种蛋白。我们的目标是通过免疫组织化学方法将PSA定位在27个石蜡包埋的乳腺组织中。开发了评分系统用于乳腺组织内PSA阳性的组织学评估。一名病理学家（DH）对所有肿瘤进行了评分，分类和分级。组织学幻灯片中记录了位点特异性PSA染色。在顶泌化生和囊性扩张管的衬里导管上皮中鉴定到强染色。硬化性腺病病灶中的上皮也常对PSA染色呈阳性。增生性导管上皮（尤其是轻度导管）偶尔染色为阳性，正常乳腺导管也是如此。分化更好的肿瘤表现出PSA染色[例如粘液癌（胶体）]。如果浸润性导管癌显示PSA染色，则也可以发现邻近的导管内癌也呈阳性染色。

BACKGROUND & AIMS: :A retrospective study of male breast cancer was undertaken at Ouagadougou University Teaching Hospital over a 3 year period (1993-1996). Authors report 5 cases representing 4.16% of all breast cancers. The patients' mean age was 61 years. The average duration of signs and symptoms before the diagnosis was 13 months. Clinically all the 5 cases presented advanced cancers (4 T4N2M0, 1 T4N2M1 according to UICC TNM System) with size ranging from 5.5, to 11.5 cm. Histology found: 2 medullary infiltrating carcinoma, 1 canalar infiltrating carcinoma, 1 colloid mucous carcinoma and 1 lobular infiltrating carcinoma. All patients had mastectomy associated with axillary clearance in 4 cases. Radiotherapy, chemotherapy and hormonotherapy were not associated because unavailable in Burkina Faso. Three patients died: the first, 10 days after surgical treatment and the 2 others respectively after 14 and 17 months. We have lost sight 1 patients. The last one is still alive. Authors find that to get better prognosis, it is important to improve medical and technical means, to increase information and to promote early detection.

背景与目标： ：在瓦加杜古大学教学医院进行了为期3年（1993年至1996年）的男性乳腺癌回顾性研究。作者报告了5例病例，占所有乳腺癌的4.16％。患者的平均年龄为61岁。诊断前平均体征和症状持续时间为13个月。临床上，所有5例患者均出现晚期癌（根据UICC TNM System，4例T4N2M0、1例T4N2M1），大小在5.5至11.5厘米之间。组织学发现：2个髓样浸润癌，1个管状浸润癌，1个胶体粘​​液癌和1个小叶浸润癌。所有患者均进行了伴有腋窝清除术的乳房切除术4例。放疗，化学疗法和激素疗法没有联系，因为布基纳法索无法使用。 3例患者死亡：第一例，手术治疗10天后死亡，另外2例分别在14个月和17个月后死亡。我们失去了视力1例患者。最后一个还活着。作者发现，要获得更好的预后，重要的是改善医学和技术手段，增加信息并促进早期发现。

BACKGROUND & AIMS: :Rhodopseudomonas palustris is a purple, facultatively phototrophic bacterium that uses hydrogen gas as an electron donor for carbon dioxide fixation during photoautotrophic growth or for ammonia synthesis during nitrogen fixation. It also uses hydrogen as an electron supplement to enable the complete assimilation of oxidized carbon compounds, such as malate, into cell material during photoheterotrophic growth. The R. palustris genome predicts a membrane-bound nickel-iron uptake hydrogenase and several regulatory proteins to control hydrogenase synthesis. There is also a novel sensor kinase gene (RPA0981) directly adjacent to the hydrogenase gene cluster. Here we show that the R. palustris regulatory sensor hydrogenase HupUV acts in conjunction with the sensor kinase-response regulator protein pair HoxJ-HoxA to activate hydrogenase expression in response to hydrogen gas. Transcriptome analysis indicated that the HupUV-HoxJA regulatory system also controls the expression of genes encoding a predicted dicarboxylic acid transport system, a putative formate transporter, and a glutamine synthetase. RPA0981 had a small effect in repressing hydrogenase synthesis. We also determined that the two-component system RegS-RegR repressed expression of the uptake hydrogenase, probably in response to changes in intracellular redox status. Transcriptome analysis indicated that about 30 genes were differentially expressed in R. palustris cells that utilized hydrogen when growing photoheterotrophically on malate under nitrogen-fixing conditions compared to a mutant strain that lacked uptake hydrogenase. From this it appears that the recycling of reductant in the form of hydrogen does not have extensive nonspecific effects on gene expression in R. palustris.

背景与目标： ：Rhodopseudomonas palustris是一种紫色的兼性光养细菌，它利用氢气作为电子供体，在光养植物生长过程中固定二氧化碳，或在固氮过程中合成氨气。它还使用氢作为电子补充剂，以在光异养生长期间将氧化的碳化合物（例如苹果酸）完全同化到细胞材料中。 R. palustris基因组预测膜结合的镍铁摄取氢化酶和几种调节蛋白来控制氢化酶的合成。与氢化酶基因簇直接相邻的还有一个新的传感器激酶基因（RPA0981）。在这里，我们显示帕氏疟原虫调节传感器氢化酶HupUV与传感器激酶响应调节蛋白对HoxJ-HoxA共同作用，以响应氢气激活氢化酶表达。转录组分析表明，HupUV-HoxJA调节系统还控制编码预测的二羧酸转运系统，推定的甲酸盐转运蛋白和谷氨酰胺合成酶的基因的表达。 RPA0981在抑制氢化酶合成方面作用很小。我们还确定了两组分系统RegS-RegR抑制摄取氢化酶的表达，可能是响应细胞内氧化还原状态的变化。转录组分析表明，与缺乏摄取氢酶的突变菌株相比，当在固氮条件下在苹果酸上光异养生长时，利用氢的pal.ris细胞中约有30个基因差异表达。由此看来，还原剂以氢的形式的循环利用对R. palustris的基因表达没有广泛的非特异性影响。

BACKGROUND & AIMS: :Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin increased dopamine receptors in the rat prefrontal cortex [Q. Wang, W.L. Ting, H. Yang, P.T. Wong, High doses of simvastatin upregulate dopamine D(1) and D(2) receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol. 144 (2005) 933-939] and restored its downregulation in a model of Parkinson's disease (PD) [Q. Wang, P.H. Wang, C. McLachlan, P.T. Wong, Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats, Brain Res. 1045 (2005) 229-233]. Here we explore the effects of simvastatin treatment on tissue dopamine content and reuptake. Sprague-Dawley rats were given simvastatin (1 and 10 mg kg(-1)day(-1), p.o.) for 4 weeks. Brain tissue from prefrontal cortex and striatum were taken out for dopamine content and its reuptake. Using high-performance liquid chromatographic-mass spectrometer (HPLC-MS), simvastatin (10 mg kg(-1)day(-1)) was found to increase dopamine content by 110% in the striatum but decreased by 76% in the prefrontal cortex compared with the saline treated group. Dopamine (DA) reuptake was unchanged in both brain regions. These results suggest that chronic treatment with high dose of simvastatin may affect DA tissue level in prefrontal cortex and striatum without changing on DA reuptake. This may have important clinical implications in psychiatric and striatal dopaminergic disorders.

背景与目标： 他汀类药物已被用于治疗多种疾病，这些症状超出了降低胆固醇的最初指标。我们先前曾报道辛伐他汀会增加大鼠前额叶皮层中的多巴胺受体[Q.王伟丁宏阳Wong，高剂量的辛伐他汀上调大鼠前额叶皮层中的多巴胺D（1）和D（2）受体表达：可能与内皮型一氧化氮合酶Br有关。 J.Pharmacol。 144（2005）933-939]，并在帕金森氏病（PD）模型中恢复了其下调[Q.王凤华Wang C.McLachlan，P.T. Wong，辛伐他汀逆转了6-羟基多巴胺诱导的帕金森病大鼠Brain Res的前额叶皮层中多巴胺D1和D2受体表达的下调。 1045（2005）229-233]。在这里，我们探讨了辛伐他汀治疗对组织多巴胺含量和再摄取的影响。 Sprague-Dawley大鼠接受辛伐他汀（1和10 mg kg（-1）day（-1），口服）4周。取出前额叶皮层和纹状体的脑组织中的多巴胺含量并重新摄取。使用高效液相色谱质谱仪（HPLC-MS），发现辛伐他汀（10 mg kg（-1）day（-1））在纹状体中可使多巴胺含量增加110％，但在前额叶中减少76％皮层与生理盐水处理组相比。在两个大脑区域中，多巴胺（DA）的再摄取均未改变。这些结果表明，高剂量辛伐他汀的长期治疗可能会影响额叶前额叶皮层和纹状体中的DA组织水平，而不会改变DA的再摄取。这在精神病和纹状体多巴胺能障碍中可能具有重要的临床意义。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： ：热休克蛋白90（HSP90）是结构折叠和维持各种蛋白质（包括与细胞信号相关的几种蛋白质）构象完整性的必需。利用HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向于多发性骨髓瘤（MM）患者，我们首先通过免疫荧光和流式细胞术分析了骨髓瘤细胞系（U266）和原发性骨髓瘤细胞中HSP90的表达。在证明HSP90在骨髓瘤细胞中表达后，通过免疫过氧化物酶染色分析了32例MM患者的档案样本。在所有患者中，骨髓瘤细胞在所有样品中均表现出强烈的HSP90细胞质表达，并且55％的患者还表现出并发的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266细胞和原代MM细胞可导致凋亡明显增加。分析与17-AAG孵育的MM细胞中的抗凋亡BCL2家族蛋白和akt，表明BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但是17AAG和硼替佐米治疗的组合显示出对U266细胞系的协同凋亡作用。这些数据表明，针对HSP90的靶向抑制可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.

背景与目标： ：氟达拉滨和阿仑单抗通常用于治疗B细胞慢性淋巴细胞性白血病（B-CLL）。本研究旨在比较氟达拉滨或alemtuzumab治疗后长期未维持的缓解/高原期的B-CLL患者的信号分子表达和T细胞的细胞因子产生与惰性/未经治疗的B-CLL患者和健康供体的长期比较。通过流式细胞术检测TCR-CD3zeta链，p56lck，p59fyn，ZAP-70，PI3-激酶和干扰素（IFN）-γ/白介素（IL）-4在CD4和CD8 T细胞中产生的频率和强度。通过用纯化的蛋白质衍生物（PPD）和植物血凝素（PHA）刺激来评估T细胞功能。尽管数量减少，但患者T细胞中IFN-γ/ IL-4的表达明显高于健康供体。与健康供体相比，已治疗患者中大多数信号分子的强度相对未受影响，但低于未治疗的惰性患者。但是，表达每种信号分子的T细胞总数在患者中减少了，在氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中，对PHA而非TPD的T细胞反应降低了。结果表明，尽管在用氟达拉滨和阿仑单抗治疗后，长期而言，尽管信号分子发生了某些变化并且T细胞数量有所减少，但总体T细胞功能仍可以得到较好的保留。

BACKGROUND & AIMS: BACKGROUND:Despite the recent improvement in techniques and patient selection, post-ERCP pancreatitis remains the most frequent and dreaded complication of ERCP. Recent studies suggest that pretreatment with glyceryl trinitrate (GTN) may prevent post-ERCP pancreatitis and improve cannulation success. OBJECTIVE:To evaluate the effect of transdermal GTN on ERCP cannulation success and post-ERCP pancreatitis. DESIGN:Prospective, double-blind, placebo-controlled trial. SETTING:Tertiary referral university hospital. PATIENTS:A total of 318 patients (mean age 62 years, 61% women) were randomized to either active (n = 155) or placebo (n = 163) arms. INTERVENTIONS:Active patch (GTN) versus placebo patch. MAIN OUTCOME MEASUREMENTS:Cannulation time and success. Post-ERCP pancreatitis rates. RESULTS:There was no significant difference between the active or placebo arms for the following: successful initial cannulation (96.8% vs 98.8%), deep cannulation (96.1% vs 98.8%), time to successful cannulation, use of guidewire (27% vs 25%) or needle knife (13% vs 13%), and post-ERCP pancreatitis (7.4% of placebo patients and 7.7% active patients). Multivariate analysis identified women, younger patients, pancreatogram, number of attempts on papilla, and poor pancreatic-duct emptying after opacification as risk factors for post-ERCP pancreatitis. Transdermal GTN did not reduce post-ERCP pancreatitis in any of the identified high-risk groups. CONCLUSIONS:Transdermal GTN did not improve the rate of success in ERCP cannulation or prevent post-ERCP pancreatitis in either average or high-risk patient groups.

背景与目标： 背景：尽管最近在技术和患者选择方面已有改进，但ERCP后胰腺炎仍然是ERCP最常见和最可怕的并发症。最近的研究表明，用三硝酸甘油酯（GTN）进行预处理可以预防ERCP后胰腺炎并提高插管成功率。
目的：评价经皮GTN对ERCP插管成功和ERCP术后胰腺炎的影响。
设计：一项前瞻性，双盲，安慰剂对照试验。
单位：大专转诊大学医院。
患者：共有318例患者（平均年龄62岁，女性占61％）被随机分配到活动组（n = 155）或安慰剂组（n = 163）。
干预措施：主动贴片（GTN）与安慰剂贴片。
主要观察指标：排尿时间和成功率。 ERCP后胰腺炎发生率。
结果：主动或安慰剂组之间在以下方面没有显着差异：成功的初始插管（96.8％vs 98.8％），深层插管（96.1％vs 98.8％），成功插管的时间，使用导丝（27％vs 25％）或针刀（13％比13％）以及ERCP后胰腺炎（安慰剂患者为7.4％，活动患者为7.7％）。多变量分析确定女性，年轻患者，胰腺造影，乳头尝试次数以及混浊后胰管排空不良是ERCP后胰腺炎的危险因素。在任何已确定的高危人群中，经皮GTN均不能减轻ERCP后胰腺炎的发生。
结论：无论是普通患者还是高危患者，经皮GTN均不能提高ERCP插管成功率或预防ERCP术后胰腺炎。

BACKGROUND & AIMS: :Responses to [D-Ala2, MePhe4, Gly-ol5]enkephalin, a selective agonist for mu-receptors, were recorded intracellularly from 26 neurons in slices of guinea-pig hypothalamus. Of eight cells tested in the supraoptic nucleus, all of which had electrical properties characteristic of magnocellular neuroendocrine cells, four were sensitive to the agonist applied in the perfusion bath or with microdrops. The main effect was a decrease or suppression of spontaneous firing. In the paraventricular nucleus, seven of 18 cells tested also had electrophysiological characteristics similar to magnocellular neurons: two of them were sensitive to the mu-agonist and the effect was similar to that observed in the supraoptic nucleus. The remaining paraventricular neurons displayed low-threshold Ca2+ spikes, and thus had electrophysiological characteristics different from putative magnocellular neurons. Ten of 11 cells with low-threshold Ca2+ spikes were hyperpolarized by more than 10 mV by the mu-agonist, and showed a 33 +/- 1.9% (S.E.M.) decrease in input resistance. In both types of cells, when synaptic transmission was blocked with tetrodotoxin, the mu-agonist could still induce a hyperpolarization, suggesting that the effect was in part direct. Hyperpolarization was also obtained when the Cl- reversal potential was shifted to more positive values by using KCl electrodes, thus excluding a Cl- conductance mechanism. These results provide evidence that opioid peptides can directly inhibit hypothalamic neurons, that the mechanism is an increase in K+ conductance, and that two types of hypothalamic neurons appear to have different sensitivities to a mu-agonist.

背景与目标： ：对豚鼠下丘脑切片中26个神经元的细胞内记录了对[D-Ala2，MePhe4，Gly-ol5]脑啡肽（一种针对mu受体的选择性激动剂）的反应。在视上核中测试的8个细胞中，所有细胞均具有大细胞神经内分泌细胞的电特性，其中4个对灌注浴或微滴中使用的激动剂敏感。主要作用是减少或抑制自发放电。在脑室旁核中，测试的18个细胞中有7个也具有类似于大细胞神经元的电生理特性：其中两个对mu激动剂敏感，作用类似于在视上核中观察到的。其余的脑室旁神经元显示低阈值的Ca2尖峰，因此具有与假定的大细胞神经元不同的电生理特性。 mu激动剂将11个具有低阈值Ca2尖峰的细胞中的10个超极化了10 mV以上，显示输入电阻降低了33 /-1.9％（S.E.M.）。在两种类型的细胞中，当突触传递被河豚毒素阻断时，mu-激动剂仍可诱导超极化，这表明这种作用部分是直接的。当通过使用KCl电极将Cl-反转电位移动到更正值时，也获得了超极化，因此排除了Cl-电导机制。这些结果提供证据证明阿片样物质肽可以直接抑制下丘脑神经元，其机制是钾电导增加，并且两种类型的下丘脑神经元似乎对μ-激动剂具有不同的敏感性。