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显示出强烈的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: Mayaro virus (alphavirus) infection of Aedes albopictus cells results in inhibition of cell protein synthesis and viral proteins are preferably synthesized. When infected cells are heat shocked, however, there is also an inhibition of viral protein synthesis, and there is preferential synthesis of heat shock proteins. Based on these observations, the distribution of Mayaro viral RNA in polysomes and the association of p34 (capsid protein) with ribosomal fractions of the cells under such conditions have been analyzed. During infection, the viral RNA is mainly observed in light polysomes (60% of total viral RNA in the cell) and also in heavy polysomes (13%). However, when infected cells are heat-shocked, the viral RNA is strongly mobilized from heavy polysomes to the light polysomes fraction and an enrichment in the unbound fraction can be noticed. The amount of p34 associated with the ribosomal fraction was also shown to be decreased in the heat shocked cells. These data lead to the suggestion that two mechanisms could be involved in the inhibition of Mayaro virus protein synthesis in response to heat shock(1) mobilization of Mayaro virus RNA from heavy to light polysomes; (2) a decrease in the amount of the p34 within the ribosomal fraction.

背景与目标： 白纹伊蚊细胞的Mayaro病毒（alphavirus）感染导致细胞蛋白合成受到抑制，并且优选合成病毒蛋白。然而，当热激感染的细胞时，也抑制了病毒蛋白的合成，并且优先合成了热激蛋白。基于这些观察，已经分析了在这种情况下Mayaro病毒RNA在多核糖体中的分布以及p34（衣壳蛋白）与细胞核糖体级分的关系。在感染过程中，病毒RNA主要在轻多核小体（细胞中总病毒RNA的60％）和重多核小体（13％）中观察到。然而，当受热细胞受到热激时，病毒RNA从重多囊泡强烈地转移到轻多囊泡部分，未结合的部分富集。在热激细胞中，与核糖体级分相关的p34的量也显示减少。这些数据表明，响应热休克反应，Mayaro病毒蛋白合成的抑制可能涉及两种机制（1）Mayaro病毒RNA从重链体到轻链体的动员； （2）核糖体组分中p34的含量减少。

BACKGROUND & AIMS: :The goal of the study was to evaluate the effect of isoproterenol prescribed in goal-directed therapy for septic shock. Out of a cohort of 89 patients with septic shock, 14 patients treated with fluid and norepinephrine had inappropriate mixed venous oxygen saturation (SvO2<70%) not responding to correction of hypoxemia and anemia (>8 g.dL-1). Isoproterenol administration was started at a dose of 0.04 microg.kg-1.minute-1 with 0.025 microg.kg-1.minute-1 increments every 30 minutes until SvO2 was greater than 70%. Mean arterial pressure was maintained>or=65 mm.Hg by adjusting the norepinephrine infusion. Hemodynamic, oxygen, and renal variables were collected during a 12-h period. Patients with a known prior history of coronary disease were not eligible. Isoproterenol administration increased significantly SvO2 (62%+/-10% to 71%+/-9%), cardiac index (3.1+/-0.6 to 4.4+/-1.4 L.min-1.m-2), stroke index (27+/-3.4 to 38+/-6.1 mL.m-2), and left ventricular stroke work index (24+/-3.4 to 40+/-5.0 g.m-1.m-2). Heart rate rise did not reach a significant level. Arterial lactate concentration decreased significantly during the study period (5.7+/-2.8 to 3.4+/-1.6 mmol.L-1). No cardiac adverse events occurred with any electrocardiographic aspects of myocardial ischemia. This study suggests that isoproterenol is efficient to improve hemodynamics and oxygen variables in septic shock patients. There is a need for future investigations in larger groups of patients to determine whether isoproterenol can be an alternative to dobutamine.

背景与目标： ：该研究的目的是评估在脓毒症休克的目标导向疗法中处方的异丙肾上腺素的疗效。在这89名败血症性休克患者中，有14名接受液体和去甲肾上腺素治疗的患者混合血氧饱和度不适当（SvO2 <70％），对低氧血症和贫血的纠正没有反应（> 8 g.dL-1）。异丙肾上腺素的给药开始于0.04 microg.kg-1.minute-1的剂量，每30分钟递增0.025 microg.kg-1.minute-1直到SvO2大于70％。通过调节去甲肾上腺素的输注量，平均动脉压维持在≥65mm.Hg。在12小时内收集血流动力学，氧气和肾脏变量。有已知冠心病病史的患者不符合条件。异丙肾上腺素给药显着增加SvO2（62％/ -10％至71％/ -9％），心脏指数（3.1 /-0.6至4.4 /-1.4 L.min-1.m-2），中风指数（27 /- 3.4至38 /-6.1 mL.m-2）和左室卒中工作指数（24 /-3.4至40 /-5.0 gm-1.m-2）。心率上升未达到显着水平。在研究期间，动脉血乳酸浓度显着下降（5.7 /-2.8至3.4 /-1.6 mmol.L-1）。心肌缺血的任何心电图方面均未发生心脏不良事件。这项研究表明，异丙肾上腺素可有效改善败血性休克患者的血流动力学和氧气变化。有必要在更大范围的患者中进行进一步的研究，以确定异丙肾上腺素是否可以替代多巴酚丁胺。

BACKGROUND & AIMS: BACKGROUND:Diagnosis of tuberculous meningitis (TBM) is difficult. Rapid confirmatory diagnosis is essential to initiate required therapy. There are very few published reports about the diagnostic significance of 65 kD heat shock protein (hsp) in TBM patients, which is present in a wide range of Mycobacterium tuberculosis species and elicits a cellular and humoral immune response. In the present study we have conducted a prospective evaluation for the demonstration of 65 kD hsp antigen in cerebrospinal fluid (CSF) of TBM patients, by indirect ELISA method using monoclonal antibodies (mAb) against the 65 kD hsp antigen, for the diagnosis of TBM. METHODS:A total of 160 CSF samples of different groups of patients (confirmed TBM {n = 18}, clinically suspected TBM {n = 62}, non TBM infectious meningitis {n = 35} and non-infectious neurological diseases {n = 45}) were analyzed by indirect ELISA method using mAb to 65 kD hsp antigen. The Kruskal Wallis test (Non-Parametric ANOVA) with the Dunnett post test was used for statistical analysis. RESULTS:The indirect ELISA method yielded 84% sensitivity and 90% specificity for the diagnosis of TBM using mAb to 65 kD hsp antigen. The mean absorbance value of 65 kD hsp antigen in TBM patients was [0.70 +/- 0.23 (0.23-1.29)], significantly higher than the non-TBM infectious meningitis group [0.32 +/- 0.14 (0.12-0.78), P < 0.001] and also higher than the non-infectious neurological disorders group [0.32 +/- 0.13 (0.20-0.78), P < 0.001]. A significant difference in the mean absorbance of 65 kD hsp antigen was noted in the CSF of culture-positive TBM patients [0.94 +/- 0.18 (0.54-1.29)] when compared with clinically suspected TBM patients [0.64 +/- 0.20 (0.23-0.98), P < 0.05]. CONCLUSION:The presence of 65 kD hsp antigen in the CSF of confirmed and suspected cases of TBM would indicate that the selected protein is specific to M. tuberculosis and could be considered as a diagnostic marker for TBM.

背景与目标： 背景：结核性脑膜炎（TBM）的诊断很困难。快速的确诊诊断对于启动所需的治疗至关重要。很少有关于65kD热休克蛋白（hsp）在TBM患者中的诊断意义的报道，该蛋白存在于广泛的结核分枝杆菌种中，并引起细胞和体液免疫应答。在本研究中，我们通过使用针对65 kD hsp抗原的单克隆抗体（mAb）的间接ELISA方法对TBM患者的脑脊液（CSF）中的65 kD hsp抗原进行了证明，以诊断TBM 。
方法：共160份不同组患者的CSF样本（已确认TBM {n = 18}，临床疑似TBM {n = 62}，非TBM传染性脑膜炎{n = 35}和非传染性神经系统疾病{n = 45 }）采用抗65 kD hsp抗原的mAb通过间接ELISA方法进行分析。使用带有Dunnett事后检验的Kruskal Wallis检验（非参数方差分析）进行统计分析。
结果：间接ELISA法对mAb至65 kD hsp抗原的TBM诊断具有84％的敏感性和90％的特异性。 TBM患者65 kD hsp抗原的平均吸光度值为[0.70 /-0.23（0.23-1.29）]，明显高于非TBM感染性脑膜炎组[0.32 // 0.14（0.12-0.78），P <0.001]并且也高于非感染性神经系统疾病组[0.32 / 0.13（0.20-0.78），P <0.001]。与临床怀疑的TBM患者相比，培养阳性的TBM患者的CSF中65 kD hsp抗原的平均吸光度存在显着差异[0.94 /-0.18（0.54-1.29）]。 ），P <0.05]。
结论：在已确诊和疑似TBM病例的脑脊液中存在65 kD hsp抗原，这表明所选蛋白对结核分枝杆菌具有特异性，可被认为是TBM的诊断标记。

BACKGROUND & AIMS: :HSP90 is a molecular chaperone that participates in folding, stabilization, activation, and assembly of several proteins, all of which are key regulators in cell signaling. In dimorphic pathogenic fungi such as Paracoccidioides brasiliensis, the adaptation to a higher temperature, acid pH and oxidative stress, is an essential event for fungal survival and also for the establishing of the infectious process. To further understand the role of this protein, we used antisense RNA technology to generate a P. brasiliensis isolate with reduced PbHSP90 gene expression (PbHSP90-aRNA). Reduced expression of HSP90 decreased yeast cell viability during batch culture growth and increased susceptibility to acid pH environments and imposed oxidative stress. Also, PbHSP90-aRNA yeast cells presented reduced viability upon interaction with macrophages. The findings presented here suggest a protective role for HSP90 during adaptation to hostile environments, one that promotes survival of the fungus during host-pathogen interactions.

背景与目标： ：HSP90是一种分子伴侣，参与多种蛋白质的折叠，稳定，激活和组装，所有这些都是细胞信号传导中的关键调控因子。在双态致病性真菌（如巴西副球菌）中，适应更高的温度，酸性pH和氧化应激，是真菌存活和建立感染过程的重要事件。为了进一步了解这种蛋白质的作用，我们使用了反义RNA技术来生成具有降低的PbHSP90基因表达的巴西假单胞菌分离物（PbHSP90-aRNA）。 HSP90的表达降低会降低分批培养物生长过程中酵母细胞的活力，并增加对酸性pH环境的敏感性和施加的氧化应激。同样，PbHSP90-aRNA酵母细胞与巨噬细胞相互作用后，活力降低。此处提出的发现表明，HSP90在适应敌对环境期间具有保护作用，可在宿主与病原体相互作用期间促进真菌的存活。

BACKGROUND & AIMS: BACKGROUND:Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas inhalation would influence the tolerance to hemorrhagic shock and improve survival. METHODS:Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation. RESULTS:The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats. CONCLUSIONS:H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock.

背景与目标： 背景：失血性休克的死亡率主要取决于患者是否可以忍受循环量的损失，直到应用根治性治疗。我们调查了吸入氢气（H2）是否会影响对出血性休克的耐受性并提高生存率。
方法：通过抽血直至平均动脉血压达到30-35 mm Hg来实现失血性休克。休克60分钟后，用相当于生理盐水四倍体积的生理盐水使大鼠复苏。将大鼠分为H2气体（1.3％H2、26％O2、72.7％N2）治疗组或对照组气体（26％O2、74％N2）治疗组。在抽血开始时开始吸入指定的气体混合物，并在进行液体复苏后继续吸入2小时。
结果：液体复苏后6小时的存活率在H2气体处理的大鼠中为80％，在对照气体处理的大鼠中为30％（p <0.05）。通过H 2气处理的大鼠，通过导管抽出的血液引起的休克量显着大于对照大鼠。尽管失去了更多的血液，但经过60分钟的电击后，H2气处理的大鼠的血清钾水平却被抑制。液体复苏完全恢复了H2气处理的大鼠的血压，而未能完全恢复对照气处理的大鼠的血压。液体复苏后2小时，H2气处理的大鼠的血压保持在正常范围内，代谢性酸中毒得到了很好的补偿，而存活的对照气处理的大鼠中血压降低，代谢性酸中毒和高钾血症没有得到补偿。
结论：吸入H2气体延迟了不可逆性休克的进展。临床上，预计吸入H2气体可使受试者稳定，直到可以进行治愈性治疗为止，从而增加失血性休克后存活的可能性。

BACKGROUND & AIMS: BACKGROUND:Increased concentrations of cell-free DNA have been found in plasma of septic and critically ill patients. We investigated the value of plasma DNA for the prediction of intensive care unit (ICU) and hospital mortality and its association with the degree of organ dysfunction and disease severity in patients with severe sepsis. METHODS:We studied 255 patients with severe sepsis or septic shock. We obtained blood samples on the day of study inclusion and 72 h later and measured cell-free plasma DNA by real-time quantitative PCR assay for the beta-globin gene. RESULTS:Cell-free plasma DNA concentrations were higher at admission in ICU nonsurvivors than in survivors (median 15 904 vs 7522 genome equivalents [GE]/mL, P < 0.001) and 72 h later (median 15 176 GE/mL vs 6758 GE/mL, P = 0.004). Plasma DNA values were also higher in hospital nonsurvivors than in survivors (P = 0.008 to 0.009). By ROC analysis, plasma DNA concentrations had moderate discriminative power for ICU mortality (AUC 0.70-0.71). In multiple regression analysis, first-day plasma DNA was an independent predictor for ICU mortality (P = 0.005) but not for hospital mortality. Maximum lactate value and Sequential Organ Failure Assessment score correlated independently with the first-day plasma DNA in linear regression analysis. CONCLUSIONS:Cell-free plasma DNA concentrations were significantly higher in ICU and hospital nonsurvivors than in survivors and showed a moderate discriminative power regarding ICU mortality. Plasma DNA concentration was an independent predictor for ICU mortality, but not for hospital mortality, a finding that decreases its clinical value in severe sepsis and septic shock.

背景与目标： 背景：在脓毒症和危重病人的血浆中发现无细胞DNA的浓度增加。我们调查了血浆DNA在重症败血症患者中预测重症监护病房（ICU）和医院死亡率及其与器官功能障碍程度和疾病严重程度的关系。
方法：我们研究了255例严重脓毒症或败血性休克患者。我们在纳入研究当日和72小时后获得了血液样本，并通过实时定量PCR检测β-珠蛋白基因来测量无细胞血浆DNA。
结果：ICU非幸存者入院时的无细胞血浆DNA浓度高于幸存者（中位数15 904 vs 7522基因组当量[GE] / mL，P <0.001）和72小时后（中位数15 176 GE / mL vs 6758 GE） /mL，P＝0.004）。住院非幸存者的血浆DNA值也高于幸存者（P = 0.008至0.009）。通过ROC分析，血浆DNA浓度对ICU死亡率具有中等判别力（AUC 0.70-0.71）。在多元回归分析中，首日血浆DNA是ICU死亡率的独立预测因子（P = 0.005），而不是医院死亡率的预测因子。在线性回归分析中，最大乳酸值和顺序器官衰竭评估得分与第一天血浆DNA独立相关。
结论：ICU和住院非幸存者的无细胞血浆DNA浓度明显高于幸存者，并且在ICU死亡率方面具有中等判别力。血浆DNA浓度是ICU死亡率的独立预测因素，但不是医院死亡率的独立预测因素，这一发现降低了其在严重败血症和败血性休克中的临床价值。

BACKGROUND & AIMS: :An understanding of the time course and correlation with injury of heat shock proteins (HSPs) released during brain and/or spinal cord cellular stress (ischemia) is critical in understanding the role of the HSPs in cellular survival, and may provide a clinically useful biomarker of severe cellular stress. We have analyzed the levels of HSPs in the cerebrospinal fluid (CSF) from patients who are undergoing thoracic aneurysm repair. Blood and CSF samples were collected at regular intervals, and CSF was analyzed by enzyme-linked immunosorbent assay for HSP70 and HSP27. These results were correlated with intraoperative somatosensory-evoked potentials measurements and postoperative paralysis. We find that the levels of these proteins in many patients are elevated and that the degree of elevation correlates with the risk of permanent paralysis. We hypothesize that sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the CSF can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery and will allow us to develop means of preventing or attenuating this severe and often fatal complication.

背景与目标： ：了解时间过程及其与脑和/或脊髓细胞应激（缺血）过程中释放的热休克蛋白（HSP）损伤的相关性对于了解HSP在细胞存活中的作用至关重要，并且可能提供临床上的帮助严重细胞应激的生物标志物。我们已经分析了正在接受胸动脉瘤修复的患者的脑脊液（CSF）中的HSPs水平。定期采集血液和脑脊液样本，并通过酶联免疫吸附法对脑脊液中的HSP70和HSP27进行分析。这些结果与术中体感诱发电位的测量和术后瘫痪有关。我们发现许多患者中这些蛋白质的水平升高，并且升高的程度与永久性麻痹的风险相关。我们假设在术中连续测量脑脊液中热休克蛋白HSP70和HSP27的水平可以预测那些在胸动脉瘤手术期间最有可能瘫痪的患者，这将使我们能够开发出预防或减轻这种严重且经常致命的并发症。

BACKGROUND & AIMS: :The purpose of this study was to examine whether selective iNOS inhibition can restore the hemodynamic changes and reduce the nitrotyrosine levels in the cerebral cortex of rats with streptozotocin-induced diabetes during endotoxin-induced shock. The study was designed to include three sets of experiments: (1) measurement of changes in systemic hemodynamics, (2) measurement of biochemical variables, including iNOS activity and nitrotyrosine formation in the brain, and (3) assessment of mortality rate. Rats were randomly divided into four groups: group 1, control; group 2, LPS: Escherichia coli endotoxin, 10.0 mg/kg (i.v.) bolus; group 3 (i.v.) LPS and L-N6-(1-iminoethyl)-lysine (L-NIL), 4mg/kg (i.p.); and group 4, LPS and NG-nitro-L-arginine methyl ester (L-NAME), 5 mg/kg (i.p.). In nondiabetic rats, administration of L-NIL prevented the hemodynamic and biochemical changes, and increases in plasma nitrite and cerebral nitrotyrosine levels induced by LPS. Administration of L-NAME partially prevented these LPS-induced changes. On the other hand, in diabetic rats, administration of L-NIL only partially prevented the hemodynamic and biochemical changes, and increases in plasma nitrite and cerebral nitrotyrosine levels associated with LPS. Administration of L-NAME, however, had no effects on these LPS-induced changes in diabetic rats. There was a significant difference in nitrotyrosine levels between nondiabetic and diabetic rats in groups 2, 3, and 4 at 2 and 3 h after the treatment (at 3 h; nondiabetic--control, 4.6 +/- 0.4; LPS (i.v.), 8.9 +/- 1.0, LPS (i.v.) + L-NIL, 4.7 +/- 0.5; LPS (i.v.) + L-NAME, 7.1 +/- 0.9; diabetic--control, 5.5 +/- 0.4; LPS (i.v.), 13.6 +/- 1.2; LPS (i.v.) + L-NIL, 9.0 +/- 0.9; LPS (i.v.) + L-NAME, 13.0 +/- 1.0; densitometric units). Insulin therapy resulted in a decrease in iNOS activity (at 3 h: 1.0 +/- 0.5 fmol mg min), nitrotyrosine formation (at 3 h; 5.0 +/- 0.5, densitometric units), and mortality rates (30% at 6 h, 50% at 12 h) in the LPS (i.v.) + L-NIL group of diabetic rats. Selective iNOS inhibition in diabetic rats could not improve hemodynamic instability, chemical changes, iNOS activity, and nitrotyrosine formation during septic shock compared with the improvements observed in nondiabetic rats. Tight glucose control along with administration of L-NIL can result in more effective restoration of the biochemical changes of septicemia in diabetic rats. Thus, hyperglycemia may be one of the mechanisms related to the aggravation of endotoxin-induced shock.

背景与目标： ：本研究的目的是研究选择性内源性iNOS抑制能否在内毒素诱导的休克期间恢复链脲佐菌素诱发的糖尿病大鼠的血流动力学变化并降低其大脑皮质的硝基酪氨酸水平。该研究设计为包括三组实验：（1）测量全身血流动力学的变化，（2）测量生化变量，包括iNOS活性和脑中硝基酪氨酸的形成，以及（3）死亡率评估。将大鼠随机分为四组：第1组，对照组；和第2组。第2组，LPS：大肠埃希菌内毒素，每次推注10.0 mg / kg（i.v.）；第3组（静脉）LPS和L-N6-（1-亚氨基乙基）-赖氨酸（L-NIL），4mg / kg（腹膜）;第4组，LPS和NG-硝基-L-精氨酸甲酯（L-NAME），5 mg / kg（腹膜内）。在非糖尿病大鼠中，L-NIL的给药阻止了血流动力学和生化变化，并增加了LPS诱导的血浆亚硝酸盐和脑硝基酪氨酸水平。 L-NAME的管理部分阻止了这些LPS引起的变化。另一方面，在糖尿病大鼠中，L-NIL的施用仅部分阻止了血流动力学和生化变化，并增加了与LPS相关的血浆亚硝酸盐和脑硝基酪氨酸水平。但是，在糖尿病大鼠中，L-NAME的给药对这些LPS诱导的变化没有影响。第2、3和4组的非糖尿病和糖尿病大鼠在治疗后2和3小时的硝酸酪氨酸水平存在显着差异（3小时;非糖尿病对照组为4.6 /-0.4; LPS（iv）为8.9） /-1.0，LPS（iv）L-NIL，4.7 /-0.5； LPS（iv）L-NAME，7.1 /-0.9；糖尿病对照，5.5 /-0.4； LPS（iv），13.6 /-1.2； LPS（iv）L-NIL，9.0 /-0.9； LPS（iv）L-NAME，13.0 /-1.0；光密度单位）。胰岛素治疗导致iNOS活性（3 h：1.0 /-0.5 fmol mg min），硝基酪氨酸形成（3 h; 5.0 /-0.5，光密度单位）和死亡率（6h，50时30％）降低LPS（iv）L-NIL组的糖尿病大鼠在12 h时的％）。与非糖尿病大鼠相比，对糖尿病大鼠的选择性iNOS抑制不能改善败血性休克期间的血流动力学不稳定，化学变化，iNOS活性和硝基酪氨酸形成。严格的葡萄糖控制以及L-NIL的使用可以使糖尿病大鼠败血病的生化变化更有效地恢复。因此，高血糖症可能是与内毒素诱发的休克加重有关的机制之一。

BACKGROUND & AIMS: PURPOSE OF REVIEW:The conventional view in severe sepsis or septic shock is that most of the lactate that accumulates in the circulation is due to cellular hypoxia and the onset of anaerobic glycolysis. A number of papers have suggested that lactate formation during sepsis is not due to hypoxia. I discuss this hypothesis and outline the recent advances in the understanding of lactate metabolism in shock. RECENT FINDINGS:Numerous experimental data have demonstrated that stimulation of aerobic glycolysis - that is, glycolysis not attributable to oxygen deficiency - and glycogenolysis occurs not only in resting, well-oxygenated skeletal muscles but also during experimental haemorrhagic shock and experimental sepsis, and is closely linked to stimulation of sarcolemmal Na+/K+ -ATPase under epinephrine stimulation. A human study of hyperkinetic septic shock demonstrated that skeletal muscle is a leading source of lactate production by exaggerated aerobic glycolysis through Na+/K+ -ATPase stimulation. SUMMARY:There is increasing evidence that sepsis is accompanied by a hypermetabolic state, with enhanced glycolysis and hyperlactataemia. This should not be rigorously interpreted as an indication of hypoxia. It now appears, at least in the hyperkinetic state, that increased lactate production and concentration as a result of hypoxia are often the exception rather than the rule.

背景与目标： 审查的目的：严重败血症或败血性休克的传统观点是，循环中积累的大多数乳酸是由于细胞缺氧和厌氧糖酵解的开始所致。许多论文表明败血症期间乳酸的形成不是由于缺氧引起的。我讨论了这一假设，并概述了休克中乳酸代谢的最新研究进展。
最近的发现：大量的实验数据表明，有氧糖酵解的刺激-即不是由于缺氧引起的糖酵解-糖原分解不仅发生在静息的，充氧的骨骼肌中，而且发生在实验性失血性休克和实验性败血症中，并且密切相关与肾上腺素刺激下肌膜Na / K -ATPase的刺激有关。一项针对运动过度性败血性休克的人体研究表明，骨骼肌是通过Na / K -ATPase刺激导致的过度有氧糖酵解产生乳酸的主要来源。
摘要：有越来越多的证据表明败血症伴有代谢亢进状态，并伴有糖酵解和高乳酸血症。不应将其严格解释为缺氧的征兆。现在看来，至少在运动亢进状态下，缺氧导致的乳酸产生和浓度增加通常是例外而不是规则。

BACKGROUND & AIMS: :For comparative examination of the pathological findings in burn shock and hemorrhagic shock, histological and immunohistochemical investigations of the lungs were performed. Histological specimens of 30 cases each were examined by means of immunohistological staining with P-selectin, von Willebrand factor (vWF) and PECAM-1. The results showed statistically significant differences between the two groups. There was strong staining for P-selectin (especially in the lumina of the blood vessels) and vWF (especially in the endothelium of medium-sized blood vessels) in the specimens of burn shock fatalities. In cases of rapid death after exposure to fire the strong expression of adhesion molecules, which are mainly responsible for the initial inflammatory reaction of leucocytes and platelets in burn shock, suggests prompt activation of inflammatory cells in the lung tissue. In cases of hemorrhagic shock, this reaction was much less distinct in the early stages. The same is true of the expression of PECAM-1, which was lower in lungs from burn shock fatalities than in those from hemorrhagic shock fatalities. The low expression of PECAM-1 in burn shock is a clue to the migration/diapedesis of leucocytes into the areas of burn damage. In total, the results of the investigation indicate different pathophysiological processes even in the very early stages of burn shock and hemorrhagic shock.

背景与目标： ：为了比较检查烧伤休克和出血性休克的病理结果，进行了肺的组织学和免疫组化研究。用P-选择蛋白，von Willebrand因子（vWF）和PECAM-1进行免疫组织染色，检查30例患者的组织学标本。结果显示两组之间在统计学上有显着差异。烧伤休克死亡标本中的P-选择蛋白（特别是在血管腔中）和vWF（特别是在中型血管内皮中）有很强的染色。在着火后迅速死亡的情况下，粘附分子的强表达主要是烧伤休克中白细胞和血小板的初始炎症反应，提示肺组织中的炎症细胞会迅速活化。在失血性休克的情况下，早期反应不明显。 PECAM-1的表达也是如此，其在烧伤性休克死亡中的肺低于在出血性休克死亡中的肺。 PECAM-1在烧伤休克中的低表达是白细胞向烧伤部位迁移/渗血的线索。总体而言，研究结果表明，即使在烧伤休克和失血性休克的早期，病理生理过程也不同。

BACKGROUND & AIMS: :A cDNA clone (Tgzy85d11.r1) obtained from the Toxoplasma Expressed Sequence Tag project was chosen due to its homology with proteins of the heat shock 90 family. The cDNA encodes 137 amino acids of the C-terminal portion of the Toxoplasma Hsp90 protein (TgHsp90). Serum samples obtained from orally infected BALB/c and C57BL/6 mice showed reactivity against a recombinant TgHsp90 (rTgHsp90) after 8 weeks postinfection. Isotype analysis showed an anti-rTgHsp90 IgG2a/IgG3 response in infected BALB/c and anti-rTgHsp90 IgG1/IgG2a/IgG2b response in infected C57BL/6 mice. Serum samples from individuals chronically and putative acutely infected with T. gondii showed a similar anti-rTgHsp90 IgG response. Our work identifies TgHsp90 as a novel parasite antigen that seems to elicit a higher relation of anti-TgHsp90/anti-T. gondii IgGs during chronic infection in comparison with the acute stage.

背景与目标： ：选择从弓形虫表达序列标签项目获得的cDNA克隆（Tgzy85d11.r1），因为它与热休克90家族蛋白同源。 cDNA编码弓形虫Hsp90蛋白（TgHsp90）C端部分的137个氨基酸。从口腔感染的BALB / c和C57BL / 6小鼠获得的血清样品在感染后8周后显示出对重组TgHsp90（rTgHsp90）的反应性。同型分析表明，在感染的BALB / c中存在抗rTgHsp90 IgG2a / IgG3反应，在感染的C57BL / 6小鼠中具有抗rTgHsp90 IgG1 / IgG2a / IgG2b反应。弓形虫被慢性和假定急性感染的个体的血清样品显示出相似的抗rTgHsp90 IgG反应。我们的工作将TgHsp90鉴定为一种新型的寄生虫抗原，似乎引起了更高的抗TgHsp90 / anti-T关系。与急性期相比，在慢性感染期间感染了刚地IgG。

BACKGROUND & AIMS: :Sepsis and its sequelae of multiple organ failure is one of the leading causes of death in the industrial countries. Several studies have shown that patients who are treated with low-dose acetyl salicylic acid (ASA) for secondary prevention of atherothrombosis may have a lower risk to develop organ failure in the case of critical illness. The benefit of ASA is probably due to an inhibition of platelet activation as well as an increase in the formation of anti-inflammatory lipoxin A4. On the other hand, the effect of ASA could be - at least partially - an indirect one, caused by atherosclerotic vascular diseases as the cause of ASA treatment. Atherosclerosis is considered as a moderate systemic inflammation and we hypothesise that this chronic condition could have an impact on the outcome in sepsis. To get more information on the benefit of ASA in critically ill patients and on possible interference with atherosclerotic vascular diseases, we analysed the medical records of 886 septic patients who were admitted to the surgical intensive care unit (ICU) of a university hospital. Logistic regression analysis indicated that patients who were treated during the ICU stay with ASA (100 mg/d) had a significantly lower mortality. Odds ratios (ORs; with 95% confidential intervals) of 0.56 (0.37-0.84) and 0.57 (0.39-0.83) were calculated for ICU and hospital mortality, respectively. In contrast, statin treatment did not have significant effect on mortality. Diagnosis of atherosclerotic vascular diseases according to ICD classification did not influence ICU mortality but lowered hospital mortality (OR = 0.71 (0.52-0.99)). Subgroup analysis provided preliminary evidence that clopidogrel when given as only anti-platelet drug may have a similar benefit as ASA, but the combination of ASA and clopidogrel failed to improve the outcome. The time course of plasma fibrinogen and procalcitonin levels indicate that ASA seems to reduce the activation of haemostasis and increase the resolution of inflammation. It is concluded that prospective interventional studies should be done to test the use of ASA as novel therapeutic approach in critically ill patients.

背景与目标： 败血症及其多器官功能衰竭的后遗症是工业化国家死亡的主要原因之一。几项研究表明，用低剂量乙酰水杨酸（ASA）进行动脉粥样硬化血栓形成二级预防的患者在危重病情况下发生器官衰竭的风险可能较低。 ASA的好处可能是由于抑制了血小板活化以及增加了抗炎脂蛋白A4的形成。另一方面，ASA的作用可能（至少部分是）由动脉粥样硬化性血管疾病（作为ASA治疗的原因）引起的间接作用。动脉粥样硬化被认为​​是中度的全身性炎症，我们假设这种慢性病可能会对败血症的预后产生影响。为了获得更多有关ASA对重症患者的益处以及对动脉粥样硬化性血管疾病可能产生的干扰的信息，我们分析了886例脓毒症患者的病历，这些患者被大学医院的外科重症监护病房（ICU）收治。 Logistic回归分析表明，在ICU期间接受ASA（100μmg/ d）治疗的患者死亡率显着降低。 ICU和医院死亡率分别计算为0.56（0.37-0.84）和0.57（0.39-0.83）的赔率（OR）。相反，他汀类药物治疗对死亡率没有显着影响。根据ICD分类诊断动脉粥样硬化性血管疾病并不影响ICU死亡率，但可以降低医院死亡率（OR = 0.71（0.52-0.99））。亚组分析提供了初步证据，表明氯吡格雷仅作为抗血小板药物使用可能具有与ASA相似的益处，但是ASA和氯吡格雷的组合未能改善结局。血浆纤维蛋白原和降钙素原水平的时间变化表明，ASA似乎减少了止血的激活并增加了炎症的缓解。结论是，应该进行前瞻性干预研究，以测试ASA在危重患者中作为新型治疗方法的应用。

BACKGROUND & AIMS: :Chronic obesity imposes an organismal state of low-grade inflammation because the physiological resolution of inflammation is progressively repressed giving rise to cellular senescence and its accompanying Senescence-Associated Secretory Phenotype (SASP), which avoids apoptosis but perpetuates the relay of inflammatory signals from adipose tissue toward the rest of the body. Conversely, resolution of inflammation depends on the integrity of heat shock response (HSR) pathway that leads to the expression of cytoprotective and anti-inflammatory protein chaperones of the 70 kDa family (HSP70). However, chronic exposure to the aforementioned injuring factors leads to SASP, which, in turn, suppresses the HSR. A main metabolic tissue severely jeopardized by obesity-related dysfunctions is the endocrine pancreas, particularly β-cells of the islets of Langerhans. Because exercise is a powerful inducer of HSR and predicted to alleviate negative health outcomes of obesity, we sought whether obesity influence HSP70 expression in pancreatic islets and other metabolic tissues (adipose tissue and skeletal muscle) of adult B6.129SF2/J mice fed on a high-fat diet (HFD) for 13 weeks since the weaning and whether acute exercise as well as moderate-intensity exercise training (8 weeks) could interfere with this scenario. We showed that acute exercise of moderate intensity protects pancreatic islets against cytokine-induced cell death. In addition, acute exercise challenge time-dependently increased islet HSP70 that peaked at 12 h post-exercise in both trained and untrained mice fed on a control diet, suggesting an adequate HSR to exercise training. Unexpectedly, however, neither exercise training nor acute exercise challenges were able to increase islet HSP70 contents in trained mice submitted to HFD, but only in untrained HFD animals. In parallel, HFD disrupted glycemic status which is accompanied by loss of muscular mass resembling sarcopenic obesity that could not be rescued by exercise training. These results suggest that exercise influences HSR in pancreatic islets but obesity undermines islet, muscle and adipose tissue HSR, which is associated with metabolic abnormalities observed in such tissues.

背景与目标： ：慢性肥胖会导致机体处于低度炎症状态，因为炎症的生理学分辨率会逐渐受到抑制，从而引起细胞衰老及其伴随的衰老相关分泌表型（SASP），从而避免了细胞凋亡，但使脂肪中的炎症信号得以延续组织朝向身体的其余部分。相反，炎症的解决取决于热休克反应（HSR）途径的完整性，该途径导致70kDa家族（HSP70）的细胞保护性和抗炎性蛋白伴侣的表达。但是，长期暴露于上述伤害因素会导致SASP，进而抑制HSR。肥胖相关功能障碍严重危害的主要代谢组织是内分泌胰腺，特别是朗格罕氏岛的β细胞。由于运动是HSR的有力诱因，并且预计可减轻肥胖对健康的负面影响，因此我们寻求肥胖是否会影响以B6,129SF2 / J成年小鼠喂养的成年B6.129SF2 / J小鼠的胰岛和其他代谢组织（脂肪组织和骨骼肌）中HSP70的表达。断奶后连续13周进行高脂饮食（HFD），以及急性运动以及中等强度的运动训练（8周）是否会干扰这种情况。我们表明中等强度的急性运动可以保护胰岛免受细胞因子诱导的细胞死亡。此外，急性运动挑战随时间增加的胰岛HSP70随时间增加，在接受对照饮食喂养的训练和未训练小鼠中均在运动后12h达到峰值，表明有足够的HSR进行运动训练。但是，出乎意料的是，运动训练和急性运动挑战均无法增加接受HFD训练的小鼠的胰岛HSP70含量，而仅在未经训练的HFD动物中增加。同时，HFD破坏了血糖状态，伴随着肌肉减少，类似于肌肉减少症，运动训练无法挽救。这些结果表明，运动会影响胰岛的HSR，但肥胖会破坏胰岛，肌肉和脂肪组织的HSR，这与在此类组织中观察到的代谢异常有关。

BACKGROUND & AIMS: :Implantable cardioverter defibrillators (ICDs) are indicated in patients with Brugada syndrome with resuscitated ventricular arrhythmias. When these patients have atrial septal defects, they also need closure to prevent paradoxic embolism of thrombus from the defibrillator leads. A 15-year-old boy with Brugada syndrome had transvenous ICD placement along with device closure of a large atrial septal defect. When the defibrillation threshold was checked during device testing, a shock was delivered to terminate the induced ventricular fibrillation. The sudden jerk during this shock resulted in device embolization into the left atrium. The device was successfully retrieved and the defect closed with a larger device. This report discusses this extremely rare association of Brugada syndrome with atrial septal defect, unreported complications after device closure, and successful management of the problem.

背景与目标： ：植入性心脏复律除颤器（ICD）适用于Brugada综合征伴有复苏性室性心律失常的患者。当这些患者患有房间隔缺损时，他们还需要关闭以防止除颤器导线产生血栓的矛盾性栓塞。一名患有Brugada综合征的15岁男孩经静脉ICD植入并关闭了一个较大的房间隔缺损。在设备测试期间检查除颤阈值时，会发出电击以终止诱发的心室纤颤。在这种电击过程中突然的急动导致装置栓塞入左心房。已成功检索设备，并使用较大的设备关闭了缺陷。本报告讨论了Brugada综合征与房间隔缺损，装置闭合后未报告的并发症以及成功解决该问题的这种极为罕见的关联。