BACKGROUND & AIMS: :Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg × 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide-dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit.

背景与目标： : 当以预防性方式或在脓毒症或内毒素血症开始后早期给药时，褪黑素可改善生存和功能障碍，包括溶血，血小板减少症和低血压。在本研究中，褪黑激素不是在全身炎症的最初症状出现之前就给予的。以0.5 mg/kg × h的速率输注脂多糖以诱导雄性Wistar大鼠全身炎症。在开始脂多糖输注后180和270分钟静脉内施用褪黑素 (单剂量3 mg/kg × 15分钟)。全身和生命参数 (例如，全身血压和呼吸频率) 以及血液和血浆参数 (酸碱参数; 电解质; 组织损伤参数，例如葡萄糖浓度，乳酸浓度，溶血和氨基转移酶活性; 血栓弹性测定参数; 和血小板计数) 定期确定。输注脂多糖会导致严重全身性炎症的特征性症状，包括低血压，代谢性酸中毒和低血糖，电解质和止血障碍，血小板减少症和溶血。褪黑素既不能降低死亡率，也不能降低脂多糖依赖性的生命，血液和血浆参数变化。尽管褪黑激素在全身性炎症的早期阶段可能具有有益的作用，但在重症监护病房中，褪黑激素很难成为明显败血症或内毒素血症的治疗选择。

BACKGROUND & AIMS: :HMGB1 is a nuclear protein that is released or secreted following trauma or severe cellular stress. Extracellular HMGB1 triggers inflammation and recruits leukocytes to the site of tissue damage. We review recent evidence that the ability of HMGB1 to recruit leukocytes may be entirely due to the formation of a heterocomplex with the homeostatic chemokine CXCL12. The HMGB1-CXCL12 heterocomplex acts on the CXCR4 receptor more potently than CXCL12 alone. Notably, only one of the redox forms of HMGB1, the one where all cysteines are reduced (all-thiol), can bind CXCL12. Both HMGB1 containing a disulfide bond between C23 and C45, which induces chemokine and cytokine release by activating TLR4, and HMGB1 terminally oxidized to contain a cysteine sulfonate are inactive in recruiting leukocytes. Thus, the chemoattractant and cytokine-inducing activities of HMGB1 are separable, and we propose that they appear sequentially during the development of inflammation and its resolution. The HMGB1-CXCL12 heterocomplex constitutes a specific target that may hold promise for the treatment of several pathologies.

背景与目标： : HMGB1是一种核蛋白，在创伤或严重的细胞应激后释放或分泌。细胞外HMGB1触发炎症并将白细胞募集到组织损伤部位。我们回顾了最近的证据，即HMGB1募集白细胞的能力可能完全是由于与稳态趋化因子cxcl12形成了异复合物。HMGB1-CXCL12的异源复合物比单独的CXCL12更有效地作用于CXCR4受体。值得注意的是，只有HMGB1的一种氧化还原形式 (所有半胱氨酸被还原的一种) 可以结合cxcl12。含有C23和C45之间的二硫键的HMGB1和通过激活TLR4诱导趋化因子和细胞因子释放的HMGB1，以及末端氧化为含有半胱氨酸磺酸盐的HMGB1在募集白细胞中均无活性。因此，HMGB1的趋化因子和细胞因子诱导活性是可分离的，我们建议它们在炎症的发展及其消退过程中依次出现。HMGB1-CXCL12的异源复合物构成特定的靶标，可以有望治疗几种病理。

BACKGROUND & AIMS: OBJECTIVES:Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. METHODS:The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. RESULTS:We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. CONCLUSIONS:Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.

背景与目标：

BACKGROUND & AIMS: :The objective of the study was to evaluate the association between peripheral venous disease (PVD) and arterial endothelial dysfunction (ED). Arterial and venous diseases have been always considered as two completely different entities, but the recent discovery of a relationship between arterial and venous thrombosis have challenged this assumption. ED, considered to be an early process in the pathophysiology of atherosclerotic disease, could represent a common pathogenetic background. We studied 39 healthy volunteers (median age: 34 years; men: 25.6%). PVD was diagnosed using ultrasound examination, arterial ED using flow-mediated dilation (FMD) and FMD normalized for the peak shear rate (nFMD). Compared with controls, participants with PVD had a lower FMD (15.2 versus 23.4%, P < 0.001) and nFMD (12.7 × 10(-3) versus 19 × 10(-3)/second, P < 0.001). People with the most clinically evident disease had the worst endothelial function. In conclusion, our findings, if confirmed in larger population, might corroborate the idea that venous and arterial disease could have common causes.

背景与目标： : 该研究的目的是评估外周静脉疾病 (PVD) 与动脉内皮功能障碍 (ED) 之间的关系。动脉和静脉疾病一直被认为是两个完全不同的实体，但是最近发现动脉和静脉血栓形成之间的关系对这一假设提出了挑战。ED被认为是动脉粥样硬化疾病病理生理的早期过程，可能代表了共同的发病背景。我们研究了39名健康志愿者 (中位年龄: 34岁; 男性: 25.6%)。使用超声检查诊断PVD，使用血流介导的扩张 (FMD) 进行动脉ED，并针对峰值剪切速率 (nFMD) 标准化FMD。与对照组相比，PVD参与者的FMD (15.2 vs 23.4%，P <0.001) 和nFMD (12.7 × 10(-3) vs 19 × 10(-3)/秒，P <0.001) 较低。临床上最明显的疾病患者的内皮功能最差。总之，如果在更多人群中得到证实，我们的发现可能证实了静脉和动脉疾病可能具有共同原因的观点。

BACKGROUND & AIMS: :Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

背景与目标： : 胆汁酸在肝脏中合成，是胆汁中的主要成分。胆汁流动受损导致胆汁淤积，其特征是肝脏和血清中胆汁酸水平升高，随后是肝细胞和胆道损伤。尽管胆汁淤积的原因已得到广泛研究，但有关胆汁酸如何引发肝损伤的分子机制仍存在争议。在本章中，我们总结了胆汁酸引起的肝损伤的发病机理的最新进展。这些包括胆汁淤积和胆汁淤积动物模型患者的肝细胞中的胆汁酸信号通路以及肝脏中胆管细胞和先天免疫细胞的反应。我们专注于胆汁酸如何触发中性粒细胞募集分子介质的产生以及炎症反应在此病理过程中的作用。这些进展指出了许多新的靶点，在这些靶点中，药物可能被认为是治疗胆汁淤积性肝损伤的有效疗法。

BACKGROUND & AIMS: Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

背景与目标： 前列腺素和血栓烷是花生四烯酸通过环氧合酶 (CO) 酶代谢的产物，并负责炎症部位常见的疼痛和肿胀。非甾体抗炎药 (NSAIDs) 抑制这些物质的产生，并用于治疗炎症性疾病，例如关节炎。然而，NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶 (5-LO) 酶途径抑制前列腺素的产生和白三烯形成的相关增加可能导致吸引炎症细胞，引起局部炎症部位并产生溃疡。为了确定5-LO抑制对该假设的影响，在大鼠中进行了研究，以评估tepoxalin (一种双重CO/LO抑制剂) 对胃粘膜中白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中，长期口服NSAID吲哚美辛 (在4天内每天2 mg/kg) 导致40% 死亡率，并在第四剂药物后24小时评估时伴有肠粘连和穿孔。此外，肠系膜小静脉中的中性粒细胞粘附增加，肠系膜间质中的细胞浸润明显。在每天吲哚美辛治疗前30分钟，在单独的大鼠组中抑制了这些胃肠道副作用。进行了进一步的研究以确定tepoxalin对与NSAID诱导的胃肠道炎症相关的早期事件的影响，包括中性粒细胞粘附，脂质过氧化物生成和LTB4生成。给药90分钟后，吲哚美辛 (100 mg/kg，p.o.) 在大鼠胃粘膜中产生升高的LTB4水平。此外，在该剂量下以及使用另一种NSAID萘普生时，肠系膜小静脉中的中性粒细胞粘附增加。此时，胃粘膜中没有明显的脂质过氧化物生成。Tepoxalin (最高400 mg/kg，p.o.) 对胃粘膜LTB4的生成和脂质过氧化物水平没有影响。在最高剂量下观察到中性粒细胞粘附减少。在另一项研究中，用tepoxalin (ED50 = 7.5 mg/kg，p.o.) 或选择性5-LO抑制剂zileuton (100 mg/kg，p.o.) 进行预处理可防止胃粘膜LTB4水平升高和中性粒细胞粘附由吲哚美辛 (100 mg/kg，p、o.)。这些数据表明，LO抑制作用可能在预防NSAID诱导的胃部炎症中起着至关重要的作用，从而深入了解tepoxalin缺乏溃疡性以及可能预防胃副作用的抗炎治疗的新方法。

BACKGROUND & AIMS: :Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-α-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 μg/ml) was examined in TNF-α-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-κB and the mitogen-activated protein kinase family such as c-Jun NH₂-terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-κB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-α by inhibiting NF-κB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development.

背景与目标： : 大量证据支持肠道炎症和癌症之间的关系。因此，最近人们的注意力集中在具有抗炎活性的天然化合物的鉴定上，以此作为抑制大肠癌早期阶段的策略。由于可可是生物活性化合物的丰富来源，因此本研究在偶氮甲烷 (AOM) 诱导的结肠癌发生的大鼠模型和TNF-α 刺激的Caco-2细胞中研究了其抗炎特性。总共40只雄性大鼠在8周内饲喂对照或富含可可的饮食 (12%)，并在第三周和第四周注射生理盐水或AOM (20 mg/kg体重) (n 10只大鼠/组)。在实验结束时，评估结肠样品中的炎症标志物。在TNF-α 刺激的Caco-2细胞 (实验诱导的肠道炎症的体外模型) 中检查了可可多酚提取物 (10 μ g/ml) 的抗炎活性。还评估了涉及的信号通路，包括NF-κ b和有丝分裂原活化的蛋白激酶家族，例如c 6月nh2末端激酶 (JNK)，细胞外信号调节激酶和p38。结果表明，富含可可的饮食可降低结肠中NF-κ b的核水平以及AOM诱导的促炎酶 (例如cyclo-oxygenase-2和诱导型NO合酶) 的表达。此外，在Caco-2细胞中的实验证实，可可多酚通过抑制NF-κ b易位和JNK磷酸化来有效下调TNF-α 诱导的炎症标志物的水平。我们得出的结论是，可可多酚抑制炎症相关的结肠癌发生，并且在饮食预防肠道炎症和相关癌症发展方面可能很有希望。

BACKGROUND & AIMS: The effects of laser light on the cellular DNA have not been extensively characterized. Low-power laser sources, such as the helium-neon (He-Ne) laser with a wavelength of 632.8 nm, have been found to produce photobiological and photodamage effects with evidence of interference with cell replication. We have investigated the effects of He-Ne laser irradiation on sister chromatid exchange (SCE) frequencies in sheep peripheral blood mononuclear cells (PBMC). Cultured cells were irradiated once at 6 selected energy intensities of laser irradiation and then stimulated with pokeweed mitogen and cultured in the presence of 5-bromodeoxyuridine (BrdUrd). The frequency of SCEs of both irradiated and non-irradiated cells were analyzed. The mean SCE of irradiated cells significantly increased with growing energy density up to a laser dose of 24 J/cm2, whereas after an energy density of 24 J/cm2, the SCE frequency decreased with increasing energy densities. We concluded that the application of He-Ne laser irradiation at energy densities ranging from 2 to 96 J/cm2 produced a different effect on SCE frequency in sheep PBMC in vitro.

背景与目标： 激光对细胞DNA的影响尚未得到广泛表征。已发现低功率激光源，例如波长为632.8 nm的氦氖 (He-Ne) 激光器，可产生光生物学和光损伤效应，并具有干扰细胞复制的证据。我们已经研究了He-Ne激光照射对绵羊外周血单核细胞 (PBMC) 中姐妹染色单体交换 (SCE) 频率的影响。以6种选定的激光照射能量强度照射培养的细胞一次，然后用商陆有丝分裂原刺激并在5-溴脱氧尿苷 (BrdUrd) 存在下培养。分析了辐照和非辐照细胞的sce频率。辐照细胞的平均SCE随着能量密度的增长而显着增加，直到激光剂量为24 J/cm2，而在能量密度为24 J/cm2之后，SCE频率随着能量密度的增加而降低。我们得出的结论是，在2至96 J/cm2的能量密度下应用He-Ne激光辐照对体外绵羊PBMC的SCE频率产生了不同的影响。

BACKGROUND & AIMS: :Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

背景与目标： : FEN1基因的功能缺陷已被认为会导致基因组不稳定性和癌症易感性。我们已经在人类癌症标本中鉴定出一组FEN1突变。这些突变中的大多数消除了皮瓣内切核酸酶1 (FEN1) 的三个核酸酶活性中的两个。为了证明这些体细胞突变的病因学意义，我们自交了一个小鼠品系，该品系包含代表人类癌症中鉴定出的突变的E160D突变。核酸酶活性的选择性消除导致凋亡细胞中频繁的自发突变和不完全消化的DNA片段的积累。突变小鼠易患自身免疫，慢性炎症和癌症。突变表型会导致癌症的发生，而慢性炎症会促进癌症的发展。当前的工作举例说明了研究个体多态性和体细胞突变在癌症发展中的机制的方法，并且可以作为通过抑制炎症反应开发新的治疗方案的参考。

BACKGROUND & AIMS: :We have investigated the relationship between cortisol and dehydroepiandrosterone (DHEA) levels and the immune response to mycobacterial antigens in peripheral venous blood, from a male population of active tuberculosis patients and age-matched healthy controls of the same sex (HCo). Peripheral blood mononuclear cells were cultured for 36 or 96 h with whole sonicated Mycobacterium tuberculosis (WSA) for measurement of proliferation, interferon gamma (IFN-gamma) and interleukin-10 (IL-10) in culture supernatants. Comparisons on the in vitro mycobacterial-driven immune responses demonstrated that TB patients had a higher IL-10 production, a decreased lymphoproliferation and a trend to reduced IFN-gamma synthesis, in relation to HCo. Active disease was also characterized by increases in the plasma levels of glucocorticoids (GC) and reduced concentrations of DHEA which resulted in a higher cortisol/DHEA ratio respect the HCo group. Plasma DHEA levels were positively correlated with IFN-gamma values. An inverse correlation was found between the cortisol/DHEA ratio and IFN-gamma levels. Novel evidence is provided showing that the balance between cortisol and DHEA is partly responsible for the immune perturbations seen in TB patients.

背景与目标： : 我们已经调查了来自活跃的结核病患者和年龄匹配的同性健康对照 (HCo) 的男性人群的皮质醇和脱氢表雄酮 (DHEA) 水平与外周静脉血中分枝杆菌抗原的免疫反应之间的关系。将外周血单核细胞与全超声结核分枝杆菌 (WSA) 一起培养36或96小时，以测量培养上清液中的增殖，干扰素 γ (IFN-γ) 和interleukin-10 (IL-10)。对体外分枝杆菌驱动的免疫反应的比较表明，与HCo相比，结核病患者具有更高的IL-10产生，淋巴增殖减少以及IFN-γ 合成减少的趋势。活动性疾病的特征还在于血浆糖皮质激素 (GC) 水平升高和DHEA浓度降低，这导致HCo组的皮质醇/DHEA比率更高。血浆DHEA水平与IFN-γ 值呈正相关。皮质醇/DHEA比率与IFN-γ 水平之间呈负相关。提供了新的证据，表明皮质醇和DHEA之间的平衡是结核病患者免疫紊乱的部分原因。

BACKGROUND & AIMS: :The functioning of the immune system partially relies on T-cell exportation from the thymus, the major site of T-cell differentiation. Although the molecular mechanisms governing this process begin to be elucidated, it is not clear if thyroid hormones can alter the homing of recent thymic emigrants (RTE) to peripheral lymphoid organs. Herein, we investigated whether triiodothyronine (T(3)) could influence the homing of thymus-derived T cells. For that we used intrathymic injection of T(3) in combination with fluorescein isothiocyanate (FITC) to trace, 16 h later, FITC(+) cells, termed RTE, in peripheral lymphoid organs. We observed that T(3) stimulated thymocyte export, increasing the frequency of CD4(+) RTE and CD8(+) RTE in the subcutaneous and mesenteric lymph nodes. By contrast, the relative numbers of CD4(+) RTE in the spleen were decreased. T(3) also changed the differential distribution pattern of CD4(+) RTE, and to a lesser extent CD8(+) RTE in the peripheral lymphoid organs. Moreover, the expression of extracellular matrix (ECM) components, such as laminin and fibronectin, which are known to be involved in T-cell migration, increased in the lymph nodes but not in the spleen following intrathymic T(3) treatment. In conclusion, our data correspond to the first demonstration that in vivo treatment with thyroid hormone stimulates thymic T-cell homing and T-cell distribution in peripheral lymphoid organs.

背景与目标： : 免疫系统的功能部分依赖于T细胞分化的主要部位胸腺的T细胞输出。尽管开始阐明控制该过程的分子机制，但尚不清楚甲状腺激素是否可以改变最近的胸腺移民 (RTE) 向周围淋巴器官的归巢。在此，我们研究了三碘甲状腺原氨酸 (T(3)) 是否会影响胸腺衍生的T细胞的归巢。为此，我们使用胸腺内注射T(3) 与异硫氰酸荧光素 (FITC) 结合，在16小时后追踪外周淋巴器官中的FITC () 细胞，称为RTE。我们观察到T(3) 刺激胸腺细胞输出，增加皮下和肠系膜淋巴结中CD4 () RTE和CD8 () RTE的频率。相比之下，脾脏中CD4 () RTE的相对数量减少。T(3) 还改变了CD4 () RTE的差异分布模式，并在较小程度上改变了外周血淋巴器官中CD8 () RTE的分布模式。此外，在胸腺内T(3) 治疗后，已知参与T细胞迁移的细胞外基质 (ECM) 成分 (例如层粘连蛋白和纤连蛋白) 的表达在淋巴结中增加，但在脾脏中却没有增加。总之，我们的数据与第一个证明相对应，即体内用甲状腺激素治疗会刺激胸腺T细胞归巢和外周淋巴器官中T细胞的分布。

BACKGROUND & AIMS: :In the present account it is proposed that in smokers the transition from peripheral airway disease to COPD is characterized by three sequential stages: Stage I, during which the closing volume eventually exceeds the functional residual capacity; Stage II, during which tidal expiratory flow limitation (EFL) is eventually exhibited; and Stage III, during which dynamic hyperinflation progressively increases leading to dyspnea and exercise limitation, which may be considered as markers of overt disease. Presence of airway closure (Stage I) and EFL (Stage II) in the tidal volume range may promote peripheral airway injury and accelerate the abnormalities of lung function. It is such injury that may determine which smoker is destined to develop COPD.

背景与目标： : 在本报告中，建议吸烟者从外周气道疾病到COPD的转变以三个连续阶段为特征: 阶段I，在此期间闭合量最终超过功能剩余容量; 阶段II，在此期间最终表现出呼气流量限制 (EFL); 第三阶段，在此期间，动态过度通货膨胀逐渐增加，导致呼吸困难和运动受限，这可能被认为是明显疾病的标志。潮气量范围内存在气道关闭 (I期) 和EFL (II期) 可能会促进周围气道损伤并加速肺功能异常。正是这种伤害可能决定了哪个吸烟者注定会发展为COPD。

BACKGROUND & AIMS: :Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

背景与目标： : 溶瘤病毒 (OVs) 被选择或设计用于通过直接感染和裂解癌细胞来消除恶性肿瘤。与通过病毒感染直接裂解肿瘤的概念相反，我们观察到两种ov，水泡性口炎病毒 (VSV) 和牛痘病毒的体内肿瘤杀伤活性的很大一部分是由间接杀死未感染的肿瘤细胞引起的。施用溶瘤病毒后不久，我们观察到有限病毒，与肿瘤内部的血流减少相吻合，这与肿瘤细胞凋亡的诱导有关。肿瘤的转录本分析表明病毒导致促炎基因 (包括中性粒细胞趋化因子CXCL1和cxcl5) 的显着转录激活。感染肿瘤的免疫组织化学检查显示中性粒细胞浸润与趋化因子诱导相关。VSV给药前动物中性粒细胞的耗竭消除了未感染的肿瘤细胞凋亡，并允许病毒在整个肿瘤中更广泛地复制和传播。总而言之，这些结果表明中性粒细胞靶向募集到感染的肿瘤床可增强恶性细胞的杀伤。我们建议炎症细胞的激活可用于增强溶溶胞病毒疗法的有效性，并且这种方法应影响治疗剂量的计划。

BACKGROUND & AIMS: :Injections of cholera toxin B subunit conjugated to horseradish peroxidase (CTB-HRP) were made into the lingual branch of the hypoglossal nerve in four species of finch in order to identify the innervation of the mechanoreceptors of the dermal papillae of the tongue, and simultaneously to determine the pattern of central projections of lingual hypoglossal afferents. The results showed that hypoglossal fibers innervate all the Herbst corpuscles and terminal cell receptors of the elaborately organized papillae of the dorsum of the tongue, of the shorter papillae in the ventral tongue, and the loose collection of Herbst corpuscles in the subpapillary region. Labelled fibers were also observed in the intralingual glands, in the intrinsic tongue muscles, and in the posterodorsal epithelium where they formed budlike structures. Retrogradely labelled cell bodies were located in the jugular ganglion and their central processes ascended and descended throughout the brainstem within the descending trigeminal tract (TTD). Terminal fields were observed within the dorsolateral part of the nucleus caudalis of TTD, predominantly ipsilaterally, and within the medial part of the dorsal horn of the first 4-6 cervical segments bilaterally. There were dense patches of termination over a dorsolateral subnucleus of the interpolated nucleus of TTD, and within two regions of the principal sensory trigeminal nucleus: a large one laterally and a small one medially. Terminal fields were also observed within the nucleus ventralis lateralis anterior of the rostral solitary complex, and within adjacent nuclei, which are probably equivalent to the dorsal sensory nuclei of the facial and glossopharyngeal nerves of other avian species. The results are interpreted in the light of the role of the tongue in species-specific patterns of feeding in finches, and the possible requirement for the central integration of touch and taste.

背景与目标： : 将与辣根过氧化物酶 (ctb-hrp) 缀合的霍乱毒素B亚基注射到四种雀科的舌下神经的舌下分支中，以鉴定舌头真皮乳头的机械感受器的神经支配，同时确定舌下舌骨传入的中央投影模式。结果表明，舌下纤维支配了舌背精心组织的乳头，腹侧舌较短的乳头以及乳头下区域松散的Herbst小体的所有Herbst小体和末端细胞受体。在舌内腺，内在舌肌和后背上皮中也观察到标记的纤维，它们形成了芽状结构。逆行标记的细胞体位于颈静脉神经节中，其中央过程在三叉神经降束 (TTD) 内的整个脑干中上升和下降。在TTD尾核的背外侧部分 (主要是同侧) 和双侧前4-6个子宫颈节段的背角内侧部分内观察到末端区域。在TTD内插核的背外侧亚核上以及在主要感觉三叉核的两个区域内有密集的终止斑块: 横向较大，中间较小。在喙状孤立复合体的前腹外侧核以及相邻核内也观察到了末端磁场，这可能相当于其他鸟类的面部和舌咽神经的背感觉核。根据舌头在雀科取食的物种特定模式中的作用以及触觉和味觉集中融合的可能要求来解释结果。

BACKGROUND & AIMS: :Particulate matter PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have shown the association between sustained high level of PM2.5 and the risk of many diseases in the respiratory system, including lung cancer. However, the precise mechanisms through which PM2.5 induces respiratory diseases are still unclear. In this study, we demonstrated that CD4+ and CD8+ T cells following PM2.5 treatment demonstrated significantly elevated mRNA and protein levels of interferon (IFN)-γ, interleukin (IL)-10, IL-17, and IL-21 production. This increase in cytokines required the presence of macrophages, such that CD4+ and CD8+ T cells treated with PM2.5 in the absence of macrophages did not present higher IFN-γ, IL-10, or IL-21 expression. In contrast, PM2.5-treated macrophages could significantly upregulate T cell cytokine secretion, even when excess PM2.5 was removed from cell culture. We also observed a macrophage-dependent upregulation of granzyme A and granzyme B expression by CD4+ and CD8+ T cells following PM2.5 treatment. These PM2.5-stimulated CD4+ and CD8+ T cells potently induced the death of human bronchial epithelial (HBE) cells. Interestingly, the CD4+ and CD8+ T cells presented synergistic effects at inducing HBE cytotoxicity, such that CD4+ T cells and CD8+ T cells combined resulted in higher HBE cell death than the sum of the separate effects of CD4+ T cells and CD8+ T cells. While blocking cytotoxic molecule release significantly compromised the T cell-mediated cytotoxicity against HBE cells, blocking IFN-γ, but not IL-10, could also slightly but significantly reduce T cell-mediated cytotoxicity. Together, these data demonstrated that PM2.5 could promote the inflammation of cytotoxicity of T cells in a macrophage-dependent manner. In addition, PM2.5-treated macrophages presented long-lasting proinflammatory effects on T cells.

背景与目标： : 颗粒物PM2.5是一类空气传播的颗粒和液滴，在许多发展中国家都具有持续的高水平。流行病学研究表明，持续高水平的PM2.5与呼吸系统中许多疾病 (包括肺癌) 的风险之间存在关联。然而，PM2.5诱发呼吸道疾病的确切机制仍不清楚。在这项研究中，我们证明了PM2.5处理后的CD4和CD8 T细胞显示出显着升高的干扰素 (IFN)-γ，白介素 (IL)-10，IL-17和IL-21产生的mRNA和蛋白质水平。细胞因子的这种增加需要巨噬细胞的存在，使得在不存在巨噬细胞的情况下用PM2.5处理的CD4 + 和CD8 + T细胞没有表现出更高的IFN-γ 、IL-10或IL-21表达。相比之下，即使从细胞培养物中去除过量的PM2.5，经PM2.5处理的巨噬细胞也可以显着上调T细胞细胞因子的分泌。我们还观察到PM2.5处理后CD4和CD8 T细胞对巨噬细胞依赖性颗粒酶a和颗粒酶B表达的上调。这些PM2.5刺激的CD4和CD8 T细胞有效诱导人支气管上皮 (HBE) 细胞死亡。有趣的是，CD4和CD8 T细胞在诱导HBE细胞毒性方面表现出协同作用，因此CD4 T细胞和CD8 T细胞的结合导致的HBE细胞死亡高于CD4 T细胞和CD8 T细胞的单独作用之和。虽然阻断细胞毒性分子释放显著损害T细胞介导的针对HBE细胞的细胞毒性，但阻断IFN-γ (但不是IL-10) 也可以轻微但显著降低T细胞介导的细胞毒性。总之，这些数据表明PM2.5可以以巨噬细胞依赖性的方式促进T细胞的细胞毒性炎症。此外，经PM2.5处理的巨噬细胞对T细胞具有持久的促炎作用。