High salt reduces the activation of IL-4– and IL-13–stimulated macrophages

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt–induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.     

呼出气一氧化氮检测在COPD诊治中的应用研究

目的探讨Fe NO检测作为气道炎症生物指标来评估COPD患者应用糖皮质激素的疗效意义。方法测定AECOPD组、COPD稳定期组、健康对照组及AECOPD短期糖皮质激素治疗后的Fe NO浓度、肺功能指标。结果稳定期COPD Fe NO水平明显低于AECOPD,高于健康对照组,差异均具有统计学意义。AECOPD静滴激素等有效治疗后FEV1、PEF均明显增高,Fe NO水平明显下降,但Fe NO与FEV1变化无明显相关性,对FEV1增加≥200 ml患者Fe NO水平明显高于FEV1增加200 ml患者。结论 Fe NO测定是一项理想的有效的评估气道炎症的检查方法,对AECOPD的诊断,以及是否应用激素治疗具有指导价值。     

A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy

During 24 weeks of hydroxyurea treatment, we monitored red blood cell (RBC) parameters in three patients with sickle cell disease, including F-cell and F-reticulocyte profiles, distributions of delay times for intracellular polymerization, sickle erythrocyte adherence to human umbilical vein endothelial cells in a laminar flow chamber, RBC phthalate density profiles, mean corpuscular hemoglobin concentration and cation content, reticulocyte mean corpuscular hemoglobin concentration, 1H-nuclear magnetic resonance transverse relaxation rates of packed RBCs, and plasma membrane lateral and rotational mobilities of band 3 and glycophorins. Hydroxyurea increases the fraction of cells with sufficiently long delay times to escape the microcirculation before polymerization begins. Furthermore, high pretreatment adherence to human umbilical vein endothelial cells of sickle RBCs decreased to normal after only 2 weeks of hydroxyurea treatment, preceding the increase in fetal hemoglobin levels. The lower adhesion of sickle RBCs to endothelium would facilitate escape from the microcirculation before polymerization begins. Hydroxyurea shifted several biochemical and biophysical parameters of sickle erythrocytes toward values observed with hemoglobin SC disease, suggesting that hydroxyurea moderates sickle cell disease toward the milder, but still clinically significant, hemoglobin SC disease. The 50% reduction in sickle crises documented in the Multicenter Study of Hydroxyurea in Sickle Cell Disease is consistent with this degree of erythrocyte improvement.     

高压氧下全肺灌洗用于伴严重呼吸衰竭的肺泡蛋白沉积症

高压氧下全肺灌洗用于伴严重呼吸衰竭的肺泡蛋白沉积症刘少滨林章树程志强郭海华陈愉生左雪辉重症的肺泡蛋白沉积症（ＰＡＰ）行全肺灌洗是最有效的治疗方案，但有一定的危险性已较少采用［１］。对伴有严重呼吸衰竭的ＰＡＰ，因单侧肺通气不足以维持动脉血氧分压（ＰａＯ...     

Baculovirus resistance in codling moth is virus isolate-dependent and the consequence of a mutation in viral gene pe38

The baculovirus Cydia pomonella granulovirus (CpGV) is widely applied as a biocontrol agent of codling moth. After field resistance of codling moth populations had been observed against the commercially used Mexican (M) isolate of CpGV, infection experiments of larvae of the resistant codling moth strain CpRR1 showed that several other naturally occurring CpGV isolates (I12, S, E2, and I07) from different geographic origins are still infectious to resistant CpRR1. Whole-genome sequencing and phylogenetic analyses of these geographic CpGV variants revealed that their genomes share only a single common difference from that of CpGV-M, which is a mutation coding for a repeat of 24 nucleotides within the gene pe38; this mutation results in an additional repeat of eight amino acids that appears to be inserted to PE38 of CpGV-M only. Deletion of pe38 from CpGV-M totally abolished virus infection in codling moth cells and larvae, demonstrating that it is an essential gene. When the CpGV-M deletion mutant was repaired with pe38 from isolate CpGV-S, which originated from the commercial product Virosoft and is infectious for the resistant codling moth strain CpRR1, the repaired CpGV-M mutant was found to be fully infectious for CpRR1. Repair using pe38 from CpGV-M restored infectivity for the virus in sensitive codling moth strains, but not in CpRR1. Therefore, we conclude that CpGV resistance of codling moth is directed to CpGV-M but not to other virus isolates. The viral gene pe38 is not only essential for the infectivity of CpGV but it is also the key factor in overcoming CpGV resistance in codling moth.The codling moth Cydia pomonella L. is a worldwide occurring insect pest that infests apples, pears, and walnuts. The larvae of codling moth bore into the fruit and cause severe economic damage if not controlled. A number of chemical and biological agents are available for the control of codling moth. One of the most efficient biological control agents (1–5) is the Cydia pomonella granulovirus (CpGV), which belongs to the dsDNA virus family Baculoviridae (genus Betabaculovirus). CpGV was first discovered in Mexico (Mexican isolate, CpGV-M) in 1963 (6); this isolate was later developed to commercial products now registered in 34 countries worldwide. The genome sequence of the in vivo cloned strain CpGV-M1 is ∼123 kbp and encodes for 143 ORFs (7). Based on SNPs in highly conserved genes, different geographic CpGV isolates were classified into four genome types, A–D (8). CpGV exhibits an extremely narrow host range that is restricted to C. pomonella and a very few closely related tortricids (Lepidoptera) (9).The development of resistance to baculovirus infection was thought to be unlikely before 2005 (10, 11), which is when the first cases of resistant codling moth populations with a 1,000- to 100,000-fold reduced susceptibility to commercial CpGV products containing the isolate CpGV-M were reported from organic apple plantations in Germany and France, where CpGV products had been intensively applied (12, 13). Since then, 38 apple plantations with CpGV resistance have been identified in Austria (2 orchards), Czech Republic (1), France (3), Germany (22), Italy (6), Switzerland (2), and the Netherlands (2) (14). For the codling moth strain CpR, which originated from a resistant field population in south Germany, as well as the genetically homogenous laboratory strain CpRR1, which derived from CpR, the mode of inheritance was revealed to be incompletely dominant, monogenic, and linked to the Z (sex) chromosome (15, 16). A similar mode of inheritance was also observed in resistant Czech and French codling moth populations arguing for a more or less universal mode of resistance in Europe (17, 18). These data led to the hypothesis that a genetic adaptation of codling moth to CpGV-M infection had occurred and was selected for by the intensive use of products containing CpGV-M (15).Insects manifest miscellaneous strategies to resist pathogens but lack an adaptive immune system. Insect defense to viral infections involves nonspecific factors such as physical barriers, enzymatic responses, and increasing ejection of infected midgut cells as larvae age, as well as specific factors involving cellular and humoral immunity (19). Physical barriers to infection include the perithropic membrane (PM), an ultrafilter for particles with size exclusion greater than 30 nm (20). Melanization of the cuticula mediated by phenoloxidase enzymes is involved in the encapsulation reaction of pathogens, such as bacteria, fungi, or virus-infected cells (21, 22). Developmental resistance, the decreasing susceptibility of larvae with increasing age, is rather common, and is mediated by infected midgut cell-sloughing (23–25). Behavior modifications also count among insect defense strategies (19). Feeding behaviors, e.g., can strongly affect the risk of insects for baculovirus infection as shown for Lymantria dispar L., which exhibit heritable cadaver-avoidance behaviors (26).An alternative way for insects to get rid of virus-infected cells is via programmed cell death—the apoptosis pathway (27). Baculoviruses, however, are able to block apoptosis with the help of different virus encoded antiapoptotic proteins. In Autographa californica multiple nucleopolyhedrovirus (AcMNPV), these proteins—namely P35 and P49—are inhibitors of the insect caspases. These inhibitors of apoptosis (IAPs), thereby, ensure a permissive virus infection (28).For codling moth, however, resistance based on the PM, the midgut, or the immune system has been excluded for CpGV (16, 29). Lack of CpGV DNA replication and a systemic resistance in all five instars indicated an early block to virus replication in resistant codling moth individuals (29, 30). At the same time, it was observed that certain CpGV isolates, such as I12 or NPP-R1/R4, were able to infect larvae from resistant codling moth strains (30, 31). Therefore, these naturally occurring CpGV isolates from different geographic origins were considered resistance-breaking isolates. Some of these isolates, meanwhile, replace CpGV-M in commercial biocontrol agents in Europe and demonstrate the importance of identifying resistance-breaking CpGV variants (30–32) for managing CpGV-resistant codling moth populations; however, their functional difference to CpGV-M allowing them to overcome CpGV resistance remained unknown.In this study we compared different naturally occurring geographic CpGV isolates representing all known CpGV genome types (8) in laboratory assays for their infectivity to susceptible (CpS) and resistant (CpRR1) codling moth strains. We found that all tested isolates—except CpGV-M—were able to overcome resistance in CpRR1 larvae. Whole-genome sequencing of these isolates revealed a single common difference in all resistance-breaking isolates, which was located in ORF24 (pe38). Therefore, occlusion bodies of bacmid-based recombinant CpGV (in the following termed pseudoviruses) knockout and recovery mutants of pe38 were established and tested for their activity in susceptible CpS and resistant CpRR1 larvae. The recovery of infectivity of a CpGV-M–based pseudovirus harboring the pe38 of the resistance-breaking CpGV-S in CpRR1 larvae demonstrated the key function of pe38 in overcoming baculovirus resistance in codling moth. In their entirety, these investigations demonstrate the significance of using multiple isolates of CpGV concurrently in field applications to avoid resistance in codling moth populations.     

Effect of initial storage at room temperature on human red blood cell ATP, 2,3-DPG, and viability

The concentrations of ATP and 2,3-DPG and post-transfusion viability were measured in human red blood cells exposed for one, four and seven hours to room temperature before refrigerated storage for 21 days. No effect of room temperature storage was observed on ATP or viability. Decrease in 2,3-DPG was accelerated by room temperature exposure but the differences in 2.3-DPG were small and unlikely to have a significant adverse effect on red blood cell oxygen delivery. Delays of up to seven hours in refrigeration of blood do not appear to have serious adverse effects on red blood cell viability or function.     

不平衡氨基酸肠内营养联合5-氟尿嘧啶对大鼠Walker-256癌肉瘤生长的影响

目的:探讨富含亮氨酸和精氨酸的不平衡氨基酸肠内营养(EN)联合5-氟尿嘧啶(5-Fu)对大鼠Walker-256癌肉瘤生长的影响。方法:SD大鼠空肠造瘘,皮下接种Walker-256癌肉瘤,36只接种成功的大鼠随机分为A组(平衡氨基酸 生理盐水组)、B组(平衡氨基酸 5-Fu组)、C组(富含亮氨酸及精氨酸的不平衡氨基酸 5-Fu组)。测定各组治疗后肿瘤重量、抑瘤率、PCNA指数、凋亡指数、肿瘤细胞周期及大鼠生存时间。结果:A、B、C组G0/G1期比例依次增高(P<0.01);凋亡指数依次增高(P<0.05或P<0.01);生存时间依次延长(P<0.05或P<0.01);S期比例依次下降(P<0.01);PCNA指数依次下降(P<0.01);瘤重依次下降(P<0.01)。结论:富含亮氨酸及精氨酸的不平衡氨基酸EN能明显抑制肿瘤生长,并能增强5-Fu的抗肿瘤效应。     

Attenuated psychotic and basic symptom characteristics in adolescents with ultra-high risk criteria for psychosis,other non-psychotic psychiatric disorders and early-onset psychosis

While attenuated psychotic symptoms (APS) and basic symptoms (BS) are the main current predictors of psychosis in adults, studies in adolescents are scarce. Thus, we (1) described the prevalence and severity of positive, negative, disorganization, general, and basic symptoms in adolescent patients at ultra-high risk for psychosis (UHR), with other non-psychotic psychiatric disorders (PC) and with early-onset psychosis (EOP); and (2) investigated BS criteria in relation to UHR criteria. Sixty-nine 12–18-year-old adolescents (15.3 ± 1.7 years, female = 58.0 %, UHR = 22, PC = 27, EOP = 20) were assessed with the structured interview for prodromal syndromes (SIPS) and the schizophrenia proneness instrument-child and youth version (SPI-CY). Despite similar current and past 12-month global functioning, both UHR and EOP had significantly higher SIPS total and subscale scores compared to PC, with moderate-large effect sizes. Expectedly, UHR had significantly lower SIPS positive symptom scores than EOP, but similar SIPS negative, disorganized, and general symptom scores. Compared to PC, both EOP and UHR had more severe basic thought and perception disturbances, and significantly more often met cognitive disturbances criteria (EOP = 50.0 %, UHR = 40.9 %, PC = 14.8 %). Compared to UHR, both EOP and PC significantly less often met cognitive-perceptive BS criteria (EOP = 35.0 %, UHR = 68.2 %, PC = 25.9 %). BS were significantly more prevalent in both EOP and UHR than PC, and UHR were similar to EOP in symptom domains. Given the uncertain outcome of adolescents at clinical high-risk of psychosis, future research is needed to determine whether the combined assessment of early subjective disturbances with observable APS can improve the accuracy of psychosis prediction.     

环孢霉素A对大鼠心肌结构及心脏功能的影响

目的探讨不同剂量环孢霉素A(cyclosporine A,CsA)对大鼠心脏功能的影响以及钙调神经磷酸酶(calcineurin,CaN)活性、mRNA表达与心功能的关系。方法 70只健康纯系Wistar大鼠,体质量(200±25)g, 随机分为A、B、C、D组及正常对照组,每组14只。A、B、C、D组分别给予CsA 5．0、12．5、25．0、50．0 mg·kg-1·-1灌胃,对照组用4 ml生理盐水灌胃。持续给药2、4周后每组各取7只进行心脏超声检测心脏功能、病理形态学、 CaN活性及RT-PCR方法检测(CaNAB mRNA的表达。结果与正常组比较,用药各组随剂量增加心脏功能降低,左室射血分数(LVEF)下降(P<0．01),左室短轴缩短率(FS)下降(P<0．01),A、B、C组左心室(LV)增大,B、 C组左心房(LA)也增大(P<0．05)。随着药物剂量增加,病理改变为心肌变性损伤加重。用药各组2周时(CaN 活性随药物剂量增加而下降(F=27．19,P<0．05),而4周时B、C组CaN活性均较2周时升高(P<0．05); CaNAB mRNA表达随着用药剂量和用药时间增加而下降(P<0．01)。结论大剂量CsA对心肌细胞损伤发生的早而且严重,心脏功能下降明显。