Summary Background Human babesiosis is an emerging zoonosis. “ Babesia venatorum ” has been identified in only four asplenic men and a child so far. We aimed to describe the epidemiological, ...clinical, and laboratory characteristics of a series of cases with “ B venatorum ” infection identified in a sentinel hospital in China. Methods We recruited participants with a recent tick bite at Mudanjiang Forestry Central Hospital, Heilongjiang province, China. Cases were diagnosed through PCR followed by sequencing, microscopic identification, or isolation by animal inoculation, or both. Findings 48 individuals (30 women or girls; median age 45 years, range 7 months to 75 years) with “ B venatorum ” infection were identified. 32 of these individuals were confirmed cases and 16 were probable cases. None of the 48 cases had received a blood transfusion or had a splenectomy. Geographically, cases were distributed diffusely throughout the hospital catchment area. Of the 32 confirmed cases, 21 (66%) presented with a fever, 13 (41%) with a headache, 12 (38%) with myalgia or arthralgia, and three (9%) with chills. 14 (44%) patients had fatigue, eight (25%) had dizziness, and eight (25%) had hypersomnia. Six (19%) patients had an erythematous non-pruritic rash around the tick-bite site and two (6%) had lymphadenopathy. Seven (22%) and four (13%) patients had anaemia and thrombocytopenia, respectively, and seven (50%) of 14 patients with confirmed infection had increased hepatic transaminase concentrations. In the confirmed cases, concentrations of intercellular adhesion molecule 3 (p<0·001), P-selectin (p<0·05), and platelet endothelial cell adhesion molecule 1 (p<0·001) were significantly reduced, whereas tumour necrosis factor α (p<0·01) and vascular cell adhesion molecule 1 (p<0·001) were significantly increased. Interpretation “ B venatorum ” infection should be included in the differential diagnosis of patients with a tick-exposure history in areas where this pathogen has previously been identified in ticks or people. Funding Natural Science Foundation of China and Mega-Project for Infectious Diseases.
Abstract The aim of this work was to investigate the effect of triblock copolymer poloxamer 188 on nanoparticle morphology, size, cancer cell uptake, and cytotoxicity. Docetaxel-loaded nanoparticles ...were prepared by oil-in-water emulsion/solvent evaporation technique using biodegradable poly(lactic- co -glycolic acid) (PLGA) with or without addition of poloxamer 188, respectively. The resulting nanoparticles were found to be spherical with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug-release profile of both nanoparticle formulations showed a biphasic release pattern. An increased level of uptake of PLGA/poloxamer 188 nanoparticles in the docetaxel-resistant MCF-7 TAX30 human breast cancer cell line could be found in comparison with that of PLGA nanoparticles. In addition, the docetaxel-loaded PLGA/poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than that of docetaxel-loaded PLGA nanoparticles and Taxotere ( P < .05). In conclusion, the results showed advantages of docetaxel-loaded PLGA nanoparticles incorporated with poloxamer 188 compared with the nanoparticles without incorporation of poloxamer 188 in terms of sustainable release and efficacy in breast cancer chemotherapy. From the Clinical Editor The effects of poloxamer 188, a triblock copolymer were studied on nanoparticle morphology, size, cancer cell uptake and cytotoxicity. An increased level of uptake of PLGA/poloxamer 188 nanoparticles in resistant human breast cancer cell line was demonstrated, resulting in a significantly higher level of cytotoxicity.
Background Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have ...shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF 1. Methods We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1–2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). Results Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p = 0.008 and five-fold increase days 1–2, p = 0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA ( p = 0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1–2 ( p = 0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. Conclusion Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.
The aberrant expression in some of the circadian clock-related proteins is associated with the pathogenesis of immune disorders.5 On the basis of results of Fig E1, we reasoned that one or some of ...the circadian clock-related proteins interfered with the expression of Foxp3 in CD4+ T cells. ...after treating with ACC, we isolated CD4+ T cells from the mouse intestine; the cells were analyzed by chromatin immunoprecipitation assay. Occurrence of food allergy after the career of day-/night-shift rotation Time (y) Patients with food allergy Percent Participants, n 668 668 40 Sex: male/female, n 334/334 334/334 20/20 Age (y), mean ± SD 38.5 ± 16 37.8 ± 15 38.8 ± 18 Total food allergy patients 86 (12.9) 26 (3.9)low * 0 Allergen distribution    Fish 18 (20.9) 5 (19.2) 0 Shell fish 12 (13.9) 3 (11.5) 0 Milk 11 (12.8) 3 (11.5) 0 Tree nuts 10 (11.6) 3 (11.5) 0 Soy 10 (11.6) 1 (3.8) 0 Fruit 8 (9.3) 6 (23.1) 0 Sesame seed 6 (6.9) 0 0 Wheat 6 (6.9) 0 0 Egg 6 (6.9) 5 (19.2) 0 Peanut 5 (5.8) 5 (19.2) 0 With other allergies    Asthma 1 (0.15) 1 (0.15)  Allergic rhinitis 2 (0.3) 0  Allergic dermatitis 1 (0.15) 2 (0.3)  Serum vitamin D (ng/mL) 30.8 ± 1.9 30.5 ± 1.3  Serum cortisol (ng/mL) 19.8 ± 2.4 20.2 ± 2.3  Height (m) 1.59 ± 0.06 1.58 ± 0.06  Weight (kg) 61.5 ± 3.5 60.6 ± 3.2  BMI (kg/m2) 24.2 ± 2.8 23.9 ± 2.1  Specific IgE (kU/L) 15.3 ± 21.6 <0.35 12.5 ± 18.2 <0.35 <0.35 Regulatory T cells (%) 2.14 ± 2.06 5.95 ± 5.14 2.28 ± 2.35 6.28 ± 7.29 6.68 ± 6.26 Serum IL-4 (pg/mL) 45.8 ± 25.9 12.6 ± 18.6 39.5 ± 31.3 9.8 ± 15.4 10.5 ± 8.6 SPT diameter (mm) 6.58 ± 4.87 2.11 ± 1.14 5.74 ± 3.85 1.86 ± 1.47 1.17 ± 1.08 1-2 5 5.8 3-4 70 81.4 5-6 9 10.5 >7 1 1.2 Table I Clinical features of human subjects Some patients were allergic to more than 1 allergen.
Abstract Background Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying I/R injury involve oxidative stress and apoptosis. Osthole, ...a natural coumarin derivative, has been reported to possess antioxidant and antiapoptotic activities. This study aimed to investigate the potential effects of osthole on renal I/R injury in an in vivo rat model. Materials and methods We induced renal I/R injury by clamping the left renal artery for 45 min followed by reperfusion, along with a contralateral nephrectomy. We randomly assigned 54 rats to three groups (18 rats/group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 30 min before renal ischemia. We harvested serum and kidneys at 1, 6, and 24 h after reperfusion. Renal function and histological changes were assessed. We also determined markers of oxidative stress and cell apoptosis in kidneys. Results Osthole treatment significantly attenuated renal dysfunction and histologic damage induced by I/R injury. The I/R-induced elevation in kidney malondialdehyde level decreased, whereas reduced kidney superoxide dismutase and catalase activities were markedly increased. Moreover, osthole-treated rats had a dramatic decrease in apoptotic tubular cells, along with a decrease in caspase-3 and an increase in the Bcl-2/Bax ratio. Conclusions Osthole treatment protects murine kidney from renal I/R injury by suppressing oxidative stress and cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury.
Summary Glucose-related proteins (GRPs) are ubiquitously expressed in endoplasmic reticulum and able to assist in protein folding and assembly; consequently, they are considered as molecular ...chaperones. GRP78 and GRP94 expression was induced by glucose starvation and up-regulated in the malignancies. To clarify the roles of both molecules in tumorigenesis and progression of gastric carcinomas, immunohistochemistry was used on tissue microarray containing gastric carcinomas, adenomas, and nonneoplastic mucosa using the antibodies against GRP78 and GRP94, with a comparison of their expression with clinicopathological parameters of carcinomas. Gastric carcinoma cell lines (MKN28, AGS, MKN45, KATO-III, and HGC-27) were studied for both proteins by immunohistochemistry and Western blot. There was more expression of both proteins in gastric carcinoma and adenoma than in nonneoplastic mucosas ( P < .05). All gastric carcinoma cell lines showed their expression at different levels. They were positively correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis, and Union Internationale Contre le Cancer staging ( P < .05), with positive relationship between both proteins ( P < .05). Univariate analysis indicated the postsurgical cumulative survival rate of patients with positive GRP78 or GRP94 expression to be lower than that in those without GRP78 or GRP94 expression ( P < .05), but the close link disappeared if stratified according to depth of invasion ( P > .05). Multivariate analysis showed that age, depth of invasion, lymphatic invasion, lymph node metastasis, Union Internationale Contre le Cancer staging, and Lauren classification ( P < .05), but not GRP78 and GRP94 expression, were independent prognostic factors for carcinomas ( P > .05). Up-regulated expression of GRP78 and GRP94 was possibly involved in pathogenesis, growth, invasion, and metastasis of gastric carcinomas. They were considered objective and effective markers for the aggressive behavior and poor prognosis in gastric carcinomas.
Abstract Background Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney failure by mechanisms that involve oxidative stress, inflammation, and apoptosis. Penehyclidine ...hydrochloride (PHC), a selective anticholinergic agent, possesses anti-inflammatory, antioxidative stress, and antiapoptotic effects. Therefore, we investigated the ability of PHC to ameliorate renal I/R injury in Sprague–Dawley rats. Materials and methods Rats were randomly assigned to three groups (35 rats per group): sham operated, saline-treated I/R, and PHC-treated I/R. After removing the right kidney, renal I/R injury was induced by clamping the left renal artery for 45 min followed by reperfusion. The rats were administered PHC (0.45 mg/kg, intravenously) or saline 30 min before renal ischemia. The blood and kidneys were harvested at 1, 3, 6, 12, or 24 h after reperfusion. Renal function and histologic changes were assessed. Markers of oxidative stress, inflammation, and apoptosis in the kidneys were also measured. Results PHC treatment significantly attenuated renal dysfunction and histologic damage caused by I/R injury. The treatment also decreased malondialdehyde level and attenuated the reduction in superoxide dismutase activity in the kidney. Moreover, the levels of activated p38 mitogen-activated protein kinase, nuclear factor kappa B, and caspase 3 were lower in the PHC-treated animals. Conclusions PHC protected rat kidneys from I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis. Thus, PHC may represent a novel practical strategy for the treatment of renal I/R injury.
Abstract Background It has been reported that ventricular repolarization dispersion resulting from transmural, apicobasal and interventricular action potential duration (APD) gradients makes the T ...wave concordant with the QRS complex. Method and results A whole-heart model integrating transmural, apicobasal, interventricular and anteroposterior APD gradients was used, and the corresponding electrocardiograms were simulated to study the influence of these APD gradients on the T-wave amplitudes. The simulation results showed that changing a single APD gradient (e.g., interventricular APD gradient alone) only made substantial changes to the T-wave amplitudes in a limited number of leads and was not able to generate T waves with amplitudes comparable with clinical findings in all leads. A combination of transmural, apicobasal and interventricular APD gradients could simulate T waves with amplitudes similar to clinical values in the limb leads only. Adding the anteroposterior APD gradient into the model greatly improved the consistency between the simulated T-wave amplitudes and the clinical values. Conclusion The simulation results support that the transmural, apicobasal, interventricular and the anteroposterior APD gradient are all essential to the genesis of the clinical T wave.
Background Mitochondrial metabolism is known to be important for T-cell activation. However, its involvement in effector T-cell differentiation has just begun to gain attention. Importantly, how ...metabolic pathways are integrated with T-cell activation and effector cell differentiation and function remains largely unknown. Objective We sought to test our hypothesis that RhoA GTPase orchestrates glycolysis for TH 2 cell differentiation and TH 2-mediated allergic airway inflammation. Methods Conditional RhoA-deficient mice were generated by crossing RhoA flox/flox mice with CD2-Cre transgenic mice. Effects of RhoA on TH 2 differentiation were evaluated based on in vitro TH 2-polarized culture conditions and in vivo in ovalbumin-induced allergic airway inflammation. Cytokine levels were measured by using intracellular staining and ELISA. T-cell metabolism was measured by using the Seahorse XF24 Analyzer and flow cytometry. Results Disruption of RhoA inhibited T-cell activation and TH 2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo , with no effect on TH 1 cells. RhoA deficiency in activated T cells led to multiple defects in metabolic pathways, such as glycolysis and oxidative phosphorylation. Importantly, RhoA couples glycolysis to TH 2 cell differentiation and allergic airway inflammation through regulating IL-4 receptor mRNA expression and TH 2-specific signaling events. Finally, inhibition of Rho-associated protein kinase, an immediate downstream effector of RhoA, blocked TH 2 differentiation and allergic airway inflammation. Conclusion RhoA is a key component of the signaling cascades leading to TH 2 differentiation and allergic airway inflammation at least in part through control of T-cell metabolism and the Rho-associated protein kinase pathway.
To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment.
The expression of miR-20a and PTEN were detected ...in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Akt pathway.
MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a-induced radioresistance.
MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC.
PDF
