106 research outputs found
Effects of maleimide-polyethylene glycol-modified human hemoglobin (MP4) on tissue necrosis in SKH1-hr hairless mice
<p>Abstract</p> <p>Objective</p> <p>Tissue hypoxia after blood loss, replantation and flap reperfusion remains a challenging task in surgery. Normovolemic hemodilution improves hemorheologic properties without increasing oxygen carrying capacity. Red blood cell transfusion is the current standard of treatment with its attendant risks. The aim of this study was to investigate the potential of the chemically modified hemoglobin, MP4, to reduce skin flap necrosis and its effect on selected blood markers and kidneys.</p> <p>Materials and methods</p> <p>Tissue ischemia was induced in the ear of hairless mice (n = 26). Hemodilution was performed by replacing one third of blood volume with the similar amount of MP4, dextran, or blood. The extent of non-perfused tissue was assessed by intravital fluorescent microscopy.</p> <p>Results</p> <p>Of all groups, MP4 showed the smallest area of no perfusion (in percentage of the ear ± SEM: 16.3% ± 2.4), the control group the largest (22.4% ± 3.5). Leukocytes showed a significant increase in the MP4 and dextran group (from 8.7 to 13.6 respectively 15.4*10<sup>9</sup>/l). On histology no changes of the kidneys could be observed.</p> <p>Conclusion</p> <p>MP4 causes an increase of leukocytes, improves the oxygen supply of the tissue and shows no evidence of renal impairment.</p
Characterization of the radiation tolerance of cryogenic diodes for the High Luminosity LHC inner triplet circuit
Cryogenic bypass diodes are part of the baseline powering layout for the circuits of the new Nb3Sn based final focus magnets of the high luminosity Large Hadron Collider. They will protect the magnets against excessive transient voltages during a nonuniform quenching process. The diodes are located inside an extension to the magnet cryostat, operated in superfluid helium and exposed to ionizing radiation. Therefore, the radiation tolerance of different types of diodes has been tested at cryogenic temperatures in CERN’s CHARM irradiation test facility during its 2018 run. The forward bias characteristics, the turn-on voltage and the reverse blocking voltage of each diode were measured weekly at 4.2 K and 77 K, as a function of the accumulated radiation dose. The diodes were submitted to a total dose close to 12 kGy and a 1 MeV neutron equivalent fluence of 2.2×1014  cm−2. After the end of the irradiation program the annealing behavior of the diodes was tested by increasing the temperature slowly to 293 K. This paper describes the experimental setup, the measurement procedure and the analysis of the measurements performed during the irradiation program as well as the results of the annealing study
Experimental Setup to Characterize the Radiation Hardness of Cryogenic Bypass Diodes for the HL-LHC Inner Triplet Circuits
For the high luminosity upgrade of the Large Hadron Collider (LHC), it is planned to replace the existing triplet quadrupole magnets with Nb₃Sn quadrupole magnets, which provide a comparable integrated field gradient with a significantly increased aperture. These magnets will be powered through a novel superconducting link based on MgB₂ cables. One option for the powering layout of this triplet circuit is the use of cryogenic bypass diodes, where the diodes are located inside an extension to the magnet cryostat and operated in superfluid helium. Hence, they are exposed to radiation. For this reason the radiation hardness of existing LHC type bypass diodes and more radiation tolerant prototype diodes needs to be tested up to the radiation doses expected at their planned position during their lifetime. A first irradiation test is planned in CERN's CHARM facility starting in spring 2018. Therefore, a cryo-cooler based cryostat to irradiate and test LHC type diodes in-situ has been designed and constructed. This paper will describe the properties of the sample diodes, the experimental roadmap and the setup installed in CHARM. Finally, the first measurement results will be discussed
Characterisation of the radiation hardness of cryogenic bypass diodes for the HL-LHC inner triplet circuit
P2Y<sub>12</sub>-dependent activation of hematopoietic stem and progenitor cells promotes emergency hematopoiesis after myocardial infarction
Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y12-mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y12. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y12 in LSK, implicating a direct effect of ADP on LSK via P2Y12 signaling. P2Y12 knockout and P2Y12 inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y12 inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y12-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y12 antagonists beyond inhibition of platelet-mediated atherothrombosis
CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies
BACKGROUND: Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L--an established marker and mediator of cardiovascular disease--induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo. METHODOLOGY/PRINCIPAL FINDINGS: WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels. CONCLUSION: We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease
Beam Impact Experiment of 440GeV/p Protons on Superconducting Wires and Tapes in a Cryogenic Environment
Peripheral Immune Cell Gene Expression Predicts Survival of Patients with Non-Small Cell Lung Cancer
Prediction of cancer recurrence in patients with non-small cell lung cancer (NSCLC) currently relies on the assessment of clinical characteristics including age, tumor stage, and smoking history. A better prediction of early stage cancer patients with poorer survival and late stage patients with better survival is needed to design patient-tailored treatment protocols. We analyzed gene expression in RNA from peripheral blood mononuclear cells (PBMC) of NSCLC patients to identify signatures predictive of overall patient survival. We find that PBMC gene expression patterns from NSCLC patients, like patterns from tumors, have information predictive of patient outcomes. We identify and validate a 26 gene prognostic panel that is independent of clinical stage. Many additional prognostic genes are specific to myeloid cells and are more highly expressed in patients with shorter survival. We also observe that significant numbers of prognostic genes change expression levels in PBMC collected after tumor resection. These post-surgery gene expression profiles may provide a means to re-evaluate prognosis over time. These studies further suggest that patient outcomes are not solely determined by tumor gene expression profiles but can also be influenced by the immune response as reflected in peripheral immune cells
Tumor Necrosis Factor Receptor Associated Factor 6 Is Not Required for Atherogenesis in Mice and Does Not Associate with Atherosclerosis in Humans
BACKGROUND: Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease. METHODOLOGY/PRINCIPAL FINDINGS: Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography. CONCLUSION: Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis
Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus
<p>Abstract</p> <p>Background</p> <p>Conotruncal heart defects (CTDs) are present in 75-85% of patients suffering from the 22q11.2 deletion syndrome. To date, no consistent phenotype has been consistently correlated with the 22q11.2 deletions. Genetic studies have implicated <it>TBX1 </it>as a critical gene in the pathogenesis of the syndrome. The aim of study was to determine the incidence of the 22q11.2 deletion in Chinese patients with CTDs and the possible mechanism for pathogenesis of CTDs.</p> <p>Methods</p> <p>We enrolled 212 patients with CTDs and 139 unrelated healthy controls. Both karyotypic analysis and multiplex ligation-dependent probe amplification were performed for all CTDs patients. Fluorescence <it>in situ </it>hybridization was performed for the patients with genetic deletions and their relatives. The <it>TBX1 </it>gene was sequenced for all patients and healthy controls. The <it>χ</it><sup>2 </sup>and Fisher's exact test were used in the statistical analysis.</p> <p>Results</p> <p>Thirteen of the 212 patients with CTDs (6.13%) were found to have the 22q11.2 deletion syndrome. Of the 13 cases, 11 presented with a hemizygous interstitial microdeletion from <it>CLTCL1 </it>to <it>LZTR1</it>; one presented with a regional deletion from <it>CLTCL1 </it>to <it>DRCR8</it>; and one presented with a regional deletion from <it>CDC45L </it>to <it>LZTR1</it>. There were eight sequence variants in the haploid <it>TBX1 </it>genes of the del22q11 CTDs patients. The frequency of one single nucleotide polymorphism (SNP) in the del22q11 patients was different from that of the non-del patients (<it>P </it>< 0.05), and the frequencies of two other SNPs were different between the non-del CTDs patients and controls (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>CTDs, especially pulmonary atresia with ventricular septal defect and tetralogy of Fallot, are the most common disorders associated with the 22q11.2 deletion syndrome. Those patients with both CTDs and 22q11.2 deletion generally have a typical or atypical deletion region within the <it>TBX1 </it>gene. Our results indicate that <it>TBX1 </it>genetic variants may be associated with CTDs.</p
- …