SummaryHigh-density hpoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion ofproinflammatory cytokine inhibitors IL-lra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.T he systemic toxicity of Gram-negative sepsis is in large part mediated by endotoxin which induces an extensive inflammatory response characterized by cytokine release and activation of leukocytes. Once in the circulation, endotoxin is bound by lipopolysaccharide-binding protein (LBP) 1 which can transfer LPS to either cell-bound CD14 (causing activation of these cells), to soluble CD14 (facihtaring activation ofceUs not expressing CD14 on their surface), or to lipoproteins (1-7). Binding of LPS to lipoproteins results in inactivation of LPS (8-11). Preincubation of endotoxin with low-density lipoprotein (LDL), very-low density lipoprotein (VLDL) and chylomicrons reduced endotoxininduced lethality (12), whereas hypolipidemic animals were more sensitive to endotoxin (13). Further, transgenic mice with elevated apolipoprotein A-1 (apoA-1) and HDL levels are protected against LPS-induced mortality (14).The endotoxin-neutralizing capacity of lipoproteins is dependent on the lipid composition. Reconstituted human HDL (rHDL), containing purified apoA-1, phosphatidyl cho1Abbreviations used in this paper: apoA-1, apohpoprotein A-l; HDL, high-density hpoprotein; LBP, hpopolysaccharide-binding protein; LDL, low-density lipoprotein; rHDL, reconstituted human HDL; VLDL, very low-density lipoprotein.line and cholesterol, neutralized endotoxin in whole blood more effectively than LDL, VLDL, and natural HDL (15, 16). Pretreatment of animals with rHDL reduced endotoxininduced TNF production, leukopenia and lethality (17)(18)(19). The present study was designed to investigate the endotoxin-neutrahzing properties of rHDL (40 mg/kg) in humans in vivo. Materials and MethodsHuman Endotoxemia. Eight healthy male volunteers (mean age 24, range 20-28 yr) were enrolled in thi...

Demonstrating improved confinement of energetic ions is one of the key goals of the Wendelstein 7-X (W7-X) stellarator. In the past campaigns, measuring confined fast ions has proven to be challenging. Future deuterium campaigns would open up the option of using fusion-produced neutrons to indirectly observe confined fast ions. There are two neutron populations: 2.45 MeV neutrons from thermonuclear and beam-target fusion, and 14.1 MeV neutrons from DT reactions between tritium fusion products and bulk deuterium. The 14.1 MeV neutron signal can be measured using a scintillating fiber neutron detector, whereas the overall neutron rate is monitored by common radiation safety detectors, for instance fission chambers. The fusion rates are dependent on the slowing-down distribution of the deuterium and tritium ions, which in turn depend on the magnetic configuration via fast ion orbits. In this work, we investigate the effect of magnetic configuration on neutron production rates in W7-X. The neutral beam injection, beam and triton slowing-down distributions, and the fusion reactivity are simulated with the ASCOT suite of codes. The results indicate that the magnetic configuration has only a small effect on the production of 2.45 MeV neutrons from DD fusion and, particularly, on the 14.1 MeV neutron production rates. Despite triton losses of up to 50 %, the amount of 14.1 MeV neutrons produced might be sufficient for a time-resolved detection using a scintillating fiber detector, although only in high-performance discharges.

After completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3  ×  1019 m−3, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.

Various attempts to detect human pituitary growth hormonereleasing hormone receptor (pGHRH-R) in neoplastic extrapituitary tissues have thus far failed. Recently, four splice variants (SVs) of GHRH-R have been described, of which SV1 has the highest structural homology to pGHRH-R and likely plays a role in tumor growth. The aim of this study was to reinvestigate whether human tumors and normal human extrapituitary tissues express the pGHRH-R and to corroborate our previous findings on its SVs. Thus, we developed a real-time PCR method for the detection of the mRNA for the pGHRH-R, its SVs, and the GHRH peptide. Using real-time PCR, Western blotting, and radioligand-binding assays, we detected the mRNA for pGHRH-R and pGHRH-R protein in various human cancer cell lines grown in nude mice and in surgical specimens of human lung cancers. The expression of mRNA for SVs of pGHRH-R and GHRH was likewise found in xenografts of human non-Hodgkin's lymphomas, pancreatic cancer, glioblastoma, smallcell lung carcinomas, and in human nonmalignant prostate, liver, lung, kidney, and pituitary. Western blots showed that these normal and malignant human tissues contain SV1 protein and immunoreactive GHRH. Our results demonstrate that some normal human tissues and tumors express mRNA and protein for the pGHRH-R and its splice variants. These findings confirm and extend the concept that GHRH and its receptors play an important role in the pathophysiology of human cancers.

Six cases of apparent and four cases of histopathologically confirmed vasculitis of the central nervous system (CNS), including one case of histopathologically documented vasculitis with encephalitis associated with coccidioidal meningitis (CM), are presented. Vasculitic complications included changes in mental status as well as stroke-like findings of aphasia, hemianopsia, and hemiparesis. Seven patients died. Vasculitic complications were unanticipated and often abrupt in onset, and delayed therapeutic intervention was characteristic. The diagnosis of vasculitis/encephalitis due to Coccidioides immitis infection must be based on clinical judgment, since serum antibody titers, cerebrospinal fluid findings, and initial radiological studies are not always helpful. Institution of both intravenous and intracisternal administration of amphotericin B and possibly concomitant intravenous administration of dexamethasone may be warranted in situations in which the association of C. immitis with CNS vasculitis or encephalitis appears likely before serologic or cultural confirmation of C. immitis infection involving the CNS is available.