Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity.

BackgroundMounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo.MethodsTNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity.ResultsTNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNF in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity.ConclusionsHere we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation

Cybertools improve reaction time in open heart surgery

Objective: Head-up displays allow the surgeons to simultaneously view the patient and the patient's vital parameters (ECG, blood pressure, etc.) using vision-through over a wireless net, potentially enhancing the speed, accuracy and safety of surgical decisions. The aim was to assess surgical reaction time to AFIB, bigeminy, trigeminy, VTACH, and VFIB and concentration during a surgical intervention comparing standard and cyber tools monitoring. Methods: Using a patient simulator for beating heart surgery able to emulate heart signals and motion (arrhythmias) a group of surgeons performed coronary bypass procedures. Measurements of reaction time, efficiency of the surgeon, time elapsed to display a coronary angiography in a realistic surgical environment were taken. Results: The duration to accomplish the experiment is not different between groups (cyber vs. standard) reaction times, however, are significantly decreased for cyber by a mean of 33%. There is also a measured time difference for displaying a coronary angiography within the head-up display as compared to a remote console. Conclusions: During surgery, modern cyber tools allow for significant improvements of reaction time and concentration due to real time access to vital informatio

Cybertools improve reaction time in open heart surgery

OBJECTIVE: Head-up displays allow the surgeons to simultaneously view the patient and the patient's vital parameters (ECG, blood pressure, etc.) using vision-through over a wireless net, potentially enhancing the speed, accuracy and safety of surgical decisions. The aim was to assess surgical reaction time to AFIB, bigeminy, trigeminy, VTACH, and VFIB and concentration during a surgical intervention comparing standard and cyber tools monitoring. METHODS: Using a patient simulator for beating heart surgery able to emulate heart signals and motion (arrhythmias) a group of surgeons performed coronary bypass procedures. Measurements of reaction time, efficiency of the surgeon, time elapsed to display a coronary angiography in a realistic surgical environment were taken. RESULTS: The duration to accomplish the experiment is not different between groups (cyber vs. standard) reaction times, however, are significantly decreased for cyber by a mean of 33%. There is also a measured time difference for displaying a coronary angiography within the head-up display as compared to a remote console. CONCLUSIONS: During surgery, modern cyber tools allow for significant improvements of reaction time and concentration due to real time access to vital information

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Background: Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin.Methods: To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)—induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE).Results: Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE.Conclusions: These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi

Abstract Background Carmustine (BCNU)-Etoposide-Citarabine-Melphalan (BEAM) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to Fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. Methods We conducted a retrospective cohort study in 18 Italian centers to compare safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. Results We enrolled 1038 patients (BEAM n=607, FEAM n=431), of which 27% had Hodgkin's lymphoma (HL), 14% indolent Non-Hodgkin's lymphoma (iNHL) and 59% aggressive NHL (aNHL). Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, overall conditioning intensity, were well balanced between BEAM and FEAM; notable exceptions were: ASCT year (median: BEAM=2011 vs FEAM=2013, p Conclusions BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, Fotemustine substitution in BEAM does not seem justified, if not for easier supply

dOCRL maintains immune cell quiescence in Drosophila by regulating endosomal traffic

Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system. Among many cell biological defects that we identified in docrl mutant hemocytes, we pinpointed the cause of innate immune cell activation to reduced Rab11-dependent recycling traffic and concomitantly increased Rab7-dependent late endosome traffic. Loss of docrl amplifies multiple immune-relevant signals, including Toll, Jun kinase, and STAT, and leads to Rab11-sensitive mis-sorting and excessive secretion of the Toll ligand Spåtzle. Thus, docrl regulation of endosomal traffic maintains hemocytes in a poised, but quiescent state, suggesting mechanisms by which endosomal misregulation of signaling may contribute to symptoms of Lowe syndrome