Extracellular signal-regulated kinase 1/2 plays a pro-life role in experimental brain stem death via MAPK signal-interacting kinase at rostral ventrolateral medulla

<p>Abstract</p> <p>Background</p> <p>As the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM during brain stem death. We further delineated the participation of MAPK signal-interacting kinase (MNK), a novel substrate of ERK in this process.</p> <p>Methods</p> <p>An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations.</p> <p>Results</p> <p>Results from ELISA showed that whereas the total ERK1/2 was not affected, augmented phosphorylation of ERK1/2 at Thr202 and Tyr204 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Furthermore, pretreatment by microinjection into the bilateral RVLM of a specific ERK2 inhibitor, ERK activation inhibitor peptide II (1 nmol); a specific MEK1/2 inhibitor, U0126 (5 pmol); or a specific MNK1/2 inhibitor, CGP57380 (5 pmol) exacerbated the hypotension and blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated nitric oxide synthase I (NOS I)/protein kinase G (PKG) signaling, the pro-life cascade that sustains central cardiovascular regulatory functions during experimental brain stem death.</p> <p>Conclusions</p> <p>Our results demonstrated that activation of MEK1/2, ERK1/2 and MNK1/2 in RVLM plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during brain stem death via upregulation of NOS I/PKG signaling cascade in RVLM.</p

Heme oxygenase-1 plays a pro-life role in experimental brain stem death via nitric oxide synthase I/protein kinase G signaling at rostral ventrolateral medulla

<p>Abstract</p> <p>Background</p> <p>Despite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. A suitable neural substrate for mechanistic delineation on brain stem death resides in the rostral ventrolateral medulla (RVLM) because it is the origin of a life-and-death signal that sequentially increases (pro-life) and decreases (pro-death) to reflect the advancing central cardiovascular regulatory dysfunction during the progression towards brain stem death in critically ill patients. The present study evaluated the hypothesis that heme oxygnase-1 (HO-1) may play a pro-life role as an interposing signal between hypoxia-inducible factor-1 (HIF-1) and nitric oxide synthase I (NOS I)/protein kinase G (PKG) cascade in RVLM, which sustains central cardiovascular regulatory functions during brain stem death.</p> <p>Methods</p> <p>We performed cardiovascular, pharmacological, biochemical and confocal microscopy experiments in conjunction with an experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of adult male Sprague-Dawley rats.</p> <p>Results</p> <p>Western blot analysis coupled with laser scanning confocal microscopy revealed that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons occurred preferentially during the pro-life phase of experimental brain stem death and was antagonized by immunoneutralization of HIF-1α or HIF-1β in RVLM. On the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested insignificant changes during both phases. Furthermore, immunoneutralization of HO-1 or knockdown of <it>ho-1 </it>gene in RVLM blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS II/peroxynitrite cascade in RVLM.</p> <p>Conclusions</p> <p>We conclude that transcriptional upregulation of HO-1 on activation by HIF-1 in RVLM plays a preferential pro-life role by sustaining central cardiovascular regulatory functions during brain stem death via upregulation of NOS I/PKG signaling pathway. Our results further showed that the pro-dead NOS II/peroxynitrite cascade in RVLM is not included in this repertoire of cellular events.</p

Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication

<p>Abstract</p> <p>Background</p> <p>Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism.</p> <p>Methods</p> <p>The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time.</p> <p>Results</p> <p>Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. <b/>The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism.</p> <p>Conclusions</p> <p>We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.</p

Differential protection against oxidative stress and nitric oxide overproduction in cardiovascular and pulmonary systems by propofol during endotoxemia

<p>Abstract</p> <p>Background</p> <p>Both overproduction of nitric oxide (NO) and oxidative injury of cardiovascular and pulmonary systems contribute to fatal cardiovascular depression during endotoxemia. We investigated in the present study the relative contribution of oxidative stress and NO to cardiovascular depression during different stages of endotoxemia, and delineated their roles in cardiovascular protective effects of a commonly used anesthetic propofol during endotoxemia.</p> <p>Methods</p> <p>Experimental endotoxemia was induced by systemic injection of <it>E. coli </it>lipopolysaccharide (LPS, 15 mg/kg) to Sprague-Dawley rats that were maintained under propofol (15 or 30 mg/kg/h, i.v.) anesthesia. Mean systemic arterial pressure (MSAP) and heart rate (HR) were monitored for 6 h after the endotoxin. Tissue level of NO was measured by chemical reduction-linked chemiluminescence and oxidative burst activity was determined using dihydroethidium method. Expression of NO synthase (NOS) was determined by immunoblotting. The Scheffé multiple range test was used for post hoc statistical analysis.</p> <p>Results</p> <p>Systemic injection of LPS (15 mg/kg) induced biphasic decreases in MSAP and HR. In the heart, lung and aorta, an abrupt increase in lipid peroxidation, our experimental index of oxidative tissue injury, was detected in early stage and sustained during late stage cardiovascular depression. LPS injection, on the other hand, induced a gradual increase in tissue nitrite and nitrate levels in the same organs that peaked during late stage endotoxemia. Propofol infusion (15 or 30 mg/kg/h, i.v.) significantly attenuated lipid peroxidation in the heart, lung and aorta during early and late stage endotoxemia. High dose (30 mg/kg/h, i.v.) propofol also reversed the LPS-induced inducible NO synthase (iNOS) upregulation and NO production in the aorta, alongside a significant amelioration of late stage cardiovascular depression and increase in survival time during endotoxemia.</p> <p>Conclusion</p> <p>Together these results suggest that oxidative injury and NO may play a differential role in LPS-induced cardiovascular depression. Oxidative tissue injury is associated with both early and late stage; whereas NO is engaged primarily in late stage cardiovascular depression. Moreover, propofol anesthesia may protect against fatal cardiovascular depression during endotoxemia by attenuating the late stage NO surge in the aorta, possibly via inhibition of iNOS upregulation by the endotoxin.</p

Sample entropy analysis of EEG signals via artificial neural networks to model patients' consciousness level based on anesthesiologists experience.

Electroencephalogram (EEG) signals, as it can express the human brain's activities and reflect awareness, have been widely used in many research and medical equipment to build a noninvasive monitoring index to the depth of anesthesia (DOA). Bispectral (BIS) index monitor is one of the famous and important indicators for anesthesiologists primarily using EEG signals when assessing the DOA. In this study, an attempt is made to build a new indicator using EEG signals to provide a more valuable reference to the DOA for clinical researchers. The EEG signals are collected from patients under anesthetic surgery which are filtered using multivariate empirical mode decomposition (MEMD) method and analyzed using sample entropy (SampEn) analysis. The calculated signals from SampEn are utilized to train an artificial neural network (ANN) model through using expert assessment of consciousness level (EACL) which is assessed by experienced anesthesiologists as the target to train, validate, and test the ANN. The results that are achieved using the proposed system are compared to BIS index. The proposed system results show that it is not only having similar characteristic to BIS index but also more close to experienced anesthesiologists which illustrates the consciousness level and reflects the DOA successfully.This research is supported by the Center forDynamical Biomarkers and Translational Medicine, National Central University, Taiwan, which is sponsored by Ministry of Science and Technology (Grant no. MOST103-2911-I-008-001). Also, it is supported by National Chung-Shan Institute of Science & Technology in Taiwan (Grant nos. CSIST-095-V301 and CSIST-095-V302)

Bioprocessing for elimination antibiotics and hormones from swine wastewater

© 2017 Elsevier B.V. Antibiotics and hormones in swine wastewater have become a critical concern worldwide due to the severe threats to human health and the eco-environment. Removal of most detectable antibiotics and hormones, such as sulfonamides (SAs), SMs, tetracyclines (TCs), macrolides, and estrogenic hormones from swine wastewater utilizing various biological processes were summarized and compared. In biological processes, biosorption and biodegradation are the two major removal mechanisms for antibiotics and hormones. The residuals in treated effluents and sludge of conventional activated sludge and anaerobic digestion processes can still pose risks to the surrounding environment, and the anaerobic processes’ removal efficiencies were inferior to those of aerobic processes. In contrast, membrane bioreactors (MBRs), constructed wetlands (CWs) and modified processes performed better because of their higher biodegradation of toxicants. Process modification on activated sludge, anaerobic digestion and conventional MBRs could also enhance the performance (e.g. removing up to 98% SMs, 88.9% TCs, and 99.6% hormones from wastewater). The hybrid process combining MBRs with biological or physical technology also led to better removal efficiency. As such, modified conventional biological processes, advanced biological technologies and MBR hybrid systems are considered as a promising technology for removing toxicants from swine wastewater

Water desalination by air-gap membrane distillation using meltblown polypropylene nanofiber membrane

This paper presents a study of air gap membrane distillation (AGMD) using meltblown polypropylene (PP) nanofiber membrane to produce fresh water via desalination process. PP nanofiber membranes with the effective area 0.17 m2 are tested with NaCl solutions (0.5 – 4.0 wt.%) and seawater as the feed solutions (9400 – 64800 µS/cm) in a tubular membrane module. Results show that the flux decreases with increasing the membrane thickness from 547 to 784 µm. The flux increases with the feed flow rate and temperature difference across the membrane. The feed concentration affects the flux insignificantly. The AGMD system can reject the salts at least 96%. Water vapor permeation rate is relatively higher than solute permeation rate resulting in the conductivity value of permeate decreases when the corresponding flux increases. The AGMD system produces the fresh water (200 – 1520 µS/cm) that is suitable for drinking, fisheries or irrigation

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology

DNA analysis of Huntington's disease in Southern Chinese

Allelic frequencies of RFLPs at loci closely linked to the HD gene, D4S95, D4S91, D4S141, and D4S90, were determined in 13 Huntington's disease (HD) patients from nine Chinese families and 129 normal subjects. These were similar for non-HD and HD chromosomes and the HD gene in Chinese is associated with multiple haplotypes. Hence the HD gene probably arose independently in the background haplotypes of the Chinese population. The heterozygosity rates for the two most useful RFLP sites are 0.659 for D4S95-AcI VNTR and 0.494 for D4S141-HindIII. (CAG)n repeat numbers ranged from 12 to 27 in 174 normal chromosomes. In 52 meiotic recombinations, the (CAG)n repeats were stably inherited in normal families. In HD families, 12 of 13 HD patients had expanded (CAG)n repeats of 40 to 58. Additionally, 10 asymptomatic family members had expanded (CAG)n repeats and the inheritance of the expanded repeat was unstable in these families.published_or_final_versio

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance