The underlying mechanisms of neuropathic pain remain to be elucidated. Basic animal research has suggested that lysophosphatidic acids, which are bioactive lipids produced by autotaxin from lysophosphatidylcholine, may play key roles in the initiation and maintenance of neuropathic pain. Here, we investigated the clinical relevance of lysophosphatidic acids signaling on neuropathic pain in humans. Eighteen patients who had been diagnosed with neuropathic pain with varied etiologies participated in the study. Cerebrospinal fluid samples were obtained by lumbar puncture and the concentrations of 12 species of lysophosphatidic acids and lysophosphatidylcholine, autotaxin, and the phosphorylated neurofilament heavy subunit were measured. Pain symptoms were assessed using an 11-point numeric rating scale and the Neuropathic Pain Symptom Inventory regarding intensity and descriptive dimensions of neuropathic pain. The total lysophosphatidic acids were significantly associated with both pain intensity and symptoms. 18:1 and 20:4 lysophosphatidic acids in particular demonstrated the most correlations with dimensions of pain symptoms. Autotaxin and the phosphorylated neurofilament heavy subunit showed no association with pain symptoms. In conclusions, lysophosphatidic acids were significantly associated with pain symptoms in neuropathic pain patients. These results suggest that lysophosphatidic acids signaling might be a potential therapeutic target for neuropathic pain.
Lysophospholipids (LPLs) are known to have potentially important roles in the initiation and maintenance of neuropathic pain in animal models. This study investigated the association between the clinical severity of lumbar spinal stenosis (LSS) and the cerebrospinal fluid (CSF) levels of LPLs, using human samples. We prospectively identified twenty-eight patients with LSS and fifteen controls with idiopathic scoliosis or bladder cancer without neurological symptoms. We quantified LPLs from CSF using liquid chromatography-tandem mass spectrometry. We assessed clinical outcome measures of LSS (Neuropathic Pain Symptom Inventory (NPSI) and Zurich Claudication Questionnaire (ZCQ)) and categorized patients into two groups according to their severity. Five species of lysophosphatidic acid (LPA), nine species of lysophosphatidylcholine (LPC), and one species of lysophosphatidylinositol (LPI) were detected. The CSF levels of all species of LPLs were significantly higher in LSS patients than controls. Patients in the severe NPSI group had significantly higher LPL levels (three species of LPA and nine species of LPC) than the mild group. Patients in the severe ZCQ group also had significantly higher LPL levels (four species of LPA and nine species of LPC). This investigation demonstrates a positive correlation between the CSF levels of LPLs and the clinical severity of LSS. LPLs are potential biomarkers for evaluating the severity of LSS.
Stroke during pregnancy is rare, but after occurring, most patients develop serious neurological conditions. Hemorrhagic stroke, including intracerebral hemorrhage and subarachnoid hemorrhage, often requires emergency surgical intervention. In addition to significant maternal physiological changes, the potential for fetal harm should be considered during anesthetic management of these patients. Whether cesarean section or neurosurgical intervention should be prioritized or performed simultaneously in pregnant women with stroke is an important issue. Whether the patients receive general or spinal and epidural anesthesia is another clinically significant issue. Finally neurosurgeons, anesthesiologists, and obstetricians should cooperate to manage pregnant women with stroke.Key words: pregnant woman, cerebral stroke, anesthesia Maternal Physiological Changes During PregnancyImportant physiological changes occur in pregnancy that could affect anesthetic management. Such physiological changes are mainly the result of hormonal and anatomical changes. I. Hormonal changesVarious hormonal alterations occur to sustain the pregnancy. Human chorionic gonadotropin allows the corpus luteum, which produces progesterone and estrogen, to be maintained. Endorphins and aldosterone are also secreted as shown in Fig. 1. Both estrogen and progesterone are important pregnancy-sustaining hormones that lead to endometrial hyperplasia. These hormones lead to dilation of blood vessels, which may cause cerebral aneurysms to increase in size. 4) In addition, meningiomas and other neoplasms expressing estrogen and progesterone receptors experience faster growth during pregnancy. 17) Increased levels of progesterone along with an increased rate of carbon dioxide production during pregnancy are responsible for increases in ventilation. Oxygen consumption also increases by as much as 60% during pregnancy. 20) As a result, functional residual capacity decreases by as much as 20% by the end of the third trimester. 11) Progesterone sensitizes the respiratory center to carbon dioxide. PaCO 2 falls to approximately 30 mmHg by the 12 th week of gestation. In the central nervous system, increased concentrations of endorphins have been found during pregnancy in animal models. 6) Beta-endorphin was identified as an endogenous agonist for
BackgroundOne of the main pathophysiological manifestations during the acute phase of sepsis is massive production of proinflammatory mediators. Clinical trials involving direct suppression of inflammatory mediators to relieve organ dysfunction in sepsis have been extensively performed; however, the clinical outcomes of such trials remain far from satisfactory. Given the need for better sepsis treatments, we have screened various agents with anti-inflammatory properties for cytoprotective effects. In this study, we identified dexamethasone and rapamycin as clinically applicable candidates with favorable synergistic effects against inflammatory cytokine-induced cytotoxicity in vitro and further explored the molecular mechanisms underlying the augmented cytoprotective effects exerted by co-treatment with both drugs.MethodsHuman alveolar epithelial cell-derived A549 cells were stimulated with a mixture of inflammatory cytokines, TNF-alpha, IL-1beta, and IFN-gamma, which induce cellular injury, including apoptosis. This in vitro model was designed to simulate acute lung injury (ALI) associated with sepsis. The cells were co-treated with dexamethasone and rapamycin under cytokine stimulation. Conditioned medium and cell lysates were subjected to further analysis.ResultsEither dexamethasone or rapamycin significantly attenuated cytokine-induced cytotoxicity in A549 cells in a dose-dependent manner. In addition, the simultaneous administration of dexamethasone and rapamycin had a synergistic cytoprotective effect. The applied doses of dexamethasone (10 nM) and rapamycin (1 nM) were considerably below the reported plasma concentrations of each drug in clinical setting. Interestingly, distinct augmentation of both of c-Jun inhibition and Akt activation were observed when the cells were co-treated with both drugs under cytokine stimulation.ConclusionsA synergistic protective effect of dexamethasone and rapamycin was observed against cytokine-induced cytotoxicity in A549 cells. Augmentation of both of c-Jun inhibition and Akt activation were likely responsible for the cytoprotective effect. The combined administration of anti-inflammatory drugs such as dexamethasone and rapamycin offers a promising treatment option for alveolar epithelial injury associated with sepsis.Electronic supplementary materialThe online version of this article (10.1186/s40560-019-0365-5) contains supplementary material, which is available to authorized users.
ScO2 measured by TRS and SjO2 showed narrow limits of agreement. Reduced ScO2 was significantly associated with impaired cerebral hemodynamics.
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