Explore the vast range of titles available.

Leukotriene B 4 (LTB 4 ) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB 4 are primarily mediated through the high-affinity LTB 4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB 4 -BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB 4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1–3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB 4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB 4 -BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB 4 -BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury.

Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference. Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients. Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02). Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.

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.

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Background and objectivesThe health benefits of peripheral nerve block (PNB) on postoperative complications after lower extremity amputation (LEA) compared with general anesthesia (GA) remains controversial. We performed a retrospective propensity score-matched cohort analysis to compare major outcomes after LEA with PNB versus GA.Materials and methodsWe used a nationwide inpatient database in Japan to compare patient outcomes after LEA with PNB versus GA from 2010 to 2016. Our primary outcome was 30-day mortality after LEA. The incidence of composite morbidity from life-threatening complications and of delirium within 30 days after LEA were secondary outcomes. We conducted propensity score-matched analyses of patients who underwent below knee or foot amputation using 36 covariates. Logistic regression analyses fitted with generalized estimating equations were performed to calculate ORs and their 95% CIs.ResultsOf 11 796 patients, 747 received PNB and 11 049 received GA. After one-to-four propensity score matching, 747 patients were included in the PNB group and 2988 in the GA group. The adjusted ORs for postoperative mortality, composite morbidity and delirium within 30 days after LEA were 1.11 (95% CI 0.75 to 1.64), 1.15 (95% CI 0.85 t o1.56) and 0.75 (95% CI 0.57 to 0.98), respectively, for the PNB group with reference to the GA group.ConclusionsThere was no significant difference between groups in 30-day mortality or composite morbidity. The PNB group showed a significantly lower risk of postoperative delirium than the GA group. Our findings suggest that PNB may have advantages over GA in preventing postoperative delirium among patients undergoing LEA.

Background Management of patients with acute respiratory distress syndrome (ARDS) remains supportive with lung protective mechanical ventilation. In this article, we discuss the physiological concept of driving pressure, current data, ongoing trials, and future directions needed to clarify the role of driving pressure in patients with ARDS. Body Driving pressure is the plateau airway pressure minus PEEP. It can also be expressed as the ratio of tidal volume to respiratory system compliance, indicating the decreased functional size of the lung observed in patients with ARDS (i.e., baby lung). Driving pressure as a strong predictor of mortality in patients with ARDS is supported by a post hoc analysis of previous randomized controlled trials and a subsequent meta-analysis. Importantly, the meta-analysis suggested targeting driving pressure below 13–15 cmH2O. Ongoing clinical trials of driving pressure in patients with ARDS focus mainly on physiological rather than clinical outcome but will provide important insights for the design of future clinical trials. Conclusion Currently, no definite clinical recommendations on the routine use of driving pressure in patients with ARDS can be made, as the available data are hypothesis-generating. Randomized controlled trials are needed to evaluate the efficacy of a driving pressure-based ventilation strategy.

PEEP is regulated by the internal PEEP/maximum peak inspiratory pressure limit (Pmax) valve. Malfunctioning of the PEEP/Pmax valve can result in the creation of unintentional or unstable PEEP, and a reduction of inspired tidal volume. Some of our Dräger Fabius® anesthesia machines were noted to exhibit changes in expiratory waveforms and unstable PEEP during general anesthesia. We considered that the cause was associated with PEEP/Pmax valve malfunction, and then investigated the problems in collaboration with the manufacturer. Seven of the 22 Dräger Fabius® anesthesia workstations at our department exhibited problems with their PEEP/Pmax valves. We replaced the PEEP membrane and sealing washers in these seven anesthesia machines, and the problems were temporarily resolved. After a short interval, however, one of the seven machines began to show a similar phenomenon. We then asked the manufacturer to overhaul the PEEP/Pmax valve and the entire breathing circuit of the machine. On close investigation, we found that the valve components and the internal surface of the breathing circuit were contaminated with unexpected deposits. The build-up of deposits occurred within a year after the previous regular inspection. Our troubleshooting process determined the issue with the PEEP/Pmax valve, which could go unnoticed because the valve is encased inside the breathing circuit, and requires disassembly for close inspection. Our findings should raise awareness regarding the importance of the preventive maintenance cycle as a safety precaution to keep the anesthetic circuit free of unexpected contamination.

Cauda equina compression (CEC) is a major cause of neurogenic claudication and progresses to neuropathic pain (NP). A lipid mediator, lysophosphatidic acid (LPA), is known to induce NP via the LPA 1 receptor. To know a possible mechanism of LPA production in neurogenic claudication, we determined the levels of LPA, lysophosphatidylcholine (LPC) and LPA-producing enzyme autotaxin (ATX), in the cerebrospinal fluid (CSF) and spinal cord (SC) using a CEC as a possible model of neurogenic claudication. Using silicon blocks within the lumbar epidural space, we developed a CEC model in rats with motor dysfunction. LPC and LPA levels in the CSF were significantly increased from day 1. Importantly, specific LPA species (16:0, 18:2, 20:4) were upregulated, which have been shown to produce by ATX detected in the CSF, without changes on its level. In SC, the LPC and LPA levels did not change, but mass spectrometry imaging analysis revealed that LPC was present in a region where the silicon blocks were inserted. These results propose a model for LPA production in SC and CSF upon neurogenic claudication that LPC produced locally by tissue damages is converted to LPA by ATX, which then leak out into the CSF.

A typical electroencephalogram (EEG) change induced by general anesthesia is anteriorization—disappearance of occipital alpha oscillations followed by the development of frontal alpha oscillations. Investigating the quantitative relationship between such a specific EEG change and the level of anesthesia has academic and clinical importance. We quantified the degree of anteriorization and investigated its detailed relationship with the level of anesthesia. We acquired 21-electrode EEG data and bispectral index (BIS) values of 50 patients undergoing surgery from before anesthesia induction until after patient arousal. For each epoch of a 10.24-s window with 1-s offsets, we calculated frontal alpha power αF, occipital alpha power αO, and their difference αF-αO to quantify anteriorization. We calculated Spearman’s rank correlation coefficients between these values and the BIS value. We used locally weighted regression to estimate αF, αO, αF-αO, ΔαF/ΔBIS, ΔαO/ΔBIS, and Δ(αF-αO)/ΔBIS at each BIS value. Thirty-six patients (26 females and 10 males aged 24–85 years) were analyzed. The 95% confidence intervals for the mean of Fisher transformations of Spearman’s rank correlation coefficients between αF, αO, and αF-αO and BIS value were [− 0.68, − 0.26], [0.02, 0.62], and [− 1.11, − 0.91], respectively. The change in αF and αO with BIS value showed different patterns by the type of anesthetic agent, whereas that in αF-αO was more consistent with smaller individual variance. Anteriorization, quantified by the difference between frontal and occipital alpha powers, continuously developed in conjunction with general anesthesia. Quantifying anteriorization may provide an objective indicator of the level of anesthesia.

Objectives. Overweight negatively affects musculoskeletal health; hence obesity is considered a risk factor for osteoarthritis and chronic low back pain. This was conducted to determine if obesity affects neuropathic pain, usually considered unrelated to the weight-load on the musculoskeletal system. Methods. Using a cut-off body mass index value of 25, 44 patients with neuropathic pain were grouped into a “high-BMI” group and a “normal-BMI” group. Results. The numeric rating scale of the high-BMI group was significantly higher than that of the normal-weight group ( P < 0.05 ). The total NPSI scores were significantly higher ( P < 0.01 ), and the paroxysmal pain and the negative symptoms were more serious in the high-BMI group than in the normal-BMI group. The high-BMI subjects also had significantly higher SF-MPQ scores ( P < 0.05 ). However, both physical and mental health status on the SF-36 were comparable between the groups. Discussion. Neuropathic pain that did not arise from musculoskeletal damage was higher in the high-BMI patients. Paroxysmal pain was more severe, suggesting that neural damage might be aggravated by obesity-associated inflammation. These findings should have needed to be confirmed in future studies.