Prolonged Double-Low Time and the Incidence of Postoperative Delirium in Surgical ICU Patients.

An intraoperative double-low condition is defined as concurrent low values for bispectral index (BIS) and mean arterial pressure (MAP), and may predict perioperative outcomes. We hypothesized that prolonged double-low times might be associated with an increased incidence of postoperative delirium. We conducted a single-center retrospective observational study on patients who had been admitted to our hospital's intensive care unit (ICU) after surgery and whose BIS and MAP data had been recorded during general anesthesia. The primary outcome was the incidence of postoperative delirium. A double-low condition was defined as BIS < 45 and MAP <75 mmHg. The total double-low time was calculated in 1-min increments and used to divide the patients into quintiles. Multiple logistic regression analyses were conducted. Among the 334 patients included in the study, the incidence of postoperative delirium was 15.6% (n=52). Multiple logistic regression analysis revealed that a prolonged double-low time, defined as a total double-low time of > 42 min (i.e., third, fourth, and fifth quintiles), was significantly associated with an increased incidence of postoperative delirium (adjusted odds ratio: 2.61, 95% confidence interval: 1.27-5.37, p=0.009). Prolonged double-low time during general anesthesia was independently associated with an increased incidence of postoperative delirium in surgical ICU patients.

Intrathecal Administration of the α1 Adrenergic Antagonist Phentolamine Upregulates Spinal GLT-1 and Improves Mirror Image Pain in SNI Model Rats.

Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes and plays a role in maintaining low glutamate levels in the synaptic cleft. Previous studies have shown that GLT-1 dysfunction induces neuropathic pain. Our previous study revealed bilateral GLT-1 downregulation in the spinal cord of a spared nerve injury (SNI) rat. We hypothesized that spinal GLT-1 is involved in the mechanism of MIP. We also previously demonstrated noradrenergic GLT-1 regulation. Therefore, this study aimed to investigate the effect of an α1 adrenergic antagonist on the development of MIP. Rats were subjected to SNI. Changes in pain behavior and GLT-1 protein levels in the SNI rat spinal cords were then examined by intrathecal administration of the α1 adrenergic antagonist phentolamine, followed by von Frey test and western blotting. SNI resulted in the development of MIP and bilateral downregulation of GLT-1 protein in the rat spinal cord. Intrathecal phentolamine increased contralateral GLT-1 protein levels and partially ameliorated the 50% paw withdrawal threshold in the contralateral hind paw. Spinal GLT-1 upregulation by intrathecal phentolamine ameliorates MIP. GLT-1 plays a role in the development of MIPs.

Prolonged Tachycardia with Higher Heart Rate Is Associated with Higher ICU and In-hospital Mortality.

Tachycardia is common in intensive care units (ICUs). It is unknown whether tachycardia or prolonged tachycardia affects patient outcomes. We investigated the association between tachycardia and mortality in critically ill patients. This retrospective cohort study's primary outcome was patient mortality in the ICU and the hospital. We stratified the patients (n=476) by heart rate (HR) as LowHR, MediumHR, and HighHR groups. We also stratified them by their durations of HR >100 (prolonged HR; tachycardia): MildT, ModerateT, and SevereT groups. We determined the six groups' mortality. The ICU mortality rates of the LowHR, MediumHR, and HighHR groups were 1.0%, 1.5%, and 7.9%, respectively; significantly higher in the HighHR vs. LowHR group. The in-hospital mortality rates of these groups were 1%, 4.5%, and 14.6%, respectively; significantly higher in the HighHR vs. LowHR group. The ICU mortality rates of the MildT, ModerateT, and SevereT groups were 0.9%, 5.6%, and 57.1%, respectively. The mortality of the HRT=0 (i.e., all HR ≤ 100) patients was 0%. The in-hospital mortality rates of the MildT, ModerateT, and SevereT groups were 1.8%, 16.7%, and 85.7%, respectively; that of the HRT=0 patients was 0.5%. Both higher HR and prolonged tachycardia were associated with poor outcomes.

Norepinephrine-induced downregulation of GLT-1 mRNA in rat astrocytes.

AIM OF THE RESEARCH: Glutamate transporter-1 (GLT-1; also known as excitatory amino acid transporter 2) plays an important role in the maintenance of glutamate homeostasis in the synaptic cleft. Downregulation of GLT-1 in the spinal cord has been reported in chronic pain models, which suggests that GLT-1 is involved in the development of chronic pain. However, the mechanism by which GLT-1 is downregulated in the spinal cord is still unknown. We hypothesized that norepinephrine is involved in the regulation of GLT-1. The aim of this study was to investigate the effect of norepinephrine on GLT-1 expression in cultured astrocytes. METHODS: This study involved both in vivo and in vitro experiments. We first validated changes in GLT-1 mRNA expression in the spinal cord of rats with spared nerve injury (SNI) using real-time RT-PCR. Next, cultured primary astrocytes from the rat spinal cord were stimulated with norepinephrine, and GLT-1 mRNA was subsequently quantitated. RNB cells, an astrocytic cell line, were also stimulated with norepinephrine and other α-adrenoceptor agonists. RESULTS: SNI resulted in bilateral downregulation of GLT-1 in rat spinal cord. The in vitro study showed that norepinephrine and phenylephrine dose-dependently downregulated GLT-1 in primary astrocytes and RNB cells. Furthermore, the effect of norepinephrine was reversed by an α-adrenoceptor antagonist. CONCLUSION: Norepinephrine downregulates GLT-1 mRNA expression in astrocytes via the α1-adrenoceptor. Our results provide new insight into the mechanisms involved in downregulation of GLT-1 in the chronic pain models.

A subclinical high tricuspid regurgitation pressure gradient independent of the mean pulmonary artery pressure is a risk factor for the survival after living donor liver transplantation.

BACKGROUND: Portopulmonary hypertension (POPH) is characterized by pulmonary vasoconstriction, while hepatopulmonary syndrome (HPS) is characterized by vasodilation. Definite POPH is a risk factor for the survival after orthotopic liver transplantation (OLT), as the congestive pressure affects the grafted liver, while subclinical pulmonary hypertension (PH) has been acknowledged as a non-risk factor for deceased donor OLT. Given that PH measurement requires cardiac catheterization, the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography is used to screen for PH and congestive pressure to the liver. We investigated the impact of a subclinical high TRPG on the survival of small grafted living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 84 LDLT candidates. Patients exhibiting a TRPG ≥25 mmHg on echocardiography were categorized as potentially having liver congestion (subclinical high TRPG; n = 34). The mean pulmonary artery pressure (mPAP) measured after general anesthesia with FIO20.6 (mPAP-FIO20.6) was also assessed. Patients exhibiting pO2 < 80 mmHg and an alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg were categorized as potentially having HPS (subclinical HPS; n = 29). The clinical course after LDLT was investigated according to subclinical high TRPG. RESULTS: A subclinical high TRPG (p = 0.012) and older donor age (p = 0.008) were correlated with a poor 40-month survival. Although a higher mPAP-FIO20.6 was expected to correlate with a worse survival, a high mPAP-FIO20.6 with a low TRPG was associated with high frequency complicating subclinical HPS and a good survival, suggesting a reduction in the PH pressure via pulmonary shunt. CONCLUSION: In cirrhosis patients, mPAP-FIO20.6 may not accurately reflect the congestive pressure to the liver, as the pressure might escape via pulmonary shunt. A subclinical high TRPG is an important marker for predicting a worse survival after LDLT, possibly reflecting congestive pressure to the grafted small liver.

Quercetin Attenuates Neuropathic Pain in Rats with Spared Nerve Injury.

Quercetin is a flavonoid widely found in plants and marketed to the public as a supplement. Several studies have reported its effect on glial cells. This study aimed to examine the effect of quercetin on the development of neuropathic pain and the underlying mechanism in a spared nerve injury (SNI) rat model. Male Sprague-Dawley rats randomly assigned to the control or the quercetin group were subjected to SNI of the sciatic nerve. We measured pain behaviors on the hind paw and glial fibrillary acidic protein (GFAP) in the dorsal root ganglion (DRG) and spinal cord. Oral administration of 1% quercetin, begun before surgery, attenuated mechanical allodynia compared to the control group at days 7 and 10 after SNI. On the other hand, established pain was not attenuated in a post-dose group in which quercetin was begun 7 days after SNI. Quercetin inhibited GFAP in the satellite glial cells of the ipsilateral L5 DRG on day 7 compared to the control group. Quercetin suppressed the development of neuropathic pain through a mechanism partly involving the inhibition of satellite glial cells. As its safety is well established, quercetin has great potential for clinical use in pain treatment.

Correlation Between the Social Network Structure and Well-Being of Health Care Workers in Intensive Care Units: Prospective Observational Study.

BACKGROUND: Effective communication strategies are becoming increasingly important in intensive care units (ICUs) where patients at high risk are treated. Distributed leadership promotes effective communication among health care professionals (HCPs). Moreover, beyond facilitating patient care, it may improve well-being among HCPs by fostering teamwork. However, the impact of distributed leadership on the communication structure and well-being of HCPs remains unclear. OBJECTIVE: We performed a social network analysis (SNA) to assess the characteristics of each HCP in the network, identify the number of HCP connections, analyze 4 centralities that can measure an HCP's importance, and evaluate the impact of distributed leadership structure on the well-being and communication structure of the medical staff. METHODS: Wearable sensors were used to obtain face-to-face interaction data from the ICU medical staff at Mie University Hospital, Japan. Participants wore a badge on the front of their clothing during working hours to measure the total frequency of face-to-face interactions. We collected data about the well-being of medical staff using the Center for Epidemiological Studies-Depression (CES-D) questionnaire and measured 4 centralities using SNA analysis. A CES-D questionnaire was administered during the study to measure the well-being of the HCPs. RESULTS: Overall, 247 ICU workers participated in this clinical study for 4 weeks yearly in February 2016, 2017, and 2018. The distributed leadership structure was established within the ICU in 2017 and 2018. We compared these results with those of the traditional leadership structure used in 2016. Most face-to-face interactions in the ICU were among nurses or between nurses and other professionals. In 2016, overall, 10 nurses could perform leadership tasks, which significantly increased to 24 in 2017 (P=.046) and 20 in 2018 (P=.046). Considering the increased number of nurses who could perform leadership duties and the collaboration created within the organization, SNA in 2018 showed that the betweenness (P=.001), degree (P<.001), and closeness (P<.001) centralities significantly increased compared with those in 2016. However, the eigenvector centrality significantly decreased in 2018 compared with that in 2016 (P=.01). The CES-D scores in 2018 also significantly decreased compared with those in 2016 (P=.01). The betweenness (r=0.269; P=.02), degree (r=0.262; P=.03), and eigenvector (r=0.261; P=.03) centralities and CES-D scores were positively correlated in 2016, whereas the closeness centrality and CES-D scores were negatively correlated (r=-0.318; P=.01). In 2018, the degree (r=-0.280; P=.01) and eigenvector (r=-0.284; P=.01) centralities were negatively correlated with CES-D scores. CONCLUSIONS: Face-to-face interactions of HCPs in the ICU were measured using wearable sensors, and nurses were found to be centrally located. However, the introduction of distributed leadership created collaboration and informal leadership in the organization, altering the social network structure of HCPs and increasing organizational well-being. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) UMIN000037046; https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000042211.

Extracellular-regulated-kinase 5-mediated renal protection against ischemia-reperfusion injury.

ERK5, a member of the mitogen activated protein kinase, expressed in the kidneys was smaller (∼80kDa) in apparent molecular mass compared to other organs (∼120kDa). A blocking peptide experiment confirmed that the ∼80kDa detected on Western blots was a specific band detected by the anti-ERK5 antibody. Expression of the known ERK5 variants ERK5a, b, c, and T confirmed that none of the known splice variants encoded for the renal-specific ∼80kDa protein. However, RT-PCR with primers targeting the potential splice sites did not reveal a novel transcript in the kidney. The smaller molecular mass of the kidney-specific ERK5-immunoreactive protein suggested that this cyto-protective molecule may not be fully functional in the kidneys. Lentivirus-mediated in vivo overexpression of full length ERK5 in the mouse kidneys provided protection against renal IR injury. The identity of the renal-specific ∼80kDa ERK5 remains unknown but a better understanding of the ERK5 expression and post-translational processing in the kidneys may reveal a novel strategy for renal protection.

Antinociceptive effects of intrathecal landiolol injection in a rat formalin pain model.

Perioperative beta-blocker administration has recently been recommended for patients undergoing cardiac or other surgery due to the beneficial cardiovascular effects of these agents. In addition, some studies have reported that perioperatively administered beta-blockers also have analgesic effects. In this study, to investigate the antinociceptive effects and the analgesic profile of landiolol, we examined the effects of intrathecal landiolol administration on nociceptive pain behavior and c-fos mRNA expression (a neural marker of pain) in the spinal cord using a rat formalin model. We found that pain-related behavior was inhibited by intrathecal landiolol administration. Moreover, the increase in c-fos mRNA expression on the formalin-injected side was less pronounced in rats administered landiolol than in saline administered controls. Thus, intrathecal administration of landiolol exhibited antinociceptive effects. Further investigation of the antinociceptive mechanism of landiolol is required.

[Effect of ultrasound-guided brachial plexus block on perioperative pain management of total elbow arthroplasty].

BACKGROUND: Ultrasound-guided brachial plexus block (UGBB) makes it possible to block both lateral and medial aspects of the skin overlying the elbow, which are mainly innervated by C5 and T1 roots of brachial plexus, respectively. The effect of UGBB on perioperative pain relief in total elbow arthroplasty (TEA) was evaluated. METHODS: Twenty-one patients scheduled to undergo TEA with general anesthesia from January 2009 to December 2010 were assigned to a group receiving UGBB (Block group, n = 10) and a group receiving general anesthesia alone (General group, n = 11). Perioperative anesthetic dose and postoperative pain intensity were recorded. Statistical analysis was performed with Mann-Whitney's U-test, and P < 0.05 was considered to be significant. RESULTS: Median fentanyl doses during the operation in the Block group and General group were 100 microg and 250 microg, respectively (P < 0.05). Numerical rating scale (NRS) in the Block group was significantly lower than that in the General group immediately after the operation (median value: Block group = 0, General group = 4). Although NRS in the two groups was not different from the night of the day of operation, no patient in the Block group needed supplementary opioids. CONCLUSIONS: Ultrasound-guided brachial plexus block in patients undergoing TEA reduces perioperative opioid consumption and wound pain in the early postoperative period.

Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats.

The mechanism underlying neuropathic pain is still largely unclear. Recently, much attention has been focused on the role of brain-derived neurotrophic factor (BDNF) as a neuromodulator in the spinal cord. We previously reported that the expression of Bdnf exon I mRNA was remarkably up-regulated in the dorsal root ganglion (DRG) neurons with the rat L5 spinal nerve ligation (SNL) model. In the present study, we investigated whether neuropathic pain response would be reduced by the inhibition of the Bdnf exon I in the rat SNL model. We identified the promoter region of exon I and synthesized the decoy ODNs targeting the region. Reverse transcription-polymerase chain reaction analysis confirmed that the decoy ODN treatment reduced SNL-induced Bdnf exon I mRNA up-regulation in ipsilateral L4 and L5 DRGs. Furthermore, post-treatment with the decoy ODNs significantly attenuated SNL-induced tactile allodynia. This study suggested that decoy ODNs targeting the Bdnf exon I might provide a novel analgesic strategy for the treatment of neuropathic pain.

Pediatric Living Donor Liver Transplantation for Congenital Absence of the Portal Vein With Pulmonary Hypertension: A Case Report.

Few reports of liver transplantation exist in patients with congenital absence of the portal vein and pulmonary hypertension. Living donor liver transplantation is usually performed before exacerbation of pulmonary hypertension. A 7-year-old girl (height: 131.5 cm; weight: 27.4 kg) with congenital absence of the portal vein was diagnosed with pulmonary hypertension (mean pulmonary artery pressure 35 mm Hg), and liver transplantation was planned before exacerbation of pulmonary hypertension. We successfully managed her hemodynamic parameters using low-dose dopamine and noradrenaline under monitoring of arterial blood pressure, central venous pressure, cardiac output, and stroke volume variation. Anesthesia was maintained using air-oxygen-sevoflurane and remifentanil 0.1 to 0.6 µg∙kg-1∙min-1. It is necessary to understand the potential perioperative complications in such cases and to adopt a multidisciplinary team approach in terms of the timing of transplantation and readiness to deal with exacerbation of pulmonary hypertension.

[Anesthetic management of pediatric patients with insulinoma using continuous glucose monitoring].

Insulinomas are rare tumors, the incidence of which is 1-2 per million. Patients with insulinomas present with symptoms of hypoglycemia secondary to insulin hypersecretion. Surgical resection is a treatment of choice and offers the only chance of cure. The important points in anesthesia are the precaution against hypoglycemia until tumor resection and the control of rebound hyperglycemia soon after tumor resection. We report the anesthetic management of a 5-year-old patient with insulinoma. Soon after the induction of anesthesia, the continuous glucose monitoring was commenced. Until the tumor resection, 10% glucose infusion was required to avoid hypoglycemia. Then, insulin infusion was continued to maintain blood glucose level around 150 mg x dl(-1). All glucose management was guided with continuous glucose monitoring. This is a first case report to show the feasibility and usefulness of continuous glucose monitoring in management of pediatric insulinoma patients. As the blood glucose was dramatically altered during perioperative period, frequent blood glucose measurements or continuous glucose monitoring is mandatory during perioperative period of insulinoma resection.

Incorporation of one N-glycosylation-deficient subunit within a tetramer of HCN2 channel is tolerated.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are glycoproteins N-glycosylated at a specific asparagine residue in the S5-S6 linker region. Previous reports suggested that N-glycosylation-deficient HCN2 N380Q (NQ) channels fail to properly target to the plasma membrane and are unable to form functional ion channels. HCN channels are known to homo- and hetero-oligomerize and it is not known whether HCN2-NQ subunits can oligomerize with wild type (wt) N-glycosylated subunits to form a tetrameric assembly. In the present study, homomeric NQ-mutant resulted in no current, cRNA titration experiments controlling the amount of wt-to-NQ injected into Xenopus oocytes indicated that the observed currents were consistent with a model where presence of a single nonglycosylated subunit in a tetrameric oligomer is tolerated forming functional channels. The activation voltage-dependence described by half-activation voltage and slope factor, and the reversal potential of the wt-NQ oligomeric channels were identical to the wt only tetrameric channels. Further incorporation of the nonglycosylated subunit rendered the channels nonconductive or not incorporated into the plasma membrane.

Radio contrast imaging for continuous epidural infusion in humans: a report of three cases.

There are no reports of human research on continuous epidural contrast injection, and there are no definite methods to investigate the spread of drugs injected continuously into the epidural space. We investigated the feasibility of continuous epidural contrast injection in patients undergoing computed tomography (CT)-guided therapy. In this study, a combination of a contrast agent mixed with 0.75% ropivacaine was used as the test drug. The main outcome evaluated was the feasibility of continuous epidural contrast imaging by CT scan following epidural injection of a contrast agent with 0.75% ropivacaine. We studied three patients who underwent CT-guided procedures and found that continuous epidural contrast injection was possible without any deleterious effects, such as an allergic reaction. The spread of the contrast agent was not consistent with the level of the clinical analgesic effect. Continuous epidural contrast injection is a feasible procedure. The results of our study might contribute to future research on continuous epidural contrast administration, as well as provide patients with superior analgesia.

Postoperative Course of Serum Albumin Levels and Organ Dysfunction After Liver Transplantation.

BACKGROUND AND AIMS: Postoperative hypoalbuminemia, especially following liver transplantation, can lead to adverse multisystem effects and even death. We investigated the relationship between postoperative albumin levels and organ failure (assessed using Sequential Organ Failure Assessment [SOFA] scores). METHODS: Sixty liver transplant recipients admitted to the intensive care unit (ICU) from 2012 to 2015 were retrospectively divided into 2 groups: lower albumin (LA) (n=28) and higher albumin (HA) (n=32), using whether serum albumin level fell below 3.0 g/dL during the first postoperative week as the stratifying factor. The SOFA scores (primary endpoint) and associated complications (ascites amount, rejection, re-intubation, abdominal re-operation, thrombosis), additional treatment (dialysis, pleural effusion drainage), and duration of ICU stay (secondary endpoints) of the 2 groups were compared. RESULTS: Average serum albumin levels were significantly different between HA and LA groups (3.6 [3.4-3.8] vs 3.1 [2.9-3.3], respectively, P<.05), although the amounts of albumin infused in the 2 groups during the first postoperative week were not different (HA vs LA: 42 [30-71] vs 40 [30-58], respectively, P=.37). Mean daily SOFA scores were not significantly different between the HA and LA groups (8.3 [6.6-9.0] vs 7.2 [6.3-8.6], P=.73), although the HA group had lower mean cardiovascular SOFA sub-scores than the LA group (0.1 [0-0.4] vs 0.4 [0-1.3], P=.032). There were no significant differences between the groups with regard to complication rates and duration of ICU and hospital stays. CONCLUSIONS: Serum albumin level might not influence cumulative organ function, but it decreases the amount of hemodynamic support required in liver transplant recipients.

Increased exhaled carbon monoxide concentration during living donor liver transplantation.

Exhaled carbon monoxide concentration (ExCO-C) has been reported to increase in oxidative tissue injuries such as systemic inflammation, and is thought to reflect increased heme breakdown in the affected organ. As a transplanted liver undergoes ischemia-reperfusion, we hypothesized that ExCO-C might also increase following liver transplantation and might serve as a measure of the severity of the graft tissue injury. We prospectively studied 67 living donor liver transplantation (LDLT) patients in a consecutive fashion. During anesthesia, ExCO-C was determined at 6 time points, ranging from anesthesia induction, to admission to the intensive care unit. We also measured two markers of endothelial cellular injury, i.e., serum soluble thrombomodulin (sTM) and intercellular adhesion molecule (ICAM)-1. At 5 min after reperfusion of the grafted liver, ExCO-C markedly increased from 5.69+/-2.34 ppm at baseline, to 9.79+/-4.72 ppm (p<0.0001). There was an excellent correlation among an increase in CO concentration, arterial carboxyhemoglobin levels at the time of reperfusion (r(2)=0.19, p=0.0003), and postoperative total bilirubin levels (day 1, 2, and 3; r(2)=0.102, 0.109 and 0.100; p=0.008, 0.007 and 0.010, respectively). Serum sTM and ICAM-1 levels were also significantly increased after reperfusion (sTM: 3.3+/-0.8 to 5.1+/-1.7 FU/ml, p=0.0001; ICAM-1: 271.9+/-86.3 to 515.0+/-157.8 FU/ml, p=0.0001). ExCO-C had a positive relationship with sTM (r(2)=0.16, p=0.035) and ICAM-1 (r(2)=0.12, p=0.08). There was however, no correlation of ExCO-C with serum AST/ALT levels or clinical outcomes. This study demonstrated that ExCO-C significantly increased after reperfusion during LDLT. The increased ExCO-C may likely reflect increased heme breakdown and endothelial cell injury in the grafted liver.

Prolonged-duration pulsed radiofrequency is associated with increased neuronal damage without further antiallodynic effects in neuropathic pain model rats.

AIM OF INVESTIGATION: Pulsed radiofrequency (PRF) is a safe and effective approach for treating neuropathic pain. However, the optimal treatment conditions and analgesic mechanisms of PRF remain unclear. The aim of our study was to assess the beneficial and adverse effects of prolonged-duration PRF and the analgesic mechanisms of PRF treatment with neuropathic pain rats. METHODS: Male Sprague Dawley rats received L5 spinal nerve ligation (SNL) for developing neuropathic pain. Fourteen days after L5 SNL surgery, they were divided into three groups according to duration of PRF current for 6 minutes, 12 minutes, and none. PRF current was delivered via direct visualization adjacent to the L5 dorsal root ganglion (DRG). Pain behavior was evaluated every week after L5 SNL surgery, until day 28. Seven days after PRF treatment, L5 DRG tissue was harvested to detect levels of activating translation factor 3 (ATF3; a marker of neuronal damage) and hyperpolarization-activated cyclic nucleotide (HCN)-gated cation channels (key factors in neuropathic pain) using quantitative PCR. RESULTS: Before PRF application, withdrawal thresholds were significantly lower than at baseline and did not differ significantly between the three groups. After PRF application, withdrawal thresholds in the PRF6 and PRF12 groups were significantly increased compared to those in the sham group. However, those in the PRF6 and PRF12 groups did not differ significantly. The expression level of ATF3 mRNA in the PRF12 group was significantly higher than that in the sham group (P<0.01), but the expression of HCN1 and HCN2 channels did not differ significantly between the three groups. CONCLUSION: Prolonged PRF exposure, from 6 to 12 minutes, was not only ineffective but also associated with increased neuronal damage. These findings do not support prolonged PRF exposure as a helpful treatment for neuropathic pain. In this study, the involvement of HCN channels in the antiallodynic effects of PRF was uncertain.

Altered response to formalin by L5 spinal nerve ligation in rats: a behavioral and molecular study.

BACKGROUND: The status of neuropathic pain alters the responsiveness to formalin injection in rats. However, the mechanism by which this alteration occurs is unknown. METHODS: We used immunocytochemistry to examine the expression of brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP) in the spinal cord of rats with L5 spinal nerve ligation (SNL)-induced neuropathy, and investigated the expression of c-Fos in the spinal cord after injection of formalin in the hindpaw of rats with SNL. RESULTS: Four weeks after SNL, the withdrawal threshold was significantly lower in the SNL group than in the sham-operated (sham) group (n = 12 per group, P < 0.05). In the SNL group, expression of BDNF in the L4 (P < 0.05) and L5 (P < 0.01) superficial dorsal horn was significantly decreased compared to that in the sham group. CGRP protein in the L5 but not in the L4, dorsal horn was significantly decreased compared to that in the sham group (P < 0.01). After formalin injection, spontaneous pain responses in the SNL group were significantly decreased compared to those in the sham group (P < 0.05). Immunolabeling for c-Fos was significantly decreased in the L4 and L5 dorsal horn in the SNL group (P < 0.01). CONCLUSION: Our examination of c-Fos distribution indicates that decreased neuronal activity in the spinal cord in response to inflammatory pain may be important for altering the perception of acute pain. Decreased BDNF expression in response to SNL-induced neuropathy may be involved in this alteration.

Increased heme oxygenase-1 and decreased delta-aminolevulinate synthase expression in the liver of patients with acute liver failure.

Acute liver failure (ALF) remains a serious problem in critical care with a high rate of mortality. Although the pathophysiology of ALF has not been fully elucidated, oxidative stress has been in part implicated in its pathogenesis. Heme oxygenase-1 (HO-1) is known to be induced not only by its substrate, heme, but also by various oxidative stresses, and thought to play an important role in the protection of the host from oxidative tissue injuries. In the present study, we examined expression of HO-1 as well as the non-specific delta-aminolevulinate synthase (ALAS-N, or ALAS1), the rate-limiting enzyme in heme catabolism and biosynthesis, respectively, in the livers of patients with ALF. Compared with livers from control subjects who had various disorders, but normal hepatic function, HO-1 in the liver of ALF patients was highly up-regulated at both transcriptional and protein levels. Immunohistochemical studies demonstrated that HO-1 expression occurred predominantly in hepatocytes, but not in non-parenchymal cells. In contrast to HO-1, ALAS1 gene expression was markedly down-regulated in ALF patients compared with controls. These findings suggest that, in the liver of ALF patients, there may be an increase in free heme concentration which up-regulates HO-1 gene expression, while down-regulating ALAS1 gene expression, resulting in markedly altered heme metabolism and liver function.