The free fatty acid receptor 1 promotes airway smooth muscle cell proliferation through MEK/ERK and PI3K/Akt signaling pathways.

Obesity is a risk factor for asthma and influences airway hyperresponsiveness, which is in part modulated by airway smooth muscle proliferative remodeling. Plasma free fatty acids (FFAs) levels are elevated in obese individuals, and long-chain FFAs act as endogenous ligands for the free fatty acid receptor 1 (FFAR1), which couples to both Gq and Gi proteins. We examined whether stimulation of FFAR1 induces airway smooth muscle cell proliferation through classical MEK/ERK and/or phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. The long-chain FFAs (oleic acid and linoleic acid) and a FFAR1 agonist (GW9508) induced human airway smooth muscle (HASM) cell proliferation, which was inhibited by the MEK inhibitor U0126 and the PI3K inhibitor LY294002 . The long-chain FFAs and GW9508 increased phosphorylation of ERK, Akt, and p70S6K in HASM cells and freshly isolated rat airway smooth muscle. Downregulation of FFAR1 in HASM cells by siRNA significantly attenuated oleic acid-induced phosphorylation of ERK and Akt. Oleic acid-induced ERK phosphorylation was blocked by either the Gαi-protein inhibitor pertussis toxin or U0126 and was partially inhibited by either the Gαq-specific inhibitor YM-254890 or the Gßγ signaling inhibitor gallein. Oleic acid significantly inhibited forskolin-stimulated cAMP activity, which was attenuated by pertussis toxin. Akt phosphorylation was inhibited by pertussis toxin, the ras inhibitor manumycin A, the Src inhibitor PP1, or LY294002 . Phosphorylation of p70S6K by oleic acid or GW9508 was significantly inhibited by LY294002 , U0126, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In conclusion, the FFAR1 promoted airway smooth muscle cell proliferation and p70S6K phosphorylation through MEK/ERK and PI3K/Akt signaling pathways.

The dopamine D1 receptor is expressed and induces CREB phosphorylation and MUC5AC expression in human airway epithelium.

Background: Dopamine receptors comprise two subgroups, Gs protein-coupled "D1-like" receptors (D1, D5) and Gicoupled "D2-like" receptors (D2, D3, D4). In airways, both dopamine D1 and D2 receptors are expressed on airway smooth muscle and regulate airway smooth muscle force. However, functional expression of the dopamine D1 receptor has never been identified on airway epithelium. Activation of Gs-coupled receptors stimulate adenylyl cyclase leading to cyclic AMP (cAMP) production, which is known to induce mucus overproduction through the cAMP response element binding protein (CREB) in airway epithelial cells. We questioned whether the dopamine D1 receptor is expressed on airway epithelium, and whether it promotes CREB phosphorylation and MUC5AC expression. Methods: We evaluated the protein expression of the dopamine D1 receptor on native human airway epithelium and three sources of cultured human airway epithelial cells including primary cultured airway epithelial cells, the bronchial epithelial cell line (16HBE14o-), and the pulmonary mucoepidermoid carcinoma cell line (NCI-H292) using immunohistochemistry and immunoblotting. To characterize the stimulation of cAMP through the dopamine D1 receptor, 16HBE14o- cells and NCI-H292 cells were treated with dopamine or the dopamine D1 receptor agonists (SKF38393 or A68930) before cAMP measurements. The phosphorylation of CREB by A68930 in both 16HBE14o- and NCI-H292 cells was measured by immunoblot. The effect of dopamine or A68930 on the expression of MUC5AC mRNA and protein in NCI-H292 cells was evaluated by real-time PCR and immunofluorescence staining, respectively. Results: The dopamine D1 receptor protein was detected in native human airway epithelium and three sources of cultured human airway epithelial cells. Dopamine or the dopamine D1-like receptor agonists stimulated cAMP production in 16HBE14o- cells and NCI-H292 cells, which was reversed by the selective dopamine D1-like receptor antagonists (SCH23390 or SCH39166). A68930 significantly increased phosphorylation of CREB in both 16HBE14o- and NCI-H292 cells, which was attenuated by the inhibitors of PKA (H89) and MEK (U0126). Expression of MUC5AC mRNA and protein were also increased by either dopamine or A68930 in NCI-H292 cells. Conclusions: These results suggest that the activation of the dopamine D1 receptor on human airway epithelium could induce mucus overproduction, which could worsen airway obstructive symptoms.

TRPC1, TRPC3, and TRPC4 in Rat Orofacial Structures.

TRPC (transient receptor potential cation channel subfamily C) members are nonselective monovalent cation channels and control Ca2+ inflow. In this study, immunohistochemistry for TRPC1, TRPC3, and TRPC4 was performed on rat oral and craniofacial structures to elucidate their distribution and function in the peripheries. In the trigeminal ganglion (TG), 56.1, 84.1, and 68.3% of sensory neurons were immunoreactive (IR) for TRPC1, TRPC3, and TRPC4, respectively. A double immunofluorescence method revealed that small to medium-sized TG neurons co-expressed TRPCs and calcitonin gene-related peptide. In the superior cervical ganglion, all sympathetic neurons showed TRPC1 and TRPC3 immunoreactivity. Parasympathetic neurons in the submandibular ganglion, tongue, and parotid gland were TRPC1, TRPC3, and TRPC4 IR. Gustatory and olfactory cells were also IR for TRPC1, TRPC3, and/or TRPC4. In the musculature, motor endplates expressed TRPC1 and TRPC4 immunoreactivity. It is likely that TRPCs are associated with sensory, autonomic, and motor functions in oral and craniofacial structures.

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. METHODS: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. RESULTS: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. CONCLUSION: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle.

Obesity is one of the major risk factors for asthma. Previous studies have demonstrated that free fatty acid levels are elevated in the plasma of obese individuals. Medium- and long-chain free fatty acids act as endogenous ligands for the free fatty acid receptors FFAR1/GPR40 and FFAR4/GPR120, which couple to Gq proteins. We investigated whether FFAR1 and FFAR4 are expressed on airway smooth muscle and whether they activate Gq-coupled signaling and modulate airway smooth muscle tone. We detected the protein expression of FFAR1 and FFAR4 in freshly dissected native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by immunoblotting and immunohistochemistry. The long-chain free fatty acids (oleic acid and linoleic acid) and GW9508 (FFAR1/FFAR4 dual agonist) dose-dependently stimulated transient intracellular Ca(2+) concentration ([Ca(2+)]i) increases and inositol phosphate synthesis in HASM cells. Downregulation of FFAR1 or FFAR4 in HASM cells by small interfering RNA led to a significant inhibition of the long-chain free fatty acids-induced transient [Ca(2+)]i increases. Oleic acid, linoleic acid, or GW9508 stimulated stress fiber formation in HASM cells, potentiated acetylcholine-contracted guinea pig tracheal rings, and attenuated the relaxant effect of isoproterenol after an acetylcholine-induced contraction. In contrast, TUG-891 (FFAR4 agonist) did not induce the stress fiber formation or potentiate acetylcholine-induced contraction. These results suggest that FFAR1 is the functionally dominant free fatty acid receptor in both human and guinea pig airway smooth muscle. The free fatty acid sensors expressed on airway smooth muscle could be an important modulator of airway smooth muscle tone.

Efficacy of intrathecal esmolol on heat-evoked responses in a postoperative pain model.

Perioperative tachycardia and hypertension are often treated with esmolol, a short-acting ß1-adrenoceptor antagonist. Besides its cardiac effect, esmolol is reported to exert antinociceptive effects. This study examined the efficacy of intrathecal (IT) esmolol on pain responses in a postoperative pain model. Male Sprague-Dawley rats (250-300 g) were anesthetized with sevoflurane and an IT catheter was implanted. Six days after catheter implantation, a postoperative pain model was established by plantar incision under sevoflurane anesthesia. Withdrawal latencies were assessed by applying a focused radiant heat source before plantar incision; 1 day after the incision (before esmolol administration); and 5, 10, and 15 minutes after bolus administration of IT esmolol. Plantar incision produced hypersensitivity in the postoperative pain model expressed as decreased withdrawal latency to heat stimulation (before incision: 13.9 ± 0.29 seconds and 1 day after incision: 6.3 ± 0.26 seconds). These decreased latencies caused by incision were significantly increased by esmolol administration (40 µg, 80 µg) at 5 minutes (10.7 ± 1.16 seconds, 10.5 ± 1.16 seconds). No postoperative antinociceptive effects of esmolol were observed at 10 or 15 minutes. IT administration of esmolol produced antinociceptive effects of short duration in a rat postoperative pain model. These results suggest that IT esmolol could offer a new strategy for managing perioperative pain, although an alternative approach is necessary to lengthen the duration of the analgesia.

The dopamine D1 receptor is expressed and facilitates relaxation in airway smooth muscle.

BACKGROUND: Dopamine signaling is mediated by Gs protein-coupled "D1-like" receptors (D1 and D5) and Gi-coupled "D2-like" receptors (D2-4). In asthmatic patients, inhaled dopamine induces bronchodilation. Although the Gi-coupled dopamine D2 receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle (ASM) cells, the Gs-coupled dopamine D1-like receptor subtypes have never been identified on these cells. Activation of Gs-coupled receptors stimulates cyclic AMP (cAMP) production through the stimulation of adenylyl cyclase, which promotes ASM relaxation. We questioned whether the dopamine D1-like receptor is expressed on ASM, and modulates its function through Gs-coupling. METHODS: The mRNA and protein expression of dopamine D1-like receptor subtypes in both native human and guinea pig ASM tissue and cultured human ASM (HASM) cells was measured. To characterize the stimulation of cAMP through the dopamine D1 receptor, HASM cells were treated with dopamine or the dopamine D1-like receptor agonists (A68930 or SKF38393) before cAMP measurements. To evaluate whether the activation of dopamine D1 receptor induces ASM relaxation, guinea pig tracheal rings suspended under isometric tension in organ baths were treated with cumulatively increasing concentrations of dopamine or A68930, following an acetylcholine-induced contraction with or without the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the large-conductance calcium-activated potassium (BKCa) channel blocker iberiotoxin, or the exchange proteins directly activated by cAMP (Epac) antagonist NSC45576. RESULTS: Messenger RNA encoding the dopamine D1 and D5 receptors were detected in native human ASM tissue and cultured HASM cells. Immunoblots confirmed the protein expression of the dopamine D1 receptor in both native human and guinea pig ASM tissue and cultured HASM cells. The dopamine D1 receptor was also immunohistochemically localized to both human and guinea pig ASM. The dopamine D1-like receptor agonists stimulated cAMP production in HASM cells, which was reversed by the selective dopamine D1-like receptor antagonists SCH23390 or SCH39166. A68930 relaxed acetylcholine-contracted guinea pig tracheal rings, which was attenuated by Rp-cAMPS but not by iberiotoxin or NSC45576. CONCLUSIONS: These results demonstrate that the dopamine D1 receptors are expressed on ASM and regulate smooth muscle force via cAMP activation of PKA, and offer a novel target for therapeutic relaxation of ASM.

[Glidescope cobalt videolaryngoscope].

GlideScope Cobalt video laryngoscope is a novel indirect laryngoscope for tracheal intubation. It consists of a reusable high-resolution miniature video camera and light source, and a disposable transparent sheath that enshrouds the video camera, thereby preventing contact with the patient. To evaluate the per- formance of GlideScope Cobalt, endotracheal intubation was performed in 100 consecutive patients requiring tracheal intubation for surgery. The time to complete instrumentation, the visualization of the glottis by the Cormack-Lehane grade and optimizing procedures were recorded. GlideScope Cobalt allowed successful intubation in all patients examined, including two patients with difficult airway with the Macintosh laryngoscope. Endotracheal intubation was performed within one minute in 83 cases. GlideScope Cobalt provided Cormack-Lehane grade 1 or 2 visualization of the glottis in 100 patients. It was easily handled not only by experienced anesthetists but also by novice personnel. GlideScope Cobalt could be an effective aid to airway management in surgical patients.

[Comparison of Pentax-AWS, GlideScope Cobalt, and Macintosh laryngoscope in patients for nasotracheal intubation].

BACKGROUND: We compared the time for instrumentation in nasotracheal intubation using Pentax-AWS and Glidescope to that using the Macintosh laryngoscope in patients with normal airway. METHODS: After local ethics board approval, 60 patients requiring dental or oral surgery were allocated randomly to Pentax-AWS, Glidescope and Macintosh groups. One experienced anesthesiologist performed nasotracheal intubation in all patients. RESULTS: The times for instrumentation using Pentax-AWS and Glidescope, and Macintosh laryngoscope were 37 +/- 12s, 33 +/- 9s, and 30 +/- 12s, respectively. There were no differences among the three devices. CCONCLUSIONS: When operated by experienced anesthesiologists, both Pentax-AWS and Glidescope showed similar performance for nasotracheal intubation compared with Macintosh laryngoscope in normal airway patients.

[Efficacy of videolaryngoscopes for nasotracheal intubation: a meta-analysis of randomized controlled trials].

BACKGROUND: Increased evidence indicates that the videolaryngoscope is useful for nasotracheal intubation. The aim of this meta-analysis is to assess the efficacy of videolaryngoscopes (Glidescope, Airtraq and Pentax-AWS) in nasotracheal intubations, comparing with that of Macintosh laryngoscopy. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated by the Comprehensive Meta-analysis version 2.2.040 software for dichotomous and continuous outcomes, respectively. RESULTS: Seven randomized controlled trials included 294 tracheal intubations by videolaryngoscopes and 253 tracheal intubations by Macintosh laryngoscopy. Videolaryngoscopes showed higher success rate (RR 1.116, 95% CI 1.021-1.220, P < 0.0155, I2 : 51%) and shorter intubation time (MD -11.9 sec, 95% CI-18.9(-) -5.0 sec, P < 0.0008, I2 84%) compared with the Macintosh laryngoscope. CONCLUSIONS: Our meta-analysis showed that the videolaryngoscope has an advantage over Macintosh laryngoscope in nasotracheal intubations.

An improved biologically transparent illumination system that increases the accuracy of detecting the correct position of a nasogastric tube in the stomach.

The aim of this study was to determine whether an improved biologically transparent illumination system results in more reliable detection of the correct position of the nasogastric tube in surgical patients. In total, 102 patients undergoing general surgery were included in this prospective observational study. After general anesthesia, all patients were inserted a nasogastric tube equipped with an improved biologically transparent illumination catheter. Identification of biologically transparent light in the epigastric area indicated successful insertion of the nasogastric tube into the stomach. The position of the tube was confirmed by X-ray examination, and its findings were compared with those of the biologically transparent illumination system. We observed biologically transparent light in epigastric area in 87 of the 102 patients. X-ray examination revealed that the nasogastric tube was placed in the stomach in all of these 87 patients. Light was not observed in the remaining 15 patients; the tube position was confirmed in the stomach in 11 of these patients but not in the other 4 by X-ray examination. Illumination had a sensitivity of 88.8% and a specificity of 100%. Our results suggest that this improved biologically transparent illumination system increased the accuracy of detecting the correct position of a nasogastric tube in the stomach. X-ray examination is required to check the position of the nasogastric tube in patients when biologically transparent illumination light is negative.

The dopamine D(2) receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle.

Dopamine receptors are G protein-coupled receptors that are divided into two subgroups, "D(1)-like" receptors (D(1) and D(5)) that couple to the G(s) protein and "D(2)-like" receptors (D(2), D(3), and D(4)) that couple to G(i). Although inhaled dopamine has been reported to induce bronchodilation in patients with asthma, functional expression of dopamine receptor subtypes has never been described on airway smooth muscle (ASM) cells. Acute activation of G(i)-coupled receptors inhibits adenylyl cyclase activity and cAMP synthesis, which classically impairs ASM relaxation. In contrast, chronic activation of G(i)-coupled receptors produces a paradoxical enhancement of adenylyl cyclase activity referred to as heterologous sensitization. We questioned whether the dopamine D(2)-like receptor is expressed on ASM, whether it exhibits classical G(i)-coupling, and whether it modulates ASM function. We detected the mRNA encoding the dopamine D(2) receptor in total RNA isolated from native human ASM and from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the dopamine D(2) receptor protein in both native human and guinea pig ASM and cultured HASM cells. The dopamine D(2) receptor protein was immunohistochemically localized to both human and guinea pig ASM. Acute activation of the dopamine D(2) receptor by quinpirole inhibited forskolin-stimulated adenylyl cyclase activity in HASM cells, which was blocked by the dopamine D(2) receptor antagonist L-741626. In contrast, the chronic pretreatment (1 h) with quinpirole potentiated forskolin-stimulated adenylyl cyclase activity, which was inhibited by L-741626, the phospholipase C inhibitor U73122, or the protein kinase C inhibitor GF109203X. Quinpirole also stimulated inositol phosphate synthesis, which was inhibited by L-741626 or U73122. Chronic pretreatment (1 h) of the guinea pig tracheal rings with quinpirole significantly potentiated forskolin-induced airway relaxation, which was inhibited by L-741626. These results demonstrate that functional dopamine D(2) receptors are expressed on ASM and could be a novel therapeutic target for the relaxation of ASM.

Gi-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle.

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system, and exerts its actions via both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. Although the functional expression of GABA(B) receptors coupled to the G(i) protein was reported for airway smooth muscle, the role of GABA(B) receptors in airway responsiveness remains unclear. We investigated whether G(i)-coupled GABA(B) receptors cross-regulate phospholipase C (PLC), an enzyme classically regulated by G(q)-coupled receptors in human airway smooth muscle cells. Both the GABA(B)-selective agonist baclofen and the endogenous ligand GABA significantly increased the synthesis of inositol phosphate, whereas GABA(A) receptor agonists, muscimol, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol exerted no effect. The baclofen-induced synthesis of inositol phosphate and transient increases in [Ca(2+)](i) were blocked by CGP35348 and CGP55845 (selective GABA(B) antagonists), pertussis toxin (PTX, which inactivates the G(i) protein), gallein (a G(ßγ) signaling inhibitor), U73122 (an inhibitor of PLC-ß), and xestospongin C, an inositol 1,4,5-triphosphate receptor blocker. Baclofen also potentiated the bradykinin-induced synthesis of inositol phosphate and transient increases in [Ca(2+)](i), which were blocked by CGP35348 or PTX. Moreover, baclofen potentiated the substance P-induced contraction of airway smooth muscle in isolated guinea pig tracheal rings. In conclusion, the stimulation of GABA(B) receptors in human airway smooth muscle cells rapidly mobilizes intracellular Ca(2+) stores by the synthesis of inositol phosphate via the activation of PLC-ß, which is stimulated by G(ßγ) protein liberated from G(i) proteins coupled to GABA(B) receptors. Furthermore, crosstalk between GABA(B) receptors and G(q)-coupled receptors potentiates the synthesis of inositol phosphate, transient increases in [Ca(2+)](i), and smooth muscle contraction through G(i) proteins.

Esmolol modulates inhibitory neurotransmission in the substantia gelatinosa of the spinal trigeminal nucleus of the rat.

BACKGROUND: ß1-adrenaline receptor antagonists are often used to avoid circulatory complications during anesthesia in patients with cardiovascular diseases. Of these drugs, esmolol, a short-acting ß antagonist, is also reported to exert antinociceptive and anesthetic sparing effects. This study was designed to identify the central mechanism underlying the antinociceptive effect of esmolol. METHODS: Wistar rats (7-21 d, 17-50 g) were anesthetized with ketamine (100-150 mg/kg) or isoflurane (5%) and decapitated. Horizontal slices (400-µm thick) of the lower brainstem containing the substantia gelatinosa (SG) of the caudal part of the spinal trigeminal nucleus (Sp5c), in which the nociceptive primary afferents form the first intracranial synapses, were made with a vibrating slicer. The miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively) were simultaneously recorded from visually identified SG neurons of the Sp5c in the presence of tetrodotoxin (1 µM). Additionally, mIPSCs were recorded during pharmacological isolation of GABA- and glycine-mediated mIPSCs with kynurenic acid (1 mM). RESULTS: Esmolol (500 µM) significantly and selectively increased the mIPSC frequency (to 214.2% ± 34.2% of the control, mean ± SEM, n = 35; P < 0.001), but not that of mEPSCs, without changing their amplitude. The increase in mIPSC frequency with esmolol was not affected by prior activation of ß receptors with isoproterenol (100 µM) but it was significantly attenuated by removal of extracellular Ca2+. CONCLUSIONS: These data suggest that esmolol modulates inhibitory transmitter release in the Sp5c through a mechanism involving Ca2+-entry but in a ß1-adrenoceptor-independent manner. The present results suggest that the facilitation of inhibitory transmitter release in the central nociceptive network underlies, at least in part, the antinociceptive effect of esmolol.

Perioperative infusion of dexmedetomidine at a high dose reduces postoperative analgesic requirements: a randomized control trial.

PURPOSE: We hypothesized that a high dose of dexmedetomidine (1 µg/kg/h) could reduce postoperative analgesic requirements of patients. METHODS: This was a prospective, randomized, double-blind, placebo-controlled study carried out in Tohoku University Hospital. Thirty-two patients who underwent open gynecological abdominal surgery were randomly divided into a control (group C) and a dexmedetomidine group (group D). In both groups of patients, an epidural catheter was put in position prior to the induction of anesthesia, and continuous epidural infusion was started using a patient-controlled epidural analgesia (PCEA) pump. During the induction of anesthesia, group D patients received a loading dose of dexmedetomidine (1 µg/kg over 10 min), followed by a continuous infusion at a rate of 1 µg/kg/h. The patients in group C received a volume-matched infusion of normal saline as placebo. Consumption of PCEA bolus (local anesthetics) during the first postoperative 24 h, postoperative pain scores, and side effects related to the use of dexmedetomidine were recorded. RESULTS: Dexmedetomidine (1 µg/kg/h) significantly reduced PCEA bolus consumption [15.9 ± 6.5 (group C) vs. 5.3 ± 5.0 ml (group D); P = 0.0001] and postoperative pain scores. The infusion of dexmedetomidine produced no serious side effects, such as hemodynamic changes. CONCLUSIONS: Among this small patient cohort, perioperative infusion of dexmedetomidine (1 µg/kg/h) resulted in antinociception without severe side effects. These results suggest that this method could be of interest with respect to improving postoperative pain status.

Biologically transparent illumination is a safe, fast, and simple technique for detecting the correct position of the nasogastric tube in surgical patients under general anesthesia.

The aim of this study was to evaluate the effectiveness of using biologically transparent illumination to detect the correct position of the nasogastric tube in surgical patients. This prospective observational study enrolled 102 patients undergoing general surgeries. In all cases, a nasogastric tube equipped with a biologically transparent illumination catheter was inserted after general anesthesia. The identification of biologically transparent light in the epigastric area either with or without finger pressure indicated that the tube had been successfully inserted into the stomach. X-ray examination was performed to ascertain the tube position and was compared with the findings of the biologically transparent illumination technique. Biologically transparent light was detected in 72 of the 102 patients. In all of these 72 patients, the position of the nasogastric tube in the stomach was confirmed by X-ray examination. The light was not detected in the other 30 patients; X-ray examination showed that the nasogastric tube was positioned in the stomach in 21 of these 30 patients but not in the other 9. The sensitivity and specificity of the illumination were 77.4% and 100%, respectively. The results suggest that biologically transparent illumination is a useful and safe technique for detecting the correct position of the nasogastric tube in surgical patients under general anesthesia. When the BT light cannot be identified, X-ray examination is mandatory to confirm the position of the nasogastric tube.

Nociceptive Sensitization by Activation of Protease-Activated Receptor 2 in a Rat Model of Incisional Pain.

Postoperative pain and consequent inflammatory responses after tissue incision adversely affects many surgical patients due to complicated mechanisms. In this study, we examined whether activation of protease-activated receptor 2 (PAR-2), which is stimulated by tryptase from mast cells, elicits nociception and whether the PAR-2 antagonist could reduce incisional nociceptive responses in vivo and in vitro. The effects of a selective PAR-2 antagonist, N3-methylbutyryl-N-6-aminohexanoyl-piperazine (ENMD-1068), pretreatment on pain behaviors were assessed after plantar incision in rats. The effects of a PAR-2 agonist, SLIGRL-NH2, on nociception was assessed after the injection into the hind paw. Furthermore, the responses of C-mechanosensitive nociceptors to the PAR-2 agonist were observed using an in vitro skin-nerve preparation as well. Intraplantar injection of SLIGRL-NH2 elicited spontaneous nociceptive behavior and hyperalgesia. Local administration of ENMD-1068 suppressed guarding behaviors, mechanical and heat hyperalgesia only within the first few hours after incision. SLIGRL-NH2 caused ongoing activity in 47% of C-mechanonociceptors in vitro. This study suggests that PAR-2 may support early nociception after incision by direct or indirect sensitization of C-fibers in rats. Moreover, PAR-2 may play a regulatory role in the early period of postoperative pain together with other co-factors to that contribute to postoperative pain.

Expression of ß-endorphin in peripheral tissues after systemic administration of lipopolysaccharide as a model of endotoxic shock in mice.

BACKGROUND: Endogenous ß-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of ß-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice. METHODS: Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of ß-endorphin, was quantified in peripheral blood cells, liver and spleen. ß-endorphin peptide was measured in the liver and spleen. RESULTS: Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced ß-endorphin expression in the liver and spleen. CONCLUSION: Expression of proopiomelanocortin mRNA and ß-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral ß-endorphin during endotoxic shock.

Obesity-induced asthma: Role of free fatty acid receptors.

Obesity is a major risk factor for the development of asthma, and worsens the key features of asthma including airway hyperresponsiveness, inflammation, and airway remodeling. Although pro- and anti-inflammatory adipocytokines may contribute to the pathogenesis of asthma in obesity, the mechanistic basis for the relationship between asthma and obesity remains unclear. In obese individuals, the increased amount of adipose tissue results in the release of more long-chain free fatty acids as compared to lean individuals, causing an elevation in plasma long-chain free fatty acid concentrations. Recent findings suggest that the free fatty acid receptor 1 (FFAR1), which is a sensor of medium- and long-chain free fatty acids, is expressed on airway smooth muscle and plays a pivotal role in airway contraction and airway smooth muscle cell proliferation. In contrast, FFAR4, which is a sensor for long-chain n-3 polyunsaturated fatty acids and also expressed on airway smooth muscle, does not contribute to airway contraction and airway smooth muscle cell proliferation. Functional roles for short-chain fatty acid receptors FFAR2 and FFAR3 in the pathogenesis of asthma is still under debate. Taken together, adipose-derived long-chain free fatty acids may contribute to the pathogenesis of asthma in obesity through FFAR1.

Acute Management of Massive Epistaxis After Nasotracheal Extubation.

Epistaxis is one of the most common complications of nasotracheal intubation and can be life-threatening. However, there is little discussion in the current literature on the acute management of massive epistaxis after nasotracheal extubation. This is a report of 2 patients who experienced severe unanticipated nasal bleeding immediately after extubation, 1 after a surgical procedure for oral cancer and another after restorative dental treatment. In both cases the significant epistaxis was managed successfully with a Foley balloon catheter used to pack the posterior nasal cavity. The Foley catheter technique may be useful for managing and arresting sudden postextubation epistaxis.