Rat model of attention-deficit hyperactivity disorder exhibits delayed recovery from acute incisional pain due to impaired descending noradrenergic inhibition.

Chronic pain and attention-deficit hyperactivity disorder (ADHD) frequently coexist. However, the common pathology is still unclear. Attenuated noradrenergic endogenous analgesia can produce acute pain chronification, and dysfunction of noradrenergic systems in the nervous system is relevant to ADHD symptoms. Noxious stimuli-induced analgesia (NSIA) is measured to estimate noradrenergic endogenous analgesia in spontaneously hypertensive rats (SHR) as an ADHD model and control. Recovery of pain-related behaviors after paw incision was assessed. Contributions of noradrenergic systems were examined by in vivo microdialysis and immunohistochemistry. The SHR showed attenuated NSIA and needed a more extended period for recovery from acute pain. These results suggest ADHD patients exhibit acute pain chronification due to pre-existing attenuated noradrenergic endogenous analgesia. Immunohistochemistry suggests abnormal noradrenaline turnover and downregulation of the target receptor (alpha2a adrenoceptor). Standard ADHD treatment with atomoxetine restored NSIA and shortened the duration of hypersensitivity after the surgery in the SHR. NSIA protocol activated the locus coeruleus, the origin of spinal noradrenaline, of both strains, but only the control exhibited an increase in spinal noradrenaline. This result suggests dysfunction in the noradrenaline-releasing process and can be recognized as a novel mechanism of attenuation of noradrenergic endogenous analgesia.

Randomized active-controlled study of a single preoperative administration of duloxetine to treat postoperative pain and numbness after posterior lumbar interbody fusion surgery.

BACKGROUND: This prospective, randomized, double-blinded, active controlled trial assessed whether a single preoperative administration of 40 mg of duloxetine could decrease postoperative pain and numbness after posterior lumbar interbody fusion surgery (PLIF). METHODS: Patients with an American Society of Anesthesiologists physical status I or II undergoing PLIF were included. At 2 hours before inducing anesthesia, patients were administered 40 mg duloxetine or 4 mg diazepam (control drug). Postoperative pain and other symptoms were evaluated on the basis of a visual analog scale, amount of fentanyl used, fentanyl dose request times, rate of use of adjunctive analgesics (diclofenac sodium or pentazocine), and lower limb numbness score (0-3) during the first 2 postoperative days. RESULTS: Forty-six patients were randomly assigned to the duloxetine and diazepam groups (n = 23 each); 6 were lost to follow-up, and analysis was performed on data from 22 patients in the duloxetine group and 18 in the diazepam group. No significant differences were detected in the patient background, postoperative visual analog scale score at rest in the lumbar region and lower limbs, fentanyl use, rate of analgesic adjuvant use, or incidence of side effects. The numbness score in the lower limbs, however, was significantly lower in the duloxetine group. CONCLUSION: A single preoperative 40-mg dose of duloxetine did not improve postoperative pain after PLIF, but did improve lower limb numbness. Duloxetine may suppress neuropathic pain-like symptoms after PLIF surgery.

Local anesthetic lidocaine induces growth suppression of HeLa cells by decreasing and changing the cellular localization of the proliferation marker Ki-67.

Although surgery is a basic therapy for cancer, it causes inflammation and immunosuppression, often resulting in recurrence and metastasis. Previous studies have suggested that anesthetic management influences the prognosis of cancer surgery patients. Administration of local anesthetics, such as lidocaine, for pain control reportedly improves their clinical outcomes; however, the precise underlying mechanism has not been fully elucidated. The growth of human embryonic kidney (HEK) 293T and cervical cancer HeLa cells was inhibited by lidocaine treatment and these cell lines showed different sensitivities for lidocaine. Ki-67 is a significant prognostic marker of cancer because it is expressed in the nucleus of actively proliferating cells. In lidocaine-treated HeLa cells, Ki-67 was detected not only in the nucleus but also in the cytoplasm. In addition, lidocaine-induced cytoplasmic Ki-67 partly colocalized with the increased ER chaperone, glucose-regulated protein 78, which is crucial for protein folding and maintenance of cellular homeostasis. Furthermore, lidocaine decreased Ki-67 levels and increased the population of HeLa cells in the G0/G1 phase. These results indicate that lidocaine plays a significant role in growth suppression by regulating the expression and distribution of Ki-67.

Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines.

Administration of local anesthetics, such as lidocaine, in the perioperative period improves outcomes of cancer patients. However, its precise mechanism is still unresolved. The growth of human cancer cell lines, including HeLa cells, are suppressed by lidocaine treatment. We identified that growth differentiation factor-15 (GDF-15) was commonly upregulated in lidocaine-treated cancer cell lines. GDF-15 is a divergent member of the transforming growth factor-ß (TGF-ß) superfamily and it is produced as an unprocessed pro-protein form and then cleaved to generate a mature form. In lidocaine-treated HeLa cells, increased production of GDF-15 in the endoplasmic reticulum (ER) was observed and unprocessed pro-protein form of GDF-15 was secreted extracellularly. Further, lidocaine induced apoptosis and apoptosis-inducible Tribbles homologue 3 (TRIB3) was also commonly upregulated in lidocaine-treated cancer cell lines. In addition, transcription factor C/EBP homologous protein (CHOP), which is a positive regulator of not only GDF-15 but TRIB3 was also induced by lidocaine. Lidocaine-induced growth suppression and apoptosis was suppressed by knockdown of GDF-15 or TRIB3 expression by small interference RNA (siRNA). These observations suggest that lidocaine suppresses the growth of cancer cells through increasing GDF-15 and TRIB3 expression, suggesting its potential application as cancer therapy.

The efficacy of duloxetine depends on spinal cholinergic plasticity in neuropathic pain model rats.

Antidepressants, such as duloxetine, are widely used to treat chronic pain, including neuropathic pain; however, their efficacy is unsatisfactory. In our previous studies, we showed that in a spinal nerve ligation (SNL) rat model, the descending noradrenergic inhibitory system, which involves in the anti-hypersensitivity mechanism of antidepressants, decrease its activity over time following peripheral nerve injury. In this study, we hypothesized that the analgesic effects of duloxetine may diminish following the attenuation of the descending noradrenergic inhibitory system. The analgesic effects of duloxetine in SNL model rats at the early (SNL2W) and chronic (SNL6W) phases following spinal nerve ligation were compared. Male Sprague-Dawley rats were randomly assigned to the SNL2W or SNL6W groups and used to evaluate the anti-allodynic effects of duloxetine using the von Frey filament test. The anti-allodynic effects of duloxetine at a dose of 10 mg/kg were lower in SNL6W rats than in SNL2W rats. Basal noradrenaline concentrations in rat spinal dorsal horns were higher in the SNL6W group than in the SNL2W group, and there was no difference in the increase in spinal noradrenaline concentrations between the 2 groups following duloxetine administration. In addition, we found that duloxetine-induced acetylcholine (ACh) release and choline acetyltransferase (ChAT) expression in the spinal dorsal horn decreased in SNL6W rats. At a dose of 30 mg/kg, duloxetine showed anti-allodynic effects even in SNL6W rats and induced ACh release in the spinal cord. Furthermore, these anti-allodynic effects were completely inhibited by intrathecal atropine (muscarinic antagonist) administration. Moreover, 5 daily intraperitoneal injections of the TrkB agonist, 7,8-dihydroxyflavone (5 mg/kg), not only restored ChAT expression, but also decreased the anti-allodynic effects of duloxetine. These findings suggest that the attenuation of the anti-allodynic effects of duloxetine at the chronic phase of SNL may be due to impaired spinal acetylcholine-mediated analgesia. In addition, the activation of BDNF-TrkB signaling may be beneficial in reversing this impairment.

Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.

GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1-/- ; Gad2-/- rats died at postnatal day 0 and showed little alveolar space in their lungs, suggesting that the cause of their death was respiratory failure. All Gad1-/- ; Gad2-/- rats and 18% of Gad1-/- ; Gad2+/- rats showed cleft palate. In contrast, none of the Gad mutant rats including Gad1-/- ; Gad2-/- rats, showed omphalocele. These results suggest that both rat GAD65 and GAD67 are involved in palate formation, while neither isoform is critical for abdominal wall formation. The GABA content in Gad1-/- ; Gad2-/- rat forebrains and retinas at embryonic day 20 was extremely low, indicating that almost all GABA was synthesized from glutamate by GADs in the perinatal period. The present study shows that Gad mutant rats are a good model for further defining the role of GABA during development.

Spinal γ-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain.

Systemic administration of morphine increases serotonin (5-HT) in the spinal dorsal horn (SDH), which attenuates the analgesic effects of morphine on neuropathic pain through spinal 5-HT3 receptors. We hypothesized that dysfunction of the descending serotonergic system, including the periaqueductal gray (PAG), contributes to attenuate the efficacy of morphine on neuropathic pain through spinal 5-HT3 receptors and GABA neurons. Morphine (100 ng) injected into the PAG produced analgesic effects in normal rats, but not in spinal nerve ligation (SNL) rats. In vivo microdialysis showed that PAG morphine increased the SDH 5-HT concentration in both groups. Intrathecal injection of the 5-HT3 receptor antagonist ondansetron and the GABAA receptor antagonist bicuculline attenuated the analgesic effects of PAG morphine in normal rats, but increased the effects in SNL rats. The increased analgesic effect of PAG morphine induced by bicuculline was reversed by pretreatment with the tropomyosin receptor kinase B (TrkB) antagonist K252a. Activation of spinal 5-HT3 receptors by 2-methyl-5-HT increased the GABA concentration in both groups. Morphine activates GABAergic interneurons in the SDH by activating descending serotonergic neurons. Functional changes in GABAA receptors from inhibitory to facilitatory through the activation of TrkB receptors may contribute to the attenuated efficacy of morphine against neuropathic pain. PERSPECTIVE: Although morphine provides strong analgesia against acute pain, it has limited efficacy against neuropathic pain. This article demonstrates that functional changes in GABAA receptors in the spinal dorsal horn after nerve injury might strongly contribute to the attenuation of opioid-induced analgesia for neuropathic pain.

Education program for prevention of outdoor accidents in middle-high aged trekkers: Monitoring of change in blood pressure and heart rate during exercise.

This is an observational study to evaluate cardiovascular parameters during an educational trekking program. The number of alpine accidents involving elderly trekkers has been increasing in developed countries in recent years. Many middle-high aged trekkers have potential cardiovascular risks of which they are unaware. More than 77% of trekkers involved in alpine accidents in Japan were aged >40 years. The most common cardiovascular conditions were stroke or heart attack while trekking at altitude. An alpine club conducted an 8-month education program with participants aged >40 years in the setting of a mountain-side town. Blood pressure and heart rate during outdoor exercise were monitored, and any other adverse effects were recorded. As a result, the cardiovascular parameters evaluated during the first and final trek presented a physiological and similar behavior, however, lower heart rate values were registered at the highest point of the route in the final trek (p < 0.05). The trend of these parameters was similar in males and females, and there was little correlation between the cardiovascular parameters and age. In conclusion, the lower heart rate values may indicate the higher risk awareness of trekkers while self-pacing the physical activity outdoors, which may indicate the positive effect of the education program in increasing the safety of such unsupervised activities.

CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia.

GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia. Furthermore, a patient with schizophrenia harboring a homozygous mutation of GAD1 has recently been discovered. However, it remains unclear whether loss of function of GAD1 leads to the symptoms observed in schizophrenia, including cognitive impairment. One of the obstacles faced in experimental studies to address this issue is the perinatal lethality of Gad1 knockout (KO) mice, which precluded characterization at the adult stage. In the present study, we successfully generated Gad1 KO rats using CRISPR/Cas9 genome editing technology. Surprisingly, 33% of Gad1 KO rats survived to adulthood and could be subjected to further characterization. The GABA concentration in the Gad1 KO cerebrum was reduced to ~52% of the level in wild-type rats. Gad1 KO rats exhibited impairments in both spatial reference and working memory without affecting adult neurogenesis in the hippocampus. In addition, Gad1 KO rats showed a wide range of behavioral alterations, such as enhanced sensitivity to an NMDA receptor antagonist, hypoactivity in a novel environment, and decreased preference for social novelty. Taken together, the results suggest that Gad1 KO rats could provide a novel model covering not only cognitive deficits but also other aspects of the disorder. Furthermore, the present study teaches an important lesson: differences between species should be considered when developing animal models of human diseases.

Comparison of four documents describing adrenaline purification, and the work of three important scientists, Keizo Uenaka, Nagai Nagayoshi and Jokichi Takamine.

The name of Keizo Uenaka has not been documented in textbooks. However, Uenaka was the scientist who worked on ephedrine and played a practical role in the purification and crystallization of adrenaline. His handwritten memorandum, "On Adrenaline, Memorandum, July to December, 1900" is now stored in a Buddhist temple, Kyougyou-ji in Nashio, Japan. In the present report, we compared Uenaka's original description and Jokichi Takamine's published scientific reports, and examined how each statement in four documents are related to each other in terms of successful adrenaline crystallization. Uenaka's memorandum contained precise procedures and experimental tips for successful purification. The experimental steps were considered to transcribed in the first published document in The American Journal of Pharmacy by Takamine in 1901, and summarized in another document in ``Journal of Physiology'' in 1901. A Japanese version was published in ``Yakugakuzasshi'' in 1903 by translating the English paper in the American Journal of Pharmacy published in 1901. Reading Uenaka's memorandum, we realized that he tirelessly and diligently undertook routine experiments that to some of us might seem boring and laborious. Although the name of Uenaka is not globally well known, he was the main scientist who did the actual work of purifying adrenaline.

Reduction of Arterial Oxygen Saturation Among Rescuers During Cardiopulmonary Resuscitation in a Hypobaric Hypoxic Environment.

We experienced a case involving prolonged cardiopulmonary resuscitation (CPR) during cardiac arrest on Mt. Fuji (3776 m), demanding lengthy exertion by the rescuers performing CPR. Considering the effects of exertion on the rescuers, we examined their percutaneous arterial oxygen saturation during simulated CPR and compared the effects of compression-only and conventional CPR at 3700 m above sea level. The effects of CPR on the physical condition of rescuers were examined at the summit of Mt. Fuji: three rescue staff equipped with pulse-oximeters performed CPR with or without breaths using a CPR mannequin. At 3700 m, the rescuers' heart rate increased during CPR regardless of the presence or absence of rescue breathing. Percutaneous arterial oxygen saturation measured in such an environment was reduced only when CPR without rescue breathing was performed. Scores on the Borg scale, a subjective score of fatigue, after CPR in a 3700 m environment were 13 to 15 of 20 (somewhat hard to hard). Performing CPR at high altitude exerts a significant physical effect upon the condition of rescuers. Compression-only CPR at high altitude may cause a deterioration in rescuer oxygenation, whereas CPR with rescue breathing might ameliorate such deterioration.

Loss of endogenous analgesia leads to delayed recovery from incisional pain in a rat model of chronic neuropathic pain.

BACKGROUND: Preoperative pain and impaired endogenous analgesia are risk factors of chronic postsurgical persistent pain (CPSP). A Chronic neuropathic pain model induced by spinal nerve ligation (SNL6W) shows impaired endogenous analgesia and delayed recovery from incisional pain. Repeated amitriptyline treatment can restore the endogenous analgesia, but its effects on delayed recovery are not clear. METHODS: A plantar incision was made on the side contralateral to the nerve ligation in SNL6W rats. Withdrawal thresholds were measured by von Frey filament test until 28 d after surgery. Amitriptyline (10 mg·kg-1·d-1) or vehicle was administered for 13 d perioperatively. To examine the roles of noradrenergic and cholinergic signals in the spinal dorsal horn, pharmacological antagonism, measurement of each neurotransmitter concentration, and immunohistochemistry were conducted. RESULTS: Recovery of the withdrawal threshold of SNL6W animals to pre-incision values required 28 d after surgery, while naive animals recovered within 14 d. Intrathecal injection of alpha2 adrenoceptor antagonist (idazoxan) or muscarinic cholinergic receptor antagonist (atropine) decreased the withdrawal threshold on POD14 and 21 in naive animals, but not in SNL6W rats. Repeated amitriptyline treatment attenuated the delayed recovery in SNL6W rats, and the effect was antagonized by muscarinic cholinergic receptor antagonist. Beside the concentration of acetylcholine and its synthetic enzyme were not altered by the treatment. CONCLUSIONS: Noradrenergic and cholinergic analgesia, which is necessary for normal recovery, is lost in the SNL6W rats. A strategy to enhance endogenous analgesia using antidepressants, rather than simple analgesia, may help to prevent CPSP in chronic pain patients.

Assessment of the skin tissue structure using an ultrasonic diagnostic imaging device in patients undergoing open surgery.

BACKGROUND: Perioperative skin injury is a major issue; therefore, several preventative measures have been developed. However, no previous studies have visualized the effects of stromal edema caused by surgical invasion of skin tissue, and therefore, the details remain unknown. We used an ultrasonic diagnostic imaging device to clarify changes in the skin tissue structure of patients after open surgery. MATERIALS AND METHODS: Twenty subjects who underwent open hepatectomy were enrolled. We selected the lateral abdomen, upper arms, and lower legs as ultrasonic imaging measurement sites. We performed measurements on the day before surgery and on postoperative days 1, 3, and 5. We calculated the epidermal/dermal tissue thickness, subcutaneous tissue thickness, and skin tissue thickness. We performed a one-way analysis of variance with repeated measurements for each of the postoperatively measured values on the basis of the preoperative values. Significantly different variables were subjected to the Bonferroni method. We evaluated ultrasonic imaging findings and skin injury. RESULTS: Epidermal/dermal tissue thickness at all measurement sites exhibited sustained thickening on postoperative day 5 compared to that preoperatively. The lateral abdomen exhibited thickening of the subcutaneous tissue and skin tissue on postoperative day 1. In addition, increased echogenicity, increased opacity of the layer structure, and a cobblestone appearance occurred during the postoperative course. Postoperatively, 80% of subjects exhibited skin injury. CONCLUSION: We evaluated the effects of surgical invasion on skin tissue over time. Continual observation and protective skincare are necessary near the surgical wound, where significant invasiveness occurs. Prevention of skin injury due to skin tissue thickening requires further study.

Cesarean section following idiopathic rupture of renal artery aneurysm leading to fetal dysfunction.

BACKGROUND: Renal artery aneurysms (RAAs) in pregnancy are uncommon, with most found after rupturing. The risk of RAA rupture increases during pregnancy and delivery. CASE PRESENTATION: A 29-year-old woman at 36 weeks and 5 days of gestation presented with severe back and abdominal pain. No fetal movements were identified. Cesarean section (C/S) was performed due to severe fetal bradycardia. No signs of placental abruption or abnormalities of the placenta were apparent intraoperatively, but gross hematoma was identified intraoperatively in the left retroperitoneal space. To evaluate persistent hypotension and retroperitoneal hematoma, contrast-enhanced computed tomography was performed and revealed ruptured RAA in the left kidney. Transcatheter arterial embolization (TAE) was performed. CONCLUSIONS: This case report describes fetal dysfunction caused by RAA rupture and controlled by TAE.

Spinal Activation of Tropomyosin Receptor Kinase-B Recovers the Impaired Endogenous Analgesia in Neuropathic Pain Rats.

BACKGROUND: Although endogenous analgesia plays an important role in controlling pain states, chronic pain patients exhibit decreased endogenous analgesia compared to healthy individuals. In rats, noxious stimulus-induced analgesia (NSIA), which is an indicator of endogenous analgesia, diminished 6 weeks after spinal nerve ligation (SNL6W). A recent study in rats with deleted noradrenergic fibers demonstrated that the noradrenergic fibers were essential to NSIA. It has also been reported that brain-derived neurotrophic factor increased spinal noradrenergic fibers. Therefore, this study examined the effect of TrkB activation, which is the receptor for brain-derived neurotrophic factor, on impaired NSIA in SNL6W rats. In addition, we also examined the effect of endogenous analgesia on acute incisional pain. METHODS: After 5 daily intraperitoneal injections of 7,8-dihydroxyflavone (7,8-DHF, TrkB agonist, 5 mg/kg), NSIA was examined by measuring the withdrawal threshold increment in the left (contralateral to nerve ligation) hindpaw at 30 minutes after capsaicin injection (250 µg) in the forepaw. K252a (TrkB antagonist, 2 µg) was administrated intrathecally for 5 days. Idazoxan (α2 adrenoceptor antagonist, 30 µg), atropine (muscarinic antagonist, 30 µg), and propranolol (nonselective ß adrenoceptor antagonist, 30 µg) were administered intrathecally for 15 minutes before capsaicin injection. Microdialysis and immunohistochemistry were performed to examine the noradrenergic plasticity in the spinal dorsal horn. A hindpaw incision was performed on the left (contralateral to nerve ligation) hindpaw. Data were analyzed by 1-way analyses of variance or 2-way repeated-measures 1-way analysis of variance followed by a Student t test with Bonferroni correction. RESULTS: Five daily intraperitoneal injections of 7,8-DHF restored the attenuated NSIA in SNL6W rats (n = 7, P = .002; estimated treatment effect [95% CI]: 62.9 [27.0-98.7] g), with this effect blocked by 5 daily intrathecal coadministrations of K252a (n = 6, P < .001; -57.8 [-78.3 to -37.2] g). This effect was also inhibited by a single intrathecal administration of idazoxan (n = 8, P < .001; -61.6 [-92.4 to -30.9] g) and atropine (n = 8, P = .003; -52.6 [-73.3 to -31.9] g), but not by propranolol. Furthermore, 7,8-DHF increased the noradrenergic fiber in the spinal dorsal horn and the noradrenaline release in response to the capsaicin injection in the forepaw in SNL6W rats. In addition, repeated injections of 7,8-DHF prevented delayed recovery from incisional pain in SNL6W rats. CONCLUSIONS: Spinal activation of TrkB may recover the attenuated endogenous analgesia by improving the adrenergic plasticity, thereby leading to prevention of pain prolongation after surgery.

Tropomyosin Receptor Kinase B Receptor Activation in the Locus Coeruleus Restores Impairment of Endogenous Analgesia at a Late Stage Following Nerve Injury in Rats.

A rat model of neuropathic pain at 6 weeks after spinal nerve ligation (SNL6w) exhibits both mechanical hypersensitivity and impaired noxious stimuli-induced analgesia (NSIA). Repeated treatment with antidepressants can produce antihypersensitivity and restore NSIA. To examine the involvement of a brain-derived neurotrophic factor-mediated mechanism, a tropomyosin receptor kinase B (TrkB) agonist, 7,8-dihydroxyflavone (DHF), was administered to SNL6w rats (5 mg/kg/d for 5 days). Mechanical hypersensitivity was evaluated using the von Frey filament test and paw pressure test. NSIA was examined by measuring the change in the hind paw withdrawal threshold 30 minutes after painful stimulation induced by capsaicin injection into the fore paw. Changes in the concentrations of glutamate and GABA in the locus coeruleus area were measured by in vivo microdialysis. DHF treatment did not affect mechanical hypersensitivity, although it restored NSIA by reducing GABA release in response to the fore paw capsaicin injection. DHF treatment did not alter the baseline concentration of glutamate or GABA. These findings suggest that DHF treatment restored the stimuli-response activity of the locus coeruleus without affecting the tonic activity of the locus coeruleus. The brain-derived neurotrophic factor-TkB signaling is also involved in the NSIA-restoring effect of amitriptyline. PERSPECTIVE: This article demonstrates that repeated treatment with TrkB agonist, DHF, restored endogenous analgesia. Repeated amitriptyline treatment showed similar effect via TrkB-mediated mechanisms, and the effect may be independent from the effect of antihypersensitivity. This effect of TrkB activation is promising for patients with chronic pain with impaired descending inhibition.

Physiological and Pharmaceutical Knowledge in "Ninja" Society: Suggestions for Modern Anesthesiologists and Intensivists.

Anesthesiologists and intensivists are modern professionals who provide conscious sedation and respiratory care and prescribe medicines with potential toxicity. Similarly, ninjas, covert agent soldiers who carried out special operations in medieval Japan, also had ample knowledge of toxicology, psychology, human consciousness and respiration. Although the extent of their knowledge remains largely unknown, that which has been described in the literature appears to be practical and scientifically explainable from the standpoint of modern medical science.

Sustained-release lidocaine sheet for pain following tooth extraction: A randomized, single-blind, dose-response, controlled, clinical study of efficacy and safety.

BACKGROUND: We have synthesized a sustained-release lidocaine sheet (SRLS) using biodegradable polymers and previously demonstrated its safety and long-term analgesic effect in the normal mucous membrane of healthy human volunteers. OBJECTIVES: The aim of this clinical study was to evaluate the efficacy, safety, and appropriate dose of the SRLS for pain following tooth extraction. DESIGN: Randomized, single-blind, dose-response, controlled, clinical study (Phase 1/2). METHODS: The patients in this trial were enrolled between January 2014 and December 2016. A total of 99 patients were randomly divided into 5 groups as follows: the Non-administration group received the conventional extraction; the Poly Lactic-co-Glycolic Acid (PLGA) 100 mg control group received the PLGA matrix without lidocaine; the SRLS 100 mg group received a single sheet of SRLS 100 mg; the SRLS 200 mg group received double sheets of SRLS 100 mg; and the SRLS 400 mg administration group received four sheets of SRLS 100 mg. A study drug was inserted into the defect socket after the extraction, and postoperative pain intensity, satisfaction with postoperative pain relief, adverse events, and postoperative supplemental analgesic rescue use (time, dose) were investigated by patient self-report. RESULTS: In total, 94 (94.9%) patients completed the study. There were no significant differences in postoperative pain intensity, satisfaction with postoperative pain relief, and postoperative supplemental analgesic rescue use among the 5 groups. There were no serious side effects, including a plasma concentration increase of lidocaine, attributable to the SRLS. CONCLUSIONS: Administration of the SRLS at 100 mg may have clinical therapeutic potential for pain relief following tooth extraction. The safety of the SRLS for patients undergoing tooth extraction was demonstrated. TRIAL REGISTRATION: The University Hospital Medical Information Network UMIN000011945.

The history and progress of local anesthesia: multiple approaches to elongate the action.

Analgesia and temporary inhibition of motor activity without interfering with central nervous function have been the essential merits of local anesthesia. Local anesthetics originated from cocaine have played a major role in local analgesia. However, the relatively short duration of action of local anesthetics has been a concern in intra- and post-operative analgesia. From the early age of modern local anesthesia, physicians and medical scientists had been struggling to control the active duration of local anesthetics. Such approach includes: development of long-acting local anesthetics, with physical tourniquet techniques, co-administration of other medicines such as vaso-constrictive agents or analgesics, development of mechanical devices to continuously or intermittently administer local anesthetics, and utilization of pharmaceutical drug delivery systems. In this review, the historical sequence of studies that have been performed in an effort to elongate the action of local anesthetics is presented, referring to epoch-making medical and scientific studies.

Cardiorespiratory dynamics of rescuers during cardiopulmonary resuscitation in a hypoxic environment.

OBJECTIVE: We had previously experienced a case involving prolonged cardiopulmonary resuscitation (CPR) on Mt. Fuji (3776 m), demanding strenuous work by the rescuers. The objective of this study was to compare the effect of compression-only and conventional CPR on oxygen saturation of rescuers in a hypoxemic environment. METHODS: Changes in percutaneous arterial oxygen saturation (SpO2) and heart rate during CPR action were measured in a hypobaric chamber with barometric pressure adjusted to be equivalent to 3700 m above sea level (630-640 hPa). Thirty-three volunteers performed CPR with or without breaths using a CPR mannequin. RESULTS: In a 3700-m-equivalent environment, SpO2 was reduced only when CPR was performed without breaths (P < .05, one-way analysis of variance (ANOVA) post hoc Tukey test). Heart rate increased during CPR regardless of the presence or absence of breaths. Mean scores on the Borg scale, a subjective measure of fatigue, after CPR action in the 3700-m-equivalent environment were significantly higher (15 ±â€¯2) than scores after CPR performed at sea level (11 ±â€¯2, P < .01, paired t-test). No lethal dysrhythmia was found in subjects with a wearable electrode shirt. CONCLUSIONS: Prolonged CPR at high altitude exerts a significant physical effect upon the condition of rescuers. Compression-only CPR at high altitude may deteriorate rescuer oxygenation, whereas CPR with breaths might ameliorate such deterioration.