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Previous studies suggest that lower BMI is a risk factor for intraoperative core hypothermia. Adipose tissue has a high insulation effect and is one of the major explanatory factors of core hypothermia. Accordingly, determining the respective influence of visceral and subcutaneous fat on changes in core temperature during laparoscopic surgery is of considerable interest. We performed a prospective study of 104 consecutive donors who underwent laparoscopic nephrectomy. Temperature data were collected from anesthesia records. Visceral and subcutaneous fat were calculated by computed tomography (CT) or ultrasound. For ultrasound measurements, preperitoneal fat thickness was used as an index of visceral fat. Multiple linear regression analysis was performed at 30, 60, and 120 minutes after the surgical incision to identify the predictive factors of body temperature change. The potential explanatory valuables were age, sex, BMI, visceral fat, and subcutaneous fat. BMI (β = 0.010, 95%CI: 0.001-0.019, p = 0.033) and waist-to-hip ratio (β = 0.424, 95%CI: 0.065-0.782, p = 0.021) were associated with increased core temperature at 30 minutes after the surgical incision. Ultrasound measured-preperitoneal fat was significantly associated with increased core temperature at 30 and 60 minutes after the surgical incision (β = 0.012, 95%CI: 0.003-0.021, p = 0.009 and β = 0.013, 95%CI: 0.002-0.024, p = 0.026). CT-measured visceral fat was also associated with increased core temperature at 30 minutes after the surgical incision (β = 0.005, 95%CI: 0.000-0.010, p = 0.046). Conversely, subcutaneous fat was not associated with intraoperative core temperature. Male sex and younger age were associated with lower intraoperative core temperature. Visceral fat protects against core temperature decrease during laparoscopic donor nephrectomy.

Linkage between early-life exposure to anesthesia and subsequent learning disabilities is of great concern to children and their families. Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and the expression of quiescence-associated genes in neural stem cells (NSCs) in the mouse hippocampus. The alterations led to a sustained restriction of NSC proliferation toward adulthood, resulting in a reduction of neurogenesis that was associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis, normalized the MDZ-perturbed transcriptome, and ameliorated cognitive ability in MDZ-exposed mice. Our findings thus explain how pediatric anesthesia provokes long-termadverse effects on brain function and provide a possible therapeutic strategy for countering them.

Background Although propofol is a common anesthetic agent for the induction of general anesthesia, hemodynamic fluctuations are occasionally prominent during induction/intubation. The aims of this study were to determine the influential factors on enhanced hemodynamic fluctuation and to establish a prediction formula to quickly determine the dose of propofol to protect against hemodynamic fluctuations. Methods This retrospective cohort study patients ( n  = 2097) were 18 years or older. They underwent general anesthesia induction using propofol and orotracheal intubation for non-cardiac surgery at Kyushu University Hospital during April 2015 to March 2016. Preoperative patient clinical information was collected from anesthesia preoperative evaluation records. Intraoperative data were obtained from computerized anesthesia records. If patients’ post-induction mean arterial blood pressure (MAP) decreased or increased 30% or more from their pre-induction MAP, they were determined to have enhanced hemodynamic fluctuations. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Structural equation modeling (SEM) was conducted to simultaneously examine the direct and indirect effect (path coefficient = r) of potential variables. Results In the SEM analysis, age was significantly associated with enhanced hemodynamic fluctuations (adjusted odds ratio = 1.008, 95% CI = 1.001–1.015, P  = 0.03). Age (path coefficient (r) = − 0.0113, 95% CI = − 0.0126–0.010, P  < 0.001), American Society of Anesthesiologists physical status (ASA-PS) ( r  = − 0.0788, 95% CI = − 0.1431–0.0145, P  = 0.02), sex ( r  = 0.057, 95% CI = 0.0149–0.9906, P  = 0.01), and fentanyl dose ( r  = 0.1087, 95% CI = 0.0707–0.1467, P  < 0.001) influenced the dose of propofol in induction. The prediction formula of “Propofol dose (mg) = [2.374 – 0.0113 × age (year) – 0.0788 (if ASA-PS 3 or 4) + 0.057 (if female) + 0.1087 × fentanyl dose (μg/kg)] × body weight (kg)” was derived. Conclusions Age was associated with hemodynamic fluctuations in induction. Although the prediction formula is considered to be acceptable, future studies validating whether it can decrease patients’ risk of enhanced hemodynamic fluctuations in clinical situations are necessary.

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a μ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.

Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β ) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.

Recently, the cortical mechanisms of tactile-induced analgesia have been investigated; however, spatiotemporal characteristics have not been fully elucidated. The insular–opercular region integrates multiple sensory inputs, and nociceptive modulation by other sensory inputs occurs in this area. In this study, we focused on the insular–opercular region to characterize the spatiotemporal signature of tactile-induced analgesia using magnetoencephalography in 11 healthy subjects. Aδ (intra-epidermal electrical stimulation) inputs were modified by Aβ (mechanical tactile stimulation) selective stimulation, either independently or concurrently, to the right forearm. The optimal inter-stimulus interval (ISI) for cortical level modulation was determined after comparing the 40-, 60-, and 80-ms ISI conditions, and the calculated cortical arrival time difference between Aδ and Aβ inputs. Subsequently, we adopted a 60-ms ISI for cortical modulation and a 0-ms ISI for spinal level modulation. Source localization using minimum norm estimates demonstrated that pain-related activity was located in the posterior insula, whereas tactile-related activity was estimated in the parietal operculum. We also found significant inhibition of pain-related activity in the posterior insula due to cortical modulation. In contrast, spinal modulation was observed both in the posterior insula and parietal operculum. Subjective pain, as evaluated by the visual analog scale, also showed significant reduction in both conditions. Therefore, our results demonstrated that the multisensory integration within the posterior insula plays a key role in tactile-induced analgesia. •We investigated cortical mechanism of tactile-induced pain relief using MEG.•Aδ inputs were modified by Aβ stimulation either at the spinal or cortical level.•Pain and tactile activities were segregated within the insular-opercular region.•Pain-related activity was suppressed in the posterior insula.•Cortical pain relief can occur in the posterior insula.

We report the successful anesthetic management of laparoscopic surgery in a 21-year-old female patient with Fontan circulation. A preoperative careful review of cardiac catheterization results helped assess the risk of the surgery and implement anesthetic management. Intraoperative management focused on minimizing the impact on pulmonary vascular resistance and venous return by optimizing ventilation and applying lower pneumoperitoneum pressure without tilting the position. Milrinone was administered to reduce pulmonary vascular resistance and provide inotropic support with minimally invasive monitoring. The patient remained stable throughout the procedure without complications. This case highlights the importance of thorough preoperative assessment, individualized intraoperative management, and collaboration with the surgical team when caring for adult Fontan patients undergoing laparoscopic surgery.

Pupil reactivity can be used to evaluate central nervous system function and can be measured using a quantitative pupillometer. However, whether anesthetic agents affect the accuracy of the technique remains unclear. We examined the effects of anesthetic agents on pupillary reactivity. Thirty-five patients scheduled for breast or thyroid surgery were enrolled in the study. Patients were divided into four groups based on the technique used to maintain anesthesia: a sevoflurane–remifentanil (SEV/REM) group, a sevoflurane (SEV) group, a desflurane–remifentanil (DES/REM) group, and a propofol–remifentanil (PRO/REM) group. We measured maximum resting pupil size (MAX), reduction pupil size ratio (%CH), latency duration (LAT) and neurological pupil index (NPi). A marked reduction in MAX and %CH compared with baseline was observed in all groups, but LAT was unchanged during surgery. NPi reduced within the first hour of surgery in the SEV/REM, SEV, and DES/REM groups, but was not significantly different in the PRO/REM group. Compared with the PRO/REM group, mean %CH and NPi in patients anesthetized with SEV/REM, SEV or DES/REM were markedly lower at 1 h after surgery had commenced. There was no correlation between NPi and bispectral index. Fentanyl given alone decreased pupil size and %CH in light reflex, but did not change the NPi. NPi was decreased by inhalational anesthesia not but intravenous anesthesia. The difference in pupil reactivity between inhalational anesthetic and propofol may indicate differences in the alteration of midbrain reflexs in patients under inhalational or intravenous anesthesia.

A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in neuronal systems and exhibits numerous biological activities. Using CGRP-knockout mice (CGRP⁻/⁻), we examined whether or not endogenous CGRP facilitates angiogenesis indispensable to tumor growth. CGRP increased tube formation by endothelial cells in vitro and enhanced sponge-induced angiogenesis in vivo. Tumor growth and tumor-associated angiogenesis in CGRP⁻/⁻ implanted with Lewis lung carcinoma (LLC) cells were significantly reduced compared with those in wild-type (WT) mice. A CGRP antagonist, CGRP8-37 or denervation of sciatic nerves (L₁₋₅) suppressed LLC growth in the sites of denervation compared with vehicle infusion or sham operation. CGRP precursor mRNA levels in the dorsal root ganglion in LLC-bearing WT were increased compared with those in non-LLC-bearing mice. This increase was abolished by denervation. The expression of VEGF in tumor stroma was down-regulated in CGRP⁻/⁻. These results indicate that endogenous CGRP facilitates tumor-associated angiogenesis and tumor growth and suggest that relevant CGRP may be derived from neuronal systems including primary sensory neurons and may become a therapeutic target for cancers.

Ultiva® is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva® is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva® provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva® contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva® potentially complicates its effects. We examined how Ultiva® directly affects nociceptive transmission in the spinal cord. We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva® onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli. Bath application of Ultiva® hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva®. Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva®-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva®-induced currents demonstrated a specific equilibrium potential similar to glycine. We found that intrathecal administration of Ultiva® to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva®-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous administrations.