ABSTRACT
BACKGROUND: Inter-scalene block (ISB) is associated with an inevitable risk of hemi-diaphragmatic paresis (HDP). To reduce the risk of HDP, an upper trunk block (UTB) has been proposed at the brachial plexus division level. OBJECTIVE: We hypothesised that UTB would be associated with a lower incidence of HDP than ISB while providing sufficient analgesia following arthroscopic shoulder surgery. DESIGN: Randomised controlled trial. SETTING: A tertiary teaching hospital. PATIENTS: Seventy patients aged 20 to 80âyears undergoing arthroscopic rotator cuff repair. INTERVENTION: Ultrasound-guided ISB or UTB was performed with 5âml 0.75% ropivacaine. MAIN OUTCOME MEASURES: The primary outcome was the incidence of complete HDP, assessed by diaphragm excursion using ultrasound, defined as a decrease to 25% or less of baseline or occurrence of paradoxical movement. Postoperative pulmonary function change, pain scores, opioid consumption and pain-related outcomes were the secondary outcomes. RESULTS: The UTB group had a significantly lower incidence of complete HDP than the ISB group [5.9% (2/34) vs. 41.7% (15/36); absolute difference, 35.8%; 95% confidence interval (CI), 17.8 to 53.7%; Pâ<â0.001]. The postblockade decline in pulmonary function was more pronounced in the ISB group than that in the UTB group. The pain score at 1âh postoperatively was not significantly different between the groups (ISB vs. UTB group: median 0 vs. 1; median difference, -1; 95% CI, -2 to 0.5). No significant difference was observed in any other secondary outcomes. CONCLUSION: UTB was associated with a lower incidence of HDP compared with ISB while providing excellent analgesia in arthroscopic shoulder surgery. TRIAL REGISTRATION: Clinical Trial Registry of Korea (https://cris.nih.go.kr) identifier: KCT0007002. IRB NUMBER: Chungnam National University Hospital Institutional Review Board No. 2021-12-069.
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Background: Perfusion index (PI) has been used as a surrogate marker of sympathetic blockade. This study evaluated changes in PI of bilateral upper extremity after thoracic paravertebral block (PVB) and intertransverse process block (ITPB). Methods: This pilot study included three groups of patients undergoing elective unilateral pulmonary resection under general anesthesia with PVB (n=11) or ITPB (n=10), or urologic procedures with general anesthesia (control group, n=10). Blockades were performed using 10 mL aliquots of 0.5% ropivacaine administered at T3-4, T5-6, and T7-8 intercostal levels immediately after general anesthesia induction. The PI value of the operating side (PI-O) was divided by the contralateral side (PI-CL), and the relative change to baseline was assessed (relative PI-O/PI-CL), with a 50% increase considered meaningful. Results: In all cases within the PVB and ITPB groups, a significant increase in PI was observed following the blockades. The median (1Q, 3Q) intraoperative relative PI-O/PI-CL values were 0.9 (0.8, 1.4), 2.1 (1.4, 2.5), and 1.4 (0.9, 1.9) in the control, PVB, and ITPB groups (P=0.01), respectively. Pairwise comparison revealed a significant difference only between the control and PVB groups (adjusted P=0.01). While the relative PI-O/PI-CL value in the control group generally remained close to 1, occasional fluctuations exceeding 1.5 were noted. Conclusions: PVB induced a noticeable unilateral increase in upper extremity PI, whereas ITPB tended to result in an inconsistent and lesser degree of increase. Monitoring PI values can serve as an indicator of upper extremity sympathetic blockade, but consideration of potential confounders impacting these observations during surgery is essential. Further research is needed to validate these findings.
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Background and Objectives: Endoscopic epidural neuroplasty (EEN) facilitates adhesiolysis through direct epiduroscopic visualization, offering more precise neural decompression than that exhibited by percutaneous epidural neuroplasty (PEN). We aimed to compare the effects of EEN and PEN for 6 months after treatment with lower back and radicular pain in patients. Methods: This retrospective study compared the visual analog scale (VAS) and Oswestry disability index (ODI) scores in patients with low back and radicular pain who underwent EEN or PEN with a steering catheter. The medical records of 107 patients were analyzed, with 73 and 34 undergoing EEN and PEN, respectively. Results: The VAS and ODI scores decreased at all time points after EEN and PEN. VAS and ODI scores decreased more in the EEN group than those in the PEN group at 1 day and 1- and 6-months post-procedure, indicating superior pain relief for both lower back and radicular pain through EEN. Conclusions: EEN is a superior treatment of pain control than PEN in lower back and radicular pain patients.
Subject(s)
Low Back Pain , Humans , Low Back Pain/surgery , Low Back Pain/therapy , Female , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Follow-Up Studies , Aged , Adult , Endoscopy/methods , Pain Measurement/methods , Epidural Space , Decompression, Surgical/methodsABSTRACT
Remimazolam's rapid onset and offset make it an innovative sedative for use during regional anesthesia. However, its respiratory safety profile is not well understood. We compared the continuous infusion of remimazolam with commonly used sedatives, propofol and dexmedetomidine, after regional anesthesia. In this retrospective study, the incidence of apnea (>10 seconds) was assessed in patients who underwent orthopedic surgery under regional anesthesia and received moderate to deep sedation using continuous infusion of remimazolam (group R: 0.1 mg/kg in 2 minutes followed by 0.5 mg/kg/hr). The incidence was compared with that of propofol (group P: 2-3 µg/mL target-controlled infusion) and dexmedetomidine (group D: 1 µg/kg in 10 minutes followed by 0.4-1 µg/kg/hr). Propensity score weighted multivariable logistic regression model was utilized to determine the effects of the sedative agents on the incidence of apnea. A total of 634 (191, 278, and 165 in group R, P, and D) cases were included in the final analysis. The incidence of apnea was 63.9%, 67.3%, and 48.5% in group R, P, and D, respectively. The adjusted odds ratios for apnea were 2.33 (95% CI, 1.50 to 3.61) and 2.50 (95% CI, 1.63 to 3.85) in group R and P, compared to group D. The incidence of apnea in patients receiving moderate to deep sedation using continuous infusion of remimazolam with dosage suggested in the current study was over 60%. Therefore, careful titration and respiratory monitoring is warranted.
Subject(s)
Benzodiazepines , Deep Sedation , Dexmedetomidine , Propofol , Humans , Retrospective Studies , Apnea , Hypnotics and SedativesABSTRACT
Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain.
Subject(s)
Neuralgia , Neuroblastoma , Rats , Humans , Animals , Sodium-Hydrogen Exchanger 1/genetics , Sodium-Hydrogen Exchanger 1/metabolism , Polylactic Acid-Polyglycolic Acid Copolymer , Glycols , Delayed-Action Preparations , RNA, Small Interfering/geneticsABSTRACT
BACKGROUND: Blood pressure measurement is an essential element during intraoperative patient management. However, errors caused by changes in transducer levels can occur during surgery. METHODS: This single center, prospective, observational study enrolled 25 consecutive patients scheduled for elective cardiac surgery with invasive arterial and central venous pressure (CVP) monitoring. Hydrostatic pressures caused by level differences (leveling pressure) between a reference point (on the center of the left biceps brachii muscle) and the transducers (fixed on the right side of the operating table) for arterial and central lines were continuously measured using a leveling transducer. Adjusted pressures were calculated as measured pressure - leveling pressure. Hypotension (mean arterial pressure < 80, <70, and < 60 mmHg), and CVP (< 6, ≥6 and < 15, or ≥ 15 mmHg) and pulmonary artery pressure (PAP, mean > 20 mmHg) levels were determined using unadjusted and adjusted pressures. RESULTS: Twenty-two patients were included in the analysis. Leveling pressure ≥ 3 mmHg and ≥ 5 mmHg observed at 46.0 and 18.7% of pooled data points, respectively. Determinations of hypotension using unadjusted and adjusted pressures showed disagreements ranging from 3.3 to 9.4% depending on the cutoffs. Disagreements in defined levels of CVP and PAP were observed at 23.0 and 17.2% of the data points, respectively. CONCLUSIONS: The errors in pressure measurement due to changes in transducer level were not trivial and caused variable disagreements in the determination of MAP, CVP, and PAP levels. To prevent distortions in intraoperative hemodynamic management, strategies should be sought to minimize or adjust for these errors in clinical practice. TRIAL REGISTRATION: cris.nih.go.kr (KCT0006510).
Subject(s)
Cardiac Surgical Procedures , Hypotension , Humans , Adult , Central Venous Pressure/physiology , Transducers, Pressure , Prospective Studies , Cardiac Surgical Procedures/adverse effects , Hypotension/diagnosisABSTRACT
(1) Background: Prolonged neck flexion is thought to cause harmful loading on the cervical spine. Along with the degenerative process, cervical alignment tends to change toward lordotic curvature. The association between cervical alignment and cervical spondylosis remains unclear. (2) Methods: Three raters retrospectively assessed cervical radiographies of outpatients at a tertiary center in 2019 using degenerative cervical spondylosis score (DCS score; a newly developed scoring system), C2-7 absolute rotational angle (ARA), and C2-7 sagittal vertical axis (SVA). (3) Results: A total of 561 patients were included in the analysis. Multiple regression analysis with adjustments for age and sex revealed that C2-7 ARA, rather than SVA, was a significant parameter for degenerative spondylosis. The interaction between age and C2-7 ARA was significant, indicating that the increase in DCS score with increasing age was more pronounced in patients with kyphotic cervical alignment. The direct effect of age on DCS score was 0.349 (95% CI 0.319 to 0.380, p < 0.001) and the proportion of the mediation effect of C2-7 ARA was −0.125 (p < 0.001). (4) Conclusions: C2-7 ARA was significantly associated with DCS after adjustment for both age and sex. Subjects with more kyphotic cervical alignment showed a greater correlation between increased DCS score and older age.
ABSTRACT
(1) Background: Although radiography performed on the subject in an upright position is considered the standard method for assessing sagittal cervical alignment, it is frequently determined, or reported, based on MRI performed on the subject in a supine position. (2) Methods: Cervical alignment observed in both imaging modalities was assessed using four methods: the C2-7 Cobb angle, the absolute rotation angle (ARA), Borden's method, and the sagittal vertical axis (SVA). Cervical alignment was determined (lordosis, kyphosis, and straight) based on radiography. Then, the diagnostic cut-off values for the MRI images and their corresponding diagnostic accuracies were assessed. (3) Results: The analysis included 142 outpatients. The determined diagnostic cut-off values for lordosis, using three measurements (Cobb angle, ARA, and Borden's method), were -8.5°, -12.5°, and 3.5 mm, respectively, and the cut-off values for kyphosis were -4.5°, 0.5°, and -1.5 mm, respectively. The cut-off value for SVA > 40 mm was 19.5 mm. The Cobb angle, ARA, and Borden's method, on MRI, showed high negative predictive values for determining kyphosis. The SVA on MRI measurements also showed high negative predictive values for determining >40 mm. (4) Conclusions: MRI measurements may be predictive of cervical alignment, especially for the exclusion of kyphosis and SVA > 40 mm. However, caution is needed in the other determinations using MRI, as their accuracies are limited.
Subject(s)
Kyphosis , Lordosis , Cervical Vertebrae/diagnostic imaging , Humans , Kyphosis/diagnostic imaging , Lordosis/diagnostic imaging , Magnetic Resonance Imaging , Retrospective StudiesABSTRACT
BACKGROUND: The clinical range of central venous pressure (CVP) (typically 5 to 15 mmHg) is much less than the range of mean arterial blood pressure (60 to 120 mmHg), suggesting that CVP may have little impact on estimation of systemic vascular resistance (SVR). The accuracy and feasibility of using an arbitrary CVP rather than actual CVP for the estimation of SVR during intraoperative period is not known. METHODS: Using vital records obtained from patients who underwent neurological and cardiac surgery, the present study retrospectively calculated SVR using fixed values of CVP (0, 5, 10, 15, and 20 mmHg) and randomly changing values of CVP (5 to 15 mmHg) and compared these calculated SVRs with actual SVR, calculated using actual CVP. Differences between actual SVR and SVRs based on fixed and random CVPs were quantified as root mean square error (RMSE) and mean absolute percentage error (MAPE). Bland-Altman analysis and four-quadrant plot analysis were performed. RESULTS: A total of 34 patients are included, including 18 who underwent neurosurgery and 16 who underwent cardiac surgery; 501,380 s (139.3 h) of data was analyzed. The SVR derived from a fixed CVP of 10 mmHg (SVRf10) showed the highest accuracy (RMSE: 115 and 104 [dynes/sec/cm- 5] and MAPE: 6.3 and 5.7% in neurological and cardiac surgery, respectively). The 95% limits of agreement between SVRf10 and actual SVR were - 208.5 (95% confidence interval [CI], - 306.3 to - 148.1) and 242.2 (95% CI, 181.8 to 340.0) dynes/sec/cm- 5 in neurosurgery and - 268.1 (95% CI, - 367.5 to - 207.7) and 163.2 (95% CI, 102.9 to 262.6) dynes/sec/cm- 5 in cardiac surgery. All the SVRs derived from the fixed CVPs (regardless of its absolute value) showed excellent trending ability (concordance rate > 0.99). CONCLUSIONS: SVR can be estimated from a fixed value of CVP without causing significant deviation or a loss of trending ability. However, caution is needed when using point estimates of SVR when the actual CVP is expected to be out of the typical clinical range. TRIAL REGISTRATION: This study was registered Clinical Research Information Service, a clinical trial registry in South Korea ( KCT0006187 ).
Subject(s)
Central Venous Pressure/physiology , Vascular Resistance/physiology , Aged , Cohort Studies , Female , Humans , Male , Retrospective StudiesABSTRACT
Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.
ABSTRACT
Duloxetine (DLX) is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) used for the treatment of pain, but it has been reported to show side effects in 10-20% of patients. Its analgesic efficacy in central pain is putatively related to its influence on descending inhibitory neuronal pathways. However, DLX can also affect the activation of microglia. This study was performed to investigate whether PLGA nanoparticles (NPs), which are expected to enhance targeting to microglia, can improve the analgesic efficacy and limit the side effects of DLX. PLGA NPs encapsulating a low dose of DLX (DLX NPs) were synthesized and characterized and their localization was determined. The analgesic and anti-inflammatory effects of DLX NPs were evaluated in a spinal nerve ligation (SNL)-induced neuropathic pain model. The analgesic effect of DLX lasted for only a few hours and disappeared within 1 day. However, DLX NPs alleviated mechanical allodynia, and the effect was maintained for 1 week. DLX NPs were localized to the spinal microglia and suppressed microglial activation, phosphorylation of p38/NF-κB-mediated pathways and the production of inflammatory cytokines in the spinal dorsal horn of SNL rats. We demonstrated that DLX NPs can provide a prolonged analgesic effect by enhanced targeting of microglia. Our observations imply that DLX delivery through nanoparticle encapsulation allows drug repositioning with a prolonged analgesic effect, and reduces the potential side effects of abuse and overdose.
Subject(s)
Nanoparticles , Neuralgia , Animals , Duloxetine Hydrochloride , Humans , Microglia , Neuralgia/drug therapy , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: The optimal insertion length for right subclavian vein catheterization in infants has not been determined. This study retrospectively compared landmark-based and linear regression model-based estimation of optimal insertion length for right subclavian vein catheterization in pediatric patients of corrected age < 1 year. METHODS: Fifty catheterizations of the right subclavian vein were analyzed. The landmark related distances were: from the needle insertion point (I) to the tip of the sternal head of the right clavicle (A) and from A to the midpoint (B) of the perpendicular line drawn from the sternal head of the right clavicle to the line connecting the nipples. The optimal length of insertion was retrospectively determined by reviewing post-procedural chest radiographs. Estimates using a landmark-based equation (IA + AB - intercept) and a linear regression model were compared with the optimal length of insertion. RESULTS: A landmark-based equation was determined as IA + AB - 5. The mean difference between the landmark-based estimate and the optimal insertion length was 1.0 mm (95% limits of agreement -18.2 to 20.3 mm). The mean difference between the linear regression model (26.681 - 4.014 × weight + 0.576 × IA + 0.537 × AB - 0.482 × postmenstrual age) and the optimal insertion length was 0 mm (95% limits of agreement -16.7 to 16.7 mm). The difference between the estimates using these two methods was not significant. CONCLUSION: A simple landmark-based equation may be useful for estimating optimal insertion length in pediatric patients of corrected age < 1 year undergoing right subclavian vein catheterization.
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BACKGROUND: Sedation using dexmedetomidine is frequently associated with hypotension. In contrast, epinephrine, a commonly used adjunctive agent in regional anesthesia, is a potent vasopressor. We hypothesized that perineural epinephrine used in brachial plexus blockade may reduce hypotension during dexmedetomidine infusion. METHODS: Patients scheduled for upper extremity surgery were randomly allocated into a control and an epinephrine group. All patients received brachial plexus blockade, consisting of 25 mL of a 1:1 mixture of 1% lidocaine and 0.75% ropivacaine, with patients in the epinephrine group also receiving 125 µg epinephrine. Intraoperative sedation was induced using dexmedetomidine at a loading dose of 1 µg/kg and maintenance dose of 0.4 µg/kg/hr. The primary outcome was the incidence of intraoperative hypotension or hypotension in the post-anesthesia care unit (PACU). RESULTS: One hundred and thirty patients were included (65 per group). The incidence of hypotension was significantly higher in the epinephrine than in the control group (80.6% vs. 56.9%, p = 0.009). The duration of hypotension and the maximal change in blood pressure were also greater in the epinephrine group. CONCLUSIONS: Perineural epinephrine for brachial plexus blockade does not reduce hypotension due to dexmedetomidine infusion and may actually augment the occurrence of hypotensive events.
ABSTRACT
BACKGROUD: The purpose of this study was to compare the histologic outcomes of rotator cuff (RC) repair with demineralized bone matrix (DBM) augmentation and those without DBM augmentation and to evaluate the role of DBM for tendon-to-bone (TB) healing in a rabbit model. METHODS: Twenty-six adult male New Zealand white rabbits were randomly allocated to the control group (n = 13) or the DBM group (n = 13). Repair was performed 8 weeks after complete transection of the right supraspinatus tendon of all rabbits. In the control group, RC repair was achieved by a standard transosseous technique. In the DBM group, RC repair was achieved using the same technique, and DBM was interposed between the cuff and bone. After 8 weeks, the RC tendon entheses from all rabbits were processed for gross and histologic examination. RESULTS: On gross TB healing, 2 of 11 specimens in the control group were unhealed and no specimen was grossly unhealed in the DBM group (p = 0.421). In the control group, the tendon midsubstance was disorganized with randomly and loosely arranged collagen fibers and rounded fibroblastic nuclei. The TB interface was predominantly fibrous with small regions of fibrocartilage, especially mineralized fibrocartilage. In the DBM group, the tendon midsubstance appeared normal and comprised densely arranged collagen fibers, with orientated crimped collagen fibers running in the longitudinal direction of the tendon. These fibers were interspersed with elongated fibroblast nuclei. The TB interface consisted of organized collagen fibers with large quantities of fibrocartilage and mineralized fibrocartilage. CONCLUSIONS: The use of DBM for TB interface healing in rabbit experiments showed good results in gross and histologic analysis. However, it is difficult to draw a solid conclusion because the sample size is small. Further evaluation in the in vivo setting is necessary to determine clinical recommendations.
Subject(s)
Bone Matrix , Rotator Cuff Injuries/surgery , Tendon Injuries/surgery , Wound Healing , Animals , Disease Models, Animal , Male , RabbitsABSTRACT
Activation of nuclear factor-kappa B (NF-κB) in microglia plays a decisive role in the progress of neuropathic pain, and the inhibitor of kappa B (IκB) is a protein that blocks the activation of NF-κB and is degraded by the inhibitor of NF-κB kinase subunit beta (IKBKB). The role of IKBKB is to break down IκB, which blocks the activity of NF-kB. Therefore, it prevents the activity of NK-kB. This study investigated whether neuropathic pain can be reduced in spinal nerve ligation (SNL) rats by reducing the activity of microglia by delivering IKBKB small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles. PLGA nanoparticles, as a carrier for the delivery of IKBKB genes silencer, were used because they have shown potential to enhance microglial targeting. SNL rats were injected with IKBKB siRNA-encapsulated PLGA nanoparticles intrathecally for behavioral tests on pain response. IKBKB siRNA was delivered for suppressing the expression of IKBKB. In rats injected with IKBKB siRNA-encapsulated PLGA nanoparticles, allodynia caused by mechanical stimulation was reduced, and the secretion of pro-inflammatory mediators due to NF-κB was reduced. Delivering IKBKB siRNA through PLGA nanoparticles can effectively control the inflammatory response and is worth studying as a treatment for neuropathic pain.
Subject(s)
Drug Carriers/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Nanoparticles/therapeutic use , Neuralgia/drug therapy , Polylactic Acid-Polyglycolic Acid Copolymer/pharmacology , RNA, Small Interfering/pharmacology , Animals , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Male , Microglia/pathology , Neuralgia/genetics , Neuralgia/metabolism , Neuralgia/pathology , RNA, Small Interfering/genetics , Rats , Rats, Sprague-DawleyABSTRACT
Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.
Subject(s)
Formaldehyde/pharmacology , Inflammation/metabolism , Pain/chemically induced , Pain/metabolism , TOR Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , Animals , Cell Line, Tumor , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , PC12 Cells , Pain Measurement/methods , Rats , Spinal Cord/metabolism , Up-Regulation/physiologyABSTRACT
While recent studies strongly suggest that a single, short anesthetic exposure does not affect neurodevelopment, the effects of multiple exposures remain unclear. Unfortunately, studying "multiple exposures" is challenging as it is an extremely heterogeneous descriptor comprising diverse factors. One potentially important, but unrecognized factor is the interval between anesthetic exposures. In order to evaluate the significance of interval, we exposed post-natal day 16, 17 mice to three sevoflurane exposures (2.5%, 1 hr) with short (2 hr) or long (24 hr) intervals. Changes in synaptic transmission, plasticity, protein expression, and behavior were assessed in male and female mice. We discovered that short-interval exposures induced a female-dependent decrease in miniature inhibitory post-synaptic current (mIPSC) frequency 5 days after the last exposure (control: 18.44 ± 2.86 Hz, sevoflurane:14.65 ± 4.54 Hz). Short-interval sevoflurane exposed mice also displayed long-term behavioral deficits at adult age (hypoactivity, anxiety). These behavioral changes were consistent with the sex-dependent changes in inhibitory transmission, as they were more robust in female mice. Although there was no change in learning and memory, short-interval sevoflurane exposures also impaired LTP in a non-sex-dependent manner (control: 171.10 ± 26.90%, sevoflurane: 149.80 ± 26.48 %). Most importantly, we were unable to find long-lasting consequences in mice that received long-interval sevoflurane exposures. Our study provides novel insights regarding the significance of the interval between multiple exposures, and also suggests that the neurotoxic effects of multiple anesthetic exposures may be reduced by simply increasing the interval between each exposure.
Subject(s)
Anesthetics, Inhalation/toxicity , Behavior, Animal/drug effects , Neuronal Plasticity/drug effects , Sevoflurane/toxicity , Synaptic Transmission/drug effects , Anesthetics, Inhalation/administration & dosage , Animals , Animals, Newborn , Brain/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Sevoflurane/administration & dosage , Sex CharacteristicsABSTRACT
Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Circadian Rhythm/genetics , Circadian Rhythm/physiology , Ganglia, Spinal/physiology , Neuralgia/etiology , Neuralgia/physiopathology , Paclitaxel/adverse effects , ARNTL Transcription Factors , Animals , Circadian Rhythm/drug effects , Disease Models, Animal , Gene Expression , In Vitro Techniques , Mice , Period Circadian Proteins , Peripheral Nerve Injuries , Rats , Spinal Cord Dorsal Horn/physiologyABSTRACT
To evaluate the efficacy and feasibility of levonorgestrel-releasing intrauterine device (LNG-IUD) use longer than 5 years in women with adenomyosis.Data were retrospectively collected from patients who were treated with LNG-IUD longer than 5 years at the Chungnam National University hospital for adenomyosis diagnosed with ultrasonography from January 2006 to November 2013.A total of 131 patients who were diagnosed with adenomyosis had treated with LNG-IUD longer than 5 years. The mean duration of keeping 1 device without replacement was 58.35â±â15.98 months, and total duration of LNG-IUD treatment was 83.86â±â23.88 months. A total of 51 patients stopped using LNG-IUD after 5 years and the mean age at the time of LNG-IUD removal was 52.46â±â6.9. LNG-IUD treatment had a significant effect on both menorrhagia and dysmenorrhea starting from the first month of insertion (Pâ<â.01), which persisted until 6 years when the effect started to plateau. The decrease in uterine volume was not consistent during the treatment period. The uterine volume decreased significantly only in the first and second year of LNG-IUD treatment and then from eighth to tenth year of LNG-IUD treatment (Pâ<â.05). Adverse events after insertion of LNG-IUD decreased significantly after 5 years.LNG-IUD treatment longer than 5 years is an effective and feasible method for patients diagnosed with adenomyosis.
Subject(s)
Adenomyosis/drug therapy , Contraceptive Agents, Hormonal/administration & dosage , Intrauterine Devices, Medicated , Levonorgestrel/administration & dosage , Adenomyosis/pathology , Adult , Contraceptive Agents, Hormonal/adverse effects , Feasibility Studies , Female , Humans , Intrauterine Devices, Medicated/adverse effects , Levonorgestrel/adverse effects , Menorrhagia/drug therapy , Middle Aged , Organ Size , Pain Management , Retrospective Studies , Time Factors , Uterus/drug effects , Uterus/pathologyABSTRACT
Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.