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Background: Morphine analgesic tolerance (MAT) limits the clinical application of morphine in the management of chronic pain. IIK7 is a melatonin type 2 (MT2) receptor agonist known to have antioxidant properties. Oxidative stress is recognized as a critical factor in MAT. This study sought to assess the impact of IIK7 on the progression of MAT and its potential to reverse pre-existing MAT., Methods: Wistar rats underwent partial sciatic nerve transection (PSNT) surgery to induce neuropathic pain (NP). Seven days post nerve transection, we implanted an intrathecal (i.t.) catheter and linked it to an osmotic pump. Rats were randomly divided into the following groups: sham-operated/vehicle, PSNT/vehicle, PSNT/IIK7 50 ng/h, PSNT/MOR 15 g/h, and PSNT/MOR 15 g + IIK7 50 ng/h. We implanted two i.t. catheters for drug administration and the evaluation of the efficacy of IIK7 in reversing pre-established MAT. We linked one to an osmotic pump for MOR or saline continuous i.t. infusion. On the 7th day, the osmotic pump was disconnected, and 50 μg of IIK7 or the vehicle was administered through the second catheter. After 3 h, 15 μg of MOR or saline was administered, and the animal behavior tests were performed. We measured the levels of mRNA for Nrf2 and HO-1, pro-inflammatory cytokines (PICs), and the microglial and astrocyte activation in the spinal cord., Results: The co-administration of IIK7 with MOR delayed MAT development in PSNT rats by restoring Nrf2 and HO-1 while also inhibiting the microglial-cell and astrocyte activation, alongside the suppression of PICs. Additionally, a single injection of high-dose 50 μg IIK7 was efficient in restoring MOR's antinociception in MOR-tolerant rats., Conclusions: Our results indicate that the co-infusion of ultra-low-dose IIK7 can delay MAT development and a high dose can reverse pre-existing MAT.

Background : Delayed and failed fracture repair and bone healing remain significant public health issues. Dietary supplements serve as a safe, inexpensive, and non-surgical means to aid in different stages of fracture repair. Studies have shown that amorphous calcium carbonate (ACC) is absorbed 2 to 4.6 times more than crystalline calcium carbonate in humans. Objectives : In the present study, we assessed the efficacy of ACC on femoral fracture healing in a male Wistar rat model. Methods : Eighty male Wistar rats were randomly divided into five groups (n = six per group): sham, fracture + water, fracture + 0.5× (206 mg/kg) ACC, fracture + 1× ACC (412 mg/kg), and fracture + 1.5× (618 mg/kg) ACC, where ACC refers to the equivalent supplemental dose of ACC for humans. A 21-gauge needle was placed in the left femoral shaft, and we then waited for three weeks. After three weeks, the sham group of rats was left without fractures, while the remaining animals had their left mid-femur fractured with an impactor, followed by treatment with different doses of oral ACC for three weeks. Weight-bearing capacity, microcomputed tomography, and serum biomarkers were evaluated weekly. After three weeks, the rats were sacrificed, and their femur bones were isolated to conduct an evaluation of biomechanical strength and histological analysis. Results : Weight-bearing tests showed that treatment with ACC at all the tested doses led to a significant increase in weight-bearing capacity compared to the controls. In addition, microcomputed tomography and histological studies revealed that ACC treatment improved callus formation dose-dependently. Moreover, biomechanical strength was improved in a dose-dependent fashion in ACC-treated rats compared to the controls. In addition, supplementation with ACC significantly lowered bone formation and resorption marker levels two-three weeks post-fracture induction, indicating accelerated fracture recovery. Conclusions : Our preliminary data demonstrate that ACC supplementation improves fracture healing, with ACC-supplemented rats healing in a shorter time than control rats.

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats., Methods: Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated., Results: SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group., Conclusions: These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.

Background: The insufficient treatment of postoperative pain is considered a major barrier to enhanced patient recovery following surgery. Opioids remain the standard therapy for postoperative pain; however, the epidemic crisis of opioid abuse in the US has resulted in opioid-sparing multimodal analgesia (MMA) strategies in anesthesia practice. Complete perioperative pain management, particularly after discharge, may be undermined, resulting in chronic postsurgical pain. Thus, anesthesiologists and pain physicians should provide comprehensive MMA guidance for perioperative pain management., Methods: The Taiwan Pain Society organized a working group, which included experts in the field of anesthesia, pain, and surgery. This group performed an extensive literature search, quality review, and drafted a consensus, which was discussed by experts and edited for feedback. Recommendations covered consent instruction, treatment interventions, intramuscular injection techniques, and prophylaxis for postoperative adverse events., Results: This consensus included (1) a comparison of the pharmacology and pharmacokinetics between nalbuphine and dinalbuphine sebacate, (2) recommendations to help clinicians establish MMA with extended-release dinalbuphine sebacate injection, and (3) management of common adverse events during the perioperative pain period., Conclusion: Extended-release dinalbuphine sebacate combined with the MMA strategy can reduce the medical burden and improve the quality of recovery following surgery.

Background: Adherence to ethical guidelines and regulations and protecting and respecting the dignity and autonomy of participants by obtaining a valid informed consent form (ICF) prior to participation in research are crucial; The subjects did not add signatures next to the corrections made to signatures or dates on the ICF, Multiple signatures in other fields, ICF missing/missing signature, Incorrect ICF version Signed after modification, Correction tape used to correct signature, Impersonated signature, Non-research-member signature, however, ICFs are often not properly completed, which must be addressed. This study analyzed ICF signing errors and implemented measures to reduce or prevent these errors., Methods: We used the plan-do-check-act (PDCA) cycle to help improve the correctness and validity of ICF signing., Results: Interim and final reports from January 2016 to February 2020 including 363 ICFs were studied. The total proportion of correct ICF signatures (200, 83.3%) following the PDCA intervention was significantly higher than that before the intervention (P < 0.05). Analysis of the types of signing error demonstrated that signature errors were significantly reduced after the intervention, particularly for subjects did not add signatures next to the corrections made to signatures or dates on the ICF (16, 6.7%) and impersonated signature (0; P < 0.05)., Conclusions: The proportions of other error types-multiple signatures in other fields, missing or unsigned ICF, incorrect signature order, incorrect ICF version, use of correction tape to correct signature, and non-medical profession members signing the ICF-did not differ significantly., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Morphine (MOR) is a commonly prescribed drug for the treatment of moderate to severe diabetic neuropathic pain (DNP). However, long-term MOR treatment is limited by morphine analgesic tolerance (MAT). The activation of microglial cells and the release of glia-derived proinflammatory cytokines are known to play an important role in the development of MAT. In this study, we aimed to investigate the effects of the dipeptidyl peptidase-4 inhibitor (DPP-4i) teneligliptin (TEN) on MOR-induced microglial cell activation and MAT in DNP rats. DNP was induced in four groups of male Wistar rats through a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Sham rats were administered with the vehicle. Seven days after STZ injection, all rats were implanted with an intrathecal (i.t) catheter connected to a mini-osmotic pump, divided into five groups, and infused with the following combinations: sham + saline (1 µL/h, i.t), DNP + saline (1 µL/h, i.t), DNP + MOR (15 µg/h, i.t), DNP + TEN (2 µg/h, i.t), and DNP + MOR (15 µg/h, i.t) + TEN (2 µg/h, i.t) for 7 days at a rate of 1 μL/h. The MAT was confirmed through the measurement of mechanical paw withdrawal threshold and tail-flick tests. The mRNA expression of neuroprotective proteins nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the dorsal horn was evaluated by quantitative PCR (qPCR). Microglial cell activation and mononucleate cell infiltration in the spinal cord dorsal horn were assessed by immunofluorescence assay (IFA) and Western blotting (WB). The results showed that co-infusion of TEN with MOR significantly attenuated MAT in DNP rats through the restoration of neuroprotective proteins Nrf2 and HO-1 and suppression of microglial cell activation in the dorsal horn. Though TEN at a dose of 2 μg has mild antinociceptive effects, it is highly effective in limiting MAT.

Aim of the Study: In this study, we investigated the therapeutic potential of vitamin D (VITD) in OA Wistar rats induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT + MMx). In ACLT + MMx-induced OA rats, pain severity, cartilage destruction, inflammatory cytokines, and MMPs were all measured., Materials and Methods: ACLT + MMx methods were used to induce OA, and pain behavioral studies such as the weight bearing test and paw withdrawal test were performed while the knee width and body weights were also measured. Furthermore, Hematoxylin and Eosin (H&E) staining was used to determine knee histopathological studies, as well as OARSI scoring, cartilage thickness, cartilage width, and cartilage degradation scores. The enzyme-linked immunosorbent assay (ELISA) studies were used to check the serum levels of VITD, C-telopeptide of Type II collagen (CTX-II), and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-10 (IL-10), and MMPs (MMP-3, MMP-9, and MMP-13). Finally, the reverse transcription polymerase chain reaction (RT-PCR) test was used to determine the levels of MMPs, nuclear factor-kappa B (NF-κB), TNF-α, IL-6, and IL-10 in IL-1β stimulated chondrocytes., Results: The oral VITD supplement significantly reduced OA pain, inflammation, cartilage destruction, and MMPs levels. Furthermore, serum VITD levels increased while CTX-II levels decreased, indicating that VITD reduced cartilage degradation effectively. Moreover, VITD supplementation reduced the expression of pro-inflammatory TNF-α, IL-1β, and IL-6 cytokines while increasing the expression of anti-inflammatory IL-10. The elevation of MMPs after ACLT + MMx surgery contributed to articular cartilage destruction, which was reduced by VITD supplementation. Finally, VITD supplementation significantly reduces serum levels of MMPs, IL-1β, TNF-α, and IL-6 while increasing IL-10 levels. Then, using the in-vitro cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) MTT assay, examine the cytotoxicity profile of VITD in rat chondrocytes after stimulated with IL-1β, which shows no toxicity in the dose range of VITD 0-500 IU. Finally, RT-PCR studies in IL-1β stimulated rat chondrocytes revealed that VITD (50, 100, and 500 IU) significantly reduced the mRNA levels of MMPs, NF-κB, TNF-α, and IL-6, while increasing IL-10 levels, indicating that VITD reduced chondrocyte destruction and overcame harsh conditions in a dose-dependent manner., Conclusion: Overall, the in vivo and in vitro findings show that VITD effectively reduces OA pain, inflammation, and chondrocyte destruction by lowering MMPs levels specifically., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Published by Elsevier Ltd.)

Background: The NALDEBAIN® has been available since 2017, and high incidence of injection reactions in the phase 3 study has been reported. Since the first year in the market, the injection site reactions were still the majority of adverse drug reactions (ADRs) in pharmacovigilance reports. The new intramuscular (IM) instruction and package was introduced in the middle of 2018. In this retrospective study, we analyzed the pharmacovigilance data and published postmarketing studies to investigate the impact of IM injection-related reactions in Taiwan between the period of 2017-2022., Methods: Individual case safety reports (ICSRs) and ADRs were classified by system organ class and preferred term. The reporting rate of ICSRs was used to evaluate the impact of the new IM instruction and package., Results: A total of 37 ICSRs were identified from pharmacovigilance reports. Among them, 51% of IM injection-related reactions were reported after one single dose of NALDEBAIN administration. The reporting rate of IM injection-related reactions in pharmacovigilance data dropped from 125.00 to 3.56 per ten thousand exposures after IM instruction and package revision in 2018. In addition, the percentage of IM injection-related reactions also reduced in postmarketing studies from 27.5% to 4.5%. There were no serious IM injection-related reactions found in the pharmacovigilance and postmarketing dataset., Conclusion: Injection site reactions were common after intramuscularly administered oil-based agents during the first year which is later markedly reduced by changing the length of the needle and injection education.

Sugammadex is a direct reversal agent of aminosteroid muscle relaxants, particularly rocuronium, with promptly and completely reverse of deep neuromuscular block (NMB), which allows better surgical conditions. Sugammadex exhibits advantages over indirect reversal agent acetylcholinesterase inhibitor neostigmine with less adverse effects. In this retrospective review, we compared the incidence of postoperative vomiting (POV), postoperative urinary retention (POUR), and hemodynamic changes between sugammadex and neostigmine/glycopyrrolate in reversal of muscular blockade. Sugammadex showed superior in all three aspects. The heart rate was 7.253 lower (P < 0.0001) and mean arterial pressure was 5.213 lower (P < 0.0001) in sugammadex group. The POV of neostigmine/glycopyrrolate group was 3.16 times more than sugammadex group (OR = 3.16, p < 0.0001), and POUR of neostigmine/glycopyrrolate group was 4.291 times more than sugammadex group (OR = 4.291, p < 0.0001). Sugammadex showed better hemodynamic stability, and lower incidence of POV and POUR than neostigmine/glycopyrrolate., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

BACKGROUND Incomplete recovery from residual neuromuscular block agent (NMBA) after anesthesia is a serious adverse event in the post-anesthesia care unit. Acetylcholinesterase neostigmine is usually used to reverse residual neuromuscular blockade and facilitate spontaneous breathing and endotracheal extubation. CASE REPORT A 40-year-old woman received general anesthesia for strabismus correction surgery. At the end of surgery, repeated doses of neostigmine up to 85 µg/kg failed to reverse the residual neuromuscular blockade (train-of-four [TOF] ratio below 21%). Sugammadex (200 mg) provided immediate reversal, with the TOF ratio up to 100%. The patient regained spontaneous breathing, and the endotracheal tube was removed. After surgery, myasthenia gravis was diagnosed. CONCLUSIONS When unexpected prolonged neuromuscular blockade presents, the TOF ratio should be used to detect its depth and guide a reasonable dose of reversal agents. Anticholinesterase has a ceiling effect; once acetylcholinesterase activity is fully inhibited, administration of additional anticholinesterase can result in no further recovery. Furthermore, excessive acetylcholine can cause muscle weakness. In contrast, sugammadex is a selective reversal agent for steroidal NMBA, which works by encapsulation via tight water-soluble complexes with amino steroids (eg, rocuronium) rather than increasing acetylcholine at the neuromuscular junction. In this case, the recovery from moderate neuromuscular blockade by sugammadex was more effective and rapid than that by neostigmine. When refractory and prolonged residual neuromuscular blockade presents after repeated doses of anticholinesterase, sugammadex should be considered as an effective reversal agent. Particularly in cases of myasthenia gravis, sugammadex is superior to neostigmine for reversing rocuronium-induced NMBA in patients undergoing surgery.

The most common joint disease in the elderly is knee osteoarthritis (OA). It is distinguished by cartilage degradation, subchondral bone loss, and a decrease in joint space. We studied the effects of carnosine (CA) on knee OA in male Wistar rats. OA is induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) method and in vitro studies are conducted in fibroblast-like synoviocyte cells (FLS). The pain was assessed using weight-bearing and paw-withdrawal tests. CA supplementation significantly reduced pain. The enzyme-linked immunosorbent assay (ELISA) method was used to detect inflammatory proteins in the blood and intra-articular synovial fluid (IASF), and CA reduced the levels of inflammatory proteins. Histopathological studies were performed on knee-tissue samples using toluidine blue and hematoxylin and eosin (H and E) assays. CA treatment improved synovial protection and decreased cartilage degradation while decreasing zonal depth lesions. Furthermore, Western blotting studies revealed that the CA-treated group activated nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) and reduced the expression of cyclooxygenase-2 (COX-2). FLS cells were isolated from the knee joints and treated with IL-1β to stimulate the inflammatory response and increase reactive oxygen species (ROS). The matrix metalloproteinase protein (MMP's) levels (MMP-3, and MMP-13) were determined using the reverse transcription-polymerase chain reaction (RT-PCR), and CA treatment reduced the MMP's expression levels. When tested using the 2',7'-dicholorodihydrofluroscene diacetate (DCFDA) assay and the 5,5',6,6'-tetracholoro-1,1',3,3'-tertraethylbenzimidazolcarboc janine iodide (JC-1) assay in augmented ROS FLS cells, CA reduced the ROS levels and improved the mitochondrial membrane permeability. This study's investigation suggests that CA significantly alleviates knee OA both in vitro and in vivo.

Introduction: Patients undergoing upper extremity fracture surgery (UEFS) commonly suffer from unbearable acute pain. Opioids remain the mainstay of moderate to severe pain alleviation, although there is a growing concern regarding the increasing trend in misuse and abuse. This study aimed to observe the safety and efficacy of dinalbuphine sebacate (DS), a novel extended-release analgesic, along with multimodal analgesia (MMA) for post-UEFS pain control., Methods: We retrospectively reviewed the records of patients undergoing UEFS between August 2020 and January 2021. Eligible patients were included and divided into two groups, depending on the analgesic regimen. In the DS group, 150 mg DS was administered intramuscularly at least 12 h pre-operatively, while in the conventional analgesia (CA) group, 40 mg parecoxib was given within 3 h before surgery. Intraoperative fentanyl administration was guided by the Analgesia Nociception Index System in both groups. For breakthrough pain, fentanyl was used as rescue medicine in the postanaesthesia care unit while tramadol and parecoxib were administered in the ward., Results: Forty-nine patients were allocated to the DS group and 60 patients were allocated to the CA group. In comparison with the CA group, the proportion of patients requiring opioids for breakthrough pain post-operatively was significantly lower in the DS group (fentanyl: 31% vs. 68%, p < 0.001; tramadol: 27% vs. 70%, p < 0.001). The DS group also consumed lower amounts of post-operative rescue opioids. Furthermore, both mean worst and least pain scores were significantly lower in the DS group from post-operative day (POD) 1 to POD 5. There was no significant difference in intraoperative consumption of fentanyl or incidence of adverse events., Conclusion: This result suggests that extended-release DS is a suitable analgesic incorporated in MMA and a promising solution to the misuse and abuse of opioids., (© 2022. The Author(s).)

Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Busa, Kuthati, Huang and Wong.)

Objective: The current therapeutic strategy for posttraumatic osteoarthritis (PTOA) focuses on early intervention to attenuate disease progression, preserve joint function, and defer joint replacement timing. Sequential transcriptomic changes of articular cartilage in a rat model were investigated to explore the molecular mechanism in early PTOA progression., Design: Anterior cruciate ligament transection and medial meniscectomy (ACLT + MMx)-induced PTOA model was applied on male Wistar rats. Articular cartilages were harvested at time 0 (naïve), 2 week, and 4 weeks after surgery. Affymetrix Rat genome 230 2.0 array was utilized to analyze the gene expression changes of articular cartilages., Results: We identified 849 differentially expressed genes (DEGs) at 2 weeks and 223 DEGs at 4 weeks post-ACLT + MMx surgery compared with time 0 (naïve group). Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to gain further insights from these DEGs. 22 novel genes and 1 novel KEGG pathway (axon guidance) in cartilage degeneration of osteoarthritis were identified. Axon guidance molecules- Gnai1, Sema4d, Plxnb1 , and Srgap2 commonly dysregulated in PTOA progression. Gnai1 gene showed a concordant change in protein expression by immunohistochemistry staining., Conclusions: Our study identified 22 novel dysregulated genes and axon guidance pathway associated with articular cartilage degeneration in PTOA progression. These findings provide the potential candidates of biomarkers and therapeutic targets for further investigation.

There have been immense advances in the safety and variety of intravenous anesthetic delivery systems including drug cost reduction, development of more effective opioids, and improvement in depth of anesthesia monitoring in the last 20 years. Propofol-based total intravenous anesthesia (TIVA) with target-controlled infusion (TCI) is relatively easy to practice. While this technique promotes a higher overall anesthesia quality and patient survival, especially for cancer patients, there are deficiencies in training and education of the technique. Therefore, the Society for Intravenous Anesthesia and the Association of Anesthetists (United Kingdom) have laid out guidelines in an attempt to highlight multiple important TIVA-related safety issues to help clinicians feel more confident. In the present article, we discuss five recommendations and four special clinical situations. Preparation, equipment familiarity, and safe delivery techniques are extremely important for the proper employment of this method. Herein, we emphasize the importance of proper education, and the clinical practice experience of the TIVA technique. Additionally, we suggest a modified connection method to set up a safely administered line. We highlight the advantages of using processed electroencephalogram monitoring (such as bispectral index or Entropy) to prevent awareness during TIVA administration in difficult clinical situations. These situations may include triple low patients (e.g., low blood pressure, low maintained effect-site concentration of propofol, and low body weight ≤ 18), obese patients, and patients with difficult infusion site monitoring or use of neuromuscular blocking agents. Due to a limited consensus among Taiwanese medical professionals, this document is intended to act as a safe practice reference for the use of TIVA with TCI. Additionally, two pithy formula codes, 4321 for propofol with fentanyl/alfentanil and 42222111 for propofol with remifentanil, are provided for the general population and one pithy formula code, 4321 for propofol with fentanyl, is provided for pediatric patients.

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Neuropathic pain (NP), is a chronic pain resulting from nerve injury, with limited treatment options. Teneligliptin (TEN) is a dipeptidyl peptidase-4 inhibitor (DPP-4i) approved to treat type 2 diabetes. DPP-4is prevent the degradation of the incretin hormone glucagon-like peptide 1 (GLP-1) and prolong its circulation. Apart from glycemic control, GLP-1 is known to have antinociceptive and anti-inflammatory effects. Herein, we investigated the antinociceptive properties of TEN on acute pain, and partial sciatic nerve transection (PSNT)-induced NP in Wistar rats. Seven days post PSNT, allodynia and hyperalgesia were confirmed as NP, and intrathecal (i.t) catheters were implanted and connected to an osmotic pump for the vehicle (1 μL/h) or TEN (5 μg/1 μL/h) or TEN (5 μg) + GLP-1R antagonist Exendin-3 (9-39) amide (EXE) 0.1 μg/1 μL/h infusion. The tail-flick response, mechanical allodynia, and thermal hyperalgesia were measured for 7 more days. On day 14, the dorsal horn was harvested and used for Western blotting and immunofluorescence assays. The results showed that TEN had mild antinociceptive effects against acute pain but remarkable analgesic effects against NP. Furthermore, co-infusion of GLP-1R antagonist EXE with TEN partially reversed allodynia but not tail-flick latency. Immunofluorescence examination of the spinal cord revealed that TEN decreased the immunoreactivity of glial fibrillary acidic protein (GFAP). Taken together, our findings suggest that TEN is efficient in attenuation of PSNT-induced NP. Hence, the pleiotropic effects of TEN open a new avenue for NP management.

Oxidative stress resulting from reactive oxygen species (ROS) is known to play a key role in numerous neurological disorders, including neuropathic pain. Morphine is one of the commonly used opioids for pain management. However, long-term administration of morphine results in morphine antinociceptive tolerance (MAT) through elevation of ROS and suppression of natural antioxidant defense mechanisms. Recently, mesoporous polydopamine (MPDA) nanoparticles (NPS) have been known to possess strong antioxidant properties. We speculated that morphine delivery through an antioxidant nanocarrier might be a reasonable strategy to alleviate MAT. MPDAs showed a high drug loading efficiency of ∼50%, which was much higher than conventional NPS. Spectral and in vitro studies suggest a superior ROS scavenging ability of NPS. Results from a rat neuropathic pain model demonstrate that MPDA-loaded morphine (MPDA@Mor) is efficient in minimizing MAT with prolonged analgesic effect and suppression of pro-inflammatory cytokines. Additionally, serum levels of liver enzymes and levels of endogenous antioxidants were measured in the liver. Treatment with free morphine resulted in elevated levels of liver enzymes and significantly lowered the activities of endogenous antioxidant enzymes in comparison with the control and MPDA@Mor-treated group. Histopathological examination of the liver revealed that MPDA@Mor can significantly reduce the hepatotoxic effects of morphine. Taken together, our current work will provide an important insight into the development of safe and effective nano-antioxidant platforms for neuropathic pain management.

Human placenta-derived multipotent stem cells (PDMCs) resembling embryonic stem cells can differentiate into three germ layer cells, including ectodermal lineage cells, such as neurons, astrocytes, and oligodendrocytes. The favorable characteristics of noninvasive cell harvesting include fewer ethical, religious, and legal considerations as well as accessible and limitless supply. Thus, PDMCs are attractive for cell-based therapy. The Schwann cell (SC) is the most common cell type used for tissue engineering such as nerve regeneration. However, the differentiation potential of human PDMCs into SCs has not been demonstrated until now. In this study, we evaluated the potential of PDMCs to differentiate into SC-like cells in a differentiation medium. After induction, PDMCs not only exhibited typical SC spindle-shaped morphology but also expressed SC markers, including S100, GFAP, p75, MBP, and Sox 10, as revealed by immunocytochemistry. Moreover, a reverse transcription-quantitative polymerase chain reaction analysis revealed the elevated gene expression of S100, GFAP, p75, MBP, Sox-10, and Krox-20 after SC induction. A neuroblastoma cell line, SH-SY5Y, was cultured in the conditioned medium (CM) collected from PDMC-differentiated SCs. The growth rate of the SH-SY5Y increased in the CM, indicating the function of PDMC-induced SCs. In conclusion, human PDMCs can be differentiated into SC-like cells and thus are an attractive alternative to SCs for cell-based therapy in the future.

Exposure to general anesthesia has been reported to induce neurotoxicity, impair learning, memory, attention, motor functions, as well as affect behavior in adult rodents and nonhuman primates. Though many have speculated similar effects in humans, previous literature has shown conflicting findings. To investigate the differences in risk of developmental delay among young children exposed to general anesthesia compared to matched unexposed individuals, a population-based cohort study was conducted with a longitudinal dataset spanning 2000 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD). Procedure codes were used to identify children who received anesthesia. For each exposed child, two unexposed children matched by gender and age were enrolled into the comparison cohort. Neurocognitive outcome was measured by the presence of ICD-9-CM codes related to developmental delay (DD). Cox regression models were used to obtain hazard ratios of developing DD after varying levels of anesthesia exposure. After excluding 4,802 individuals who met the exclusion criteria, a total of 11,457 children who received general anesthesia before two years of age was compared to 22,914 children (matched by gender and age) unexposed to anesthesia. Increased risk of DD was observed in the exposure group with a hazard ratio (HR) of 1.320 (95% CI 1.143-1.522, P < 0.001). Subgroup analysis demonstrated further elevated risks of DD with multiple anesthesia exposures (1 anesthesia event: HR 1.145, 95% CI 1.010-1.246, P = 0.04; 2 anesthesia events: HR 1.476, 95% CI 1.155-1.887, P = 0.005; ≥3 anesthesia events: HR 2.222, 95% CI 1.810-2.621, P < 0.001) and longer total anesthesia durations (Total anesthesia <2 hours: HR 1.124, 95% CI 1.003-1.499, P = 0.047; Total anesthesia 2-4 hours: HR 1.450, 95% CI 1.157-1.800, P = 0.004; Total anesthesia > 4 hours: HR 1.598, 95% CI 1.343-1.982, P < 0.001) compared with children unexposed to anesthesia. These results suggest that children exposed to general anesthesia before two years of age have an increased risk of DD. This risk is further elevated with increased frequency of anesthesia, and longer total anesthesia duration. The findings of this study should prompt clinical practitioners to proceed with caution when assessing young patients and planning managements involving procedures requiring general anesthesia., Competing Interests: The authors have declared that no competing interests exist.

Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment., Methods: Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression., Results: constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats., Conclusion: Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.

Background: Reducing anesthesia-controlled time (ACT) such as extubation time may improve operation room (OR) efficiency result from different anesthetic techniques. However, the information about the difference in ACT between desflurane (DES) anesthesia and propofol-based total intravenous anesthesia (TIVA) techniques for open liver resection under general anesthesia is not available in the literature., Methods: This retrospective study uses our hospital database to analyze the ACT of open liver resection after either DES/fentanyl-based anesthesia or TIVA via target-controlled infusion (TCI) with fentanyl/propofol from January 2010 to December 2011. The various time intervals including waiting for anesthesia time, anesthesia time, surgical time, extubation time, exit from OR after extubation, total OR time, and post-anesthetic care unit stay time and percentage of prolonged extubation (≥ 15 minutes) were compared between the two anesthetic techniques., Results: We included 143 hepatocellular carcinoma patients, with 82 patients receiving TIVA and 61 patients receiving DES. The extubation time was faster (10.1 ± 3.2 min vs. 11.8 ± 5.2 min; P = 0.03), and the incidence of prolonged extubation was lower (9.8% vs. 26.8%; P = 0.02) in the DES group than in the TIVA group. The factors contributed to prolonged extubation were age, sex, anesthetic technique, and anesthesia time., Conclusion: The DES anesthesia provided faster extubation time and lower incidence of prolonged extubation compared with propofol-based TIVA by TCI in elective open liver resection. Besides, older age, male, TIVA, and lengthy anesthesia time were factors affecting prolonged extubation.

Neuropathic pain, resulting from the dysfunction of the peripheral and central nervous system, occurs in a variety of pathological conditions including trauma, diabetes, cancer, HIV, surgery, multiple sclerosis, ischemic attack, alcoholism, spinal cord damage, and many others. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. The clinical failure of most effective drugs is often not due to a lack of drug efficacy but due to the dose-limiting central nervous system (CNS) toxicity of the drugs that preclude dose escalation. There is a need for cross-disciplinary collaborations to meet these challenges. In this regard, the integration of nanotechnology with neuroscience is one of the most important fields. In recent years, promising preclinical research has been reported in this field. This review highlights the current challenges associated with conventional neuropathic pain treatments, the scope for nanomaterials in delivering drugs across the blood-brain barrier, and the state and prospects of nanomaterials for the management of neuropathic pain.

Osteoarthritis (OA) progression is associated with joint pain and stiffness. Intra-articular hyaluronic acid (IAHA) injection in knee OA restores the viscoelasticity of the joint and prevents cartilage damage. Shea nut oil extract (SNO) was shown to provide chondroprotection on surgically-induced OA progression in rats. Here we aim to examine IAHA injection supplemented with SNO diet for a synergetic evaluation on the disease progression in OA rats. We employed an anterior cruciate ligament transection plus medial meniscectomy-induced knee OA rat model with up to 12 weeks of sign/behavior observation (knee width, weight-bearing) and histological assessments of joint damage. We found both IAHA and SNO alone significantly attenuated histological changes of cartilage degeneration and synovial reactions in these knee OA rats. Nonetheless, oral SNO alone mitigated OA pain and inflammation while IAHA alone had no significant impact on the weight-bearing test and knee joint swelling. Moreover, with IAHA-treated rats fed with oral SNO diet, additional anti-inflammatory and anti-nociceptive effects were found, which further enhanced and maintained IAHA protection. Given the differential phenotype of oral SNO vs. IAHA, a regimen of IAHA coupled with SNO supplement provides a long-term effect of IAHA treatment. Taken together, the SNO supplement can be safely used as an adjuvant diet for chronic symptomatic relief of OA coupled with IAHA management.

Statins are a therapeutic drug with reducing plasma cholesterol levels and have been linked with potential antitumor effects. However, epidemiological studies on statin use and renal cell carcinoma (RCC) risk have been inconsistent. This cohort study aimed to examine this association in an Asian population. We identified patients who filled initial prescriptions for statins in the inpatient and ambulatory care order files from Taiwan's National Health Insurance Research Database between January 1, 1998 and December 31, 2005 as the statin users cohort (n=14,067). The comparison cohort comprised of patients who had not taken any statin in the previous years prior to January 1, 1998 or had used statins for less than 28 cumulative defined daily doses between January 1, 1998 and December 31, 2005 (n=56 268). The outcome of interest was pathologically verified RCC occurred between January 1, 1999 and December 31, 2013. The Fine-Gray competing risk model was fitted to estimate HRs accompanying 95% CI. Patients with the use of statins had a significantly lower risk of RCC as compared with the non-users cohort, yielding an adjusted HR of 0.64 (95% CI, 0.38 to 0.87). Moreover, we found a significant inverse association between cumulative statin use and the risk of RCC. Further, the inverse association between statin use and risk of RCC was evident in both sexes. This population-based cohort study provides longitudinal evidence that the use of statins was associated with a reduced risk of RCC., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Reactive oxygen species (ROS) induced oxidative stress is linked to numerous neurological diseases, including neuropathic pain. Natural ROS scavenging enzymes like superoxide dismutase (SOD) and catalase have been found to be efficient in alleviating neuropathic pain. However, their sensitivity towards extreme pH and a short half-life limit their efficacy in vivo. Manganese oxide nanoparticles (MONPs) are recently known to possess ROS scavenging properties. In this study, MONPs were examined for their therapeutic effect on neuropathic pain., Methods: The MONPs were synthesized by a hydrothermal method. The synthesized MONPs were characterized by UV/Vis, TEM, SEM, FTIR, NTA and XRD. The biocompatibility of the nanoparticles is evaluated in neural cells using LDH assay. MONPs were evaluated for their antioxidant activity by DPPH assay. In addition, in vitro ROS scavenging properties were examined in bone marrow-derived macrophage (BMDM) cells using 2',7'-dichlorofluorescin diacetate (DCFDA) assay. To evaluate the in vivo efficacy of nanoparticles, neuropathic pain was induced in Wistar rats by partial sciatic nerve transection (PSNT). On post-transection days 14 to 18, rats were intrathecally injected with MONPs and paw withdrawal threshold was measured. The spinal cords were collected and processed for Western blotting and histological analysis., Results: The synthesized MONPs were biocompatible and showed effective antioxidant activity against DPPH free radical scavenging. Further, the nanoparticles scavenged ROS efficiently in vitro in BMDM and their intrathecal administration significantly reduced mechanical allodynia as well as the expression of cyclooxygenase-2 (COX-2), an important mediator of chronic and inflammatory pain in the spinal dorsal horns of PSNT rats., Conclusion: As ROS play a significant role in neuropathic pain, we expect that MONPs could be a promising tool for the treatment of various inflammatory diseases and might also serve as a potential nanocarrier for the delivery of analgesics., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Kuthati et al.)

Background: Breast cancer is the most common cancer in women and several perioperative factors may account for tumor recurrence and metastasis. The anesthetic agents employed during cancer surgery might play a crucial role in cancer cell survival and patient outcomes. We conducted a retrospective cohort study to investigate the relationship between the type of anesthesia and overall survival in patients who underwent breast cancer surgery performed by one experienced surgeon., Methods: All patients who underwent breast cancer surgery by an experienced surgeon between January 2006 and December 2010 were included in this study. Patients were separated into two groups according to the use of desflurane or propofol anesthesia during surgery. Locoregional recurrence and overall survival rates were assessed for the two groups (desflurane or propofol anesthesia). Univariable and multivariable Cox regression models and propensity score matching analyses were used to compare the hazard ratios for death and adjust for potential confounders (age, body mass index, American Society of Anesthesiologists physical status classification, TNM stage, neoadjuvant chemotherapy, Charlson Comorbidity Index, anesthesiologists, and functional status)., Results: Of the 976 breast cancer patients, 632 patients underwent breast cancer surgery with desflurane anesthesia, while 344 received propofol anesthesia. After propensity scoring, 592 patients remained in the desflurane group and 296 patients in the propofol group. The mortality rate was similar in the desflurane (38 deaths, 4%) and propofol (22 deaths, 4%; p = 0.812) groups in 5-year follow-up. The crude hazard ratio (HR) for all patients was 1.13 (95% confidence interval [CI] 0.67-1.92, p = 0.646). No significant difference in the locoregional recurrence or overall 5-year survival rates were found after breast surgery using desflurane or propofol anesthesia (p = 0.454). Propensity score-matched analyses demonstrated similar outcomes in both groups. Patients who received propofol anesthesia had a higher mortality rate than those who received desflurane anesthesia in the matched groups (7% vs 6%, respectively) without significant difference (p = 0.561). In the propensity score-matched analyses, univariable analysis showed an insignificant finding (HR = 1.23, 95% CI 0.72-2.11, p = 0.449). After adjustment for the time since the earliest included patient, the HR remained insignificant (HR = 1.23, 95% CI 0.70-2.16, p = 0.475)., Conclusion: In our non-randomized retrospective analysis, neither propofol nor desflurane anesthesia for breast cancer surgery by an experienced surgeon can affect patient prognosis and survival. The influence of propofol anesthesia on breast cancer outcome requires further investigation., Competing Interests: The authors have declared that no competing interests exist.

Background: In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown., Objective: To investigate the effect of melatonin type 2 receptor agonist IIK-7 on partial sciatic nerve transection-induced NP in rats and elucidate the underlying molecular mechanisms., Methods: NP was induced by the PSNT in the left leg of adult male Wistar rats. On post-transection day 7, rats were implanted with intrathecal (i.t) catheter connected to an infusion pump and divided in to four groups: sham-operated/vehicle, PSNT/vehicle, PSNT/0.5 μg/hr IIK-7 and PSNT/0.5 μg IIK-7/1 μg 4-p/hr. To test the MT-2 dependence on IIK-7 activity, the animals were implanted with a single i.t catheter and injected MT-2 antagonist 4-Phenyl-2-propionamidotetralin (4-p) 20 mins prior to IIK-7 injection on day 7 after PSNT. The antinociceptive response was measured using a mechanical paw withdrawal threshold. Activation of microglial cells and the expression of NP-associated proteins in the spinal cord dorsal horn was assessed by immunofluorescence assay (IFA) and Western blotting (WB). Reactive oxygen species (ROS) scavenging ability of IIK-7 was evaluated by using bone marrow-derived macrophages (BMDM)., Results: Treatment with the MT-2 agonist IIK-7 significantly alleviated PSNT-induced mechanical allodynia and glial activation along with the inhibition of P44/42 MAPK, HMGB-1, STAT3, iNOS and casp-3 proteins., Conclusion: IIK-7 attenuates NP through the suppression of glial activation and suppression of proteins involved in inflammation and apoptosis. MT-2 receptor agonists may establish a promising and unique therapeutic approach for the treatment of NP., Competing Interests: The authors report no conflicts of interest in this work.

Background: Previous studies have shown that anaesthetic technique can affect outcomes of cancer surgery. We investigated the association between anaesthetic technique and patient outcomes after elective hepatectomy for hepatocellular carcinoma., Methods: This was a retrospective single-centre cohort study of patients who received elective hepatectomy for hepatocellular carcinoma from January 2005 to December 2014. Patients were grouped according to propofol or desflurane anaesthesia. Kaplan-Meier analysis was performed and survival curves were constructed from the date of surgery to death. After propensity matching, univariable and multivariable Cox regression models were used to compare hazard ratios for death. Subgroup analyses were performed for tumour-node-metastasis staging and distant metastasis and local recurrence., Results: A total of 492 patients (369 deaths, 75.0%) with desflurane anaesthesia and 452 (139 deaths, 30.8%) with propofol anaesthesia were eligible for analysis. After propensity matching, 335 patients remained in each group. In the matched analysis, propofol anaesthesia had a better survival with hazard ratio of 0.47 (95% confidence interval, 0.38-0.59; P<0.001). Subgroup analyses also showed significantly better survival in the absence of distant metastasis (hazard ratio, 0.47; 95% confidence interval, 0.37-0.60; P<0.001) or local recurrence (hazard ratio, 0.22; 95% confidence interval, 0.14-0.34; P<0.001) in the matched groups., Conclusions: Propofol anaesthesia was associated with better survival in hepatocellular carcinoma patients who underwent hepatectomy. Prospective studies are warranted to evaluate the effects of propofol anaesthesia on surgical outcomes in hepatocellular carcinoma patients., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Melatonin (N-acetyl-5-methoxytryptamine), secreted by the pineal gland is known to perform multiple functions including, antioxidant, anti-hypertensive, anti-cancerous, immunomodulatory, sedative and tranquilizing functions. Melatonin is also known to be involved in the regulation of body mass index, control the gastrointestinal system and play an important role in cardioprotection, thermoregulation, and reproduction. Recently, several studies have reported the efficacy of Melatonin in treating various pain syndromes. The current paper reviews the studies on Melatonin and its analogs, particularly in Neuropathic pain. Here, we first briefly summarized research in preclinical studies showing the possible mechanisms through which Melatonin and its analogs induce analgesia in Neuropathic pain. Second, we reviewed research indicating the role of Melatonin in attenuating analgesic tolerance. Finally, we discussed the recent studies that reported novel Melatonin agonists, which were proven to be effective in treating Neuropathic pain., (Copyright © 2018. Published by Elsevier B.V.)

Osteoarthritis (OA) is a multifactorial joint disease and a common disabling condition in the elderly population. The associated pain and pathohistological changes in cartilage are common features of OA in both humans and animal models. Shea nut oil extract (SheaFlex75) contains a high triterpenoid concentration and has demonstrated anti-inflammatory and antiarthritic effects in both human and animal studies. In this study, we aim to investigate the potential of SheaFlex75 to prevent articular cartilage deterioration in a rat model of chronic OA progression. By employing anterior cruciate ligament transection (ACLT) with medial meniscectomy (MMx)-induced OA, we found attenuation of both early and chronic onset OA pain and cartilage degeneration in ACLT+MMx rats receiving SheaFlex75 dietary supplementation. Under long-term oral administration, the rats with induced OA presented sustained protection of both pain and OA cartilage integrity compared to the OA-control rats. Moreover, rats subjected to long-term SheaFlex75 ingestion showed normal biochemical profiles (AST, BUN and total cholesterol) and presented relatively lower triglycerides (TGs) and body weights than the OA-control rats, which suggested the safety of prolonged use of this oil extract. Based on the present evidence, preventive management is advised to delay/prevent onset and progression in OA patients. Therefore, we suggest that SheaFlex75 may be an effective management strategy for symptom relief and cartilage protection in patients with both acute and chronic OA., Competing Interests: The authors were contracted by Universal Integrated Corp., a commercial company located in Taipei, Taiwan, to study the effect of the product SheaFlex75 on their well-established OA animal model, ACLT plus MMx. Additionally, neither we nor any of our team members received any extra financial support outside of that stated in the Financial Disclosure, and none of our research team members are company consultants or own patents and benefits from the product’s sales. There are no products in development to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

We investigated effects of magnesium sulfate (MgSO 4 ) on modulating lipopolysaccharide (LPS)-macrophage binding and cluster of differentiation 14 (CD14) expression. Flow cytometry data revealed that the mean levels of LPS-macrophage binding and membrane-bound CD14 expression (mCD14) in differentiated THP-1 cells (a human monocytic cell line) treated with LPS plus MgSO 4 (the LPS + M group) decreased by 28.2% and 25.3% compared with those THP-1 cells treated with LPS only (the LPS group) (P < 0.001 and P = 0.037), indicating that MgSO 4 significantly inhibits LPS-macrophage binding and mCD14 expression. Notably, these effects of MgSO 4 were counteracted by L-type calcium channel activation. Moreover, the mean level of soluble CD14 (sCD14; proteolytic cleavage product of CD14) in the LPS + M group was 25.6% higher than in the LPS group (P < 0.001), indicating that MgSO 4 significantly enhances CD14 proteolytic cleavage. Of note, serine protease inhibition mitigated effects of MgSO 4 on both decreasing mCD14 and increasing sCD14. In conclusion, MgSO 4 inhibits LPS-macrophage binding through reducing CD14 expression. The mechanisms may involve antagonizing L-type calcium channels and activating serine proteases.

Background: As reported, patients experience less postoperative pain after propofol-based total intravenous anesthesia (TIVA). In the present study, we investigated the postoperative analgesic effects between propofol-based TIVA and desflurane anesthesia after spine surgery., Methods: Sixty patients were included who received (surgical time >180 minutes) lumbar spine surgery. Patients were randomly assigned to receive either TIVA (with target-controlled infusion) with propofol/fentanyl-based anesthesia (TIVA group) or desflurane/fentanyl-based anesthesia (DES group), titrated to maintain Bispectral Index values between 45 and 55. All patients received patient-controlled analgesia (PCA) with fentanyl for postoperative pain relief. Numeric pain rating scale (NRS) pain scores, postoperative fentanyl consumption, postoperative rescue tramadol use, and fentanyl-related side effects were recorded., Results: The TIVA group patients reported lower NRS pain scores during coughing on postoperative day 1 but not day 2 and 3 (P = .002, P = .133, P = .161, respectively). Less fentanyl consumption was observed on postoperative days 1 and 2, but not on day 3 (375 μg vs 485 μg, P = .032, 414 μg vs 572 μg, P = .033, and 421 μg vs 479 μg, P = .209, respectively), less cumulative fentanyl consumption at postoperative 48 hours (790 μg vs 1057 μg, P = .004) and 72 hours (1210 μg vs 1536 μg, P = .004), and total fentanyl consumption (1393 μg vs 1704 μg, P = .007) when compared with the DES group. No difference was found in rescue tramadol use and fentanyl-related side effects., Conclusion: Patients anesthetized with propofol-based TIVA reported less pain during coughing and consumed less daily and total PCA fentanyl after lumbar spine surgery.

Tolerance and associated hyperalgesia induced by long‑term morphine administration substantially restrict the clinical use of morphine in pain treatment. Melatonin, a neurohormone released by the pineal gland, has been demonstrated to attenuate anti‑nociceptive morphine tolerance. The present study investigates differentially expressed genes in the process of morphine tolerance and altered gene expression subsequent to melatonin treatment in chronic morphine‑infused ratspinal cords. Morphine tolerance was induced in male Wistar rats by intrathecal morphine infusion (the MO group). Melatonin (the MOMa group) was administered to overcome the effects derived by morphine. The mRNA collected from L5‑S3 of the spinal cord was extracted and analysed by rat expression microarray. Principal component analysis and clustering analysis revealed that the overall gene profiles were different in morphine and melatonin treatments. Subsequent to Gene Ontology analysis, the biological processes of differentially expressed genes of MO and MOMa compared with the control group were constructed. Furthermore, a panel of genes exclusively expressed following melatonin treatment and another panel of genes with inverse expression between the MO and MOMa group were also established. Subsequent to PANTHER pathway analysis, a group of genes with inverse expression following melatonin administrated compared with morphine alone were identified. The expression levels of genes of interest were also confirmed using a reverse transcription‑quantitative polymerase chain reaction. The gene panel that was constructed suggests a potential signaling pathway in morphine tolerance development and is valuable for investigating the mechanism of morphine tolerance and the regulatory gene profiles of melatonin treatment. These results may contribute to the discovery of potential drug targets in morphine tolerance treatments in the future.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Previous research has shown different effects of anesthetics on cancer cell growth. Here, the authors investigated the association between type of anesthetic and patient survival after elective colon cancer surgery., Methods: A retrospective cohort study included patients who received elective colon cancer surgery between January 2005 and December 2014. Patients were grouped according to anesthesia received: propofol or desflurane. After exclusion of those who received combined propofol anesthesia with inhalation anesthesia or epidural anesthesia, survival curves were constructed from the date of surgery to death. After propensity matching, univariable and multivariable Cox regression models were used to compare hazard ratios for death. Subgroup analyses were performed for tumor-node-metastasis staging and postoperative metastasis., Results: A total of 706 patients (307 deaths, 43.5%) with desflurane anesthesia and 657 (88 deaths, 13.4%) with propofol anesthesia were eligible for analysis. After propensity matching, 579 patients remained in each group (189 deaths, 32.6%, in the desflurane group vs. 87, 15.0%, in the propofol group). In the matched analyses, the propofol-treated group had a better survival, irrespective of lower tumor-node-metastasis stage (hazard ratio, 0.22; 95% CI, 0.11 to 0.42; P < 0.001) or higher tumor-node-metastasis stage (hazard ratio, 0.42; 95% CI, 0.32 to 0.55; P < 0.001) and presence of metastases (hazard ratio, 0.67; 95% CI, 0.51 to 0.86; P = 0.002) or absence of metastases (hazard ratio, 0.08; 95% CI, 0.01 to 0.62; P = 0.016). Simple propensity score adjustment produced similar findings., Conclusions: Propofol anesthesia for colon cancer surgery is associated with better survival irrespective of tumor-node-metastasis stage.

Background: Modulating the inflammatory response to nerve injury may provide therapeutic opportunities by aborting the neurobiological alterations that support the development of persistent pain. Baicalein, a 12-lipoxygenase inhibitor, has anti-inflammation properties. It also demonstrates anti-inflammatory functions by inhibiting lipopolysaccharide-induced barrier disruption, expression of cell adhesion molecules, and adhesion and migration of leukocytes. The aim of the present study was to assess the possibility of early treatment of neuropathic pain via the systemic injection of baicalein in rats with left partial sciatic nerve transection (PST)., Methods: Wistar rats were divided into Sham, Vehicle, and Baicalein groups. The Vehicle and Baicalein rats underwent PST, whereas the Sham rats were not transected. Baicalein was administered 20 mg/kg/day intraperitoneally for 7 days after PST and after behaviour tests. After PST, rats developed mechanical and cold allodynia, and impaired sciatic nerve function., Results: Baicalein attenuated mechanical and cold allodynia and improved sciatic nerve function after PST. Baicalein significantly inhibited the expression of tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-1β on days 14 and 28, and attenuated the activation of astrocytes in the L4-5 spinal cord less than day 28 after PST., Conclusion: Our study revealed that early and multiple doses of systemic baicalein attenuated neuropathic pain and improved sciatic nerve function by inhibiting pro-inflammatory cytokine expression and attenuating the activation of astrocytes in the spinal cord., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Background: The use of lengthy, detailed, and complex informed consent forms (ICFs) is of paramount concern in biomedical research as it may not truly promote the rights and interests of research participants. The extent of information in ICFs has been the subject of debates for decades; however, no clear guidance is given. Thus, the objective of this study was to determine the perspectives of research participants about the type and extent of information they need when they are invited to participate in biomedical research., Methods: This multi-center, cross-sectional, descriptive survey was conducted at 54 study sites in seven Asia-Pacific countries. A modified Likert-scale questionnaire was used to determine the importance of each element in the ICF among research participants of a biomedical study, with an anchored rating scale from 1 (not important) to 5 (very important)., Results: Of the 2484 questionnaires distributed, 2113 (85.1%) were returned. The majority of respondents considered most elements required in the ICF to be 'moderately important' to 'very important' for their decision making (mean score, ranging from 3.58 to 4.47). Major foreseeable risk, direct benefit, and common adverse effects of the intervention were considered to be of most concerned elements in the ICF (mean score = 4.47, 4.47, and 4.45, respectively)., Conclusions: Research participants would like to be informed of the ICF elements required by ethical guidelines and regulations; however, the importance of each element varied, e.g., risk and benefit associated with research participants were considered to be more important than the general nature or technical details of research. Using a participant-oriented approach by providing more details of the participant-interested elements while avoiding unnecessarily lengthy details of other less important elements would enhance the quality of the ICF.

Abstract: Chronic post-surgical pain (CPSP) is a chronic pain condition, affecting many people who have undergone surgery. The development of CPSP is complex and the treatment options are limited; therefore, postsurgical pain management is crucial for satisfactory pain relief and prevention of CPSP development. In this review, we analyzed the existing treatment modalities for patients with CPSP. The treatments include opioids, acetaminophen, N-methyl-D-aspartate (NMDA) receptor antagonists, anticonvulsants, and local anesthesia. All treatments had signifi cant effect on CPSP and opioid-sparing effect; moreover, preventive analgesic treatment is important for improving quality of postoperative pain management. However, since most of the studies had limitations, further research on determining effective combinations and treatment modalities is required.

Dexmedetomidine, an α-2 adrenergic receptor agonist, provides analgesia, sedation, anxiolysis, sympatholysis and anesthetic-sparing effect, without inducing significant respiratory depression. Due to these properties, its clinical use is no longer limited to serving as a sedative agent in the intensive care unit. Proper airway management and the avoidance of cardiac and respiratory complications are common goals of everyday anesthesia practice. Ensuring airway safety is pivotal during the anesthesia stages of induction, maintenance and recovery. In this review, we focus on the advantages of dexmedetomidine in awake fiberoptic intubation (AFOI), diagnostic examinations and surgeries of patients with obstructed airways, and reducing emergence delirium effectively without causing further adverse events. With increasing implementation in different anesthetic scenarios, dexmedetomidine provides a favorable option to enhance patient safety and comfort.

Background: Countries at higher latitudes have higher incidence rates of Kawasaki disease (KD) than do countries at lower latitudes in the Asian and West Pacific area. However, the precise influence of latitude on KD incidence rates requires further clarification. Methods: We searched the Longitudinal Health Insurance Database 2005 to retrieve patients&rsquo; medical records from 1996 to 2009. The patients with KD were categorized as living in northern, middle, and southern Taiwan; the period prevalence of KD for each area was determined. Climate variables, including temperature, sunshine duration, precipitation, and relative humidity, were collected from the Taiwan Central Weather Bureau. The effect of latitude on the period KD prevalence and the correlation between climate variables and KD prevalence were calculated. Results: After patients without complete data excluded, a total of 61,830 children up to 10 years old were retrieved, from which 404 patients with KD were recognized. The period prevalence of KD increased significantly with latitude ( p = 0.0004). Climate variables associated with high temperature demonstrated a connection with KD prevalence; however, this correlation was not statistically significant. Conclusions: Our study demonstrated that higher latitude is associated with a higher KD prevalence in Taiwan.

Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain. Activation of NLRP3 inflammasome leads to interleukin-1β (IL-1β) upregulation and pyroptosis, a proinflammatory cell death characterized by increased cell size. Of note, calcium signaling is crucial for NLRP3 inflammasome activation. This study elucidated the effects of magnesium sulfate (MgSO 4 ), a potent calcium antagonist, on modulating NLRP3 inflammasome., Materials and Methods: THP-1 cells, the human monocytic leukemia cell line, were treated with lipopolysaccharide (LPS, 1 μg/ml) plus nigericin (5 μM) (the LPS + Nig group) and LPS plus nigericin plus MgSO 4 (20 mM) [the LPS + Nig + M(20)] to facilitate investigations. Levels of IL-1β, pyroptosis, and NLRP3 inflammasome induction as well as intracellular calcium were assayed., Results: IL-1β concentration of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.001). Cell size of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P < 0.001). Level of pyroptotic cell death of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.004). NLRP3 mRNA and protein concentrations of the LPS + Nig + M(20) group were also significantly lower than the LPS + Nig group (P = 0.021 and P < 0.001). Similarly, apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation ratio and caspase-1 concentration of the LPS + Nig + M(20) group were significantly lower than the LPS + Nig group (both P < 0.001). The change in intracellular calcium level of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P = 0.001)., Conclusions: MgSO 4 inhibits NLRP3 inflammasome, IL-1β upregulation, and pyroptosis. The mechanism is consistent with decreased intracellular calcium levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

While anaesthetics are frequently used on cancer patients during surgical procedures, their consequence on cancer progression remains to be elucidated. In this study, we sought to investigate the influence of local anesthetics on lung cancer cell dissemination in vitro and in vivo. A549 human non-small lung cancer cells were treated with various local anaesthetics including ropivacaine, lidocaine, levobupivacaine and bupivacaine. Cell barrier property was assessed using an electric cell-substrate impedance sensing (ECIS) system. The epithelial-to-mesenchymal transition (EMT) of treated cells was studied by immunofluorescence staining. In vitro and in vivo cancer cell dissemination were investigated.Gene expression microarray and quantitative real-time PCR (qrt-PCR) assays were used to identify the genes responsible for levobupivacaine-mediated cancer cell dissemination.The results illustrated that only levobupivacaine induced EMT in the treated cells and also caused the dissemination of cancer cells in vitro. In addition, after intravenous injection, levobupivacaine encouraged cancer cell dissemination in vivo. Gene expression microarray, qrt-PCR and immunoblotting revealed that after levobupivacaine treatment, the hypoxia-inducible factor (HIF)- 2α gene was upregulated in cancer cells. Our findings suggest that levobupivacaine may induce A549 lung cancer cell dissemination both in vitro and in vivo. More specifically, HIF-2α signaling possibly contributes to levobupivacaine-mediated A549 lung cancer cell dissemination.

Aims: We previously demonstrated that intrathecal IL-1β upregulated phosphorylation of p38 mitogen-activated protein kinase (P-p38 MAPK) and inducible nitric oxide synthase (iNOS) in microglia and astrocytes in spinal cord, increased nitric oxide (NO) release into cerebrospinal fluid, and induced thermal hyperalgesia in rats. This study investigated the role of spinal glutamatergic response in intrathecal IL-1β-induced nociception in rats., Methods: The pretreatment effects of MK-801 (5 μg), minocycline (20 μg), and SB203580 (5 μg) on intrathecal IL-1β (100 ng) in rats were measured by behavior, Western blotting, CSF analysis, and immunofluorescence studies., Results: IL-1β increased phosphorylation of NR-1 (p-NR1) subunit of N-methyl-D-aspartate receptors in neurons and microglia, reduced glutamate transporters (GTs; glutamate/aspartate transporter by 60.9%, glutamate transporter-1 by 55.0%, excitatory amino acid carrier-1 by 39.8%; P<.05 for all), and increased glutamate (29%-133% increase from 1.5 to 12 hours; P<.05) and NO (44%-101% increase from 4 to 12 hours; P<.05) levels in cerebrospinal fluid. MK-801 significantly inhibited all the IL-1β-induced responses; however, minocycline and SB203580 blocked the IL-1β-downregulated GTs and elevated glutamate but not the upregulated p-NR1., Conclusion: The enhanced glutamatergic response and neuron-glia interaction potentiate the intrathecal IL-1β-activated P-p38/iNOS/NO signaling and thermal hyperalgesia., (© 2017 John Wiley & Sons Ltd.)

Objective: This study aimed to support the potential protective role of anterior cruciate ligament (ACL) reconstruction against the development of osteoarthritis (OA)., Methods: In this retrospective cohort study, the long-term results of ACL reconstruction in Taiwan were evaluated based on data from the National Health Insurance Research Database (NHIRD). In total, 8,769 eligible cases were included from 11,921 ACL-injured patients. The cumulative incidence rates of OA and total knee replacement (TKR) were analyzed using the Kaplan-Meier estimator. Cox proportional hazards models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of OA., Results: There was a lower cumulative incidence of OA among ACL-reconstructed patients (271, 33.1%) than among non-reconstructed patients (1,874, 40.3%; p < 0.001). Patients who underwent ACL reconstruction had a lower cumulative incidence of TKR during the follow-up period (0.6%) than the non-reconstructed patients (4.6%, p < 0.001). After adjusting for covariates, ACL-injured patients who underwent reconstruction within one month after ACL injury showed a significantly lower risk of OA than those who never underwent reconstruction (adjusted HR = 0.83, 95% CI = 0.69-0.99)., Conclusions: These results indicate that ACL reconstruction might not provide complete protection from OA development after traumatic knee injury but does yield a lower cumulative incidence of OA development and TKR. Moreover, based on the present study, ACL-injured patients should undergo reconstruction as early as possible (within one month) to lower the risk of OA.