Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

This study aimed to investigate the effects of nanoparticles PLGA-NPs and mesoporous silicon nanoparticles(MSNs) of different stiffness before and after combination with menthol or curcumol on the mechanical properties of bEnd.3 cells. The particle size distributions of PLGA-NPs and MSNs were measured by Malvern particle size analyzer, and the stiffness of the two nanoparticles was quantified by atomic force microscopy(AFM). The bEnd.3 cells were cultured in vitro, and the cell surface morphology, roughness, and Young's modulus were examined to characterize the roughness and stiffness of the cell surface. The changes in the mechanical properties of the cells were observed by AFM, and the structure and expression of cytoskeletal F-actin were observed by a laser-scanning confocal microscope. The results showed that both nanoparticles had good dispersion. The particle size of PLGA-NPs was(98.77±2.04) nm, the PDI was(0.140±0.030), and Young's modulus value was(104.717±8.475) MPa. The particle size of MSNs was(97.47±3.92) nm, the PDI was(0.380±0.016), and Young's modulus value was(306.019±8.822) MPa. The stiffness of PLGA-NPs was significantly lower than that of MSNs. After bEnd.3 cells were treated by PLGA-NPs and MSNs separately, the cells showed fine pores on the cell surface, increased roughness, decreased Young's modulus, blurred and broken F-actin bands, and reduced mean gray value. Compared with PLGA-NPs alone, PLGA-NPs combined with menthol or curcumol could allow deepened and densely distributed surface pores of bEnd.3 cells, increase roughness, reduce Young's modulus, aggravate F-actin band breakage, and diminish mean gray value. Compared with MSNs alone, MSNs combined with menthol could allow deepened and densely distributed surface pores of bEnd.3 cells, increase roughness, reduce Young's modulus, aggravate F-actin band breakage, and diminish mean gray value, while no significant difference was observed in combination with curcumol. Therefore, it is inferred that the aromatic components can increase the intracellular uptake and transport of nanoparticles by altering the biomechanical properties of bEnd.3 cells.
Animals ; Mice ; Menthol/pharmacology* ; Actins/metabolism* ; Endothelial Cells/metabolism* ; Nanoparticles/chemistry*

Objective: To analyze the spatiotemporal characteristics of hand,foot and mouth disease (HFMD) in China, explore the association of socioeconomic, population and health services factors with the incidence of HFMD in China, and provide information for the prevention and control of HFMD. Methods: Bayesian spatiotemporal model was used to fit the data of HFMD, evaluate the spatiotemporal variation of HFMD, and identify the potential association between the risk of HFMD and social, economic, population and health services. Results: From 2011 to 2018, a total of 17 118 050 HFMD cases, including 2 283 deaths, were reported in China. The reported incidence showed a fluctuating increase trend from 2011 to 2014, and a fluctuating decrease trend from 2014 to 2018. Meanwhile, there was a fluctuating decrease trend of mortality rate. The incidence of HFMD had spatial clustering, with the highest incidence in southern China with hot spot and high risk areas, and the lowest incidence in northwestern China where cold spot and low risk areas were found. The risk for HFMD was associated with GDP per capita (RR=3.54), number of industrial enterprises above designated size of 10 000 people (RR=1.61), urbanization rate (RR=3.00), birth rate (RR=2.36), number of beds in medical institutions per 10 000 people (RR=3.40), and green area in parks per capita (RR=0.57). Conclusions: The hotspot area for HFMD prevention and control in China was in the southeast coastal provinces from 2011 to 2018. In order to reduce the incidence of HFMD, it is necessary to increase the green area in parks per capita while accelerating urbanization process.
Humans ; Animals ; Bayes Theorem ; Foot-and-Mouth Disease ; China/epidemiology* ; Hand, Foot and Mouth Disease/epidemiology* ; Menthol

OBJECTIVE: To investigate the effect of interleukin (IL) -13 combined with cold stimulation on synthesis and secretion of mucin (MUC) 5AC in human bronchial epithelial cell line 16HBE and explore the role of transient receptor potential 8 (TRPM8) and anti-apoptotic factor B-cell lymphoblast-2 (Bcl-2) in this process. METHODS: 16HBE cells were stimulated with 10 ng/mL IL-13, 1 mmol/L menthol, or both (1 mmol/L menthol was added after 6 days of IL-13 stimulation), and the changes in the expression of MUC5AC, intracellular Ca RESULTS: The mRNA and protein expressions of MUC5AC increased significantly in 16HBE cells following stimulation with IL-13, menthol, and both ( CONCLUSIONS Menthol combined with IL-13 produces a synergistic effect to promote the synthesis and secretion of MUC5AC in 16HBE cells possibly by activating TRPM8 receptor to upregulate the expression of Bcl-2.
Bronchi ; Epithelial Cells/drug effects* ; Humans ; Interleukin-13 ; Menthol/pharmacology* ; Mucin 5AC

Antidepressant drugs can be advantageous in treating psychiatric and non-psychiatric illnesses, including spinal disorders. However, spine surgeons remain unfamiliar with the advantages and disadvantages of the use of antidepressant drugs as a part of the medical management of diseases of the spine. Our review article describes a systematic method using the PubMed/Medline database with a specific set of keywords to identify such benefits and drawbacks based on 17 original relevant articles published between January 2000 and February 2018; this provides the community of spine surgeons with available cumulative evidence contained within two tables illustrating both observational (10 studies; three cross-sectional, three case-control, and four cohort studies) and interventional (seven randomized clinical trials) studies. While tricyclic antidepressants (e.g., amitriptyline) and duloxetine can be effective in the treatment of neuropathic pain caused by root compression, venlafaxine may be more appropriate for patients with spinal cord injury presenting with depression and/or nociceptive pain. Despite the potential associated consequences of a prolonged hospital stay, higher cost, and controversial reports regarding the lowering of bone mineral density in the elderly, antidepressants may improve patient satisfaction and quality of life following surgery, and reduce postoperative pain and risk of delirium. The preoperative treatment of preexisting psychiatric diseases, such as anxiety and depression, can improve outcomes for patients with spinal cord injury-related disabilities; however, a preoperative platelet function assay is advocated prior to major spine surgical procedures to protect against significant intraoperative blood loss, as serotonergic antidepressants (e.g., selective serotonin reuptake inhibitors) and bupropion can increase the likelihood of bleeding intraoperatively due to drug-induced platelet dysfunction. This comprehensive review of this evolving topic can assist spine surgeons in better understanding the benefits and risks of antidepressant drugs to optimize outcomes and avoid potential hazards in a spine surgical setting.
Aged ; Antidepressive Agents ; Antidepressive Agents, Tricyclic ; Anxiety ; Blood Platelets ; Bone Density ; Bupropion ; Case-Control Studies ; Cohort Studies ; Delirium ; Depression ; Duloxetine Hydrochloride ; Hemorrhage ; Humans ; Length of Stay ; Methods ; Neuralgia ; Nociceptive Pain ; Pain, Postoperative ; Patient Satisfaction ; Quality of Life ; Risk Assessment ; Serotonin ; Spinal Cord ; Spinal Cord Injuries ; Spine ; Surgeons ; Venlafaxine Hydrochloride

OBJECTIVES: Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran.METHODS: Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose.RESULTS: In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score <15, having taken a tramadol dose of >1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose.CONCLUSIONS: Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.
Demography ; Glasgow Coma Scale ; Hospitals, Teaching ; Humans ; Hypertension ; Incidence ; Iran ; Logistic Models ; Male ; Poisoning ; Referral and Consultation ; Seizures ; Serotonin ; Serotonin Syndrome ; Shock, Cardiogenic ; Tachycardia ; Tramadol

PURPOSE: The efficacy of periarticular multimodal drug injection and adductor canal block after a medial opening-wedge high tibial osteotomy was compared in terms of the postoperative pain level. MATERIALS AND METHODS: From November 2016 to March 2017, 60 patients underwent a medial opening-wedge high tibial osteotomy under spinal anesthesia. Preemptive analgesic medication, intravenous patient controlled anesthesia were used for pain control in all patients. Thirty patients received a periarticular multimodal drug injection (group I), and 30 patients received an adductor canal block (group II). These two groups were compared regarding the postoperative pain level, frequency of additional tramadol injections, total amount of patient-controlled analgesia, and number of times that the patients pushed the patient-controlled analgesia button at each time interval. RESULTS: The visual analogue scale scores over the two-week postoperative period showed no statistical significance. The frequency of additional tramadol hydrochloride injections was similar in the two groups over time. The mean number of times that patients pushed the patient-controlled analgesia button was similar in two groups over time. The total amount of patient-controlled analgesia was similar in the two groups over time. CONCLUSION: This study shows that intraoperative periarticular multimodal drug injections and adductor canal block may have a similar effect on postoperative pain control in patients who have undergone a medial opening-wedge high tibial osteotomy for unicompartmental osteoarthritis of the knee.
Analgesia, Patient-Controlled ; Anesthesia ; Anesthesia, Spinal ; Humans ; Knee ; Nerve Block ; Osteoarthritis ; Osteotomy ; Pain, Postoperative ; Postoperative Period ; Tramadol

OBJECTIVE: To explore the effectiveness and safety of the combined treatment with acupuncture and venlafaxine hydrochloride on depression in terms of the microstructure change of white matter fiber tracts of brain based on diffusion tensor imaging technology (DTI). METHODS: The prospective study design was adopted. All of 60 patients with depression were randomized into an acupuncture-medication group and a medication group, 30 cases in each one. In the medication group, venlafaxine hydrochloride was used, 75 mg per day in the 1st week, 150 mg per day in the 2nd week and 225 mg per day from the 3rd to 6th week. In the acupuncture-medication group, on the base of the treatment in the medication group, acupuncture was combined. Baihui (GV 20) and Yintang (GV 29) were the main acupoints. The supplementary acupoints were selected according to the clinical symptoms of individuals. The needles were retained for 30 min. Acupuncture was provided once every 2 days, 3 times a week. The consecutive 12 weeks of treatment were required in the two groups. Additionally, a normal group was prepared with 30 healthy volunteers. Separately, before treatment, in 2, 8 and 12 weeks of treatment, Hamilton's depression scale (HAMD-17), Beck depression inventory scale (BDI) and the antidepressant side effect scale (SERS) were adopted to evaluate the effectiveness and safety of the two groups. Moreover, before and after 12 weeks of treatment, DTI was adopted to detect the fractional anisotropy score (FA) of each brain region in the patients. RESULTS: After treatment, the scores of HAMD-17 and BDI were all reduced in the two groups (<0.05). In 8 and 12 weeks of treatment, the scores of HAMD-17 and BDI in the acupuncture-medication group were less than those in the medication group (<0.05). The difference in SERS score was not significant statistically between the two groups (>0.05). Compared with the healthy volunteers, FA scores in 6 brain regions changed obviously in the patients with depression, including the white matter of bilateral frontal lobes, splenium of corpus callosum, left cingulated gyrus, white matter of bilateral inferior temporal gyrus, white matter of bilateral inferior parietal lobe and white matter of bilateral deep temporal occipital region separately. Before treatment, the differences in FA scores of these 6 brain regions were not significant statistically between the two groups (>0.05). After treatment, FA scores in the white matter of bilateral frontal lobes, white matter of bilateral inferior temporal gyrus and white matter of bilateral deep temporal occipital region in the acupuncture-medication group were all higher than those in the medication group (<0.05). CONCLUSION Acupuncture repairs the brain white matter fiber tracts in some brain regions to certain extent and the therapeutic effects are enhanced with the adjuvant medication of venlafaxine hydrochloride.
Acupuncture Therapy ; Brain ; Depression ; therapy ; Diffusion Tensor Imaging ; Humans ; Prospective Studies ; Venlafaxine Hydrochloride

BACKGROUND: The transversus abdominis plane (TAP) block is an effective technique to block the thoracolumbar nerves innervating the anterolateral abdominal wall. This study was conducted to evaluate the analgesic efficacy and opioid consumption with the use of perineural buprenorphine or dexamethasone in TAP blocks after unilateral inguinal hernioplasties. METHODS: This prospective, randomized, double-blinded, placebo-controlled study enrolled 93 patients scheduled for unilateral inguinal hernioplasty, followed by an ultrasound-guided TAP block. The participants were randomized into 3 groups (31 patients each). Group L received 20 ml 0.25% levobupivacaine + 1 ml normal saline (NS); group LB, 20 ml 0.25% levobupivacaine + 0.3 mg (1 ml) buprenorphine; and group LD, 20 ml 0.25% levobupivacaine + 4 mg (1 ml) dexamethasone. The patients were observed postoperatively for 24 h for first rescue analgesic requirement, total rescue analgesic consumption, and pain scores on the numeric rating scale (NRS). RESULTS: The time to first rescue analgesic requirement was significantly longer in Group LB than in groups LD and L (688.87 ± 36.11 min, 601.45 ± 39.85 min, and 383.06 ± 36.21 min, respectively; P < 0.001). The mean total tramadol consumption in the first 24 h was the lowest in group LB (P < 0.001, L vs. LB / LD). Groups LB and LD displayed significantly lower NRS scores than group L (P < 0.001 both). CONCLUSIONS: Levobupivacaine with perineural buprenorphine in a TAP block after unilateral open inguinal hernioplasty facilitates prolonged analgesia and reduced requirement for rescue analgesics compared to perineural dexamethasone, without significant side effects.
Abdominal Wall ; Analgesia ; Analgesics ; Buprenorphine ; Dexamethasone ; Hernia, Inguinal ; Herniorrhaphy ; Humans ; Prospective Studies ; Tramadol ; Ultrasonography

Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo. The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (V(D)) of [³H]paeonol in rat brain was about 6-fold higher than that of [¹⁴C]sucrose, the vascular space marker of BBB. The uptake of [³H]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [³H]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.
Animals ; Blood-Brain Barrier ; Brain ; Carotid Arteries ; Carotid Artery, Internal ; Central Nervous System ; Diphenhydramine ; Endothelial Cells ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Membrane Potentials ; Perfusion ; Pyrilamine ; Rats ; RNA, Small Interfering ; Sodium ; Tramadol ; Transfection