Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke.

BACKGROUND: Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients' lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. METHODS: Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. RESULTS: Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. CONCLUSION: This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.

Single-Layer GaInSe3: Promising Water-Splitting Photocatalyst with Solar Conversion Efficiency over 30% from Theoretical Calculations.

Hydrogen energy from solar water-splitting is known as an ideal method with which to address the energy crisis and global environmental pollution. Herein, the first-principles calculations are carried out to study the photocatalytic water-splitting performance of single-layer GaInSe3 under biaxial strains from -2% to +2%. Calculations reveal that single-layer GaInSe3 under various biaxial strains has electronic bandgaps ranging from 1.11 to 1.28 eV under biaxial strain from -2% to +2%, as well as a completely separated valence band maximum and conduction band minimum. Meanwhile, the appropriate band edges for water-splitting and visible optical absorption up to ~3 × 105 cm-1 are obtained under biaxial strains from -2% to 0%. More impressively, the solar conversion efficiency of single-layer GaInSe3 under biaxial strains from -2% to 0% reaches over 30%. The OER of unstrained single-layer GaInSe3 can proceed without co-catalysts. These demonstrate that single-layer GaInSe3 is a viable material for solar water-splitting.

Lymphopenia during routine follow-up may predict relapse in patients with extranodal NK/T cell lymphoma.

Recently, absolute lymphocyte count (ALC) at diagnosis, as a surrogate marker of host immunity, has been reported to be a prognostic factor for clinical outcomes in extranodal NK/T cell lymphoma (ENKTL). In this retrospective study, we set out to investigate whether ALC at the time of confirmed relapse or at last follow-up is a marker for relapse after chemoradiotherapy in 84 patients with stage I/II ENKTL. Receiver operating characteristics (ROC) curve and area under the curve (AUC) analysis showed that ALC at follow-up was a significant marker for relapse (AUC = 0.883, P < 0.001). Using 1.215 × 10(9)/L as the optimal cutoff value of ALC, 44 patients (52.4%) were in lower ALC group and 40 patients (47.6%) were in higher ALC group. The sensitivity and specificity for ALC at the time of confirmed relapse or at last follow-up was 94.1 and 76.0%, respectively. The relative risk of relapse with an ALC < 1.215 × 10(9)/L was 14.5. The positive predictive value with an ALC < 1.215 × 10(9)/L was 72.7%, and the negative predictive value with an ALC ≥ 1.215 × 10(9)/L was 95.0%. The 4-year cumulative incidence rate for an ALC < 1.215 × 10(9)/L was 73.2% compared with 3.2% for an ALC ≥ 1.215 × 10(9)/L (P < 0.001). In a multivariate regression analysis, ALC at the time of confirmed relapse or last follow-up remained to be a significant factor for relapse (P < 0.001). In conclusion, lymphopenia observed during routine follow-up can predict relapse in patients with ENKTL, which needs further validation in prospective trials.

Spinal MCP-1 Contributes to Central Post-stroke Pain by Inducing Central Sensitization in Rats.

Central post-stroke pain (CPSP) is a highly refractory form of central neuropathic pain that has been poorly studied mechanistically. Recent observations have emphasized the critical role of the spinal dorsal horn in CPSP. However, the underlying mechanisms remain unclear. In this study, rats were subjected to thalamic hemorrhage to investigate the role of spinal monocyte chemoattractant protein-1 (MCP-1) and C-C motif chemokine receptor 2 (CCR2) in the development of CPSP. Immunohistochemical staining and ELISA were used to assess the expression changes of c-Fos, Iba-1, GFAP, MCP-1, and CCR2 in the dorsal horn of the lumbar spinal cord following thalamic hemorrhage, and the involvement of spinal MCP-1 in CPSP was examined by performing intrathecal anti-MCP-1 mAb injection to neutralize the spinal extracellular MCP-1. We demonstrated that intra-thalamic collagenase microinjection induced persistent bilateral mechanical pain hypersensitivity and facilitated the spontaneous pain behaviors evoked by intraplantar bee venom injection. Accompanying CPSP, the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn was significantly increased up to 28 days post-intra-thalamic collagenase microinjection. Intrathecal injection of minocycline and fluorocitrate dramatically reverses the bilateral mechanical pain hypersensitivity. Moreover, intra-thalamic collagenase microinjection dramatically induced the up-regulation of MCP-1 but had no effect on the expression of CCR2 in the bilateral lumbar spinal dorsal horn, and MCP-1 was primarily localized in the neuron. Intrathecal injection of anti-MCP-1 mAb was also able to reverse CPSP and reduce the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn. These findings indicated that spinal MCP-1 contributes to CPSP by mediating the activation of spinal neurons and glial cells following thalamic hemorrhage stroke, which may provide insights into pharmacologic treatment for CPSP.

Ropivacaine-induced seizures evoked pain sensitization in rats: Participation of 5-HT/5-HT3R.

Due to the increasing use of local anesthetic techniques in various healthcare settings, local anesthetic toxicity still occurs. Seizures are the most common symptom of local anesthetic toxicity. The relationship between local anesthetic-induced seizures and the sensation of pain has not been established till now. Here, we assessed the development of pain hypersensitivity after ropivacaine-induced seizures (RIS) and the influence of RIS on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. In addition, the involvement of spinal 5-HT/5-HT3R in RIS-induced pain sensitization was investigated. According to a sequential exploratory experimental strategy, we first calculated the 50% seizure dosage of ropivacaine to be 42.66 mg/kg (95% confidence interval: 40.19-45.28 mg/kg). We showed that RIS induced significant bilateral mechanical pain hypersensitivity that lasted around 5 days, accompanied by an increase in spinal 5-HT. Moreover, RIS considerably protracted postsurgical pain and enhanced formalin-induced spontaneous flinching in the second phase. Depletion of spinal 5-HT with intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT) reduced RIS-induced pain hypersensitivity and prevented the prolonging of postsurgical pain following RIS. Likewise, blocking spinal 5-HT3R by intrathecal administration of ondansetron reversed RIS-induced pain hypersensitivity and attenuated the pronociception of RIS in the formalin test. Our findings revealed that acute RIS led to pain hypersensitivity and had pronociceptive effects on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. Moreover, our data implied that RIS-induced pain sensitization depends on spinal 5-HT/5-HT3R signaling. Thus, targeting the descending serotonergic facilitation system should be an important element of the precise treatment for local anesthetic toxicity.

Positive Emotions and Entrepreneurial Intention: The Mediating Role of Entrepreneurial Cognition.

Under the background of "mass entrepreneurship and innovation," entrepreneurship and innovation for college students not only alleviates the current social employment pressure but also sets off the upsurge of their entrepreneurship. It is a significant field to research the entrepreneurial intention of undergraduates as potential entrepreneurs, which covers the study of entrepreneurial intention from the perspective of personal traits and entrepreneurial cognition. This article studies entrepreneurial intention from two aspects: irrational positive emotions and rational entrepreneurial cognition, which aims to reveal the mechanism of positive emotions and entrepreneurial cognition on entrepreneurial intention. After investigating 288 college students participating in entrepreneurial competitions, establishing structural equations, and using SmartPLS software for data analysis, the research result showed that positive emotions significantly positively impact the three scripts of entrepreneurial cognition: arrangement scripts, willing scripts, and ability scripts. The arrangement, willing, and ability scripts positively influence entrepreneurial intention, while positive emotions do not affect entrepreneurial intention. Arrangement scripts and ability scripts have a full mediating effect between positive emotions and entrepreneurial intention. Based on these findings, we provide suggestions for the government and society, schools, and individual students on innovation and entrepreneurship.

Intervertebral foramen injection of plerixafor attenuates neuropathic pain after chronic compression of the dorsal root ganglion: Possible involvement of the down-regulation of Nav1.8 and Nav1.9.

Neuropathic pain is a common chronic pain condition with major impact on quality of life. However, its physiopathologic mechanism remains unknown and pain management is still a challenge. Accumulating evidence indicated that C-X-C chemokine receptor type 4 (CXCR4) played a critical role in the process of pain. Thus, the present study aimed to investigate whether intervertebral foramen injection of CXCR4 antagonist, plerixafor, was able to relieve neuropathic pain and explore the possible underlying mechanism. Chronic compression of the dorsal root ganglion (CCD) was established as a typical model of neuropathic pain. The results indicated that CCD induced multiple pain-related behaviors and the expression of CXCR4, Nav1.8 and Nav1.9 was significantly increased in compressed dorsal root ganglion (DRG) neurons. Knocking down CXCR4 expression could significantly reduce neuropathic pain and intervertebral foramen plerixafor injection (IVFP) dramatically decreased the up-regulation of Nav1.8 and Nav1.9 and attenuated neuropathic pain. The analgesic duration of IVFP was maintained at least for 24 h which was much longer than intervertebral foramen injection of Nav1.8 blocker and local anesthetics. Therefore, our study provided evidence that IVFP could reduce the expression of Nav1.8 and Nav1.9 in DRG neurons which might contribute to, at least in part, the analgesic effect of plerixafor on CCD-induced neuropathic pain. It is concluded that IVFP was an effective and applicable treatment approach for neuropathic pain.

The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain.

Ulinastatin is a broad-spectrum protease inhibitor widely used for the treatment of various inflammation-related diseases owing to its recognized excellent anti-inflammatory and cytoprotective properties. However, whether ulinastatin can relieve postoperative pain remains unclear. In this study, we evaluated the analgesic effects of ulinastatin administered either as a single agent or in combination with sufentanil in a validated preclinical rat model of postoperative pain induced by plantar incision. We found that incisional surgery on the hind paw of these rats induced sustained ipsilateral mechanical pain hypersensitivity that lasted for at least 10 days. A single intraperitoneal (i.p.) injection of ulinastatin prevented the development and reversed the maintenance of incision-induced mechanical pain hypersensitivity in a dose-dependent manner. However, ulinastatin had no effect on the baseline nociceptive threshold. Moreover, repeated i.p. injections of ulinastatin persistently attenuated incision-induced mechanical pain hypersensitivity and promoted recovery from the surgery. The rats did not develop any analgesic tolerance over the course of repeated injections of ulinastatin. A single i.p. injection of ulinastatin was also sufficient to inhibit the initiation and maintenance of incision-induced hyperalgesic priming when the rats were subsequently challenged with an ipsilateral intraplantar prostaglandin E2 injection. Furthermore, the combined administration of ulinastatin and sufentanil significantly enhanced the analgesic effect of sufentanil on postoperative pain, which involved mechanisms other than a direct influence on opioid receptors. These findings demonstrated that ulinastatin had a significant analgesic effect on postoperative pain and might be a novel pharmacotherapeutic agent for managing postoperative pain either alone or as an adjuvant.

Involvement of the p38 MAPK-pHsp27 pathway in vascular hyporeactivity induced by obstructive jaundice in rats.

Patients with obstructive jaundice are prone to develop cardiovascular complications during surgery. However, the underlying mechanisms remain largely unknown. The present study was aimed to investigate the role of p38 MAPK-pHsp27 pathway in vascular hyporesponsiveness induced by obstructive jaundice. Firstly, an experimental rat obstructive jaundice model was established by bile duct ligation (BDL). We found that the thoracic aorta rings isolated from BDL rats showed decreased response to norepinephrine and acetylcholine, while continuous intraperitoneal injection with SB203580, a selective P38 MAPK inhibitor, could significantly prevented BDL-induced hyporeactivity. Also, the immunohistochemistry and Western blot assays revealed that the up-regulation of pHsp27 and F-actin in thoracic aorta rings from BDL rats and bilirubin-treated vascular smooth muscle cells (VSMCs) were also inhibited by SB203580. Moreover, we identified that bilirubin could induced decreased cell proliferation of VSMCs by using CCK8 assay and which was also prevented by SB203580. All these data demonstrated that p38 MAPK-pHsp27 mediates vascular hyporesponsiveness in rats with obstructive jaundice by modulating the expression level of pHsp27 and F-actin, and that inhibition of p38 MAPK signaling could remodel the vascular activity.

[Effects of high thoracic epidural anesthesia on ventricular remodeling and expression of beta(3)-adrenoceptor in rats with heart failure induced by acute myocardial infarction].

OBJECTIVE: To investigate the effect of high thoracic epidural anesthesia on ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction, and to investigate their mechanism. METHODS: Rats that had been established successively model were randomly divided into S group (n = 12), HTEA group and CHF group (24/group). 9.0 g/L normal sodium 100 microl/kg was injected to epidural cavity twice a day separately in group S and group CHF. 1.25 g/L bupivacaine 100 microl/kg was injected to epidural cavity twice a day in group HTEA. Epidural injection was started 24 hrs after the epidural surgery and continued 4 weeks. Then the change of cardiac function was observed by using echocardiogram. The ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW) were measured. Noninfarct ventricular tissue were stained with hematoxylin-eosin (HE) and Masson's trichrome respectively. beta(3)-adrenoceptor levels and eNOS levels were detected with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: LVEDD and LVESD were significantly decreased in the group HTEA compared with group CHF (P < 0.01), while LVEF% and LVFS% were significantly increased (P < 0.01). The ratios HW/BW and LVW/BW were significantly increase in the group CHF compared with the group S (P < 0.01), but they were limited in the group HTEA (P < 0.01). Hypertrophy and edema, degeneration and necrosis of myocytes can be seen in rats with CHF, as well as muscle fibers disruption and collagen fiber increase, while the pathological amorphous were attenuated in HTEA rats. beta(3)AR and eNOS mRNA levels were significantly decreased in the group THEA compared with the group CHF. CONCLUSIONS: These results indicate that HTEA could ameliorate ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction. The mechanism could involve decreases of beta(3)AR expression in rats of heart failure.

Comparison of Continuous Noninvasive Blood Pressure Monitoring by TL-300 With Standard Invasive Blood Pressure Measurement in Patients Undergoing Elective Neurosurgery.

BACKGROUND: Intraoperative blood pressure (BP) is one of the basic vital signs monitoring. Compared with standard invasive BP measurement, TL-300 allows for a continuous and beat-to-beat noninvasive intraoperative BP monitoring. The current retrospective study compared the accuracy and precision of this noninvasive technique for continuous BP monitoring with that of standard invasive BP measurement in patients undergoing elective neurosurgery. MATERIALS AND METHODS: BP records of 23 patients undergoing elective neurosurgery, measured by both noninvasive TL-300 and invasive radial arterial catheter method, were retrospectively analyzed. Variability in BP data was analyzed by using linear regressions and Bland-Altman analysis. RESULTS: Four thousand three hundred eighty-one pairs of BP measurements from a total of 23 patients were included. The coefficient of determination of systolic, diastolic, and mean BP were 0.908, 0.803, and 0.922, respectively. And their bias was found to be 1.3±5.87 mm Hg (95% limits of agreement: -10.2 to +12.8 mm Hg), 2.8±6.40 mm Hg (95% limits of agreement: -9.8 to +15.3 mm Hg), and 1.8±4.20 mm Hg (95% limits of agreement: -6.4 to +10.1 mm Hg), respectively. CONCLUSIONS: TL-300 system is a promising noninvasive alternative to the invasive arterial catheter method for intraoperative BP monitoring, with a high accuracy and precision. With the limitation of the current retrospective study, further prospective method comparison studies are needed.

Neuromuscular effect of dexmedetomidine on sevoflurane: an open-label, dose-escalation clinical trial.

BACKGROUND: Sevoflurane presents reliable central neuromuscular effects. However, little knowledge is available regarding the interaction between sevoflurane and demedetomidine. We evaluated the neuromuscular effect of dexmedetomidine on sevoflurane in patients with normal neuromuscular transmission and calculated the 50% effective concentration (EC50). METHODS: One-hundred and forty-four ASA grade I~II patients with normal neuromuscular transmission, aged 20~60 years old, undergoing lower limbs surgery were enrolled in this open-label, dose-escalation clinical trial. Patients were randomly assigned into 12 groups. Each patient received intravenous 0, 0.5, or 1.0 µg/kg dexmedetomidine 15 min after inhaling 0.7, 1.0, 1.4, or 2.0 MAC sevoflurane. Neuromuscular monitoring was recorded from the adductor pollicis muscle by using acceleromyography with train-of-four (TOF) stimulation of the ulnar nerve (2 Hz every 20 s). TOF ratio was recorded before inhaling sevoflurane, 15 min after keeping constant at target MAC of sevoflurane, 30 min after receiving target dose of dexmedetomidine, and 15 min after sevoflurane washing out. RESULTS: Sevoflurane produced a concentration-dependent decrease in TOF ratio. Mean TOF ratio in 0.7, 1.0, 1.4, and 2.0 MAC groups was 97.9%, 94.9%, 84.7%, and 77.2%, respectively. Neuromuscular EC50 of sevoflurane was 1.31 MAC (95% CI: 1.236~1.388 MAC). Intravenous 0.5 and 1.0 µg/kg dexmedetomidine decreased 3.1% (EC50: 1.27 MAC [95% CI: 1.206~1.327 MAC]) and 10.7% (EC50: 1.17 MAC [95% CI: 1.122~1.217 MAC]) of neuromuscular EC50, respectively. CONCLUSIONS: Sevoflurane has a concentration-dependent central neuromuscular effect in patients with normal neuromuscular transmission. Intravenous dexmedetomidine dose-dependently decreases the neuromuscular EC50 of sevoflurane.

Hepatitis B virus infection correlates with poor prognosis of extranodal natural killer/T cell lymphoma.

Studies have shown that hepatitis B virus (HBV) infection may play an important role in the lymphomagenesis of lymphoma, but no studies regarding the relationship between HBV infection and extranodal natural killer/T cell lymphoma (ENKTL) have been reported previously. One hundred and seven patients diagnosed with ENKTL were retrospectively reviewed. The hepatitis B surface antigen (HBsAg)-positive rate was 13.1%, and no significant correlation existed between HBV infection and clinical characteristics (p > 0.05). No significant difference existed in complete remission rate between HBsAg-positive and -negative groups (42.9% vs. 44.1%, p = 1.000). In a multivariate Cox regression model that included international prognostic index (IPI) score, induction chemotherapy regimen and HBsAg status, all these variables were independent prognostic factors for overall survival (OS) and progression-free survival (PFS) (p < 0.05). In conclusion, the HBsAg-positive rate in ENKTL was similar to that of the normal population in a high HBV endemic area, and HBsAg-positive status was an independent prognostic factor for OS and PFS.

Serum C-reactive protein (CRP) as a simple and independent prognostic factor in extranodal natural killer/T-cell lymphoma, nasal type.

BACKGROUND: C-reactive protein (CRP) is a biomarker of the inflammatory response, and it shows significant prognostic value for several types of solid tumors. The prognostic significance of CRP for lymphoma has not been fully examined. We evaluated the prognostic role of baseline serum CRP levels in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL). METHODS: We retrospectively analyzed 185 patients with newly diagnosed ENKTL. The prognostic value of the serum CRP level was evaluated for the low-CRP group (CRP≤10 mg/L) versus the high-CRP group (CRP>10 mg/L). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were evaluated and compared with the newly developed prognostic model. RESULTS: Patients in the high-CRP group tended to display increased adverse clinical characteristics, lower rates of complete remission (P<0.001), inferior progression-free survival (PFS, P = 0.001), and inferior overall survival (OS, P<0.001). Multivariate analysis demonstrated that elevated serum CRP levels, age >60 years, hypoalbuminemia, and elevated lactate dehydrogenase levels were independent adverse predictors of OS. Based on these four independent predictors, we constructed a new prognostic model that identified 4 groups with varying OS: group 1, no adverse factors; group 2, 1 factor; group 3, 2 factors; and group 4, 3 or 4 factors (P<0.001). The novel prognostic model was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the low- and intermediate-low-risk groups, the intermediate-low- and high-intermediate-risk groups, and the high-intermediate- and high-risk groups. CONCLUSIONS: Our results suggest that pretreatment serum CRP levels represent an independent predictor of clinical outcome for patients with ENKTL. The prognostic value of the new prognostic model is superior to both IPI and KPI.