Causal effect of gut microbiota on the risk of prostatitis: a two-sample Mendelian randomization study.

BACKGROUND: Recent studies demonstrated that chronic prostatitis (CP) is closely related to the gut microbiota (GM). Nevertheless, the causal relationship between GM and CP has not been fully elucidated. Therefore, the two-sample Mendelian randomization (MR) analysis was employed to investigate this association. METHODS: The summary data of gut microbiota derived from a genome-wide association study (GWAS) involving 18,340 individuals in the MiBioGen study served as the exposure, and the corresponding summary statistics for CP risk, representing the outcome, were obtained from the FinnGen databases (R9). The causal effects between GM and CP were estimated using the inverse-variance weighted (IVW) method supplemented with MR-Egger, weighted median, weighted mode, and simple mode methods. Additionally, the false discovery rate (FDR) correction was performed to adjust results. The detection and quantification of heterogeneity and pleiotropy were accomplished through the MR pleiotropy residual sum and outlier method, Cochran's Q statistics, and MR-Egger regression. RESULTS: The IVW estimates indicated that a total of 11 GM taxa were related to the risk of CP. Seven of them was correlated with an increased risk of CP, while the remained linked with a decreased risk of CP. However, only Methanobacteria (OR 0.86; 95% CI 0.74-0.99), Methanobacteriales (OR 0.86; 95% CI 0.74-0.99), NB1n (OR 1.16; 95% CI 1.16-1.34), Methanobacteriaceae (OR 0.86; 95% CI 0.74-0.99), Odoribactergenus Odoribacter (OR 1.43; 95% CI 1.05-1.94), and Sutterellagenus Sutterella (OR 1.33; 95% CI 1.01-1.76) still maintain significant association with CP after FDR correction. Consistent directional effects for all analyses were observed in the supplementary methods. Subsequently, sensitivity analyses indicated the absence of heterogeneity, directional pleiotropy, or outliers concerning the causal effect of specific gut microbiota on CP (p > 0.05). CONCLUSION: Our study demonstrated a gut microbiota-prostate axis, offering crucial data supporting the promising use of the GM as a candidate target for CP prevention, diagnosis, and treatment. There is a necessity for randomized controlled trials to validate the protective effect of the linked GM against the risk of CP, and to further investigate the underlying mechanisms involved.

Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain.

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.

The Presence of Circulating Nucleated Red Blood Cells Is Associated With Disease Severity in Patients of Hemorrhagic Fever With Renal Syndrome.

Hemorrhagic fever with renal syndrome (HFRS) is a regional infectious disease of epidemic potential caused by the Hantaan virus (HTNV). Red blood cells (RBCs) are the major components of peripheral blood. However, pathological changes in RBCs and the underlying mechanisms during HTNV infection remain largely unclear. Therefore, this study sought to explore changes in RBCs in the peripheral blood of HFRS patients. We isolated PBMCs from HFRS patients and performed single-cell RNA sequencing. The results showed that clusters of RBCs in the peripheral blood of HFRS could be classified as nucleated red blood cells (NRBC) based on their cellular components, gene expression profiles and cell surface markers. In addition, it was shown that the higher the count of NRBC in peripheral blood, the more severe the disease status was. Moreover, hematological indices related to RBCs were analyzed and the results showed that impairment in the folate pathway might be the possible reason behind the presence of NRBCs. This study, for the first time showed that the presence of NRBCs in the peripheral blood of HFRS patients was associated with disease severity. This was also the first study to show that infection with the HTNV virus hindered the maturation of RBCs. Therefore, this work provides further insights on the role of and pathological changes in RBCs during HTNV infection.

Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p.

BACKGROUND: Patients with severe acute pancreatitis (SAP), which is characterized by high morbidity and mortality, account for an increasing medical burden worldwide. We previously found that mesenchymal stem cells (MSCs) could attenuate SAP and that expression of long noncoding RNA H19 (LncRNA H19) was upregulated in rats receiving MSCs. In the present study, we investigated the mechanisms of LncRNA H19 regulating the therapeutic efficacy of MSCs in the alleviation of SAP. METHODS: MSCs transfected with LncRNA H19 overexpression and knockdown plasmids were intravenously injected into rats 12 h after sodium taurocholate (NaT) administration to induce SAP. RESULTS: Overexpressing LncRNA H19 in MSCs significantly enhanced the anti-inflammatory capacity of the MSCs, inhibited autophagy via promotion of focal adhesion kinase (FAK)-associated pathways, and facilitated cell proliferation by increasing the level of ß-catenin in rats with SAP. LncRNA H19 functioned as a competing endogenous RNA by sponging miR-138-5p and miR-141-3p. Knocking down miR-138-5p in MSCs increased the expression of protein tyrosine kinase 2 (PTK2, encoding FAK) to suppress autophagy, while downregulating miR-141-3p enhanced the level of ß-catenin to promote cell proliferation. CONCLUSIONS: In conclusion, LncRNA H19 effectively increased the therapeutic efficacy of MSCs in rats with SAP via the miR-138-5p/PTK2/FAK and miR-141-3p/ß-catenin pathways.

Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis.

OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BMSCs) are effective in the treatment of severe acute pancreatitis (SAP), but their therapeutic effects could still be improved. In order to optimize the clinical application of BMSCs, we adopted the strategy of resveratrol (Res) pretreatment of BMSCs (Res-BMSCs) and applied it to a rat model of sodium taurocholate (NaT)-induced acute pancreatitis. METHODS: SAP was induced by injection of 3% NaT into the pancreatic duct and successful induction of SAP occurred after 12 h. Rats were treated with BMSCs, Res or BMSCs primed with Res at 40 mmol/L, Vandetanib (ZD6474) daily oral dosages of 50 mg/kg vandetanib. RESULTS: Res stimulated BMSCs to secrete vascular endothelial growth factor A (VEGFA), activated the downstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and inhibited pancreatic cell apoptosis. In addition, conditioned medium (CM) from Res-BMSCs enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, increased resistance to apoptosis and promoted the expression of angiogenesis-related proteins CD31, VEGF and VEGFR2 in pancreatic tissue, but Vandetanib partly abolished these effects by blocking the VEGFA- mediated pathway. CONCLUSION: Resveratrol-preprocessed BMSCs can activate the PI3K/AKT signaling pathway in pancreatic cells and HUVECs through paracrine release of VEGFA; thus, achieving the therapeutic effect of resisting apoptosis of pancreatic cells and promoting regeneration of damaged blood vessels. Res pretreatment may be a new strategy to improve the therapeutic effect of BMSCs on SAP.

Bone marrow-derived mesenchymal stem cells alleviate severe acute pancreatitis-induced multiple-organ injury in rats via suppression of autophagy.

Patients with severe acute pancreatitis (SAP) represent a substantial challenge to medical practitioners due to the high associated rates of morbidity and mortality and a lack of satisfactory therapeutic outcomes. In a previous study, our group demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate SAP; however, the mechanisms of action remain to be fully understood. BMSCs were intravenously injected into SAP rats 12 h after experimental induction of SAP using sodium taurocholate (NaT). Histopathological changes and the levels of pro-inflammatory mediators were assessed by hematoxylin and eosin (H&E) staining and ELISA, respectively. Autophagy levels were assessed using qRT-PCR, western blotting, immunohistochemistry, immunofluorescence, and transmission electron microscopy. AR42J cells and human umbilical vein endothelial cells (HUVECs) were administered BMSC-conditioned media (BMSC-CM) after NaT treatment, and cell viability was measured using a Cell Counting Kit-8 (CCK-8) and flow cytometry. In vivo, BMSCs effectively reduced multiple systematic inflammatory responses, suppressed the activation of autophagy, and improved intestinal dysfunction. In vitro, BMSC-CM significantly improved the viability of injured cells, promoted angiogenesis, and decreased autophagy. We therefore propose that the administration of BMSCs alleviates SAP-induced multiple organ injury by inhibiting autophagy.

Clinical role of frequency-doubled double-pulse neodymium YAG laser lithotripsy for removal of difficult biliary stones in laparoscopic common bile duct exploration.

BACKGROUND: The optimal methods for patients with difficult biliary stones remain under debate. The aim of this study was to evaluate the role of frequency-doubled double-pulse neodymium YAG (FREDDY) laser lithotripsy for removing difficult biliary stones during laparoscopic common bile duct exploration (LCBDE). METHODS: Between March 2013 and January 2015, 42 consecutive patients with difficult biliary stones who underwent LCBDE with FREDDY laser lithotripsy were included in this study. The clinical data of all patients were retrospectively collected and analysed. RESULTS: Bile ducts were completely cleared in all patients. The complications related to laser lithotripsy were not noted. A total of 38 patients (90.5%) underwent primary closure of common bile duct, and T-tube drainage was applied to four patients (9.5%). No bile duct injury, bleeding and perforation were observed. There were no post-operative surgery-related deaths. Bile leakage occurred in four patients (9.5%) with primary closure procedure, and all of them were managed successfully with conservative therapy. The median follow-up period was 42.8 months, with no evidence of bile duct stricture and stone recurrence in all patients. CONCLUSIONS: The LCBDE combined with FREDDY laser lithotripsy appear to be effective and safe for the treatment of difficult biliary stones.

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting necroptosis in rats.

The treatment and prognosis for severe acute pancreatitis (SAP) is currently unsatisfactory showing a high incidence of morbidity and mortality. Here, we investigated the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on SAP in rats and explored the possible mechanisms. The common bile duct of each model rat was occluded at the liver hilum, and the induction of SAP was achieved by retrograde perfusion of 3% sodium taurocholate (NaT). Prepared BMSCs were intravenously injected via the tail vein. Pancreatic acinar cells (PACs) were isolated from rat pancreas, and induced by TNF-α. In the present study, we found that necroptosis was activated in NaT-induced acute-necrotized pancreatitis, and transplanted BMSCs could inhibit necroptosis, repair pancreatic injury, and reduce systemic inflammatory response. In addition, necrostatin-1 (Nec-1), as the inhibitor of receptor-interacting protein kinase 1 (RIPK1), could also reduce SAP to some extent. Besides, we detected that BMSCs could also promote regeneration of damaged pancreatic tissues. Furthermore, in vitro, we also investigated that BMSCs could suppress TNF-α-induced necroptosis and improve the viability of PACs. In addition, Nec-1 and knockdown of receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) could also inhibit necrosis of PACs induced by TNF-α. BMSCs ameliorated SAP and reduced injury of PACs by suppressing the activation of the necroptosis signaling pathway.

Bone marrow-derived mesenchymal stem cells attenuate severe acute pancreatitis via regulation of microRNA-9 to inhibit necroptosis in rats.

AIMS: Severe acute pancreatitis (SAP) is an acute disease of the digestive system accompanied by pancreatic necrosis. We have found that bone marrow-derived mesenchymal stem cells (BMSCs) can attenuate SAP, but the underlying mechanism remains unclear. The present study was conducted to explore the possible mechanisms by which BMSCs alleviate SAP. MAIN METHODS: BMSCs and BMSCs engineered to overexpress microRNA (miR)-9 (miR-9-BMSCs) were transplanted into rat models of SAP via the tail vein. Pancreatic acinar cells (PACs) were isolated from rat pancreatic tissues and induced by tumor necrosis factor-α (TNF-α) in vitro. KEY FINDINGS: miR-9-BMSCs significantly reduced the systemic inflammatory response, impeded the necroptosis signaling pathway and promoted regeneration of damaged pancreas in vivo. miR-9-BMSCs secreted miR-9, which targeted the gene encoding receptor interacting protein kinase 1 in PACs induced by TNF-α, to inhibit necroptosis and ameliorate SAP. SIGNIFICANCE: miR-9-BMSCs can reduce SAP-induced injury to pancreatic tissues and PACs by regulating miR-9 to suppress necroptosis.

Author Correction: PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1.

In the version of this article initially published, what was originally described as 'conditioned place preference' in a two-chamber mouse experiment could be better described as 'conditioned place avoidance'.

Bone marrow-derived mesenchymal stromal cells ameliorate severe acute pancreatitis in rats via hemeoxygenase-1-mediated anti-oxidant and anti-inflammatory effects.

BACKGROUND AND AIMS: It has been previously verified that mesenchymal stromal cells (MSCs) have a good therapeutic effect on severe acute pancreatitis (SAP) and the potential for regeneration of damaged pancreatic tissue, but the exact molecular mechanism remains unclear. In this study, we demonstrated the therapeutic effect of bone morrow MSCs (BMSCs) on SAP, probably by targeting heme oxygenase-1 (HO-1). METHODS: Six hours after SAP induction, either phosphate-buffered saline (PBS) or BMSCs were transfused into the caudal vein of rats, zinc protoporphyrin (ZnPP) was administered intraperitoneally. Pancreatic pathological scoring, serum levels of amylase and inflammatory factors, as well as levels of reactive oxygen species (ROS), malondialdehyde (MDA) and myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) activity in the pancreas were evaluated. RESULTS: Our data showed that BMSCs significantly reduce inflammation and oxidative stress, reduce apoptosis and promote angiogenesis of damaged pancreas. Moreover, BMSCs increased the level of HO-1 in the serum and pancreatic tissue in rats with SAP. In addition, the protective effect of BMSCs was partially neutralized by the HO-1 activity inhibitor ZnPP, suggesting a key role of HO-1 in the therapeutic effect of BMSCs on SAP. CONCLUSIONS: BMSCs ameliorated SAP, probably by inducing expression of HO-1, which can exert anti-inflammatory and anti-oxidant effects, reduce apoptosis and promote angiogenesis.

N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a high mortality disease, for which there is a lack of effective therapies. Previous research has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs), which have immunomodulatory and antioxidant properties, have potential for the treatment of SAP. It remains unclear, however, whether the free radical scavenger N-acetylcysteine (NAC) can enhance the therapeutic efficacy of BMSC transplantation in SAP. In this study, we investigated the effect of combining treatment with NAC and BMSCs in a rat model of SAP. METHODS: SAP was induced by injection of sodium taurocholate into the pancreatic duct and, after successful induction of SAP, the rats were treated with BMSCs and NAC, either singly or in combination. RESULTS: After 3 days, serum levels of amylase, proinflammatory factors, malondialdehyde, and reactive oxygen species were significantly decreased in animals treated with BMSCs or NAC, compared with vehicle-treated animals. In contrast, total glutathione, superoxide dismutase and catalase were markedly increased after treatment with BMSCs or NAC. However, oxidative stress markers and inflammatory factors were significantly improved in the SAP + BMSCs + NAC group compared with those in the SAP + NAC group and the SAP + BMSCs group. CONCLUSIONS: Combined NAC and BMSC therapy was found to alleviate oxidative stress damage to the pancreas and to inhibit the inflammatory response to a significantly greater extent than single therapy with either BMSCs or NAC. Because NAC enhances the therapeutic efficacy of BMSC transplantation in a rat model of SAP, combined therapy may provide a promising new approach for the treatment of SAP.

Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current ( Ih) in large-diameter dorsal root ganglion neurons.

Cervical radiculopathic pain is a very common symptom that may occur with cervical spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain and is inadequately treated with current therapies. However, the precise mechanisms underlying cervical radiculopathic pain-associated mechanical allodynia have remained elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal root ganglion neurons and plasticity of spinal circuitry attached with Aß fibers in mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these changes are yet to be known. With combination of patch-clamp recording, immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon chronic compression of C7/8 dorsal root ganglions, large-diameter cervical dorsal root ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability. Quantitative analysis of hyperpolarization-activated cation current ( Ih) revealed that Ih was greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic pain rats. This increased Ih was supported by the enhanced expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3 in large dorsal root ganglion neurons. Blockade of Ih with selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated with cervical radiculopathic pain. This study sheds new light on the functional plasticity of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel mechanism that could underlie the mechanical allodynia associated with cervical radiculopathy.

PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1.

Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K+ channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.

Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord.

Previous studies have shown that activation of p38 mitogen-activating kinase (MAPK) in spinal microglia participates in the generation of inflammatory and neuropathic pain in various rodent models. However, these studies focused on male mice to avoid confounding effects of the estrous cycle of females. Recent studies have shown that some spinal pro-inflammatory signaling such as Toll-like receptor 4-mediated signaling contributes to pain hypersensitivity only in male mice. In this study we investigated the distinct role of spinal p38 in inflammatory and neuropathic pain using a highly selective p38 inhibitor skepinone. Intrathecal injection of skepinone prevented formalin induced inflammatory pain in male but not female mice. Furthermore, intrathecal skepinone reduced chronic constriction injury (CCI) induced neuropathic pain (mechanical allodynia) in male mice on CCI-day 7 but not CCI-day 21. This male-dependent inhibition of neuropathic pain also occurred in rats following intrathecal skepinone. Nerve injury induced spinal p38 activation (phosphorylation) in CX3CR1-GFP(+) microglia on CCI-day 7, and this activation was more prominent in male mice. In contrast, CCI induced comparable microgliosis and expression of the microglial markers CX3CR1 and IBA-1 in both sexes. Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Finally, skepinone only reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of males 7days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions.

Upregulation of Ih expressed in IB4-negative Aδ nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain.

Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron's ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4(-) Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4(-) Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy.

Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity.

Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity.

Research progress in transient receptor potential vanilloid 1 of sensory nervous system.

The transient receptor potential vanilloid subfamily member 1 (TRPV1) is a protein mainly expressed in sensory neurons and fibers, such as in trigeminal ganglion and dorsal root ganglion, and has been indicated to be involved in several physiological and pathological processes. Studies on thermal activation have revealed that phosphorylation is involved in TRPV1 activation and 2 putative phosphorylation sites, Ser residues 502 (Ser-502) and Ser residues 800 (Ser-800), have been recently confirmed to possess the capability of resensitizing TRPV1. In addition to acidification, alkalization has also been proved to be a highly effective stimulator for TRPV1. TRPV1 could be regulated by various physical and chemical modulators, as well as the chronic pain. TRPV1 plays a crucial role in the transmission of pain signals, especially under inflammation and the neoplasm conditions, and it can also modulate nociceptive afferents by reinforcing morphine tolerance. The present review mainly focused on the structural and functional complexities of TRPV1, together with its activation and modulation by a wide variety of physical and chemical stimuli. Its pharmacological manipulation (sensitization/desensitization) and therapeutical targets were also discussed.

[Nonlinear analysis of multi-channel EEG and its application to mental workload detection].

Mental workload research is important to people's health and work efficiency, Psychophysiological measures such as electroencephalography (EEG), ECG and respiration measures can be used to predict mental workload level. A Multi-channel phase-space reconstruction method is proposed in this paper which rearranges signal serials by the correlation coefficients and select time delay by signal determinism. The study of determinism and correlation dimension on simulative data exhibits a good performance. The result of EEG series shows a clearly consistency to workload level variety. The method is useful for multi-channel signals nonlinear analysis and mental workload detection.

[Analyzing sleep EEG using correlation dimension and approximate entropy].

Correct sleep scoring is the base of sleep studying; nonlinear features of EEG can represent different sleep stages. In this paper, correlation dimension (D2) and approximate entropy (ApEn) of sleep EEG have been calculated. The statistical results reveal that: D2 does not come to be saturated when the embedding dimension increases, but the relative value of D2 can effectively distinguish different sleep stages. ApEn has the advantage of calculating simply, steady result and representing preferably different sleep stages. ApEn and the relative value of D2 reveal, from different point of view, the same rule about EEG (brain) complexity changing, that is, both complexity and its fluctuation are maximal in the subject's awake hour, are decreasing with the deepening of sleep, but the complexity in REM is about the level between S1 and S2.