Long-Term Efficacy and Safety of High-Frequency Spinal Stimulation for Chronic Pain: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of our meta-analysis was to systematically assess the enduring effectiveness and safety of high-frequency spinal stimulation (HF-SCS) in the management of chronic pain. METHODS: We developed a comprehensive literature search strategy to identify clinical trials investigating the efficacy of high-frequency spinal stimulation for chronic pain. The search was conducted in multiple databases, including Web of Science, Cochrane, PubMed, and Embase, covering the period from 2004 to 2023. The inclusion and exclusion criteria established for this study were applied to screen the eligible literature by carefully reviewing abstracts and, when necessary, examining the full text of selected articles. To assess the quality of the included studies, we utilized the Risk of Bias assessment tool provided by the Cochrane Collaboration. The PRISMA method was followed for the selection of articles, and the quality of the articles was evaluated using the risk assessment table for bias provided by the Cochrane Collaboration. Meta-analysis of the selected studies was performed using Review Manager 5.4 and STATA 16.0. Effect sizes for continuous data were reported as mean differences (MD) or standardized mean differences (SMD), while categorical data were analyzed using relative risks (RR). RESULTS: According to our predefined literature screening criteria, a total of seven English-language randomized controlled trials (RCTs) were included in the meta-analysis. The findings from the meta-analysis demonstrated that HF-SCS exhibited superior efficacy in the long-term treatment of chronic pain when compared with the control group (RR=2.44, 95% CI: 1.20-4.96, P =0.01). Furthermore, HF-SCS demonstrated a statistically significant improvement in the Oswestry Disability Index score (mean difference MD=3.77, 95% CI: 1.17-6.38, P =0.005). However, for pain assessment (standardized mean difference SMD=-0.59, 95% CI: -1.28 to 0.10, P =0.09), Patient Global Impression of Improvement (PGI-I) score (MD=0.11, 95% CI: -0.66 to 0.88, P =0.78 for 6 months; MD=0.02, 95% CI: -0.42 to 0.43, P =0.97 for 12 mo), Clinical Global Impression of Improvement (CGI-I) score (MD=-0.58, 95% CI: -1.62 to 0.43, P =0.27 for 6 mo; MD=-0.23, 95% CI: -0.94 to 0.48, P =0.52 for 12 mo), and occurrence of adverse effects (odds ratio [OR]=0.77, 95% CI: 0.23-2.59, P =0.67), HF-SCS did not show statistically sufficient effects compared with the control group. CONCLUSIONS: The findings from our comprehensive review and meta-analysis offer encouraging data about the prolonged efficacy and safety of HF-SCS in chronic pain management on some but not all outcomes. Recognizing the constraints of the existing evidence is crucial. Additional clinical trials, meticulously planned and stringent, are essential to bolster the current body of evidence and reach more conclusive findings.

Translocator protein alleviates allodynia and improves Schwann cell function against diabetic peripheral neuropathy via activation of the Nrf2-dependent antioxidant system and promoting autophagy.

AIMS: In diabetes, autophagy and the nuclear factor erythroid-derived-2-like 2 (Nrf2)-dependent antioxidant system are impaired. Translocator protein (TSPO) agonist Ro5-4864 alleviates neuropathic pain, including diabetic peripheral neuropathy (DPN). However, the precise mechanisms remain unclear. Thus, we investigated the effects of Ro5-4864 on autophagy and the Nrf2-dependent antioxidant system in the sciatic nerves of DPN rats. METHODS: All rats were randomly assigned to Sham or DPN group. After type 2 diabetes modelling (established by high-fat diet and streptozotocin injection) followed by behavioural tests, established DPN rats were randomly assigned to the DPN group, the Ro (TSPO agonist Ro5-4864) group, the Ro + 3-MA (autophagy inhibitor) group and the Ro + ML385 (Nrf2 inhibitor) group. Behavioural assessments were performed at baseline, on days 3, 7, 14, 21 and 28. Sciatic nerves were collected on day 28 for immunofluorescence, morphological and western blot analyses. RESULTS: Ro5-4864 alleviated allodynia and increased myelin sheath thickness and myelin protein expression after DPN. Beclin-1 (p < 0.01) and LC3-II/LC3-I ratio (p < 0.01) decreased and p62 (p < 0.01) accumulated in the DPN rats. Ro5-4864 administration increased the Beclin-1 and LC3-II/LC3-I ratio and decreased p62 accumulation. Furthermore, nuclear Nrf2 contents (p < 0.01) and cytoplasmic HO-1 (p < 0.01) and NQO1 (p < 0.01) expressions were significantly inhibited in the DPN rat, which was also improved by Ro5-4864. All the beneficial effects were abrogated by 3-MA or ML385. CONCLUSION: TSPO exhibited a potent analgesic effect and improved Schwann cell function and regeneration against DPN by activating the Nrf2-dependent antioxidant system and promoting autophagy.

Blind-noise image denoising with block-matching domain transformation filtering and improved guided filtering.

The adaptive block size processing method in different image areas makes block-matching and 3D-filtering (BM3D) have a very good image denoising effect. Based on these observation, in this paper, we improve BM3D in three aspects: adaptive noise variance estimation, domain transformation filtering and nonlinear filtering. First, we improve the noise-variance estimation method of principle component analysis using multilayer wavelet decomposition. Second, we propose compressive sensing based Gaussian sequence Hartley domain transform filtering to reduce noise. Finally, we perform edge-preserving smoothing on the preprocessed image using the guided filtering based on total variation. Experimental results show that the proposed denoising method can be competitive with many representative denoising methods on the evaluation criteria of PSNR. However, it is worth further research on the visual quality of denoised images.

[Acupoint selection rules of acupuncture for pseudobulbar palsy dysphagia].

OBJECTIVE: To analyze the acupoint selection rules of acupuncture for pseudobulbar palsy dysphagia using data mining technology. METHODS: The literature of acupuncture for pseudobulbar palsy dysphagia published from January 1, 1990 to May 1, 2021 was retrieved from CNKI, SinoMed, Wanfang, VIP, and PubMed databases. Acupuncture prescription database was established. The frequency of acupoint selection was analyzed by Microsoft Excel 2016; Apriori algorithm was used to analyze the association rules and draw the high-frequency acupoint co-occurrence network diagram; SPSS21.0 was used to perform clustering analysis. RESULTS: A total of 87 literature was included, involving 89 acupuncture prescriptions and 71 acupoints. Fengchi (GB 20) was the most frequently-used acupoint; the commonly-selected meridians were gallbladder meridian, conception vessel, governor vessel and stomach meridian; the acupoints located at the neck were the most frequently-used acupoints; the crossing points were commonly selected among the special acupoints. The most commonly-used acupoint combination was Jinjin (EX-HN 12) plus Yuye (EX-HN 13). CONCLUSION: The modern acupuncture for pseudobulbar palsy dysphagia usually selects local acupoints, especially the neck acupoints such as Fengchi (GB 20) and Lianquan (CV 23). The acupoints in the front and back are concurrently selected with needles towards the disease location.

Dithiane-Induced [3+2] Cycloaddition Tactic for the Convergent Synthesis of Dihydropyrrole and Pyrrole Derivatives.

An efficient transition-metal-free tactic for the convergent synthesis of substituted dihydropyrroles and pyrroles by ß-chloro-vinyl dithiane cyclization with a broad range of imines was developed. [3+2] Cyclization and aromatization occur under these reaction conditions providing biologically relevant dihydropyrroles and pyrroles in good yields.

Highly Sensitive Gas-Sensing Films for Volatile Organic Acids from Imidazolium-Based Poly(ionic liquid)s.

Imidazolium-based poly(ionic liquid)s were synthesized and used as sensing film for the adsorption of volatile organic compounds. Based on a quartz crystal microbalance system, the sensing properties of the imidazolium-based poly(ionic liquid)s on volatile organic compounds was assessed according to the position of imidazolium cation in the polymer chain (the main-chain or side-chain type) and the varied counterions. The results indicated that the imidazolium-based poly(ionic liquid)s films have much higher adsorption capability on volatile organic acids than other volatile organic compounds, which is due to the strong affinity between imidazolium group and the carboxyl group. The position of imidazolium cation in the polymer chain and counterions of the imidazolium-based poly(ionic liquid)s was found to be able to influence the selectivity and sensitivity of volatile organic acids. The main-chain imidazolium-based poly(ionic liquid)s were shown strengthen the adsorption of propionic acid vapor, while the counter ion of dicyanamide showed the highest selectivity on volatile organic acids. Based on the quartz crystal microbalance sensing system, the imidazoliumbased poly(ionic liquid)s film was shown capable of detecting volatile organic acids with a theoretical detection limit of about 3.1 ppb and a quick recovery time less than 40 seconds. The sensing performance is also stable for repeated usage and after long-time storage.

Suspicious outbreak of ventilator-associated pneumonia caused by Burkholderia cepacia in a surgical intensive care unit.

BACKGROUND: We reviewed Burkholderia cepacia infections in a hospital from 2013-2016 to report a suspicious outbreak that occurred in a surgical intensive care unit in 2015, and to outline the infection control measures adopted thereafter. METHODS: Review of the health care-associated infection data regarding B cepacia via the surveillance system, hospital information system, electronic medical records, and laboratory information system together with the outbreak investigation was managed by the health care-associated infection control team. RESULTS: During June 1-14, 2015, 4 cases of ventilator-associated pneumonia (VAP) were identified; B cepacia was isolated from endotracheal aspirate samples. On June 16, 120 environmental samples were collected and analyzed for microbiologic differentiation. Thirteen strains of B cepacia were prominently found in the expiratory blocks of ventilators, revealing the biocontamination source. After chemical disinfection without damaging ventilator components, repeat microbiologic testing of random ventilator samples yielded negative results until July 30, 2015. Retrospective data showed that isolation rates of B cepacia strains had increased since 2014. Although the resistance phenotype of these strains varied slightly, they exhibited similar patterns of antibiotic susceptibility. CONCLUSIONS: Routine cleaning and disinfection of ventilators, in addition to an intervention bundle, should form part of an integrated VAP prevention and management approach.

siRNA-mediated silencing of phosphodiesterase 4B expression affects the production of cytokines in endotoxin-stimulated primary cultured microglia.

Phosphodiesterase 4 (PDE4) has four subtypes: PDE4A, PDE4B, PDE4C and PDE4D. The expression of PDE4 subtypes in microglial cells and the specific contribution of each subtype to inflammation remain unclear. In this study, the expression of PDE4 subtypes in primary microglial cells was assayed. Primary microglial cells were then transfected with specific small interfering RNA (siRNA) against each PDE4 subtype. PDE4 subtype A-D knockdown was confirmed by quantitative polymerase chain reaction. Secreted cytokines in the supernatant and intracellular cyclic adenosine monophosphate (cAMP) levels of transfected cells were measured. The effect of PDE4B siRNA on the activation of extracellular regulated protein kinase (ERK) induced by lipopolysaccharide (LPS) in microglia was further tested by western blotting. Results showed that the primary microglial cells expressed all four types of PDE4s at the protein level. Transfection with the four siRNAs inhibited PDE4 subtype A-D mRNA expression, respectively. In primary microglial cells, treatment with PDE4B siRNA significantly inhibited the expression of tumor necrosis factor-α and interleukin (IL)-1ß, and enhanced the expression of cAMP, while siRNAs to other subtypes had no significant effects. However, none of the four siRNAs had any significant effect on the expression of IL-10. Furthermore, in the PDE4B group, the level of phosphorylated ERK was reduced. Among the four PDE4 subtypes, PDE4B plays an important role in regulating inflammatory responses in microglia, potentially through initially regulating the intracellular cAMP concentration.

Effect of pioglitazone on neuropathic pain and spinal expression of TLR-4 and cytokines.

The molecular mechanisms underlying neuropathic pain have yet to be elucidated. The present study aimed to examine the modulation of neuroimmune activation in the spinal cord by the synthetic peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, pioglitazone (Pio), in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Rats were randomly assigned into four groups: Sham surgery with vehicle, chronic constriction injury with vehicle or Pio (10 mg/kg), and chronic constriction injury with Pio and a PPAR-γ antagonist GW9662 (2 mg/kg). Pio or vehicle was administered 1 h prior to the surgery and continued daily until day 7 post-surgery. Paw pressure threshold was measured prior to surgery and on days 0, 1, 3 and 7 post-surgery. Microglia activation markers macrophage antigen complex-1, the mRNA expression levels of tumor necrosis factor α and interleukin-1ß, and the mRNA expression levels of toll like receptor (TLR-4) in the lumbar spinal cord were determined. Administration of Pio resulted in the prominent attenuation of mechanical hyperalgesia. In addition, Pio was able to significantly inhibit neuroimmune activation characterized by glial activation, the production of cytokines and expression levels of TLR-4. Concurrent administration of a PPAR-γ antagonist, GW9662, reversed the effects of Pio. The antihyperalgesic effect of administration of Pio in rats receiving CCI may, in part, be attributed to the inhibition of neuroimmune activation associated with the sustaining of neuropathic pain.

Spinal Heme Oxygenase-1 (HO-1) Exerts Antinociceptive Effects Against Neuropathic Pain in a Mouse Model of L5 Spinal Nerve Ligation.

OBJECTIVE: Heme oxygenase-1 (HO-1) exerts protective effects against ischemia and inflammation in the central nervous system. However, its role in neuropathic pain is still unclear. This study was undertaken to explore the distribution and possible mechanism of HO-1 in a mouse model of peripheral nerve injury. DESIGN AND METHODS: The experiment was conducted using a mouse model of L5 spinal nerve ligation (SNL). Mice received repeated intraperitoneal injection of Carbon monoxide-releasing molecule-2 (CO-RM-2), HO-1 inducer cobalt protoporphyrin IX (CoPP) or single intraspinal injection of lentivirus (LV) over-expressing HO-1. The behavior analyses were conducted. The distribution and expression of HO-1 in the spinal cord were analyzed. RESULTS: HO-1 but not HO-2 was upregulated in spinal cord microglia cells after nerve injury, and the repeated intraperitoneal administration of CORM-2 (10 mg/kg/d) or CoPP (5 mg/kg/d) both significantly reduced the mechanical allodynia and thermal hyperalgesia induced by SNL (P < 0.01). Intraspinal injection of LV-HO-1 persistently suppresses SNL-induced neuropathic pain (P < 0.01 or P < 0.05), significantly induced the spinal HO-1 protein content (P < 0.01) and inhibited the microglia activation (P < 0.01) 7 days after SNL. CONCLUSION: HO-1 upregulation could elicit potent analgesic effects against neuropathic pain, which might partly be attributed to inhibition of spinal microglia activation. HO-1 signaling pathway may present a novel strategy for the treatment of neuropathic pain.

Spinal neuroimmune activation inhibited by repeated administration of pioglitazone in rats after L5 spinal nerve transection.

Neuroimmune activation contributes to the generation and maintenance of neuropathic pain after peripheral nerve injury. Peroxisome proliferator activated receptor gamma (PPAR-γ) agonists have potential neuroprotection. The current study aimed to determine the effects of a PPAR-γ agonist pioglitazone on mechanical hyperalgesia and neuroimmune activation in a rat model of neuropathic pain induced by L5 spinal nerve transection (SNT). Thirty-two rats were equally randomized into 4 groups: sham operation with vehicle; L5 SNT with vehicle or pioglitazone; or L5 SNT with pioglitazone and a PPAR-γ antagonist GW9662. Pioglitazone or vehicle was administered 1h before operation and continued daily to day 14 after operation. The paw pressure threshold (PPT) was measured before operation and on days 3, 7, 14 after operation. Glial fibrillary acidic protein (GFAP) expression, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels, and nuclear factor-kappa B (NF-κB) activity in the lumbar spinal cord were determined on day 14 after operation. The results displayed pioglitazone improved the mechanical hyperalgesia, and attenuated the astrocyte and NF-κB activation and the inflammatory cytokine upregulation in nerve-injured rats, which might be reversed by GW9662. In conclusion, pioglitazone ameliorates the mechanical hyperalgesia induced by L5 SNT via inhibiting the spinal neuroimmune activation in rats, suggesting spinal PPAR-γ signaling pathway may be involved in the pathogenesis of mechanical hyperalgesia.

Pichia fabianii blood infection in a premature infant in China: case report.

BACKGROUND: Invasive fungal infections caused by uncommon fungi have increased in recent years. Hospitalized low-birth-weight infants are at high risk for neonatal fungal infections. Pichia fabianii is a rare pathogen causing blood infection, which has reportedly caused only 4 cases of fungemia and 1 case of endocarditis worldwide. Here, we describe the first case of a P. fabianii blood infection in a premature infant in China. CASE PRESENTATION: On July 28th, a low-birth-weight (LBW, 1760 g) female infant born at 33+4 weeks of gestation was admitted to the pediatric intensive care unit with mild neonatal asphyxia. Until August 2nd, a mechanical respirator was used to assist respiration under the Continuous Positive Airway Pressure (CPAP) model. The baby had an increased body temperature and a fever. To prevent infection, Ceftriaxone Sodium (CS) was administered intravenously for three days, after which Cefepime was administered until August 13th. Chest X-rays showed suspected plaque-like shadows in the right lung. Blood cultures twice tested positive for fungal infection caused by Candida pelliculosa (recognized as Pichia fabianii later), which is first mis-identified by commercial kit. Hence, intravenous fluconazole was administered. However, cultures of other body fluids (e.g., urine, feces and sputum) tested negative for fungal infection. Routine tests and biochemistry of cerebrospinal fluid (CSF) were normal. Latex agglutination of Cryptococcus neoformans and fungi cultures in the CSF were also negative. After 14 days of intravenous fluconazole, blood was re-cultured, the result of which was negative. On August 30th, intravenous fluconazole was suspended. On Sep 3rd, the infant left the hospital in good health. CONCLUSIONS: This is the first case of a blood infection caused by P. fabianii in a LBW premature female infant in China. Risk factors for fungal infection include premature birth, as well as mechanical invasive operation and antibacterial drug usage. Whether such risk factors necessitate prophylactic use of antifungal drugs is an important question that has yet to be fully addressed. Additionally, the pathogen P. fabianii collected in this study was resistant to amphotericin B (AMB) and itraconazole (ITR). With the exception of the azole-resistant endocarditis case, all other cases have not demonstrated such a resistance. Finally, commercial biochemical methods used in routine practice are limited in their ability to identify P. fabianii. Molecular genetic based methods are imperative for identification of uncommon fungal species from disseminated infections.

Repeated administration of pioglitazone attenuates development of hyperalgesia in a rat model of neuropathic pain.

Recent studies indicate the central neuroimmune and neuroinflammation activation play a critical role in the pathological states of pain. Pioglitazone, a potent synthetic agonists of PPARgamma, has shown to control neuroinflammation in many nervous system-related disorders. The present study was designed to explore the effects of pioglitazone in treating neuropathic pain and its possible neuroimmune mechanisms in the neuropathic pain using lumbar 5 (L5) spinal nerve transection rat model. L5 spinal nerve transection was done to produce hyperalgesia in rats. Pioglitazone (2.5, 5, and 10 mg/kg) was orally administered daily for 14 days, beginning from 1 hour before nerve transection. Mechanical hyperalgesia was measured using Von-Frey filament tests before and after the surgery. Rats were then sacrificed on day 14 postsurgery. The mRNA of inflammatory cytokines such as tumor necrosis factor (TNF-alpha), interleukin (IL-1beta) and nuclear factor kappa B (NF-kappaB) activity in brain were detected using reverse transcription-polymerase chain reaction and electrophoretic mobility shift assay. We found that pioglitazone (5 and 10 mg/kg) can markedly attenuate mechanical hyperalgesia produced by nerve transection, most significantly on the 14th day. The elevated TNF-alpha, IL-1beta, and NF-kappaB in brain were accordingly reduced. Our data could conclude that pioglitazone has ameliorative potential in attenuating the painful state associated with L5 nerve transection, which may further be attributed to inhibiting cerebral proinflammatory cytokines production and NF-kappaB activation in central nervous system.

Protective effects of pentoxifylline on the brain following remote burn injury.

INTRODUCTION: Brains are often subject to injurious effect following remote burn injury and increased productions of inflammatory cytokines are involved. It is also known that pentoxifylline (PTX) exerts multiple beneficial effects on the inflammatory cascade. Therefore, we investigated whether a single dose of PTX given immediately following severe remote burn would protect the brain from the injurious effects. METHODS: Rats were divided randomly into the sham burn group, burn placebo-treated group and burn PTX-treated group. Single dose of PTX was injected 15 min following initial burn injury. We measured the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 in the brain tissue at 0.5, 1, 2, 4, 8 and 16 h after burn. Other measures included the level of nuclear factor-kappaB (NF-κB) activation, glial activation and apoptosis of cortical cells. RESULTS: PTX substantially suppressed the burn-induced surge in the levels of TNF-α, IL-1ß, and IL-6 in the rat-brain tissues. PTX reduced the level of burn-induced apoptosis. PTX also significantly reduced the activation of nuclear transcription factor NF-κB and reduced the activation of glial cells in the brain tissue. CONCLUSION: An early, single dose of PTX dramatically reduced brain inflammation and apoptosis for up to 16 h post-injury.

Effects of retroperitoneal or transperitoneal laparoscopic surgery on hemodynamic and respiratory function in old patients.

PURPOSE: To compare the effects of retroperitoneal laparoscopic surgery (RPL) and transperitoneal laparoscopic surgery (TPL) on the hemodynamic and ventilatory functions in old patients. METHODS: Thirty-two senior patients underwent either RPL or TPL. Swan-Ganz and radial artery catheters were placed to monitor hemodynamic functions. Artery blood samples were obtained to analyze ventilatory functions. RESULTS: For hemodynamic changes in both TPL and RPL, central venous pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure significantly increased 10 min after CO(2) insufflation and decreased to preanesthesia levels roughly 30 min after insufflation relief. For ventilatory functions, in both TPL and RPL, peak airway pressure, partial pressure of arterial carbon dioxide (PaCO(2)), end-tidal carbon dioxide tension (PetCO(2)), carbon dioxide output (VCO(2)), and the difference between PaCO(2) and PetCO(2) (Pa-PetCO(2)) all increased significantly 10 min after CO(2) insufflation and returned to the preanesthesia level 20 min after CO(2) desufflation. However, increments of PaCO(2), VCO(2) and Pa-PetCO(2) were significantly higher in RPL than in TPL, and did not return to the preanesthesia level until 30 min after CO(2) desufflation. CONCLUSION: For senior patients, TPL and RPL have similar effects on hemodynamic functions. However, RPL tends to cause much more change in the respiratory measurements.

Effects of recombinant human erythropoietin on neuropathic pain and cerebral expressions of cytokines and nuclear factor-kappa B.

PURPOSE: The effect of recombinant human erythropoietin (rhEPO) on neuropathic pain remains unclear. This study aimed to determine the effects of preemptive administration of rhEPO on the behavioural changes and neuroinflammatory responses in a rat model of neuropathic pain. METHODS: Fifty rats were randomly allocated into five groups, sham-operation treated with saline and L5 spinal nerve transection treated with different doses of rhEPO (0 [saline], 1000, 3000, or 5000 U x kg(-1), respectively). The rats were intraperitoneally treated from 1 day before surgery to post-surgery day 7. The mechanical (paw pressure thresholds, PPT) and thermal thresholds (paw withdrawal latencies, PWL) were measured on post-surgery days 1, 3, and 7. The contralateral brain was obtained on post-surgery day 7 to determine the expressions of tumour necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, L-10, and nuclear factor-kappa B (NF-kappaB) activity. RESULTS: There were significant decreases in PPT and PWL after L5 spinal nerve transection (P < 0.001). Compared with the saline group, the rhEPO 3000 and 5000 U x kg(-1) groups resulted in significant increases in PPT and PWL (P < 0.001) and reduced the cerebral expressions of TNF-alpha, IL-1beta, IL-6, and NF-kappaB activity associated with the increase in IL-10 (rhEPO3000 group, P < 0.05, and rhEPO5000 group, P < 0.001, respectively). Administration of rhEPO 1000 U x kg(-1) had no significant effects on these variables. CONCLUSIONS: Preemptive rhEPO dose-dependently attenuated the mechanical and thermal hyperalgesia in L5 spinal nerve transection rats, which correlated with the decreased cerebral expressions of TNF-alpha, IL-1beta, and IL-6 via downregulating NF-kappaB activity and the increased expression of IL-10.

Recombinant human erythropoietin attenuates spinal neuroimmune activation of neuropathic pain in rats.

Neuropathic pain is a complex syndrome resulting from damage to the peripheral nervous system. Central neuroimmune activation contributes to the generation and maintenance of chronic pain after nerve injury. The current study determined the effects of recombinant human erythropoietin (rhEPO) on behavioral hyperalgesia and neuroimmune activation in a rat model of neuropathic pain induced by L5 spinal nerve transection. Animals were randomly assigned into 3 groups: sham-operation with saline; L5 spinal nerve transection with rhEPO (5000 units/kg); or L5 transection with saline. The rhEPO or saline was given ip on the day before surgery and continued daily to day 7 post-transection. The paw pressure threshold and paw withdrawal latencies were measured before surgery and on days 1, 3, and 7 post-operation. Glial activation markers such as macrophage antigen complex-1 (Mac-1, OX-42) and glial fibrillary acidic protein (GFAP), production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10, as well as nuclear factor-kappa B (NF-kappaB) activation were determined in the lumbar spinal cord. Administration of rhEPO resulted in attenuation of mechanical and thermal hyperalgesia. Furthermore, rhEPO markedly inhibited neuroimmune activation characterized by glial activation, production of proinflammatory cytokines like TNF-alpha, IL-1beta, and NF-kappaB activation, but rhEPO enhanced the level of IL-10. These results support the significance of neuroinflammation and neuroimmune activation in the initiation and persistence of behavioral pain responses. The data indicate that rhEPO attenuates behavioral hyperalgesia and neuroimmune activation in neuropathic pain induced by L5 nerve transection.

Pentoxifylline decreases up-regulated nuclear factor kappa B activation and cytokine production in the rat retina following transient ischemia.

AIM: To investigate whether pentoxifylline (PTX) could influence the increased cytokine gene expression in the retina flowing transient ischemia, and if so, whether it acts through the modulation of nuclear factor kappa B (NF-kappaB) activation. METHODS: Sprague-Dawley rats were randomly divided into three equal groups: control group, saline-treated group, and PTX-treated group. Increased intraocular pressure was applied for 90 min to induce retinal ischemia, and reperfusion was established by lowering the bottle to eye level. The reperfusion period lasted for 48 h. In the PTX-treated group, an initial dose of 20 mg PTX was injected via tail vein at the beginning of reperfusion. Then the rat received infusion of PTX at a rate of 6 mg/kg/h throughout the entire reperfusion period. The retinal tissues were collected at the end of 1, 6, 12, 24, and 48 h of reperfusion, respectively, for biochemical analysis. Histological examination was done on the tissues collected at the end of 48 h after reperfusion. RESULTS: Histological examination revealed reduction of overall retinal thickness and thinning of the inner retinal layer in saline-treated rats after 48-hour reperfusion. However, PTX treatment significantly reduced the loss of overall retinal thickness and thinning of inner retinal layers. Dramatic increase in NF-kappaB activation, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production and mRNA expression were observed in the saline-treated group after reperfusion, with the peak reached around 12 h. In the PTX-treated group, NF-kappaB activation, TNF-alpha and IL-1beta production and mRNA expression were significantly reduced at each corresponding time point compared to the saline-treated group. CONCLUSION: PTX decreased the up-regulated activation of NF-kappaB and the expression of proinflammatory cytokines, TNF-alpha and IL-1beta in rat retinas following ischemia/reperfusion. This may contribute to significantly reduce the loss of overall retinal thickness and thinning of inner retinal layers.

Pentoxifylline reduces indirect lung injury of fresh water drowning in canis.

BACKGROUND: Previous studies have suggested that pentoxifylline (PTX) exerts multiple beneficial effects on the inflammatory cascade, particularly on the function of neutrophils. We investigated whether continuous infusion of PTX could reduce indirect lung injury (ILI) caused by fresh water drowning and if so, what is the possible molecular mechanism. METHODS: Twenty 4 male canis were divided randomly into control group, fresh water drowning group (right lung), drowning treated with PTX group and PTX alone group. At different time points after drowning, the changes of hemodynamic parameters and wet/dry weight of indirect lung (left lung) tissues were compared among these 4 groups. Other measures included lung histopathology, PMN infiltration assessed by immune staining, CD11b, ICAM-1 mRNA and TNF-alphamRNA in left lung detected by RT-PCR. NF-kappaB activation in blood neutrophils and lungs were measured with electrophoretic mobility shift assay (EMSA). RESULTS: Animals treated with PTX showed a significant reduction in lung injury. PTX suppressed drowning-induced ICAM-1 and TNF-alphamRNA elevation and inhibited NF-kappaB activation in blood neutrophils and lungs. CONCLUSIONS: Continuous infusion of PTX reduces ILI caused by fresh water drowning. PTX decreases expression of ICAM-1 and TNF-alpha, possibly via inhibition of NF-kappaB.

Pentoxifylline inhibits endotoxin-induced NF-kappa B activation and associated production of proinflammatory cytokines.

The effects of graded doses of pentoxifylline (PTX) on endotoxin-induced production of inflammatory cytokines and activation of nuclear factor kappa B (NF-kappaB) were studied in vivo in rat intestine. Sepsis was induced in rats by ip injection of lipopolysaccharide (LPS, 5 mg/kg). PTX was injected via the tail vein at dosages of 6.25, 12.5, 25, 50, or 100 mg/kg at 1 min after LPS challenge. NF-kappaB activation in intestine was investigated by electrophoretic mobility shift assay (EMSA). Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were measured in intestine by enzyme-linked immunosorbance assays (ELISA). Intestinal TNF-alpha, IL-6, and IL-10 mRNA expression were studied by the reverse-transcription polymerase chain reaction (RT-PCR). The measurements of NF-kappaB, TNF-alpha, IL-6, and IL-10 were performed, respectively, at 1, 4, 4, and 1 hr after endotoxin injection. The results showed that LPS elevated the production of TNF-alpha, IL-6, and IL-10 and enhanced NF-kappaB activation in rat intestine. At all dosages, PTX reduced the activation of NF-kappaB and the production of TNF-alpha and IL-6, but enhanced the release of IL-10. These effects were greatest at dosages of 50 mg/kg for TNF-alpha and IL-6, and 25 mg/kg for IL-10. In conclusion, PTX suppressed the production of proinflammatory cytokines such as TNF-alpha and IL-6 in rat intestine, and enhanced the endotoxin-induced production of IL-10. The suppressive effect of proinflammatory cytokines may act by inhibiting NF-kappaB activation, but not by induction of IL-10.