Systemic immune-inflammation index for predicting postoperative atrial fibrillation following cardiac surgery: a meta-analysis.

Background: Postoperative atrial fibrillation (POAF) is a frequent complication that may increase morbidity and mortality risk following cardiac surgery. The systemic immune-inflammation index (SII) is an emerging biomarker that provides an integrated measure of inflammation by incorporating neutrophil, lymphocyte, and platelet counts. Recent studies have reported associations between elevated SII and increased POAF risk; however, significant heterogeneity exists regarding its predictive efficacy. This meta-analysis aimed to assess SII's diagnostic efficacy for predicting POAF risk. Methods: To synthesize existing evidence on the ability of perioperative SII for predicting POAF in patients undergoing cardiac surgery, a systematic review and meta-analysis was conducted. In August 2023, a comprehensive literature search was performed to identify relevant studies reporting SII cutoff values with corresponding sensitivity and specificity. The primary aim was to evaluate SII's diagnostic utility for predicting POAF, whereas secondary outcomes included the pooled incidence of POAF and the relationship between the SII and POAF. Results: Eight studies published between 2021 and 2023 with 3,245 patients were included. Six studies involved coronary artery bypass grafting (CABG) surgery; one encompassed various cardiac procedures, and another focused solely on mitral valve surgery. The pooled incidence of POAF was 23.6% [95% confidence interval (CI), 18.7%-29.2%]. Elevated SII significantly increased the odds of POAF by 3.24-fold (odds ratio, 3.24; 95% CI, 1.6-6.55; p = 0.001). SII's pooled sensitivity and specificity for predicting POAF were 0.80 (95% CI, 0.68-0.89) and 0.53 (95% CI, 0.23-0.8), respectively. The SII had moderate predictive accuracy based on a hierarchical summary receiver operating characteristic (HSROC) area under the curve of 0.78 (95% CI, 0.74-0.81). Subgroup analyses, whether focusing on CABG alone or CABG with cardiopulmonary bypass (CPB), both indicated an area under the HSROC curve of 0.78 (95% CI, 0.74-0.81). Conclusion: Elevated SII is significantly correlated with an increased POAF risk following cardiac surgery, highlighting its utility as a predictive biomarker. Considering its moderate diagnostic accuracy, further research is essential for clarifying SII's clinical effectiveness, either as an independent predictor or combined with other risk factors, for stratifying patients at high POAF risk. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42023456128].

Efficacy of propofol-based anesthesia against risk of brain swelling during craniotomy: A meta-analysis of randomized controlled studies.

STUDY OBJECTIVE: This meta-analysis aimed to compare the risk of brain swelling during craniotomy between propofol-based and volatile-based anesthesia. DESIGN: Meta-analysis of randomized controlled trials (RCTs). SETTING: Operating room. INTERVENTION: Propofol-based anesthesia. PATIENTS: Adult patients undergoing craniotomy. MEASUREMENTS: Databases, including EMBASE, MEDLINE, Google Scholar, and Cochrane Library, were searched from inception to April 2023. The primary outcome was the risk of brain swelling, while the secondary outcomes included the impact of anesthetic regimens on surgical and recovery outcomes, as well as the risk of hemodynamic instability. MAIN RESULTS: Our meta-analysis of 17 RCTs showed a significantly lower risk of brain swelling (risk ratio [RR]: 0.85, p = 0.03, I2 = 21%, n = 1976) in patients receiving propofol than in those using volatile agents, without significant differences in surgical time or blood loss between the two groups. Moreover, propofol was associated with a lower intracranial pressure (ICP) (mean difference: -4.06 mmHg, p < 0.00001, I2 = 44%, n = 409) as well as a lower risk of tachycardia (RR = 0.54, p = 0.005, I2 = 0%, n = 822) and postoperative nausea/vomiting (PONV) (RR = 0.59, p = 0.002, I2 = 19%, n = 1382). There were no significant differences in other recovery outcomes (e.g., extubation time), risk of bradycardia, hypertension, or hypotension between the two groups. Subgroup analysis indicated that propofol was not associated with a reduced risk of brain swelling when compared to individual volatile agents. Stratified by craniotomy indications, propofol reduced brain swelling in elective craniotomy, but not in emergency craniotomy (e.g., traumatic brain injury), when compared to volatile anesthetics. CONCLUSIONS: By reviewing the available evidence, our results demonstrate the beneficial effects of propofol on the risk of brain swelling, ICP, PONV, and intraoperative tachycardia. In emergency craniotomy for traumatic brain injury and subarachnoid hemorrhage, brain swelling showed no significant difference between propofol and volatile agents. Further large-scale studies are warranted for verification.

Association between the neutrophil-to-lymphocyte ratio and cognitive impairment: a meta-analysis of observational studies.

Background: Systemic inflammation is one of the underlying mechanisms of cognitive impairment. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a systemic inflammation indicator. This meta-analysis aimed to evaluate the association between high NLR and cognitive impairment (CI) risk. Method: A comprehensive systematic search was conducted to identify eligible studies published until May 30, 2023. The reference group comprised patients with the lowest NLR level, whereas the exposure group comprised those with the highest NLR level. The main outcome was to examine the relationship between NLR and CI risk. The secondary outcome included the association between patient characteristics or comorbidities and CI risk. Results: This meta-analysis included 11 studies published between 2018 and 2023, involving 10,357 patients. Patients with CI had a higher NLR than those without (mean difference=0.35, 95% confidence interval [CI]: 0.26-0.44, p < 00001, I2 = 86%). Consistently, pooled results revealed an association between high NLR and CI risk (odds ratio [OR]=2.53, 95% CI:1.67-3.82, p<0.0001, I2 = 84%). Furthermore, aging (mean difference =4.31 years, 95% CI:2.83-5.8, p < 0.00001, I2 = 92%), diabetes (OR=1.59, 95% CI:1.35-1.88, p < 0.00001, I2 = 66%), and hypertension (OR=1.36, 95% CI:1.19-1.57, p < 0.00001, I2 = 0%) were significant risk factors for CI. However, no significant associations were observed between CI and male gender (OR = 0.84, 95% CI:0.64-1.11, p = 0.22, I2 = 81%), body mass index (mean = -0.32 kg/m2, 95% CI: -0.82, 0.18, p = 0.2, I2 = 82%), alcohol consumption (OR = 1.11, 95% CI:0.95-1.3, p = 1.35, I2 = 0%), and smoking (OR = 0.99, 95% CI:0.87-1.13, p = 0.86, I2 = 0%). Meta-regression found that diabetes and hypertension, but not age, significantly moderated the association between NLR and CI. Conclusion: This meta-analysis showed a significant association between high NLR and increased CI risk. Moreover, meta-regression identified diabetes and hypertension, but not age, as significant moderating factors in the relationship between NLR and CI. To validate and strengthen these findings, further large-scale studies are required. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023430384, identifier CRD42023430384.

Diagnostic efficacy of the triglyceride-glucose index in the prediction of contrast-induced nephropathy following percutaneous coronary intervention.

Introduction: Contrast-induced nephropathy (CIN) is a common complication of percutaneous coronary intervention (PCI). Identifying patients at high CIN risk remains challenging. The triglyceride-glucose (TyG) index may help predict CIN but evidence is limited. We conducted a meta-analysis to evaluate the diagnostic value of TyG index for CIN after PCI. Methods: A systematic literature search was performed in MEDLINE, Cochrane, and EMBASE until August 2023 (PROSPERO registration: CRD42023452257). Observational studies examining TyG index for predicting CIN risk in PCI patients were included. This diagnostic meta-analysis aimed to evaluate the accuracy of the TyG index in predicting the likelihood of CIN. Secondary outcomes aimed to assess the pooled incidence of CIN and the association between an elevated TyG index and the risk of CIN. Results: Five studies (Turkey, n=2; China, n=3) with 3518 patients (age range: 57.6 to 68.22 years) were included. The pooled incidence of CIN was 15.3% [95% confidence interval (CI) 11-20.8%]. A high TyG index associated with increased CIN risk (odds ratio: 2.25, 95% CI 1.82-2.77). Pooled sensitivity and specificity were 0.77 (95% CI 0.59-0.88) and 0.55 (95% CI 0.43-0.68) respectively. Analysis of the summary receiver operating characteristic (sROC) curve revealed an area under the curve of 0.69 (95% CI 0.65-0.73). There was a low risk of publication bias (p = 0.81). Conclusion: The TyG index displayed a noteworthy correlation with the risk of CIN subsequent to PCI. However, its overall diagnostic accuracy was found to be moderate in nature. While promising, the TyG index should not be used in isolation for CIN screening given the heterogeneity between studies. In addition, the findings cannot be considered conclusive given the scarcity of data. Further large-scale studies are warranted to validate TyG cutoffs and determine how to optimally incorporate it into current risk prediction models. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023452257, identifier CRD42023452257.

The efficacy of Perfusion Index for identifying failed nerve block in patients receiving upper extremity surgery: a meta-analysis.

INTRODUCTION: Nerve block success is commonly assessed through a variety of techniques, including testing sensations for temperature over the relevant dermatomes and evaluating pain response (e.g., pin-prick). This meta-analysis aimed to investigate the diagnostic efficacy of Perfusion Index (PI) in identifying failed nerve blocks in patients undergoing upper extremity surgery. EVIDENCE ACQUISITION: A literature search was conducted using four databases, including Medline (OVID), Google Scholar, EMBASE (OVID), and the Cochrane Database of Systematic Reviews, to identify relevant studies from the inception of the databases until June 2023. The main purpose of this study was to evaluate the diagnostic accuracy of PI values and PI ratios in identifying failed nerve blocks. EVIDENCE SYNTHESIS: Nine studies (published from 2006 to 2022) involving 533 participants (age ranged from 31.8 to 52 years) were included. The failure rate of nerve blocks ranged from 0% to 18.9%. Pooled results demonstrated promising diagnostic accuracy when using PI values as a predictor of failed nerve block (sensitivity, 77%; specificity, 88.1%; diagnostic odds ratio [DOR], 30.585). Additionally, the analysis of PI ratios as a diagnostic measure showed even higher diagnostic efficacy than using PI values alone, with a sensitivity of 82.9%, specificity of 93.1%, and DOR of 74.543. CONCLUSIONS: Our meta-analysis confirmed that the PI values and ratios are promising objective predictors of nerve block failure. The simplicity of these techniques supports their feasibility for routine clinical practice. Further studies focusing on different patient populations, such as pregnant women or the elderly, are needed to validate and expand upon our findings.

Efficacy of the visual cognitive assessment test for mild cognitive impairment/mild dementia diagnosis: a meta-analysis.

Background: Mild cognitive impairment (MCI) is an intermediate stage between normal ageing and dementia. The early identification of MCI is important for timely intervention. The visual cognitive assessment test (VCAT) is a brief language-neutral screening tool for detecting MCI/mild dementia. This meta-analysis evaluated the diagnostic efficacy of the VCAT for MCI/mild dementia. Methods: Medline, Embase, Google Scholar, and Cochrane Library were searched from their inception until August 2023 to identify studies using VCAT to diagnose MCI/mild dementia. The primary outcome was to assess the diagnostic accuracy of the VCAT for detecting MCI/mild dementia through area under the receiver operating characteristic curve (AU-ROC) analysis. The secondary outcome was to explore the correlation between VCAT scores and MCI/mild dementia presence by comparing scores among patients with and without MCI/mild dementia. Pooled sensitivity, specificity, and area under the curve (AUC) were calculated. Results: Five studies with 1,446 older adults (mean age 64-68.3 years) were included. The percentage of participants with MCI/mild dementia versus controls ranged from 16.5% to 87% across studies. All studies were conducted in Asian populations, mostly Chinese, in Singapore and Malaysia. The pooled sensitivity was 80% [95% confidence interval (CI) 68%-88%] and the specificity was 75% (95% CI 68%-80%). The AU-ROCC was 0.77 (95% CI 0.73-0.81). Patients with MCI/mild dementia had lower VCAT scores than the controls (mean difference -6.85 points, p < 0.00001). Conclusion: VCAT demonstrated acceptable diagnostic accuracy in distinguishing MCI/mild dementia in cognitively normal older adults. As a language-neutral and culturally unbiased tool, the VCAT shows promise in detecting MCI/mild dementia. Further studies in non-Asian populations are required. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023453453.

A systematic review and meta-analysis comparing the efficacy and safety of ciprofol (HSK3486) versus propofol for anesthetic induction and non-ICU sedation.

Background: Ciprofol (HSK3486) is a novel intravenous anesthetic agent that bears structural similarity to propofol and displays favorable pharmacodynamic characteristics such as rapid onset and offset. The meta-analysis aimed at comparing the efficacy and safety of ciprofol versus propofol in clinical practice. Methods: Medline, EMBASE, Google Scholar, Cochrane Library were searched from inception to April 2023. The primary outcome was success rate of sedation/anesthetic induction and differences in sedation/induction time. The secondary outcomes included risks of hemodynamic instability, respiratory complications, and pain on injection, as well as recovery profiles, satisfaction score, and top-up dose requirement. Results: Twelve RCTs (sedation: n = 6, anesthetic induction, n = 6, all conducted in China) involving 1,793 patients (age: 34-58 years) published from 2021 to 2023 were analyzed. Pooled results revealed no differences in success rate [risk ratio (RR) = 1, 95% confidence interval (CI): 0.99 to 1.01, I2 = 0%, 1,106 patients, p = 1] and time required for successful anesthetic induction/sedation [mean difference (MD) = 7.95 s, 95% CI: -1.09 to 16.99, I2 = 97%, 1,594 patients, p = 0.08]. The risks of top-up dose requirement (RR = 0.94, p = 0.48), cardiopulmonary complications [i.e., bradycardia (RR = 0.94, p = 0.67), tachycardia (RR = 0.83, p = 0.68), hypertension (RR = 1.28, p = 0.2), hypoxemia/pulmonary depression (RR = 0.78, p = 0.24)], and postoperative nausea/vomiting (RR = 0.85, p = 0.72), as well as discharge time (MD = 1.39 min, p = 0.14) and satisfaction score (standardized MD = 0.23, p = 0.16) did not differ significantly between the two groups. However, the ciprofol group had lower risks of hypotension (RR = 0.85, p = 0.02) and pain on injection (RR = 0.17, p < 0.00001) than the propofol group. The time to full alertness was statistically shorter in the propofol group (i.e., 0.66 min), but without clinical significance. Conclusion: Our results demonstrated similar efficacy between ciprofol and propofol for sedation and anesthetic induction, while ciprofol was associated with lower risks of hypotension and pain on injection. Future studies are warranted to evaluate the efficacy and safety of ciprofol in pediatric or the elderly populations. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/), identifier (CRD42023421278).

Efficacy of the Geriatric Nutritional Risk Index for Predicting Overall Survival in Patients with Head and Neck Cancer: A Meta-Analysis.

Head and neck cancer (HNC) is a prevalent malignancy with a poor prognosis, necessitating the identification of prognostic biomarkers to guide management. The geriatric nutritional risk index (GNRI), calculated from serum albumin and body weight, may predict survival in patients with HNC. We performed a systematic review and meta-analysis to clarify this relationship. Databases were searched for studies examining the association between pretreatment GNRI and overall survival in patients with HNC. Ten studies with 2793 patients were included. Meta-analysis demonstrated that low GNRI was associated with significantly worse overall survival compared to high GNRI (hazard ratio [HR]:2.84, 95% CI 2.07-3.91, p < 0.00001). Older age (HR:1.73; 95% CI, 1.35-2.22; p < 0.0001), male sex (HR:1.7; 95% CI, 1.12-2.6; p = 0.01), advanced tumor stage (HR: 2.5; 95% CI, 1.72-3.63; p < 0.00001), and higher T-/N-stage (HR = 1.69 and 1.98, respectively) were also predictive of unfavorable outcomes. The GNRI had the highest HR, suggesting potent predictive ability. Despite limitations, including retrospective design and potential publication bias, our study indicates that low pretreatment GNRI predicts poor overall survival in patients with HNC. The GNRI is an inexpensive, routinely available biomarker that could improve prognostication and guide management decisions. Additional research is warranted to validate these findings.

Assessing the Efficacy of Inferior Vena Cava Collapsibility Index for Predicting Hypotension after Central Neuraxial Block: A Systematic Review and Meta-Analysis.

The use of ultrasonography to predict spinal-induced hypotension (SIH) has gained significant attention. This diagnostic meta-analysis aimed to investigate the reliability of the inferior vena cava collapsibility index (IVCCI) in predicting SIH in patients undergoing various surgeries. Databases, including Embase, Cochrane Library, Medline, and Google Scholar, were screened until 28 July 2023, yielding 12 studies with 1076 patients (age range: 25.6-79 years) undergoing cesarean section (CS) (n = 4) or non-CS surgeries (n = 8). Patients with SIH had a significantly higher IVCCI than those without SIH (mean difference: 11.12%, 95% confidence interval (CI): 7.83-14.41). The pooled incidence rate of SIH was 40.5%. IVCCI demonstrated satisfactory overall diagnostic reliability (sensitivity, 77%; specificity, 82%). The pooled area under the curve (AUC) was 0.85, indicating its high capability to differentiate patients at risk of PSH. The Fagan nomogram plot demonstrated a positive likelihood ratio (PLR) of 4 and a negative likelihood ratio (NLR) of 0.28. The results underscore the robustness and discriminative ability of IVCCI as a predictive tool for SIH. Nevertheless, future investigations should focus on assessing its applicability to high-risk patients and exploring the potential enhancement in patient safety through its incorporation into clinical practice.

Association of general anesthesia exposure with risk of postoperative delirium in patients receiving transcatheter aortic valve replacement: a meta-analysis and systematic review.

The aim of this meta-analysis was to assess the association of general anesthesia (GA) exposure with the risk of POD in this patient population. Databases including Medline, EMBASE, Cochrane library, and Google Scholar were searched from inception to December 2022. Analysis of 17 studies published between 2015 and 2021 involving 10,678 individuals revealed an association of GA exposure with an elevated risk of POD [odd ratio (OR) = 1.846, 95% CI 1.329 to 2.563, p = 0.0003, I2 = 68.4%, 10,678 patients]. Subgroup analysis of the diagnostic methods also demonstrated a positive correlation between GA exposure and POD risk when validated methods were used for POD diagnosis (OR = 2.199, 95% CI 1.46 to 3.31, p = 0.0002). Meta-regression analyses showed no significant impact of age, male proportion, and sample size on the correlation between GA and the risk of POD. The reported overall incidence of POD from the included studies regardless of the type of anesthesia was between 0.8 and 27%. Our meta-analysis showed a pooled incidence of 10.3% (95% CI 7% to 15%). This meta-analysis suggested an association of general anesthesia with an elevated risk of postoperative delirium, implying the necessity of implementing appropriate prophylactic strategies against this complication when general anesthesia was used in this clinical setting.

Predictive Efficacy of the Perfusion Index for Hypotension following Spinal Anesthesia in Parturient Undergoing Elective Cesarean Section: A Systematic Review and Meta-Analysis.

This meta-analysis assessed the predictive efficacy of perfusion index for hypotension following spinal anesthesia (SA) in parturients undergoing elective cesarean section (CS). Electronic databases, including Google Scholar, EMBASE, Cochrane Library, and MEDLINE, were searched from inception to June 2023. The primary outcome was the diagnostic accuracy of the perfusion index in predicting the probability of perioperative hypotension following SA. The review included 12 studies involving 2009 patients, published between 2017 and 2023. The pooled sensitivity and specificity were 0.81 (95% confidence interval (CI) = 0.72-0.87) and 0.75 (95% CI = 0.67-0.82), respectively. Additionally, the pooled area under the curve (AUC) was calculated as 0.84 (95% CI = 0.81-0.87), suggesting a moderate to good accuracy of the diagnostic test. Using Fagan's nomogram plot, the positive likelihood ratio (LR) and negative LR were found to be 3 and 0.26, respectively. The results demonstrated that the perfusion index exhibited an acceptable level of accuracy in predicting perioperative hypotension after spinal anesthesia in parturients undergoing elective CS. These findings highlight the potential value of incorporating a perfusion index as a useful tool for clinicians to integrate into routine clinical practice, which necessitates further large-scale studies for verification.

The efficacy and safety of cuttlebone for lowering serum phosphate in patients with end-stage renal disease: a meta-analysis of randomized controlled trials.

Background: The efficacy of cuttlebone for treating hyperphosphatemia in patients with end-stage renal disease and its safety remained unclear. Methods: Randomized controlled trials comparing the efficacy of cuttlebone with conventional interventions were retrieved from MEDLINE, EMBASE, Cochrane Library, Airiti Library, and other major Chinese databases until 1 February 2023. The primary outcome was circulating phosphate concentration, while secondary outcomes included circulating calcium and intact parathyroid hormone levels, calcium-phosphorus product, and treatment-related side-effects. Results: Analysis of nine studies published between 2000 and 2019 including 726 participants showed a lower circulating phosphate concentration in the cuttlebone group than in controls [mean difference (MD) = -0.23, 95% CI: -0.39 to -0.06, p = 0.006, I2 = 94%, 726 patients] and a dose-dependent effect of cuttlebone against hyperphosphatemia. Therapeutic benefits were noted after both short-term (1-2 months) and long-term (3-6 months) treatments. Besides, patients receiving hemodialysis showed a better response to cuttlebone than those receiving peritoneal dialysis. There was no difference in circulating calcium level (mean difference = 0.03, 95% CI: -0.01 to 0.07, p = 0.17, I2 = 34%, 654 patients), while patients receiving cuttlebone showed lower circulating iPTH level and calcium-phosphorus product (MD = -43.63, 95% CI: -74.1 to -13.16, p = 0.005, I2 = 76%, 654 patients), (MD = -0.38, 95% CI: -0.38 to -0.01, p = 0.04, I2 = 83%, 520 patients). No difference in the risks of constipation, gastrointestinal discomfort, and elevated blood calcium was noted between the two groups. Conclusion: Compared with conventional phosphate-binding agents, cuttlebone more efficiently suppressed hyperphosphatemia with a dose-dependent effect. The limited number of included studies warrants further clinical investigations to verify our findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023396300.

Association of Preoperative Prognostic Nutritional Index with Risk of Postoperative Acute Kidney Injury: A Meta-Analysis of Observational Studies.

This meta-analysis aimed to assess the clinical association of the preoperative prognostic nutritional index (pre-PNI) with the risk of postoperative acute kidney injury. Four databases (e.g., Medline) were searched from inception to December 2022 to investigate the association between pre-PNI (i.e., low vs. high) and PO-PNI as well as the correlation between pre-PNI and other postoperative prognostic indices. Overall, 13 observational studies, including 9185 patients, were eligible for analysis. A low PNI was related to increased risks of PO-AKI [odd ratio (OR) = 1.65, p = 0.001, 3811 patients], postoperative infection (OR = 2.1, p < 0.00001, 2291 patients), and mortality (OR = 1.93, p < 0.0001, 2159 patients). Albeit statistically nonsignificant, a trend was noted, linking a low PNI to higher risks of postoperative bleeding (OR = 2.5, p = 0.12, 1157 patients) and stroke (OR = 1.62, p = 0.07, 2036 patients). Pooled results revealed a prolonged intensive care unit (ICU) stay in patients with low PNIs compared to those with high PNIs (MD: 0.98 days, p = 0.02, 2209 patients) without a difference in hospital stay between the two groups (MD: 1.58 days, p = 0.35, 2249 patients). This meta-analysis demonstrated an inverse correlation between PNI and the risks of PO-AKI, postoperative infection, and mortality, as well as the length of ICU stay, which warrants further investigations for verification.

Interferon-ß suppresses inflammatory pain through activating µ-opioid receptor.

Interferons (IFNs) are cytokines secreted by infected cells that can interfere with viral replication. Besides activating antiviral defenses, type I IFNs also exhibit diverse biological functions. IFN-ß has been shown to have a protective effect against neurotoxic and inflammatory insults on neurons. Therefore, we aimed to investigate the possible role of IFN-ß in reducing mechanical allodynia caused by Complete Freund's Adjuvant (CFA) injection in rats. We assessed the antinociceptive effect of intrathecal IFN-ß in naïve rats and the rats with CFA-induced inflammatory pain. After the behavioral test, the spinal cords of the rats were harvested for western blot and immunohistochemical double staining. We found that intrathecal administration of IFN-ß in naïve rats can significantly increase the paw withdrawal threshold and paw withdrawal latency. Further, the intrathecal injection of a neutralizing IFN-ß antibody can reduce the paw withdrawal threshold and paw withdrawal latency, suggesting that IFN-ß is produced in the spinal cord in normal conditions and serves as a tonic inhibitor of pain. In addition, intrathecal injection of IFN-ß at dosages from 1000 U to 10000 U demonstrates a significant transient dose-dependent inhibition of CFA-induced inflammatory pain. This analgesic effect is reversed by intrathecal naloxone, suggesting that IFN-ß produces an analgesic effect through central opioid receptor-mediated signaling. Increased expression of phospho-µ-opioid receptors after IFN-ß injection was observed on western blot, and immunohistochemical staining showed that µ-opioids co-localized with IFN-α/ßR in the dorsal horn of the spinal cord. The findings of this study demonstrate that the analgesic effect of IFN-ß is through µ-opioid receptors activation in spial cord.

Transplantation of viable mitochondria attenuates neurologic injury after spinal cord ischemia.

OBJECTIVES: Spinal cord ischemia (SCI) is one of the major concerns of postoperative paraplegia during major vascular or aortic surgery. Since mitochondrial dysfunction develops at the early stage of SCI, this study tested the neuronal protective effect of transplantation of viable mitochondria to the ischemic cord in rats. METHODS: SCI was induced by crossclamping of thoracic aorta at T6 level for 25 minutes, followed by release of vascular clip to restore aortic blood flow in the anesthetized rats. Mitochondria (100 µg) were isolated from freshly harvested soleus muscle and delivered via the internal jugular vein before releasing of vascular clip. The motor function was assessed independently up to 7 days after reperfusion. Spinal cords were harvested and analyzed for molecular and histological changes. RESULTS: Whole-body in vivo images acquired by an in vivo imaging system confirmed the enhancement of MitoTracker fluorescence at the regions below crossclamping and in the ischemic cord. Compared with control vehicles, transplantation of mitochondria significantly improved the lower-limb locomotor function of rats subjected to cord ischemia up to 7 days after surgery. Mitochondrial transplantation suppressed the regional endoplasmic reticulum stress in the ischemic cord by attenuating CCAAT-enhancer-binding protein homologous protein expression and restoring binding immunoglobulin protein levels. In accordance, tissue levels of interleukin-6, tumor necrosis factor-α, and caspase-3 were attenuated in the mitochondrial transplanted group. Histologic examination also showed significant increase in numbers of Nissls bodies in the neurons at the ventral horn of ischemic cord following mitochondrial transplantation. CONCLUSIONS: Our study showed that transplantation of freshly isolated mitochondria during the early stage of spinal cord ischemia-reperfusion injury suppressed the oxidative stress in endoplasmic reticulum of the injured cord, thereby reducing neuroapoptosis and improving locomotor function of rats with SCI.

Integrated analysis of microRNA and mRNA expression profiles in the rat spinal cord under inflammatory pain conditions.

Recent studies using microarray-based approaches have demonstrated that microRNAs (miRNAs) are involved in pain processing pathways. However, a significant proportion of computational predictions of miRNA targets are false-positive interactions. To increase the chance of identifying biologically relevant targets, we performed an integrated analysis of both miRNA and mRNA expression profiles in the rat spinal cord during complete Freund's adjuvant (CFA)-induced inflammatory pain. We generated miRNA and mRNA arrays from the same corresponding samples on days 5 and 14 after CFA injection. Five miRNAs and 1096 mRNAs in the CFA 5d group and 16 miRNAs and 647 mRNAs in the CFA 14d group were differentially expressed based on a filter of at least a 1.5-fold change in either direction. An integrated analysis revealed 54 mRNA targets with an inverse correlation to the expression patterns of three miRNAs in the CFA 5d group. Seventy-five targets were inversely correlated to six miRNAs in the CFA 14d group. The miRNA-mRNA interaction networks revealed significant changes in miR-124, miR-149, miR-3584 and their target genes, IL-6R, ADAM19, LAMC1 and CERS2, in the CFA 5d group. In the CFA 14d group, significant changes were noted in miR-124, miR-29, miR-34, miR-30, miR-338 and their target genes, TIMP2, CREB5 and EFNB1. We also investigated an interaction pair, miR-124-3p and IL-6R, and the results showed that miR-124-3p could attenuate inflammatory pain and decrease IL-6R expression in the spinal cord. These specific miRNAs and their target genes provide possible avenues for the diagnosis and treatment of inflammatory pain.

The Antinociceptive Effect of Light-Emitting Diode Irradiation on Incised Wounds Is Correlated with Changes in Cyclooxygenase 2 Activity, Prostaglandin E2, and Proinflammatory Cytokines.

Background. Light-emitting diode (LED) phototherapy has been reported to relieve pain and enhance tissue repair through several mechanisms. However, the analgesic effect of LED on incised wounds has never been examined. Objectives. We examined the analgesic effect of LED therapy on incision pain and the changes in cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), and the proinflammatory cytokines interleukin 6 (IL-6), IL-1ß, and tumor necrosis factor α (TNF-α). Methods. Rats received LED therapy on incised skin 6 days before incision (L-I group) or 6 days after incision (I-L group) or from 3 days before incision to 3 days after incision (L-I-L group). Behavioral tests and analysis of skin tissue were performed after LED therapy. Results. LED therapy attenuated the decrease in thermal withdrawal latency in all the irradiated groups and the decrease in the mechanical withdrawal threshold in the L-I group only. The expression levels of COX-2, PGE2, and IL-6 were significantly decreased in the three LED-treated groups, whereas IL-1ß and TNF-α were significantly decreased only in the L-I group compared with their levels in the I groups (p < 0.05). Conclusions. LED therapy provides an analgesic effect and modifies the expression of COX-2, PGE2, and proinflammatory cytokines in incised skin.

Lentiviral vector-encoded microRNA-based shRNA-mediated gene knockdown of N-methyl-D-aspartate receptors in skin reduces pain.

BACKGROUND AND PURPOSE: RNA polymerase II promoters that drive the expression of rationally designed primary microRNA-based shRNA, for example, shRNAmir, can produce more potent gene knockdown than RNA polymerase III promoters. Antagonists of peripheral N methyl-D-aspartate (NMDA) receptors that do not interfere with central glutamate processing would prevent the development of adverse central nervous system effects. Thus, in this study, we examined the effects of gene silencing and antinociception on formalin- and Complete Freund's adjuvant (CFA)-induced pain in rats by subcutaneously injecting a lentiviral vector encoding a shRNAmir that targets the NR1 subunit of the NMDA receptor. METHODS: Rats received intradermal injections of different doses of NR1 shRNAmir at different time points before injection of formalin. Pain behavior was assessed by monitoring the paw flinch response, paw withdrawal threshold, and thermal withdrawal latency. We then analyzed NR1 messenger RNA and protein expression in skin and the L5 dorsal root ganglion (DRG). RESULTS: We found that intradermal injection of 1, 5, and 10 µg of shRNAmir significantly inhibited flinch responses (p < .05). Administration of 5 µg of shRNAmir resulted in the attenuation of CFA-induced mechanical allodynia, but did not affect the time spent on the rotarod. Real-time polymerase chain reaction and western blotting revealed that NR1 mRNA and protein levels were significantly lower in all NR1 shRNAmir1 groups than in controls (p < .05). There was a significant reduction in the percentage of NR1- and pERK-positive neurons in the DRG ipsilateral to shRNAmir treated paws (p < .05). The effect of antinociception and inhibition of NR1 expression by NR1 shRNAmir was evident on day 3 and persisted for 7 days after injection of 5 µg of vector. CONCLUSION: Peripheral administration of the vector-encoded NR1 shRNAmir is a promising therapy for persistent inflammatory pain.

Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions.

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/ß receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

Perceptions about preventing hepatocellular carcinoma among patients with chronic hepatitis in Taiwan.

AIM: To measure patient perceptions about preventing hepatocellular carcinoma (HCC) and to predict the factors that influence patient willingness to receive therapy. METHODS: A cross-sectional descriptive study was conducted at an outpatient clinic of a medical institution in southern Taiwan. Four hundred patients with chronic hepatitis B/C were recruited as participants. Two structured questionnaires based on the health belief model were utilized in this study, including the scales of perceptions about preventing HCC and knowledge of hepatitis B/C. RESULTS: The statistical results demonstrated that the participants' perceived susceptibility (r = -0.22, P < 0.001), benefits (r = -0.11, P = 0.028) and cues to action (r = -0.12, P = 0.014) about the prevention of HCC was significantly correlated with their age. The participants' perceptions were also associated with their educational levels, household incomes and knowledge of hepatitis. Older patients and those with a lower socioeconomic status tended to have negative perceptions and less knowledge of hepatitis. Multivariate logistic regression further indicated that the participants' age (B = -0.044, SE = 0.017, odds ratio = 0.957, P = 0.008, 95%CI: 0.926-0.989) and perceived barriers (B = -0.111, SE = 0.030, odds ratio = 0.895, P < 0.001, 95%CI: 0.845-0.949) were correlated with their willingness to receive antiviral therapy. CONCLUSION: Healthcare professionals should provide appropriate and effective guidance to increase their patients' awareness and to decrease the perceived barriers for continuing surveillance and antiviral therapy.