Interleukin-18 in chronic pain: Focus on pathogenic mechanisms and potential therapeutic targets.

Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.

Development and validation of a fully automated system using deep learning for opportunistic osteoporosis screening using low-dose computed tomography scans.

Background: Bone density measurement is an important examination for the diagnosis and screening of osteoporosis. The aim of this study was to develop a deep learning (DL) system for automatic measurement of bone mineral density (BMD) for osteoporosis screening using low-dose computed tomography (LDCT) images. Methods: This retrospective study included 500 individuals who underwent LDCT scanning from April 2018 to July 2021. All images were manually annotated by a radiologist for the cancellous bone of target vertebrae and post-processed using quantitative computed tomography (QCT) software to identify osteoporosis. Patients were divided into the training, validation, and testing sets in a ratio of 6:2:2 using a 4-fold cross validation method. A localization model using faster region-based convolutional neural network (R-CNN) was trained to identify and locate the target vertebrae (T12-L2), then a 3-dimensional (3D) AnatomyNet was trained to finely segment the cancellous bone of target vertebrae in the localized image. A 3D DenseNet was applied for calculating BMD. The Dice coefficient was used to evaluate segmentation performance. Linear regression and Bland-Altman (BA) analyses were performed to compare the calculated BMD values using the proposed system with QCT. The diagnostic performance of the system for osteoporosis and osteopenia was evaluated with receiver operating characteristic (ROC) curve analysis. Results: Our segmentation model achieved a mean Dice coefficient of 0.95, with Dice coefficients greater than 0.9 accounting for 96.6%. The correlation coefficient (R2) and mean errors between the proposed system and QCT in the testing set were 0.967 and 2.21 mg/cm3, respectively. The area under the curve (AUC) of the ROC was 0.984 for detecting osteoporosis and 0.993 for distinguishing abnormal BMD (osteopenia and osteoporosis). Conclusions: The fully automated DL-based system is able to perform automatic BMD calculation for opportunistic osteoporosis screening with high accuracy using LDCT scans.

The value of using a deep learning image reconstruction algorithm of thinner slice thickness to balance the image noise and spatial resolution in low-dose abdominal CT.

Background: Traditional reconstruction techniques have certain limitations in balancing image quality and reducing radiation dose. The deep learning image reconstruction (DLIR) algorithm opens the door to a new era of medical image reconstruction. The purpose of the study was to evaluate the DLIR images at 1.25 mm thickness in balancing image noise and spatial resolution in low-dose abdominal computed tomography (CT) in comparison with the conventional adaptive statistical iterative reconstruction-V at 40% strength (ASIR-V40%) at 5 and 1.25 mm. Methods: This retrospective study included 89 patients who underwent low-dose abdominal CT. Five sets of images were generated using ASIR-V40% at a 5 mm slice thickness and 1.25 mm (high-resolution) with DLIR at 1.25 mm using 3 strengths: low (DLIR-L), medium (DLIR-M), and high (DLIR-H). Qualitative evaluation was performed for image noise, artifacts, and visualization of small structures, while quantitative evaluation was performed for standard deviation (SD), signal-to-noise ratio (SNR), and spatial resolution (defined as the edge rising slope). Results: At 1.25 mm, DLIR-M and DLIR-H images had significantly lower noise (SD in fat: 14.29±3.37 and 9.65±3.44 HU, respectively), higher SNR for liver (3.70±0.78 and 5.64±1.20, respectively), and higher overall image quality (4.30±0.44 and 4.67±0.40, respectively) than did the respective values in ASIR-V40% images (20.60±4.04 HU, 2.60±0.63, and 3.77±0.43; all P values <0.05). Compared with the 5 mm ASIR-V40% images, the 1.25 mm DLIR-H images had lower noise (SD: 9.65±3.44 vs. 13.63±10.03 HU), higher SNR (5.64±1.20 vs. 4.69±1.28), and higher overall image quality scores (4.67±0.40 vs. 3.94±0.46) (all P values <0.001). In addition, DLIR-L, DLIR-M, and DLIR-H images had a significantly higher spatial resolution in terms of edge rising slope (59.66±21.46, 58.52±17.48, and 59.26±13.33, respectively, vs. 33.79±9.23) and significantly higher image quality scores in the visualization of fine structures (4.43±0.50, 4.41±0.49, and 4.38±0.49, respectively vs. 2.62±0.49) than did the 5 mm ASIR-V40 images. Conclusions: The 1.25 mm DLIR-M and DLIR-H images had significantly reduced image noise and improved SNR and overall image quality compared to the 1.25 mm ASIR-V40% images, and they had significantly improved the spatial resolution and visualization of fine structures compared to the 5 mm ASIR-V40% images. DLIR-H images had further reduced image noise compared with the 5 mm ASIR-V40% images, and DLIR-H was the most effective technique at balancing the image noise and spatial resolution in low-dose abdominal CT.

Passive Smoking Is Associated with Multiple Heavy Metal Concentrations among Housewives in Shanxi Province, China.

BACKGROUND: Passive smoking may increase the content of heavy metals in housewives. However, this association remains a subject of debate. Female passive smoking is widespread, particularly in Chinese rural areas. OBJECTIVE: This study aimed to assess the association between heavy metal accumulation and passive smoking status among rural housewives. METHODS: 405 women were recruited in Shanxi Province of Northern China, and 384 (94.8%, 384/405) participants were included in the final study, of whom 117 women were exposed to passive smoking. The information on their basic characteristics was collected via a structured questionnaire. We used inductively coupled plasma mass spectrometry (ICP-MS) to analyze the concentrations of nine heavy metals, including cadmium (Cd), germanium (Ge), arsenic (As), lead (Pb), titanium (Ti), copper (Cu), iron (Fe), cobalt (Co), and chromium (Cr), in hair samples. RESULTS: The results indicated that higher As, Ge, Ti, and Fe concentrations were significantly associated with passive smoking. After adjusting for potential confounders, the adjusted odds ratios and the 95% confidence intervals of As, Ge, Ti, and Fe were (1.80 (1.13-2.90), p = 0.028), (1.78 (1.14-2.80), p = 0.007), (1.70 (1.09-2.67), p = 0.019), and (1.67 (1.07-2.63), p = 0.035), respectively. The statistically significant linear trend of the adjusted odds ratios at different levels further supported their association. CONCLUSION: Our research concluded that exposure to environmental tobacco smoke might contribute to As, Ge, Ti, and Fe accumulation among housewives.

A Response Surface Analysis of the Combination of Dexmedetomidine and Sufentanil for Attenuating the Haemodynamic Response to Endotracheal Intubation.

Purpose: Dexmedetomidine combined with opioids has been extensively used to blunt cardiovascular responses to endotracheal intubation. To determine their interaction, we aimed to develop a response surface model between dexmedetomidine and sufentanil. Methods: One hundred and twenty patients undergoing scheduled gynaecological surgery were recruited. According to a simulation of slice design, patients received different dose pairs of dexmedetomidine (0 to 1.1 µg/kg) and sufentanil (.1 to .5 µg/kg). The mean arterial blood pressure and heart rate of patients were recorded just before endotracheal intubation, immediately after intubation, and during the first 3 min after intubation. The primary outcomes were haemodynamic changes. The full dose-response relationship between dexmedetomidine and sufentanil was analysed using a logit model. Results: This response surface model revealed that the interaction between dexmedetomidine and sufentanil was additive. The dose pairs that could effectively attenuate the haemodynamic response to endotracheal intubation primarily ranged from .3 to .4 µg/kg and .5 to 1.1 µg/kg for sufentanil and dexmedetomidine, respectively. Conclusion: When used propofol as the main hypnotic drug during anaesthesia induction, dexmedetomidine could effectively reduce the requirement of sufentanil in an additive manner. However, it is not an effective drug for ablating the cardiovascular response to endotracheal intubation when used alone. The clinical trial registry. The trial registry name: Chinese Clinical Trial Registry. Registration number: ChiCTR1800015273. URL:http://www.chictr.org.cn.

Passive Smoking and Risk of Gestational Diabetes Mellitus among Nonsmoking Women: A Prospective Cohort Study in China.

Background: Increasing evidence has shown that active smoking can increase the risk of gestational diabetes mellitus (GDM), but the effect of passive smoking is still unknown. Women in pregnancy are vulnerable to secondhand smoke. This study explored the association of passive smoking with GDM in China. Method: A total of 3083 nonsmoking pregnant women living in Beijing were recruited into a prospective cohort study. Sociodemographic and passive smoking data were collected with structured questionnaires during face-to-face interviews. Glucose levels were measured by physicians according to standard protocols. Multivariate logistic regression was performed for the association estimation after accounting for potential confounders. Result: In total, 562 of the 3083 participants developed GDM (18.23%); 779 participants (25.27%) reported exposure to passive smoking. After adjusting for age, BMI, ethnicity, education, occupation, and parity, passive smoking conferred an approximately 1.4-fold risk increase in GDM (adjusted odds ratio (OR) = 1.37, 95% confidence interval (CI): (1.11, 1.70)). The adjusted ORs with 95% CIs for passive smoking levels of <1, 1−6, and ≥7 times per week were 1.21 (0.94, 1.55), 1.81 (1.22, 2.69), and 1.70 (1.02, 2.84), respectively. An obvious passive-smoking−GDM association was observed among only nulliparous women (adjusted OR = 1.45, 95% CI: (1.14, 1.85)). Conclusion: Frequent exposure to secondhand smoke could increase the risk of GDM among nonsmoking pregnant women. Parity status might modify their association. Public policies should be advocated to prevent passive smoking among this population.

Chemokine CXCL10 regulates pain behaviors via PI3K-AKT signaling pathway in mice.

The analgesic efficacy of morphine can be affected by a variety of factors. Our previous studies demonstrated that chemokine (CXC motif) ligand 10 (CXCL10) could induce algesia directly and attenuate the analgesic effect produced by a single dose of morphine. However, the underlying mechanism remains unclear. In the present study, we aimed to further investigate the mechanism of CXCL10-mediated inhibition on morphine analgesic effect. According to our findings, recombinant CXCL10 protein (rmCXCL10) could increase the phosphorylation of serine-threonine kinase AKT reduced by morphine in spinal cord. Blocking AKT activation by phosphoinositide 3-kinase (PI3K) inhibitor could effectively attenuate CXCL10-induced algesia, and reverse the decrease of paw withdrawal thresholds caused by the co-administration of morphine and rmCXCL10. Furthermore, rmCXCL10 could enhance the spinal expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, which could be blocked by PI3K inhibitor. In summary, these findings suggest that PI3K-AKT signaling pathway mediates the effect of CXCL10 on the regulation of morphine analgesia and the release of cytokines in spinal cord. Our study provides a new insight into the mechanism of chemokine-relative pain regulation.

NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.

Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.

Individualized protocol for radiation and contrast medium dose reduction in one-stop assessment for kidney transplantation patients.

OBJECTIVE: To compare image quality, radiation, and contrast medium (CM) doses between individualized and conventional scan protocols in combined coronary CT angiography (CCTA) and iliac artery CTA for kidney transplantation patients. METHODS: 148 patients needing assessment for coronary and iliac arteries before kidney transplantation were prospectively enrolled and randomly divided into the conventional and individualized groups. All patients underwent one-stop combined scans on a 256-row CT scanner with automatic tube current modulation, 50 % pre-ASIR-V to control radiation dose. CCTA was performed first using one heartbeat axial scan mode with bolus tracking technique and iliac CTA was performed 3 s after CCTA using a spiral scan. The conventional group (n = 72) used the standard protocol: 100 kVp, 60 mL of 350 mgI/mL CM at 4.5 mL/s flow rate. The individualized group (n = 76) used a body-mass-index (BMI)-dependent protocol: kVp: 80 (BMI < 24) and 100 (BMI ≥ 24) and CM: 19 mgI/kg (BMI < 18); 21 mgI/kg (18 ≤ BMI < 24); and 22 mgI/kg (BMI ≥ 24). Image quality radiation and CM doses of the two groups were compared. RESULTS: There was no significant difference in patient demographic data. Compared with the conventional group, the individualized group reduced contrast flow rate (in mL/s) by 14.4 % (3.85 ±â€¯0.72 vs. 4.5), contrast dose (in mL) by 35.8 % (38.53 ±â€¯7.18 vs. 60) and radiation dose (in mSv) by 34.3 % (4.30 ±â€¯1.73 vs. 6.54 ±â€¯1.45). The individualized group had significantly higher subjective image quality score (P ＜ 0.05), lower noise (17.30 ±â€¯4.97 HU vs. 19.13 ±â€¯4.73 HU, P = 0.02) and higher signal-to-noise ratio (22.09 ±â€¯7.41 vs. 19.55 ±â€¯6.18, P = 0.03) for the three main vessels in CCTA compared with the conventional group. There were no differences in both subjective scores and objective measurements in iliac artery CTA between the two groups. CONCLUSION: The individualized scanning protocol in the one-stop assessment of coronary and iliac arteries before kidney transplantation significantly reduces both radiation and CM doses while maintaining image quality in iliac artery CTA and providing better coronary artery images in CCTA.

Association between tea drinking and plasma folate concentration among women aged 18-30 years in China.

OBJECTIVE: Association was found between tea and neural tube defects. However, few studies investigated the relationship between tea consumption and blood folate levels. We aimed to investigate the association between tea consumption and plasma folate concentrations among women aged 18-30 years in different ethnicities of China. DESIGN: Data were obtained from a national cross-sectional study conducted from 2005 to 2006 of women aged 18-30 years in China. Socio-demographic characteristics and lifestyle were obtained from a questionnaire. Dietary folate intake was determined by 24-h dietary recall. Plasma folate concentrations were measured by a microbiological assay. Multiple linear regression model was used to calculate partial regression coefficients after adjusting for confounding factors. SETTING: Nine provinces or autonomous regions in China. PARTICIPANTS: A total of 2932 women aged 18-30 years in China. RESULTS: After stratifying by ethnicity and tea type, tea consumption was significantly positively associated with plasma folate levels in Han women who drank unfermented tea weekly (ß = 0·067, and P = 0·037) or daily (ß = 0·119, and P = 0·031) and in Uighur women who drank fermented tea weekly (ß = 0·325, and P = 0·028). For women who drank unfermented tea in Han ethnicity, weekly and daily tea drinkers had 6·77 % (95 % CI: 6·36 %, 7·21 %) and 7·13 % (95 % CI: 6·40 %, 7·96 %) increase in plasma folate concentration compared with no tea drinkers. CONCLUSIONS: There is a suggestion of possible positive association between unfermented tea drinking in Han ethnicity and plasma folate concentrations, for Chinese women aged 18-30 years. The relationship between tea drinking in other ethnic groups and plasma folate still needs to be further explored.

Novel Core-Shell (ε-MnO2/CeO2)@CeO2 Composite Catalyst with a Synergistic Effect for Efficient Formaldehyde Oxidation.

A novel core-shell (ε-MnO2/CeO2)@CeO2 composite catalyst with a synergistic effect was prepared by hydrothermal reaction and thermal decomposition and its application to high-efficiency oxidation removal of formaldehyde (HCHO) was systemically investigated. The (MnCO3/CeO2)@CeO2 precursor was prepared first by the one-pot hydrothermal reaction of Mn2+ and Ce3+ solutions with a CO2-storage material (CO2SM) without any external templates or surfactants required. The thermal decomposition of the precursor afforded the core-shell (ε-MnO2/CeO2)@CeO2 composite catalyst with excellent catalytic performance. HCHO in the feed gas (180 ppm HCHO, 21% O2, N2 balanced) at a gas hourly space velocity of 100 L/(gcat h) is 100% converted over the catalyst at 80 °C. The conversion rate remains above 95% in 72 h and above 73.8% in 140 h, suggesting the strong stability of the catalyst at high gas flow rates and relatively low temperatures. The synergistic mechanism of the catalyst was explored by X-ray diffraction, Raman, Brunauer-Emmett-Teller, transmission electron microscopy, and X-ray photoelectron spectroscopy. The number of defects in the catalyst and the strength of the Mn-O bond in ε-MnO2 can be tuned by adjusting the synthesis conditions. More oxygen vacancies on the surface of CeO2 can make the synergistic effect of the catalyst stronger, which significantly improves the lattice oxygen (Olatt) activity on the surface of ε-MnO2. Our work has provided new insights into the preparation of the desired composite catalysts with excellent performances.

Spinal heat shock protein 27 participates in PDGFRß-mediated morphine tolerance through PI3K/Akt and p38 MAPK signalling pathways.

BACKGROUND AND PURPOSE: The development of antinociceptive morphine tolerance is a clinically intractable problem. Earlier work has demonstrated the pivotal roles of PDGF and its receptor PDGFRß in morphine tolerance. Here, we have investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFRß activation. EXPERIMENTAL APPROACH: Rats were treated with morphine for 9 days, and its anti-nociceptive effect against thermal pain was evaluated by a tail-flick latency test. Western blot, real-time PCR, immunofluorescent staining, and various antagonists, agonists, and siRNA lentiviral vectors elucidated the roles of HSP27, PDGFRß, and related signalling pathways in morphine tolerance. KEY RESULTS: Chronic morphine administration increased expression and phosphorylation of HSP27 in the spinal cord. Down-regulating HSP27 attenuated the development of morphine tolerance. PDGFRß antagonism inhibited HSP27 activation and attenuated and reversed morphine tolerance. PDGFRß induction increased HSP27 expression and activation and partly decreased morphine analgesia. PDGFRß inhibition reduced Akt and p38 MAPK activity in morphine tolerance. PI3K and p38 inhibitors reversed morphine tolerance and suppressed morphine-induced HSP27 phosphorylation. CONCLUSION AND IMPLICATIONS: This study demonstrated for the first time that spinal HSP27 participates in PDGFRß-mediated morphine tolerance via the PI3K/Akt and p38 MAPK signalling pathways. These findings suggest a potential clinical strategy for prolonging the antinociceptive effects of opioids during long-term pain control.

Organochlorine pesticides exposure may disturb homocysteine metabolism in pregnant women.

Maternal exposure to organochlorine pesticides (OCPs) has an adverse impact on maternal and fetal health, and excessive homocysteine is related to a variety of adverse pregnancy outcomes. Biomimetic studies suggest that OCPs interfere with folate-dependent pathways, but little evidence is available from studies with human subjects. This study explored whether exposure to OCPs interferes with the metabolism of homocysteine, which is folate dependent. A total of 313 pregnant women at 12-20 weeks gestation were recruited in Shanxi province, China, from 2014 to 2015. Plasma concentrations of 20 OCPs, including dichlorodiphenyltrichloroethane and metabolites (DDTs), hexachlorobenzene (HCB), and hexachlorocyclohexanes (HCHs), were analyzed by gas chromatography-mass spectrometry. Blood folate concentrations were analyzed by microbiological assay, and plasma homocysteine concentrations were determined by enzyme-linked immunosorbent assay. Information on demographics, lifestyle behaviors, and folic acid supplementation was collected by in-person interview. Of the women, 99% reported having taken folic acid supplements. Results of a logistic regression analysis showed that higher plasma levels of OCPs were associated with increased odds of higher plasma homocysteine after adjustment for potential confounding factors. Positive correlations were observed between plasma OCPs and plasma homocysteine concentrations: HCB (r = 0.176, p = 0.002), ß-HCH (r = 0.172, p = 0.002), ρ,ρ'-DDE (r = 0.132, p = 0.020), ρ,ρ'-DDD (r = 0.161, p = 0.004), and ο,ρ'-DDT (r = 0.144, p = 0.011). Plasma concentrations of OCPs were negatively correlated with red blood cell (RBC) folate in the low-RBC-folate subgroup, but the correlations were not statistically significant. A positive correlation was observed between OCPs and homocysteine in the low-RBC-folate subgroup. These findings suggest that OCPs may disturb the folate-dependent homocysteine metabolism pathway.

An efficient method to simultaneously analyze multi-class organic pollutants in human serum.

The degree of population exposure to various organic pollutants (OPs), including polycyclic aromatic hydrocarbons, organochlorinated pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers, can be determined by measuring their concentrations in human serum. However, performing large-scale measurements with such a variety of compounds in serum is challenging in terms of efficiency and cost. We describe herein the development of a high-efficiency extraction and sample cleanup protocol for simultaneous and quantitative analyses of OPs using gas chromatography-mass spectrometry. OPs, together with crude lipid impurities, were extracted from human serum with a mixture of n-hexane and methyl tert-butyl ether. A disperse sorbent composed of primary secondary amine and C18 (PSA/C18) was used to roughly remove co-extracted impurities. A combined column of neutral silica gel and neutral alumina oxide (AlO/SiG) was then used for deep cleanup. For the removal of impurities, the overall performance of our protocol for the analysis of OPs in serum was comparable to that of traditional gel permeation chromatography (GPC) and dramatically better than that of PSA/C18, which is a frequently used QuEChERS (quick, easy, cheap, effective, rugged, safe) based method. While both the proposed protocol and GPC yielded recoveries of 80%-110% for four classes of OPs, our protocol consumed about 10 times less solvent, resulting in lower experimental expenses and a lower risk of contamination from residual OPs in the solvent and other supplies. In contrast to GPC, our protocol also permits efficient batch processing of serum samples, allowing for large sample sizes such as those encountered in epidemiological studies.

Nanostructured lipid carriers co-delivering lapachone and doxorubicin for overcoming multidrug resistance in breast cancer therapy.

BACKGROUND: Multidrug resistance is responsible for the poor outcome in breast cancer therapy. Lapa is a novel therapeutic agent that generates ROS through the catalysis of the NAD(P) H:quinone oxidoreductase-1 (NQO1) enzyme which significantly facilitate the intracellular accumulation of the co-delivered DOX to overcome MDR in cancer cells. PURPOSE: Herein, in our study, nanostructured lipid carrier (NLC) co-delivering ß-lapachone (Lapa) and doxorubicin (DOX) was developed (LDNLC) with the aim to overcome the multidrug resistance (MDR) in breast cancer therapy. PATIENTS AND METHODS: Lapa and DOX were loaded into NLC to prepare LDNLC using melted ultrasonic dispersion method. RESULTS: The well designed LDNLC was nanoscaled particles that exhibited preferable stability in physiological environment. In vitro cell experiments on MCF-7 ADR cells showed increased DOX retention as compared to DOX mono-delivery NLC (DNLC). In vivo anti-cancer assays on MCF-7 ADR tumor bearing mice model also revealed significantly enhanced efficacy of LDNLC than mono-delivery NLCs (DNLC and LNLC). CONCLUSION: LDNLC might be a promising platform for effective breast cancer therapy.