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Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

The rostral ventromedial medulla (RVM) is a bulbospinal nuclei in the descending pain modulation system, and directly affects spinal nociceptive transmission through pronociceptive ON cells and antinociceptive OFF cells in this area. The functional status of ON and OFF neurons play a pivotal role in pain chronification. As distinct pain modulative information converges in the RVM and affects ON and OFF cell excitability, neural circuits and transmitters correlated to RVM need to be defined for an in-depth understanding of central-mediated pain sensitivity. In this review, neural circuits including the role of the periaqueductal gray, locus coeruleus, parabrachial complex, hypothalamus, amygdala input to the RVM, and RVM output to the spinal dorsal horn are discussed. Meanwhile, the role of neurotransmitters is concluded, including serotonin, opioids, amino acids, cannabinoids, TRPV1, substance P and cholecystokinin, and their dynamic impact on both ON and OFF cell activities in modulating pain transmission. Via clarifying potential specific receptors of ON and OFF cells, more targeted therapies can be raised to generate pain relief for patients who suffer from chronic pain.

PurposeShort-term spinal cord stimulation (st-SCS) has been widely used to treat herpetic-related neuralgia (HN) in China for several years, but is still heavily debated as it has no strong evidence in clinical application. Therefore, a questionnaire survey among the Chinese pain specialist workgroup of the Chinese Neuromodulation Society and Chinese Medical Doctor Association was carried out to achieve a consensus about the clinical use of st-SCS for HN treatment.MethodsThe contents of the questionnaire include basic information about doctors (hospital level, work experience, training, procedure numbers, etc.), efficacy, indications, and contraindications of st-SCS, operation conditions, and preoperative preparation of st-SCS, and the prospect of the st-SCS procedure. Initially, the survey was conducted on 110 experts who have practiced the st-SCS procedure from all over the provinces in China. Finally, valuable data was calculated from the 110 questionnaires excluding the doctors with

Background and AimsHepatic ischemia–reperfusion injury (IRI) is a common phenomenon that occurs after liver transplantation and liver tumor surgery. It can cause liver dysfunction and recovery failure after liver surgery, even leading to acute liver failure. Our aim is to investigate the protective effect and related potential mechanism of [D-Ala2, D-Leu5] enkephalin (DADLE) treatment on hepatic IRI in cirrhotic livers of rats.MethodsThe models of liver cirrhosis and hepatic IRI were established with male Sprague–Dawley rats. DADLE at a dose series of 0.5, 1, or 5 mg·kg−1 was injected intravenously to rats 10 min prior hepatic ischemia, followed by a 6- h reperfusion. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological changes, and liver cell apoptosis were used to assess liver IRI. The optimal dose of DADLE was assessed by using the Suzuki score and ALT and AST levels. We repeated the hepatic IRI procedure on the optimal dose of the DADLE group and the delta opioid receptor (DOR) antagonist natrindole hydrochloride (NTD) injection group. Serum ALT and AST levels, histological staining, hepatic apoptosis, and serum levels of tumor necrosis factor alpha (TNF-α) and interleukin 1 β (IL-1β) were measured. The expression of protein kinase B (Akt) and its downstream proteins were evaluated by using quantitative real-time polymerase chain action (qRT-PCR) and Western blotting.ResultsCompared with the control group, DADLE treatment at a dose of 5 mg·kg−1 reduced the Suzuki score (mean: 5.8, range: 5.0–6.6 vs. mean: 8.0, range: 7.0–8.9), the ALT level (134.3 ± 44.7 vs. 247.8 ± 104.6), and the AST (297.1 ± 112.7 vs. 660.8 ± 104.3) level. DOR antagonist NTD aggravated hepatic IRI. Compared with the control group, DADLE treatment decreased the number of apoptosis cells and microphages and neutrophils, increased the expression of Akt and its mRNA to much higher levels, and upregulated the mRNA and protein expression of Bcl-2 and Bcl-2-associated death promoter (BAD).ConclusionDADLE treatment at a dose of 5 mg·kg−1 injected intravenously 10 min prior hepatic ischemia could contain rats’ hepatic IRI by activating DOR in cirrhotic livers. The effects of DADLE could be offset by NTD. The potential molecular mechanism seems to be involved in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway.

After the completion of in situ pyrolysis, oil shale can be used as a natural place for CO2 sequestration. However, the effects of chemical action and formation stress-state changes on the deformation of oil shale should be considered when CO2 is injected into oil shale after pyrolysis. In this study, combined with statistical damage mechanics, a transverse isotropic model of oil shale with coupled damage mechanisms was established by considering the decreased mechanical properties and the chemical damage caused by CO2 injection. The process of injecting supercritical CO2 into oil shale after pyrolysis was simulated by COMSOL6.0. The volume distribution of CO2 and the stress evolution in oil shale were analyzed. It is found that CO2 injection into oil shale after pyrolysis will not produce new force damage, and the force damage caused by the decrease in the mechanical properties of oil shale after pyrolysis can offset the ground uplift caused by CO2 injection to a certain extent. Under the combined action of chemical damage and mechanical damage, the uplift of a formation with a thickness of 200 m is only 10 cm. The injection of supercritical CO2 is beneficial for maintaining the stability of oil shale after in situ pyrolysis.

Abstract Objective The purpose of this study was to develop a scale of clinician training elements in the new period and test its reliability and validity. Methods Our approach was based on interdisciplinary theory, systematology, collaborative innovation theory, and whole person education theory combined with the existing post competency model of Chinese doctors and the responsibilities and requirements endowed clinicians in the new historical period. The scale elements were extracted by referring to the relevant literature, and the training elements scale for clinicians in the new period were preliminarily formed. From July to August 2022, 1,086 clinicians from tertiary medical institutions in eastern, central, and western China were sampled and investigated. The questionnaire was revised via the critical ratio method and homogeneity test method, and the reliability and validity of the scale were also tested. Results The training elements scale for clinicians in the new period included the following eight dimensions: basic clinical knowledge, interdisciplinary knowledge, clinical skill operation, public health knowledge, technological innovation capability, lifelong learning needs, medical humanistic literacy, and international exchange vision, as well as 51 other items. The Cronbach’s α coefficient of the scale was 0.981, the half-reliability was 0.903, and the average variance extraction of each dimension was greater than 0.5. An exploratory factor analysis extracted eight main factors, and the cumulative variance contribution rate was 78.524%. Confirmatory factor analysis showed that the model fit was ideal and the factor structure was stable. Conclusion The clinician training factor scale in the new era can fully meet the current training needs of r clinicians, and has good reliability and validity. It can be widely used in medical colleges and universities as a reference to reform the content of medical training and education, and can also be used in the continuing education of clinicians after graduation to compensate for gaps in knowledge during clinical work.

Abstract Bone morphogenetic protein 4 (BMP4) is an important member of the transforming growth factor-β superfamily. BMP4 is expressed in the Leydig cell lineage. We hypothesized that BMP4 might regulate the development of stem/progenitor Leydig cells. The BMP4 receptors, BMPR1A, BMPR1B, and BMPR2 were found to be expressed in progenitor Leydig cells of prepubertal testis and isolated cells. BMP4 at 1 and 10 ng/mL significantly reduced androgen production and down-regulated steroidogenesis-related gene and protein expression possibly by activating the SMAD signaling pathway (increasing SMAD1/5 phosphorylation and SMAD4) at 24 h treatment. BMP4 at 0.1 ng/mL and higher concentrations markedly reduced the EdU labeling index of CD90+ stem Leydig cells after 24 h treatment and significantly reduced the number of EdU+ stem Leydig cells on the surface of seminiferous tubules after 7 days of culture. BMP4 at 0.01 ng/mL and higher concentrations significantly blocked the differentiation of stem Leydig cells into adult cells, as shown by the reduction of testosterone secretion and the downregulation of Lhcgr, Scarb1, Cyp11a1, Hsd11b1, and Insl3 and their function after 3D seminiferous tubule culture for 3 weeks, and this effect was reversed by co-treatment with the BMP4 antagonists noggin and doxomorphine. In addition, BMP4 also blocked stem Leydig cell differentiation through SMAD-independent signaling pathways (ERK1/2 and AMPK). Ethanedimethane sulfonate (EDS) single injection can result in reduction of testosterone, restoration can happen post treatment. In an in vivo model of Leydig cell regeneration following EDS treatment, intratesticular injection of BMP4 from day 14 to day 28 post-elimination significantly reduced serum testosterone levels and down-regulated the expression of Scarb1, Star, Hsd11b1, and Insl3 and its proteins, possibly through SMAD-dependent and SMAD-independent (ERK1/2 and AMPK) signaling pathways. In conclusion, BMP4 is expressed in cells of the Leydig cell lineage and blocks entry of stem/progenitor Leydig cells into adult Leydig cells through SMAD-dependent and SMAD-independent signaling pathways.

Glucocorticoid hormone might cause intrauterine growth restriction. The glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) in the placenta eliminates excess levels of glucocorticoids during pregnancy. The aim of the current study was to define the effects of diethylstilbestrol (DES) on HS D11B2 activity in the mammalian placentas and identify its mode of action. Rat and human placental microsomal HSD11B2 were incubated with different concentrations of DES, and IC50 values were determined. The mode of action was analyzed by incubation of DES together with substrates, glucocorticoid and NAD+. DES suppressed rat and human HSD11B2 with IC50 values of 5.33 and 12.62 μM, respectively. DES was a competitive inhibitor of rat and human HSD11B2 when steroid substrates were added, while it was an uncompetitive inhibitor when cofactor NAD+ was exposed. Oral administration of DES (0.5 mg/kg) to the rat delayed the cortisol metabolism in adult female Sprague–Daw ley rats, as indicated by the increases in cortisol’s elimination half-life, maximum concentration and area under the curve. In conclusion, DES is a potent HSD11B2 inhibitor, possibly contributing to the intrauterine growth restriction.

Atrazine (ATR) is a commonly used agricultural herbicide and a potential endocrine disruptor that may cause testicular dysgenesis. The objective of the present study was to investigate the effects of atrazine on fetal testis development after in utero exposure. Female Sprague-Dawley rats were gavaged daily with vehicle (corn oil, control) or atrazine (25, 50, and 100 mg/kg body weight/day) from gestational day 12 to 21. Atrazine dose-dependently decreased serum testosterone levels of male pups, with a significant difference from the control recorded at a dose of 100 mg/kg. In addition, atrazine significantly increased fetal Leydig cell aggregation at a dose of 100 mg/kg. Atrazine increased fetal Leydig cell number but not Sertoli cell number. However, atrazine down-regulated Scarb1 and Cyp17a1 in the fetal Leydig cell per se and Hsd17b3 and Dhh in the Sertoli cell per se. These results demonstrated that in utero exposure to atrazine disrupted rat fetal testis development.

Background Long COVID is a common problem in the recovery period of coronavirus disease (COVID-19). The prevention and treatment of long COVID has become the focus of the medical fields of COVID-19. It is important to clarify the situation of long COVID in China and find out the follow-up research route, thus providing evidence-based evidence for clinical practice. Objective To explore the characteristics of long COVID in China, aiming to provide references for the follow-up research. Methods From January 2023 to August 2023, a self-made survey questionnaire was used to investigate the current situation of long COVID in China. The questionnaire included general information, such as gender and age, treatment expectations, symptoms and signs in acute and recovery period, etc. Results A total of 1 001 questionnaires were collected, including 901 people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and 585 (64.9%) people with long COVID. Binary Logistic regression analysis showed that female (OR=2.000, 95%CI=1.477-2.705, P

Background: Decompression sickness (DCS) induced by fast buoyancy ascent escape (FBAE) is a special DCS, characterized with cardiopulmonary injuries. Serum metabonomics of this type of DCS has not yet been studied. We proposed a metabonomics approach for assessing serum metabonomics changes and evaluating the preventive effect of pyrrolidine dithiocarbamic acid (PDTC) in FBAE-induced DCS rats., Methods: Sixty-five (65) rats were divided into three groups, including the Control, DCS and PDTC groups. After receiving physiological saline or PDTC pretreatment, rats in the DCS and PDTC groups received the same protocol of simulated FBAE. Following this, a metabonomics approach - combined with pattern recognition methods including PCA and PLS-DA - was used to characterize the global serum metabolic profile on survival rats (five rats per group) associated with abnormal FBAE-induced DCS. As the VIP-value threshold cutoff of the metabolites was set to 2, metabolites above this threshold were filtered out as potential target biomarkers., Results: Sixteen (16) distinct potential biomarkers in rat plasma were identified. PDTC significantly lowered DSC mortality from 60% to 10%, and alleviated ultrastructural alteration of the left ventricular apex compared to the DCS group. It was found that abnormal FBAE-induced DCS was closely related to disturbed fatty acid metabolism, glycerophospholipid metabolism, sterol lipid metabolism, and bile acid metabolism. With the presented metabonomic method, we systematically analyzed the protective effects of PDTC., Conclusion: The results demonstrated that PDTC administration could provide satisfactory effects on abnormal FBAE-induced DCS through partially regulating the perturbed metabolic pathways., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission.

Background: Postherpetic neuralgia (PHN) is often refractory to existing treatments. Pulsed radiofrequency (PRF) is known to be effective for treating neuropathic pain. In common, the targets of PRF treatment were the segmental dorsal root ganglion (DRG) neurons responsible for the pain. A potential complication that can occasionally occur with PRF treatment is damage to the adjacent tissue and organ. The effectiveness of the angulus costae as a puncture site for PRF has not been tested in thoracic PHN treatment., Objective: The goal of this study was to investigate the therapeutic efficacy and safety of PRF for treating thoracic PHN through the puncture of the angulus costae., Study Design: Prospective, randomized, double-blinded study., Setting: Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine., Methods: Ninety-six patients with thoracic (T2-11) PHN were equally randomized assigned into 2 groups. The electrode needle punctured through the angulus costae of each patient guided by x-ray; PRF at 42° C for 120 seconds was applied after inducing paresthesia involving the affected dermatome area. PRF was applied in the PRF group (n = 48) twice. It was also applied in the sham group (n = 48) twice without radiofrequency energy output. The treatment was done once a week for 3 weeks. Tramadol was used for flare pain when the visual analog scale (VAS) ≥ 3., Outcomes Assessment: The therapeutic effect was evaluated by VAS, SF-36 health survey questionnaire, side effects (type, frequency, and onset time) before treatment, at days 3, 7, and 14, and at months one, 2, 3 and 6 after PRF. The average of tramadol (mg/d) administered within the first  month after treatment was also recorded., Results: The postprocedure VAS scores in the PRF group were significantly lower than those in the sham group and lasted for 6 months after treatment (P < 0.05). The SF-36 score, such as physical functioning, physical role, bodily pain, general health perceptions, social function, emotional role, and mental health index were significantly improved until 6 months after treatment in the PRF group compared to the sham group (P < 0.01-0.05). The average dosage of tramadol  administrated (mg/d) within the first  month after treatment was also significantly reduced in the PRF group compared to the sham group (P < 0.05). There were no obvious signs of pneumothorax, bleeding, infection, or other severe side effects in either group (P > 0.05)., Limitations: Single center study, relatively small number of patients., Conclusions: The strategy that the angulus costae be used as the PRF puncture point of an electrode needle and the final localization of the needle tip as determined by sensory testing is an effective and safe therapeutic alternative for thoracic PHN treatment. Benefits include that the procedure is minimally invasive, provides short-term pain relief, and improves quality of life., Clinical Trial Registration: NO ISRCTN25588650.