Nerve Growth Factor/Tyrosine Kinase A Receptor Pathway Enhances Analgesia in an Experimental Mouse Model of Bone Cancer Pain by Increasing Membrane Levels of δ-Opioid Receptors.

BACKGROUND: The role of nerve growth factor (NGF)/tyrosine kinase A receptor (TrKA) signaling, which is activated in a variety of pain states, in regulating membrane-associated δ-opioid receptor (mDOR) expression is poorly understood. The hypothesis was that elevated NGF in bone cancer tumors could upregulate mDOR expression in spinal cord neurons and that mDOR agonism might alleviate bone cancer pain. METHODS: Bone cancer pain (BCP) was induced by inoculating Lewis lung carcinoma cells into the femoral marrow cavity of adult C57BL/6J mice of both sexes. Nociceptive behaviors were evaluated by the von Frey and Hargreaves tests. Protein expression in the spinal dorsal horn of animals was measured by biochemical analyses, and excitatory synaptic transmission was recorded in miniature excitatory synaptic currents. RESULTS: The authors found that mDOR expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.18 ± 0.01 g vs. mean ± SD: 0.13 ± 0.01 g, n = 4, P < 0.001) and that administration of the DOR agonist deltorphin 2 (Del2) increased nociceptive thresholds (Del2 vs. vehicle, median [25th, 75th percentiles]: 1.00 [0.60, 1.40] g vs. median [25th, 75th percentiles]: 0.40 [0.16, 0.45] g, n = 10, P = 0.001) and reduced miniature excitatory synaptic current frequency in lamina II outer neurons (Del2 vs. baseline, mean ± SD: 2.21 ± 0.81 Hz vs. mean ± SD: 2.43 ± 0.90 Hz, n = 12, P < 0.001). Additionally, NGF expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.36 ± 0.03 vs. mean ± SD: 0.16 ± 0.02, n = 4, P < 0.001), and elevated NGF was associated with enhanced mDOR expression via TrKA signaling. CONCLUSIONS: Activation of mDOR produces analgesia that is dependent on the upregulation of the NGF/TrKA pathway by increasing mDOR levels under conditions of BCP in mice.

ABO blood types may affect transient neurological events after surgical revascularization in patients with moyamoya disease: a retrospective single center study.

BACKGROUND: Moyamoya disease (MMD) is a cerebrovascular disease with unknown cause. Patients with MMD disease usually experience transient neurological events (TNEs) after revascularization surgery. This retrospective single-center study was aimed to explore the risk factors of postoperative TNEs after surgical revascularization in patients with MMD. METHODS: We selected 324 patients who underwent surgical revascularization between January 2017 and September 2022 in our center. The perioperative characteristics of the patients were recorded and the outcome was TNEs after surgery. An analysis of risk factors contributing to postoperative TNEs by using logistic regression model. RESULTS: Three hundred twelve patients were enrolled, and the incidence of postoperative TNEs was 34% in our study. Males were more likely to suffer from postoperative TNEs (OR = 2.344, p = 0.002). Preoperative ischemic presentation (OR = 1.849, p = 0.048) and intraoperative hypotension (OR = 2.332, p = 0.002) were associated with postoperative TNEs. Compared to patients with blood type O, patients with blood type A (OR = 2.325, p = 0.028), B (OR = 2.239, p = 0.027) and AB (OR = 2.938, p = 0.019) had a significantly higher incidence of postoperative TNEs. A risk prediction model for postoperative TNEs was established, and the established risk prediction area under the receiver operating characteristic curve (ROC) of the model was 0.741. CONCLUSIONS: Males, preoperative ischemic presentation and intraoperative hypotension were associated with postoperative TNEs. We also found a possible link between postoperative TNEs and ABO blood types after surgical revascularization for moyamoya patients.

Effects of berberine hydrochloride on immune response in the crab Charybdis japonica.

Berberine hydrochloride is the main effective component of Coptis spp. used in Chinese herbal medicine and its underlying molecular mechanisms, responsible for inducing effects in crustacean species, are not fully understood. In this study, the molecular response of the crab Charybdis japonica to berberine hydrochloride exposure was studied using transcriptome sequencing. The survival rate, gene expression and activities of several immune enzymes were measured after berberine hydrochloride treatments, with or without injection of the pathogenic bacterium Aeromonas hydrophila. A total of 962 differentially expressed genes (464 up-regulated and 498 down-regulated) were observed during exposure to 100 mg/L of berberine hydrochloride and in the control group after 48 h. Enrichment analysis revealed that these genes are involved in metabolism, cellular processes, signal transduction and immune functions, indicating that exposure to berberine hydrochloride activated the immune complement system. This bioactive compound simultaneously activated fibrinogen beta (FGB), fibrinogen alpha (FGA), alpha-2-macroglobulin (A2M), kininogen (KNG), fibrinogen gamma chain (FGB), alpha-2-HS-glycoprotein (AHSG), caspase-8 (CASP8), cathepsin L (CTSL), adenylate cyclase 3 (Adcy3) and MMP1. Its action could significantly increase the survival rate of the crabs injected with A. hydrophila and promote the activity of LZM, Caspas8, FGA, ACP and AKP in the hepatopancreas. When A. hydrophila was added, the neutralization of 300 mg/L berberine hydrochloride maximized the activities of Caspas8, LZM, ACP and AKP. Our results provide a new understanding of the potential effects of berberine hydrochloride on the immune system mechanisms in crustaceans.

[Effect of acupuncture at " three points of ilioumbar" on lumbar function and pain in patients with iliopsoas muscle strain].

OBJECTIVE: To compare the clinical effect of acupuncture at "three points of iliolumbar" combined with celecoxib and celecoxib alone in the treatment of iliopsoas muscle strain. METHODS: A total of 60 patients with iliopsoas muscle strain were randomly divided into an observation group and a control group, 30 patients in each group. Celecoxib was given orally to both groups, 200 mg once a day for 3 days. On the basis of the above drugs, acupuncture was applied at Yaoda (Extra), Wushu (GB 27), Qiayao (Extra) in the observation group, once a day for 3 days. The Japanese Orthopaedic Association (JOA) score and visual analogue scale (VAS) score were observed and compared before and after treatment, and the content of 5-hydroxytryptamine (5-HT) in serum was detected by enzyme-linked immunosorbent assay (ELISA) before and after treatment in the two groups. RESULTS: After treatment, the JOA scores in the two groups were increased (both P<0.05), and the VAS scores and 5-HT contents were decreased (all P<0.05). The increase of JOA score in the observation group was greater than that in the control group (P<0.05), and the decrease of VAS score and 5-HT content in the observation group was greater than that in the control group (both P<0.05). CONCLUSION: Acupuncture at "three points of ilioumbar" combined with celecoxib in the treatment of iliopsoas muscle strain can improve lumbar function, relieve pain and reduce 5-HT content in serum, which is better than celecoxib alone.

CCND1 rs9344 polymorphism is associated with the risk of hepatocellular carcinoma in Caucasian population.

AIMS: Some studies investigated the association between CCND1 rs9344 polymorphism and hepatocellular carcinoma (HCC) risk. However, the results were inconclusive. Thus, we did a meta-analysis to determine this relationship. MATERIALS AND METHODS: Relevant studies were systematically searched using the PubMed, CNKI, and EMBASE databases. The strength of the association was calculated with the odds ratio (OR) and respective 95% confidence intervals (Cis). RESULTS: We investigated the association between CCND1 rs9344 polymorphism and HCC risk in the dominant models. The result of this meta-analysis showed that CCND1 rs9344 polymorphism did not significantly associated with HCC risk (OR = 1.09; 95% CI 0.88-1.34). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with HCC risk in Caucasians (OR = 1.55; 95% CI, 1.05-2.29). However, we did not find any significant association between this polymorphism and HCC risk in Asians (OR = 0.91; 95% CI, 0.71-1.18). CONCLUSIONS: This meta-analysis suggested that CCND1 rs9344 polymorphism might be associated with the risk of HCC among Caucasians.

Blockage of spinal endothelin A receptors attenuates bone cancer pain via regulation of the Akt/ERK signaling pathway in mice.

Bone cancer pain (BCP) is a common source of pain in patients with advanced stage and metastatic cancer; however, existing treatment for this kind of pain remains deficient. Being closely related to sensory change and inflammatory pain in both the central and peripheral nervous systems, endothelin A receptor (ETAR) plays an essential role in pain processing. As a result, ETAR antagonist has been reported to alleviate both neuropathic and inflammatory pain. Thus far, the role of ETAR in the process of BCP is still ambiguous. In this study, by using a BCP mouse model, the analgesic effect and molecular mechanism of the ETAR antagonist BQ-123 was investigated. Pain sensation in the BCP mouse model was investigated by the number of spontaneous flinches (NSF) and pain withdrawal threshold (PWT), and the mechanism of BCP was assessed by measuring p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 levels in L4-6 segments of the spinal cord. Our results demonstrated that BCP mice showed a higher NSF and a lower PWT score than Sham mice. In addition to the development of nociceptive sensitization, p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 were up-regulated correspondingly in L4-6 segments of the spinal cord in BCP mice. BQ-123 treatment showed a promising analgesic effect, and the effect was correlated to the down-regulation of p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 in spinal cord cells. The results suggested that intrathecal administration of BQ-123 was able to relieve BCP in mice as a consequence of suppressing the Akt and ERK signalling pathways.

Intrathecal pramoxine causes long-lasting spinal sensory and motor block in rats.

OBJECTIVES: The objective of this experiment was to investigate spinal anaesthetic effects of pramoxine and its comparison with bupivacaine, a long-lasting local anaesthetic. METHODS: After intrathecal injection, three neurobehavioural assessments, which consisted of nociceptive, proprioceptive and motor block, were constructed in rats. The effects of bupivacaine and pramoxine (four doses of each drug) in a dose-related manner were conducted to obtain the ED50 (50% effective dose). Pramoxine potency and duration at provoking spinal nociceptive, proprioceptive and motor block were compared with those of bupivacaine. KEY FINDINGS: We manifested that pramoxine provoked dose-relatedly spinal blockades of nociception, proprioception and motor function. Based on the ED50 , the rank potency at producing spinal nociceptive, proprioceptive and motor block was bupivacaine (0.90 (0.82-1.02), 1.00 (0.92-1.08) and 1.16 (1.02-1.34) µmol/kg) greater (P < 0.01 for the differences) than pramoxine (15.47 (14.04-17.05), 16.46 (15.06-17.99), and 17.77 (16.48-19.15) µmol/kg). The spinal block duration created by bupivacaine was not predominantly different (P > 0.05 for the differences) from that created by pramoxine at the equipotent doses (ED75 , ED50 and ED25 ). CONCLUSIONS: Our preclinical experiment indicated that pramoxine elicited a dose-related spinal block, was less potent than bupivacaine and had a similar duration of spinal block compared with bupivacaine.

Mexiletine co-injected with clonidine increases the quality and duration of cutaneous analgesia in response to skin pinpricks in the rat.

The goal of the experimental design was to assess the cutaneous analgesic effect of mexiletine by co-injection with clonidine. The effect of nociceptive block was evaluated according to the inhibition of the cutaneous trunci muscle reflex (CTMR) in response to skin pinpricks in rats. The dose-related analgesic effect of mexiletine alone or mexiletine co-administrated with clonidine was constructed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous analgesia. Compared with mexiletine (1.8µmol), adding clonidine to mexiletine (1.8µmol) solutions for skin nociceptive block potentiated and prolonged the action (p<0.01). Mexiletine (6µmol) combined with clonidine extended the duration of cutaneous analgesia when compared with mexiletine (6µmol) alone (p<0.01). Co-administration of clonidine increases the potency and extends the duration of cutaneous analgesia by mexiletine, and the minimal dose of clonidine to intensify the analgesic effect is 0.06µmol.

Epidemiology of cancer in end-stage renal disease dialysis patients: a national cohort study in Taiwan.

The incidence and mortality of site-specific cancers in patients with end-stage renal disease (ESRD) on maintenance dialysis have been rarely studied for Asian populations. We tapped Taiwan`s National Health Insurance Research Database to identify and recruit patients starting maintenance dialysis between 1999 and 2004. They were followed from initiation of dialysis until death, discontinuation of dialysis, or the end of 2008. We calculated the survival rate and mortality risk of dialysis patients with cancer. Of 40,833 dialysis patients, 2352 (5.8%) had been newly diagnosed with cancer. Being older, being male, and having chronic liver disease were factors associated with a higher risk for new cancer in ESRD dialysis patients. In men, liver cancer (20.63%) was the most frequent, followed by cancers of the bladder (16.88%) and kidney (11.61%). In women, bladder cancer (25.57%) was the most frequent, followed by cancers of the kidney (16.31%) and breast (11.20%). The 5-year survival rates for kidney and bladder cancer were higher than for other cancers; the survival rates for lung, stomach, and liver cancer were lower. In conclusion, the distribution of site-specific cancer was different between men and women in patients with ESRD on dialysis. More attention should be paid to teaching dialysis patients how to avoid the well-known cancer risks and carcinogens and individualized regular cancer screenings.

Identfication of key miRNAs in pancreatitis using bioinformatics analysis of microarray data.

Pancreatitis is a type of inflammation in the pancreas, which frequently occurs due to alcohol and gallstones. The present study aimed to identify pancreatitis­associated microRNAs (miRNAs) by analyzing the microarray of GSE24279. GSE24279 was downloaded from the Gene Expression Omnibus, composed of a collective of 27 pancreatitis and 22 normal control samples. The differentially expressed miRNAs (DE­miRNAs) in pancreatitis samples were screened using the Limma package in Bioconductor. Subsequently, target genes of the DE­miRNAs were predicted using the miRecords and miRWalk databases. Their potential functions were analyzed by functional and pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery online tool. Finally, pancreatitis­associated genes among the target genes identified were searched using the Comparative Toxicogenomics Database, and a regulatory network of pancreatitis­associated genes and their target miRNAs were constructed using Cytoscape software. A total 14 upregulated and 39 downregulated miRNAs were identified in pancreatitis samples compared with control samples and 290 target genes of DE­miRNAs were determined. Cyclin D1 (CCND1), v­akt murine thymoma viral oncogene homolog 2 (AKT2), cyclin­dependent kinase 6 (CDK6) and SMAD family member 2 (SMAD2) were involved in the pathway of pancreatic cancer. Among the target genes, 279 genes were pancreatitis­associated genes, which in turn were targeted by 37 miRNAs in the regulatory network. Hsa­miR­15a, hsa­miR­16, hsa­miR­155, hsa­miR­375 and hsa­miR­429 in particular may be involved in pancreatitis by targeting genes in the regulatory network, including hsa­miR­15a→CCND1, hsa­miR­16→CCND1, hsa­miR­155→CCND1/SMAD2, hsa­miR­375→AKT2/CDK6 and hsa­miR­429→CCND1. The above miRNAs and their targets may contribute to the pathogenesis of pancreatitis; therefore, they may be potential therapeutic targets.

HIV-related behaviors, social support and health-related quality of life among men who have sex with men and women (MSMW): a cross-sectional study in Chongqing, China.

BACKGROUND: Health-related quality of life (HRQOL) has become commonly used both as a concept and as a field of research. However, little is known about the HRQOL of men who have sex with men and women (MSMW). The aim of this study was to examine HIV-related behaviors, social support, and HRQOL status and explore its predictors among MSMW. METHODS: An anonymous cross-sectional study was conducted by snowball sampling method in 2013. A total of 563 Chinese MSM completed a structured questionnaire. The HRQOL and social support were measured with the Chinese version of the World Health Organization Quality of Life Scale (WHOQOL-BRFE) and the Social Support Rating Scale (SSRS), respectively. RESULTS: Of the 563 MSM analyzed, 77 (13.68%) were MSMW who had a higher proportion of in-marriage and preference for an insertive role as compared with the men who have sex with men only (MSMO) (P<0.05). As high as 70.13% of MSMW had no regular sex partners and 72.73% of MSMW reported engaging in unprotected anal sex in the last six months. 36.36% had tested for HIV, while only 12.99% had accepted HIV voluntary counseling and testing (VCT) services. The scores of objective support and subjective support in MSMW were significantly higher than that of MSMO (P<0.05). No statistically significant difference was found in scores of all the four domains of the HRQOL between MSMW and MSMO. When comparing the HRQOL scores of MSMW with the Chinese general population reference group, the scores of MSMW were significantly lower in physical health domain. In a multivariate regression model, age, monthly income, sexual role, VCT acceptability, subjective support were associated with variability in HRQOL. CONCLUSIONS: To improve the HRQOL among MSMW, more attention needs to be paid to those with low social support, low-income, the old and those prefer a receptive role during anal sex populations.

Should temporary extracorporeal continuous portal diversion replace meso/porta-caval shunts in "small-for-size" syndrome in porcine hepatectomy?

AIM: To investigate the feasibility of temporary extracorporeal continuous porta-caval diversion (ECPD) to relieve portal hyperperfusion in "small-for-size" syndrome following massive hepatectomy in pigs. METHODS: Fourteen pigs underwent 85%-90% liver resection and were then randomly divided into the control group (n = 7) and diversion group (n = 7). In the diversion group, portal venous blood was aspirated through the portal catheter and into a tube connected to a centrifugal pump. After filtration, the blood was returned to the pig through a double-lumen catheter inserted into the internal jugular or subclavian vein. With the conversion pump, portal venous inflow was partially diverted to the inferior vena cava through a catheter inserted via the gastroduodenal vein at 100-130 mL/min. Portal hemodynamics, injury, and regeneration in the liver remnant were compared between the two groups. RESULTS: Compared to the control group, porta-caval diversion via ECPD significantly mitigated excessive portal venous flow and portal vein pressure (PVP); the portal vein flow (PVF), hepatic artery flow (HAF), and PVP in the two groups were not significantly different at baseline; however, the PVF (431.8 ± 36.6 vs 238.8 ± 29.3, P < 0.01; 210.3 ± 23.4 vs 122.3 ± 20.6, P < 0.01) and PVP (13.8 ± 2.6 vs 8.7 ± 1.4, P < 0.01; 15.6 ± 2.1 vs 10.1 ± 1.3, P < 0.05) in the control group were significantly higher than those in the diversion group, respectively. The HAF in the control group was significantly lower than that in the diversion group at 2 h and 48 h post hepatectomy, and ECPD significantly attenuated injury to the sinusoidal lining and hepatocytes, increased the regeneration index of the liver remnant, and relieved damage that the liver remnant suffered due to endotoxin and bacterial translocation. CONCLUSION: ECPD, which can dynamically modulate portal inflow, can reduce injury to the liver remnant and facilitate liver regeneration, and therefore should replace permanent meso/porta-caval shunts in "small-for-size" syndrome.

Comparison analysis in synchronous and metachronous metastatic colorectal cancer based on microarray expression profile.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis. METHODOLOGY: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted. RESULTS: Total of 36 DEGs including 35 down-regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny. CONCLUSIONS: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment.

ERIC-PCR genotyping of Pseudomonas aeruginosa isolates from haemorrhagic pneumonia cases in mink.

BACKGROUND: Pseudomonas aeruginosa is a significant pathogen of mink and the cause of haemorrhagic pneumonia, an acute fatal disease in farmed mink. RESULTS: Among 90 P. aeruginosa isolates from haemorrhagic pneumonia in mink from 16 farms in Shandong province, China, 43 genotypes were identified by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR), with a diversity index of 0.96. The most prevalent ERIC-PCR types were type 18, found in 16 isolates, and type 39, found in 15 isolates. Four serotypes were detected, with serotype G (55.6 per cent) being the most frequent. CONCLUSIONS: These results showed that there was a high degree of clonal diversity among mink P. aeruginosa clinical isolates in this study.

Hydrogen peroxide-mediated growth of the root system occurs via auxin signaling modification and variations in the expression of cell-cycle genes in rice seedlings exposed to cadmium stress.

The link between root growth, H2O2, auxin signaling, and the cell cycle in cadmium (Cd)-stressed rice (Oryza sativa L. cv. Zhonghua No. 11) was analyzed in this study. Exposure to Cd induced a significant accumulation of Cd, but caused a decrease in zinc (Zn) content which resulted from the decreased expression of OsHMA9 and OsZIP. Analysis using a Cd-specific probe showed that Cd was mainly localized in the meristematic zone and vascular tissues. Formation and elongation of the root system were significantly promoted by 3-amino-1,2,4-triazole (AT), but were markedly inhibited by N,N'-dimethylthiourea (DMTU) under Cd stress. The effect of H2O2 on Cd-stressed root growth was further confirmed by examining a gain-of-function rice mutant (carrying catalase1 and glutathione-S-transferase) in the presence or absence of diphenylene iodonium. DR5-GUS staining revealed close associations between H2O2 and the concentration and distribution of auxin. H2O2 affected the expression of key genes, including OsYUCCA, OsPIN, OsARF, and OsIAA, in the auxin signaling pathway in Cd-treated plants. These results suggest that H2O2 functions upstream of the auxin signaling pathway. Furthermore, H2O2 modified the expression of cell-cycle genes in Cd-treated roots. The effects of H2O2 on root system growth are therefore linked to auxin signal modification and to variations in the expression of cell-cycle genes in Cd-stressed rice. A working model for the effects of H2O2 on Cd-stressed root system growth is thus proposed and discussed in this paper.