[Advances in diagnosis and treatment of Wolfram syndrome and related molecular mechanism].

Wolfram syndrome is a rare genetic spectrum disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, accompanied by other variable clinical manifestations. At present, the prognosis of this syndrome is very poor, the specific molecular mechanism is not clear, effective treatments are lacking to delay, prevent or reverse the development of Wolfram syndrome, and many patients die prematurely due to severe neurological dysfunction. This increases the urgency of the research on the pathogenic molecular mechanism related to Wolfram syndrome and the development of new therapies. This article summarizes the research progress on the pathogenic molecular mechanism and treatment status of Wolfram syndrome, in order to provide reference for the further mechanism research, prevention and treatment of Wolfram syndrome.

[Application guidelines and research progress of biomarkers for Alzheimer's disease].

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. It is expected that the incidence of AD will increase exponentially in the coming decades. The clinical and research application of AD biomarkers has gone through a long process. At present, the clinical diagnostic criteria for AD mainly include the IWG-2 criteria developed by International Working Group (IWG), the NIA-AA criteria formulated by the National Institute on Aging and Alzheimer's Association (NIA-AA) and the "Guidelines for the Diagnosis and Treatment of Alzheimer's Disease in China (2020 version)" released by the Professional Committee on Alzheimer's Disease and Related Diseases of the Chinese Geriatric Health Care Association (Alzheimer's Disease Chinese, ADC). Cerebrospinal fluid biomarkers such as Aß42, T-tau and P-tau are recognized as central biomarkers for AD, besides, the development of new molecules in other pathophysiological pathway that can be used as biomarkers for the diagnosis of AD have made great progress in the last decade. This article elaborates studies of the application guidelines of AD biomarkers and highlights the research progress of biomarkers in AD pathophysiological pathway.

[Comparison of application effects of colonoscopy, fecal immunochemical test and a novel risk-adapted screening approach in colorectal cancer screening in Xuzhou population].

Objective: To compare the application effect of the colonoscopy, fecal immunochemical test (FIT) and novel risk-adapted screening approach in colorectal cancer screening in Xuzhou population. Methods: From May 2018 to April 2019, 4 280 subjects aged 50-74 were recruited from Gulou district, Yunlong district and Quanshan district of Xuzhou. They were randomly assigned to the colonoscopy group (n=863), FIT group (n=1 723) and novel risk-adapted screening approach group (n=1 694) according to the ratio of 1∶2∶2. For the novel risk-adapted screening approach group, after the risk assessment, high-risk subjects were invited to undergo colonoscopy and low-risk subjects were invited to undergo FIT examination. All FIT positive subjects were invited to undergo colonoscopy. Colonoscopy participation rate [(the number of colonoscopies completed/the number of colonoscopies invited to participate)×100%], detection rate of colorectal lesions [(the number of diagnosed patients/the number of colonoscopies completed)×100%], colonoscopy resource load (the number of colonoscopies completed/the number of diagnosed advanced tumors) and FIT resource load in each group were calculated and compared. Results: The age of all subjects was (61±6) years old, including 1 816 males (42.43%). There was no statistically significant difference in the socio-demographic characteristics of the subjects in different screening groups. The colonoscopy participation rate was 22.60% (195/863) in the colonoscopy group, 57.04% (77/135) in the FIT group, and 33.94% (149/439) in the novel risk-adapted screening approach group, respectively. The colonoscopy participation rate was higher in the FIT group than in the colonoscopy group and the novel risk-adapted screening approach group (P<0.001). The colonoscopy participation rate of novel risk-adapted screening group was significantly higher than the colonoscopy group (P<0.001). The detection rates of advanced tumors were 6.67% (13/195), 9.09% (7/77) and 8.72% (13/149), respectively, and the difference was not statistically significant (P>0.05). The colonoscopy resource load (95%CI) was 15 (13-17) in the colonoscopy group, 11 (9-14) in the FIT group and 11 (10-13) in the novel risk-adapted screening approach group, respectively. Among them, the colonoscopy resource load of high-risk individuals in the novel risk-adapted screening approach group was 12 (9-15). FIT resource loads (95%CI) were 207 (196-218) and 88 (83-94) in the FIT group and the novel risk-adapted screening approach group. Conclusion: The combined application of risk-adapted screening approach and FIT may have a good application effect in colorectal cancer screening.

Identification of a large dataset of SNPs in hair-fin anchovy (Setipinna tenuifilis) based on RAD-seq.

Hair-fin anchovy (Setipinna tenuifilis) is an economically important fish distributed in the West Indian Ocean and the Northwest Pacific Ocean. In this study, 154 individuals in eight populations of S. tenuifilis were sequenced and 850 million raw reads were obtained using restriction site-associated DNA sequencing (RAD-seq). First, we identified 14 012 044 hypothetical SNP markers. A dataset of 199 903 high-quality SNPs was collected after further screening. These SNPs have a strong ability to test the genetic diversity between the eight populations. The differentiation and genetic law between samples were explored based on SNPs in populations of S. tenuifilis. The results of this study will provide data for protecting the genetic resources of the species.

[A case of subacute combined degeneration of spinal cord caused by inhaling laughing gas].

Laughing gas (Nitrogen monoxide) is currently abused due to its low price and easy availability. This article discussed the clinical manifestations of a patient with subacute combined degeneration of the spinal cord caused by inhalation of laughing gas. The patient developed numbness of extremities, unstable walking, and decreased serum vitamin B(12) level. MRI of the cervical spine showed abnormal signals in the lateral and posterior cords of the cervical spinal cord (C2-6) , neuroelectrophysiological examination showed peripheral nerve damage in the extremities. After treatment with vitamin B(12) supplementation, the patient's condition gradually improved. Clinicians diagnose subacute combined degeneration of the spinal cord, especially when the patient has no gastrointestinal disease, diet, malnutrition, etc., they need to carefully inquire about the history of nitrous oxide inhalation to avoid missed diagnosis.

[Research progress on the association between sarcopenia and cardiometabolic diseases among older adults].

Sarcopenia and cardiometabolic diseases have become important public health problems affecting the health and quality of life of the elderly. Reducing the incidence of sarcopenia is of positive significance for preventing and treating cardiometabolic diseases. This paper reviews the diagnostic criteria of sarcopenia in the elderly, the relationship between sarcopenia and cardiometabolic diseases, and the possible mechanisms. It provides support for the prevention and control of sarcopenia combined with cardiometabolic diseases.

Endothelial progenitor cells are influenced by serum of patients with systemic inflammatory response syndrome or multiple organ dysfunction.

BACKGROUND AND AIM: To investigate the effects of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS) on human peripheral blood endothelial progenitor cells. PATIENTS AND METHODS: Twenty patients admitted to Changhai Hospital, Second Military Medical University, from February, 2011 to November, 2011 were recruited consecutively. The serum samples were collected from the twenty patients who were divided into four groups as following: normal group, post-traumatic group without SIRS, post-traumatic group with SIRS, and post-traumatic group with MODS. Endothelial progenitor cells (EPCs) were isolated from peripheral blood of healthy subjects by using density gradient centrifugation and the effect of the serum on EPCs was detected after stimulating by the serum samples for 0, 6, 12, 24, and 36 h. RESULTS: Compared with the normal group, the proliferation of EPCs was significantly increased in a time-independent manner in the other three groups, especially in the SIRS serum treated group. The expression of pro-inflammation cytokines was increased in the other three groups compared with the normal group, but the expression of IL-10 in the normal group was higher than the other groups. CONCLUSIONS: Oxidative stress balance was also broken as the disease progressed. Serum from patients with sepsis could influence proliferation and the inflammation and oxidative stress states of EPCs.

Phylogenetic relationships among Octopodidae species in coastal waters of China inferred from two mitochondrial DNA gene sequences.

Octopus in the family Octopodidae (Mollusca: Cephalopoda) has been generally recognized as a "catch-all" genus. The monophyly of octopus species in China's coastal waters has not yet been studied. In this paper, we inferred the phylogeny of 11 octopus species (family Octopodidae) in China's coastal waters using nucleotide sequences of two mitochondrial DNA genes: cytochrome c oxidase subunit I (COI) and 16S rRNA. Sequence analysis of both genes revealed that the 11 species of Octopodidae fell into four distinct groups, which were genetically distant from one another and exhibited identical phylogenetic resolution. The phylogenies indicated strongly that the genus Octopus in China's coastal waters is also not monophyletic, and it is therefore clear that the Octopodidae systematics in this area requires major revision. It is demonstrated that partial sequence information of both the mitochondrial genes 16S rRNA and COI could be used as diagnostic molecular markers in the identification and resolution of the taxonomic ambiguity of Octopodidae species.

Lipolysis is accompanied by immune microenvironment remodeling in adipose tissue of obesity with different exercise intensity.

OBJECTIVE: Obesity and overweight are risk factors for chronic disease worldwide. The purpose of this study was to compare the transcriptome of exercise-induced fat mobilization in obese people, and to explore the effect of different exercise intensity on the correlation of immune microenvironment remodeling and lipolysis in adipose tissue. MATERIALS AND METHODS: Microarray datasets of adipose tissue before and after exercise were downloaded from the Gene Expression Omnibus. Then, we used gene-enrichment analysis and PPI-network construction to elucidate the function and enrichment pathways of the differentially expressed genes (DEGs) and to identify the central genes. A network of protein-protein interactions was obtained using STRING and visualized with Cytoscape. RESULTS: A total of 929 DEGs were identified between 40 pre-exercise (BX) samples and 65 post-exercise (AX) samples from GSE58559, GSE116801, and GSE43471. Among these DEGs, adipose tissue-expressed genes were duly recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DEGs were mostly enriched in lipid metabolism. Studies have found that mitogen-activated protein kinase (MAPK) signaling pathway and forkhead box O (FOXO) signaling pathway are up-regulated, while Ribosome, coronavirus disease (COVID-19) and IGF-1 gene are down-regulated. Although we found the up-regulated genes that noted IL-1 among others, and the down-regulated gene was IL-34. The increase of inflammatory factors leads to changes in cellular immune microenvironment, and high-intensity exercise leads to increased expression of inflammatory factors in adipose tissue, leading to inflammatory responses. CONCLUSIONS: Exercise at different intensities leads to the degradation of adipose and is accompanied by changes in the immune microenvironment within adipose tissue. High intensity exercise can cause the imbalance of immune microenvironment of adipose tissue while causing fat degradation. Therefore, moderate intensity and below exercise is the best way for the general population to reduce fat and weight.

Potential implication of activating killer cell immunoglobulin-like receptor and HLA in onset of pulmonary tuberculosis.

Killer cell immunoglobulin-like receptor (KIR) and human leucocyte antigen (HLA) play crucial role in maintaining immune homoeostasis and controlling immune responses. To investigate the influence of KIR and HLA-C ligands on the risk of pulmonary tuberculosis (PTB), we studied 200 patients who were confirmed to have PTB and 200 healthy controls on the different frequencies of KIR and HLA-C ligands. Genotyping of these genes was conducted by sequence-specific primer polymerase chain reaction (SSP-PCR) method. Gene frequencies were compared between PTB group and the control group by χ(2) test, and P < 0.05 was regarded as statistically significant. As a result, the frequency of KIR genotype A/B was increased in PTB than controls but A/A was decreased. Moreover, striking differences were observed in the frequencies of HLA-Cw*08 between the two groups. Besides, the frequencies of '2DL2/3 with C1' in PTB were increased compared with control group. In addition, individuals with no KIR2DS3 and no Cw*08 were higher in controls than in PTB. KIR2DS1 was increased in PTB when HLA-C group 2 alleles were missing. In conclusion, KIR and HLA-C gene polymorphisms were related to susceptibility to PTB.

Association of killer cell immunoglobulin-like receptors with pulmonary tuberculosis in Chinese Han.

Killer cell immunoglobulin-like receptors (KIRs) are involved in the pathogenesis of a variety of diseases. However, whether KIR polymorphism is associated with susceptibility to pulmonary tuberculosis was unknown. We examined a possible association of KIR polymorphism with susceptibility to pulmonary tuberculosis in Chinese Han. We analyzed 15 KIR genes in 109 pulmonary tuberculosis patients and 110 healthy controls using sequence-specific primer PCR analysis of genomic DNA. We found that the frequencies of KIR2DS1, 2DS3 and 3DS1 were significantly higher in patients than in the control group. In addition, the number of subjects carrying more than two activating KIR genes in the patient group was significantly higher than in the control group. The gene cluster containing KIR3DS1-2DL5-2DS1-2DS5 was also significantly more frequent in the patient group. In conclusion, KIR genes 2DS1, 2DS3 and 3DS1 appear to be associated with resistance to pulmonary tuberculosis in the Chinese Han population. KIR genes apparently have a role in resistance to pulmonary tuberculosis.

[Analysis on epidemiologic characteristics of fall in old people: results from Chinese National Injury Surveillance System, 2015-2018].

Objective: To understand the epidemiologic characteristics of fall in people aged 60 years and above in China from 2015 to 2018, and provide basis for the prevention of fall in old people and the development of related policies. Methods: Descriptive analysis was conducted on general information, injury occurrence information and injury clinical characteristics of fall cases in people aged 60 years and above by using the data from Chinese National Injury Surveillance System(NISS). Results: A total of 205 670 fall cases were reported to NISS from 2015 to 2018 with the male to female ratio of 1.37. Falls mainly occurred during 10:00-10:59 am (11.91%). The top three places where fall might occur were home (56.41%), road (17.24%) and public residence (14.36%). Leisure activity(37.56%), housework (24.20%) and walk (15.07%) were top three activities in which fall occurred. Bruise/scrape (42.17%), fracture (31.79%) and sprain/strain (14.62%) were the major injuries. The most common body parts involved were low limbs (31.38%), head (22.46%) and truncus(20.71%). Moderate and severe injuries accounted for 37.21% of all cases, and 22.49% of the elderly seeking medical care due to fall required hospitalization. Conclusions: The number of fall in people aged 60 years and above increased from 2015 to 2018. The elderly is a key population in the prevention and control of fall.

[Prevalence of injury among children in 28 counties of 6 provinces in China in 2017].

Objective: To investigate the incidence of injuries among children aged 0-17 years from 28 counties in six provinces. Methods: According to the earlier study on data in different local areas and the current work plan, we selected the survey objects for a general survey on child injury prevalence in the last 12 months. The subjects included guardians of children who did not attend kindergartens, children from kindergartens, and primary school grades 1-3. Children from grades 4-6 primary school, junior high school, and senior high school were also included. Results: The overall rate of injured children was 4.83%, with the incidence of injuries as 5.75% in the last 12 months before the survey. Both the rate of injured children and incidence of injuries were higher in boys than that in girls. Children whose primary caregivers were relatives, grandparents, minors, or with an education level below the primary school had a relatively higher rate of both injured children and incidence of injuries. The first cause of child injury was fall. The time of child injury was mainly from June to October, mainly at home, with the main activity as playing. The significant injuries in children were contusion and abrasion, and the main parts injured were lower limbs, upper limbs, and head. Most of the injuries were cured, and the primary treatment was outpatient and emergency treatment. Conclusions: Boys and children whose parents can not take care of are the priority population for child injury prevention and control. Targeted prevention and control measures should be implemented according to the characteristics of injuries among children of different ages.

[The epidemiological characteristics and influencing factors of animal injuries among children from 28 counties in 6 provinces, China].

Objective: To understand the epidemiological characteristic and influencing factors of animal injuries among children from 28 counties/districts in 6 provinces of China to provide evidence for formulating related prevention measures and strategies. Methods: Data was obtained from 'Children injury prevention project, 2016-2020'. Variables on the characteristics, including incidence, locations, related activities, time, and outcomes among children, were described. The negative binomial regression model analyzed animal injury frequency influencing factors. Results: There were 107 029 boys and 97 599 girls, with a gender ratio of 1.10, among the 204 628 children aged 0-17 in 28 counties/districts in 6 provinces of China. Per-person and per-time incidence rates of animal injuries were 0.70% and 0.72%, both higher in boys than in girls. Animal injuries among children mainly occurred in home (73.20%), road/street (7.51%), and open space of community/village (6.77%), during playing (63.15%), with the peak time between 12:01-18:00 (45.03%). Upper limbs (47.89%), lower limbs (35.31%), and head (8.44%) were the most injured body parts. Outpatient or emergency treatment (85.19%) had been carried out. The negative binomial regression showed that sex, grade, guardian educational level, urban or rural, and daily communication between guardians and children as influencing factors in the frequency of animal injuries among children. Conclusions: Special attention should be given to boys, at home, in projects on animal injury prevention and control. There were many influencing factors of animal injury frequency. Knowledge of injury prevention should be popularized to children and guardians. Related comprehensive intervention should be developed in families, schools, and social settings.

[Prevalence and prevention of traffic injury among children in 28 counties of 6 provinces in China, 2017].

Objective: To investigate the incidence of traffic injuries among children aged 0-17 years in 28 counties of 6 provinces and to provide prevention suggestions. Methods: Using the general survey method, a questionnaire survey was conducted on the road traffic injuries of children in 28 counties of 6 provinces in 2017. Results: A total of 204 628 students were surveyed, 908 of whom had experiences of road traffic injuries. Road traffic injuries were 0.44% among children in 28 counties of 6 provinces in China and 0.94% among children who did not attend kindergartens. July is a high incidence period of road traffic injuries among children (12.92%). When children suffer from road traffic injuries, the first three activities were playing (21.61%), riding an electric bicycle (20.40%), walking (20.07%). Most injuries appeared as contusion/abrasion, accounting for 42.26% of the total cases. The injured parts were mainly lower limbs, upper limbs, and heads, accounting for 38.85%, 23.29%, and 20.20%. Most children with road traffic injuries recovered after related treatments, accounting for 85.43% of all cases. The median length of hospital stay of children with road traffic injuries was seven days, and the median expense in hospitals was 3 000 Yuan (RMB). Conclusions: The incidence of road traffic injuries among males appeared higher than females, and the children who did not attend the kindergartens were the highest. During playing, riding an electric bicycle and walking were the top three activities prone to road traffic injuries.

[A comparison between endoscopic CO2 laser cauterization and open neck surgery in the treatment of congenital piriform fistula].

Objective: To compare the efficacy, advantages and disadvantages of endoscopic CO2 laser cauterization (ECLC) and open neck surgery in the treatment of congenital pyriform sinus fistula (CPSF). Methods: From September 2014 to March 2017, 80 cases with confirmed diagnosis of CPSF received initial treatment at Guangdong Provincial People's Hospital were prospectively analyzed, including 34 males and 46 females, aged 18 to 672 (194.17±141.18) months. They were consecutively divided into endoscopic group and open-surgery group, with 40 cases in each group. Both groups of patients received surgical treatment under general anesthesia. The endoscopic group was treated by endoscopic CO2 laser cauterization, and the open-surgery group underwent the following surgery: first, we performed suspension laryngoscopy examination to confirm the presence of fistula in the bottom of the piriform fossa, then open-neck resection of congenital piriform sinus fistula with recurrent laryngeal nerve and/or lateral branch of superior laryngeal nerve anatomy plus partial thyroidectomy were performed. The data between the two groups were compared, including the operative time, intraoperative blood loss, postoperative pain, average length of stay, neck cosmetic scores, complications and cure rates. All patients were followed up in outpatient clinics. Statistical analysis was performed using SPSS 20.0 software. P<0.05 indicates that the difference is statistically significant. Results: All patients were successfully completed the operation. The operative time, intraoperative blood loss, postoperative pain and average length of hospital stay in the endoscopic group were significantly less than those in the open group [(27.4±5.5) min to (105.8±52.5) min, (0.6±0.5) ml to (33.6±41.5) ml, (1.7±0.9) points to (4.6±0.7) points, (5.9±2.9)d to(8.9±3.3)d, t values were-9.400, -5.031, -16.199, -4.293, P values were all<0.01]; The neck cosmetic score in the endoscopy group was significantly greater than that of the open group [(9.9±0.4) against (5.8±0.9) points, t=25.847, P<0.01]. Compared with the open group (15.0%, 6/40), the complication rate of the endoscopic group (7.5%, 3/40) was not statistically significant (χ²=0.50, P>0.05). Three months after the first treatment, the cure rate in the endoscopic group (82.5%, 33/40) was significantly lower than that in the open-neck group (100.0%, 40/40), χ²=5.64, P<0.05. The follow-up time was 12 months after the last treatment. Eighty cases were followed up and none was lost to follow-up. During the follow-up period, the cure rate of the endoscopy group (97.5%, 39/40) was compared with that of the open group (100.0%, 40/40), and the difference was not statistically significant. Conclusions: In the treatment of CPSF, the two-surgical method each has their advantages. Compared with open-neck surgery, ECLC is simpler, repeatable. ECLC has shorter time in operation and hospital stay, less complications, and less postoperative pain and more precise cosmetic results. It could be preferred for the initial treatment of CPSF and relapsed cases after cauterization. But subject to relatively low cure rate of one-time cauterization and uncertain long-term efficacy, it cannot completely replace the open-neck surgery at present.

Sildenafil might impair maternal-fetal immunotolerance by suppressing myeloid-derived suppressor cells in mice.

Myeloid-derived suppressor cells (MDSCs) as an important population of immune cells were found to restrain T cell function, polarize T-helper cells (Th) 1/Th2 toward Th2 response and induce regulatory T cells (Tregs), therefore enhancing the immunotolerance during pregnancy. Sildenafil has been applied for poor endometrial quality in implantation failure patients. Nevertheless, investigations have shown that sildenafil could reduce MDSCs-dependent immunosuppression. Whether sildenafil affects embryo implantation by suppressing MDSCs? To address this question, using the mice model, we investigated the amounts of immune cells in peripheral blood and endometrial cells from control group (CG), sildenafil low-dose group (LDG) and high-dose group (HDG). We found that both treatment groups displayed a marked deficiency in polymorphonuclear (PMN)-MDSCs and Th2 from mice blood and endometrium as compared to these from CG. The frequency of Tregs in endometrium from HDG was lower than those from CG. Th1/Th2 ratio in both periphery and uterus from study groups showed a significant increase as compared to those from CG. By relevance analysis, we found that the level of Tregs positively correlated with the level of PMN-MDSCs, whereas the Th1/Th2 ratio negatively correlated with the frequency of PMN-MDSCs in uterus. Moreover, there was a positive relationship between the amount of blood PMN-MDSCs and endometrial PMN-MDSCs. These results suggest that we should carefully weigh the pros and cons of using sildenafil when applied to patients with poor endometrial receptivity.

Association study of IFNAR2 and IL10RB genes with the susceptibility and interferon response in HBV infection.

A recent genome-wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR-2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self-limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg-IFN-alpha-2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self-limited HBV infection. Further, we found that the IFNAR2-8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121-0.825, P = 0.019) and that the IFNAR2-8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148-2.420, P = 0.007). In addition, the IFNAR2-8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129-0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single-nucleotide polymorphisms, MxA - 88 G/T, IFNAR-2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.

Distinct roles of the anterior cingulate cortex in spinal and supraspinal bee venom-induced pain behaviors.

A wide variety of human and animal experiments suggest that the anterior cingulate cortex (ACC) is one of the key brain substrates subserving higher order processing of noxious information. However, no sufficient data are now available regarding the mediation by ACC of different levels of pain processing as well as its potential descending modulation of spinal nociception. Using the well-developed rat bee venom (BV) model, the present study evaluated the effect of lesions of bilateral ACC on two levels of spontaneous nociceptive behaviors (spinally-processed persistent paw flinching reflex and supraspinally-processed paw lifting/licking) and heat or mechanical hypersensitivity under the inflammatory pain state. In contrast to the sham lesion group (saline microinjection into the ACC), bilateral complete ACC chemical lesions (kainic acid microinjection into the ACC) significantly decreased the BV-induced paw lifting and licking behavior (less time spent by the animal in paw lifting/licking) but produced no influence upon spinally-processed spontaneous paw flinching reflex (no change in number of paw flinches following subcutaneous BV injection). Moreover, the bilateral ACC lesions relieved the BV-evoked primary thermal or mechanical hypersensitivity compared with the sham control group. However, incomplete lesions of bilateral ACC failed to affect the abovementioned pain-related behaviors. No effects were seen on basal pain sensitivity in either group of rats. Motor coordination, as measured by Rota-Rod treadmill test, was not impaired by bilateral ACC lesions. These results implicate that the ACC area of the brain plays differential roles in the mediation of different levels of spontaneous pain-related behaviors. The present study also provides additional evidence for the ACC-mediated descending facilitation of primary hyperalgesia (pain hypersensitivity) identified in the injured area under inflammatory pain state.

Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia.

Recently, we have reported that melittin, a major toxic peptide of the whole bee venom, plays a central role in production of local inflammation, nociception and hyperalgesia following the experimental honeybee's sting. However, the exact peripheral mechanisms underlying melittin-induced multiple pain-related behaviors are still less characterized. In the present study, we sought to investigate the potential roles of peripheral mitogen-activated protein kinases (MAPKs) in melittin-induced nociception and hyperalgesia by pre- and post-administration of three MAPK inhibitors, namely U0126 (1 mug, 10 mug) for extracellular signal-regulated kinase (ERK), SP600125 (10 mug, 100 mug) for c-Jun N-terminal kinase (JNK) and SB239063 (10 mug, 100 mug) for p38 MAPK, into the local inflamed area of one hind paw of rats. Both pre- and post-treatment with three drugs significantly suppressed the occurrence and maintenance of melittin-evoked persistent spontaneous nociception (PSN) and primary heat hyperalgesia, with little antinociceptive effect on mechanical hyperalgesia. In vehicle-treated group, ipsilateral injection of melittin produced no impact on thermal and mechanical sensitivity of the other hind paw, suggesting no occurrence of contralateral heat and mechanical hyperalgesia in the melittin test. In addition, local administration of each inhibitor into the contralateral hind paw exerted no significant influence on either PSN or heat/mechanical hyperalgesia tested in the primary injured hind paw, excluding the systemically pharmacological effects of the three drugs. Furthermore, local administration of the three compounds in naïve animals, respectively, did not change the basal pain sensitivity to either thermal or mechanical stimuli, suggesting lack of peripherally functional roles of the three MAPK subfamily members in normal pain sensitivity under the physiological state. Taken together, we conclude that activation of peripheral MAPKs, including ERK, JNK and p38, might contribute to the induction and maintenance of persistent ongoing pain and primary heat hyperalgesia in the melittin test. However, they are not likely to be involved in the processing of melittin-induced primary mechanical hyperalgesia, implicating a mechanistic separation between mechanical and thermal hyperalgesia in the periphery.