Peripheral EphrinB1/EphB1 signalling attenuates muscle hyperalgesia in MPS patients and a rat model of taut band-associated persistent muscle pain.

BACKGROUND: Myofascial pain syndrome (MPS) is an important clinical condition that is characterized by chronic muscle pain and a myofascial trigger point (MTrP) located in a taut band (TB). Previous studies showed that EphrinB1 was involved in the regulation of pathological pain via EphB1 signalling, but whether EphrinB1-EphB1 plays a role in MTrP is not clear. METHODS: The present study analysed the levels of p-EphB1/p-EphB2/p-EphB3 in biopsies of MTrPs in the trapezius muscle of 11 MPS patients and seven healthy controls using a protein microarray kit. EphrinB1-Fc was injected intramuscularly to detect EphrinB1s/EphB1s signalling in peripheral sensitization. We applied a blunt strike to the left gastrocnemius muscles (GM) and eccentric exercise for 8 weeks with 4 weeks of recovery to analyse the function of EphrinB1/EphB1 in the muscle pain model. RESULTS: P-EphB1, p-EphB2, and p-EphB3 expression was highly increased in human muscles with MTrPs compared to healthy muscle. EphB1 (r = 0.723, n = 11, P < 0.05), EphB2 (r = 0.610, n = 11, P < 0.05), and EphB3 levels (r = 0.670, n = 11, P < 0.05) in the MPS group were significantly correlated with the numerical rating scale (NRS) in the MTrPs. Intramuscular injection of EphrinB1-Fc produces hyperalgesia, which can be partially prevented by pre-treatment with EphB1-Fc. The p-EphB1 contents in MTrPs of MPS animals were significantly higher than that among control animals (P < 0.01). Intramuscular administration of the EphB1 inhibitor EphB1-Fr significantly suppressed mechanical hyperalgesia. CONCLUSIONS: The present study showed that the increased expression of p-EphB1/p-EphB2/p-EphB3 was related to MTrPs in patients with MPS. This report is the first study to examine the function of EphrinB1-EphB1 signalling in primary muscle afferent neurons in MPS patients and a rat animal model. This pathway may be one of the most important and promising targets for MPS.

TIPE2 protein prevents injury-induced restenosis in mice.

Proliferation of vascular smooth muscle cells (VSMCs) plays an important role in restenosis, a disease characterized by smooth muscle cell hyperplasia and neointimal formation. How proliferation signals are controlled to avoid restenosis is not fully understood. Here we report that TIPE2, the tumor necrosis factor (TNF) α-induced protein 8-like 2 (TNFAIP8L2), suppresses injury-induced restenosis by inhibiting VSMCs proliferation. TIPE2 was significantly upregulated in VSMCs in response to PDGF-BB stimuli and injury. Enforced TIPE2 expression significantly suppressed VSMCs proliferation and cell cycle progression, whereas TIPE2 deficiency in VSMCs promoted cell proliferation and upregulated the expression of Cyclins D1 and D3. TIPE2 likely regulated VSMC proliferation via Rac1-STAT3 and ERK1/2 signaling pathways. It blocked STAT3 activation and nuclear translocation in a Rac1-dependent manner. As a result, TIPE2-deficient VSMCs exhibited enhanced proliferation whereas TIPE2-deficient mice developed more severe restenosis in response to vascular injury. Conversely, adenovirus-mediated gene transfer of TIPE2 significantly reduced injury-induced restenosis in mice. These results indicate that TIPE2 plays a suppressive role in injury-induced restenosis and may serve as a new therapeutic target for treating the disease.

The association between polymorphism of P53 Codon72 Arg/Pro and hepatocellular carcinoma susceptibility: evidence from a meta-analysis of 15 studies with 3,704 cases.

Emerging evidence has shown that p53gene participates in human carcinogenesis as tumor suppressors. Polymorphism of p53 gene codon72 arginine (Arg)/proline (Pro) (rs1042522) may influence the function of p53 protein and then affect the processing of carcinogenesis. It has been suggested that p53 codon72 Arg/Pro polymorphism is associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To examine the validity of the association between the polymorphism and HCC risk, we performed this meta-analysis. We have conducted a search of case-control studies on the associations of p53 codon72 polymorphism with susceptibility to HCC in PubMed, ScienceDirect, BioMed central, Springer, EBSCO, Wanfang databases, and Chinese National Knowledge Infrastructure databases. A total of 15 studies were identified with 3,704 cases and 4,559 controls for codon72 Arg/Pro polymorphism. The result did support a significant genetic association between Pro allele and susceptibility to HCC in all the genetic models. Similarly, subgroup analysis showed significant associations between the Arg/Pro polymorphism and susceptibility to HCC when stratifying by race, gender, source of controls, and hepatitis virus infection status. This meta-analysis suggests that p53 codon72 Arg/Pro polymorphism may be associated with the risk of HCC, especially in subgroup analysis of Asian and Caucasian population, hospital-based population, the female, and the individuals infected with hepatitis virus. However, well-designed studies based on different ethnic groups with larger sample size and more detailed data are needed to confirm these conclusions.

Estimating the plasma effect-site equilibrium rate constant (Ke0) of propofol by fitting time of loss and recovery of consciousness.

The present paper proposes a new approach for fitting the plasma effect-site equilibrium rate constant (Ke0) of propofol to satisfy the condition that the effect-site concentration (Ce) is equal at the time of loss of consciousness (LOC) and recovery of consciousness (ROC). Forty patients receiving intravenous anesthesia were divided into 4 groups and injected propofol 1.4, 1.6, 1.8, or 2 mg/kg at 1,200 mL/h. Durations from the start of injection to LOC and to ROC were recorded. LOC and ROC were defined as an observer's assessment of alertness and sedation scale change from 3 to 2 and from 2 to 3, respectively. Software utilizing bisection method iteration algorithms was built. Then, Ke0 satisfying the CeLOC=CeROC condition was estimated. The accuracy of the Ke0 estimated by our method was compared with the Diprifusor TCI Pump built-in Ke0 (0.26 min(-1)), and the Orchestra Workstation built-in Ke0 (1.21 min(-1)) in another group of 21 patients who were injected propofol 1.4 to 2 mg/kg. Our results show that the population Ke0 of propofol was 0.53 ± 0.18 min(-1). The regression equation for adjustment by dose (mg/kg) and age was Ke0=1.42-0.30 × dose-0.0074 × age. Only Ke0 adjusted by dose and age achieved the level of accuracy required for clinical applications. We conclude that the Ke0 estimated based on clinical signs and the two-point fitting method significantly improved the ability of CeLOC to predict CeROC. However, only the Ke0 adjusted by dose and age and not a fixed Ke0 value can meet clinical requirements of accuracy.

Diabetes mellitus and the incidence of colorectal cancer: an updated systematic review and meta-analysis.

AIM: The purpose of this study was to determine whether diabetes mellitus is associated with an increased risk of colorectal cancer. METHODS: Relevant studies were identified in MEDLINE and EMBASE (up until November 1st, 2011). Inclusion criteria were original, peer-reviewed publications, with case-control and cohort studies (for studies on diabetes mellitus and colorectal cancer). Summary relative risks with 95% confidence intervals were calculated with a random-effects model. RESULTS: Twenty-four studies including eight case-control and 16 cohort studies, with a total of 3,659,341 participants, were included in this updated systematic review and meta-analysis, and all involved diabetes mellitus and colorectal cancer risk. Meta-analysis of the 24 included studies indicated that diabetes was associated with an increased risk of colorectal cancer, compared with no diabetes (summary RR of colorectal cancer incidence = 1.26, 95% CI = 1.20-1.31), without heterogeneity between studies (P(heterogeneity) = 0.296). Sub-group analyses found that these results were consistent between case-control and cohort studies and among studies conducted in different areas. The association between diabetes and colorectal cancer incidence did not differ significantly by sex and sub-sites. Insulin therapy was also positively associated with risk of colorectal cancer (summary RR = 1.61, 95% CI 1.18-1.35), with evidence of heterogeneity between studies (P(heterogeneity) = 0.014). CONCLUSIONS: Our findings further support a relationship between diabetes and increased risk of colon and rectal cancer in both women and men, and insulin therapy for diabetes may increase this risk.

Impact of intravenous dexmedetomidine on postoperative bowel movement recovery after laparoscopic nephrectomy: A consort-prospective, randomized, controlled trial.

BACKGROUND: Postoperative ileus is a frequent postoperative complication, especially after abdominal surgery. Sympathetic excitation is the primary factor for postoperative ileus. Sympathetic activation becomes increased by surgical stress, postoperative pain, and inflammation. Dexmedetomidine (DEX) can inhibit sympathetic nerve activity, inflammation, and pain. AIM: To observe whether DEX promotes bowel movements in patients after laparoscopic nephrectomy. METHODS: One hundred and twenty patients undergoing laparoscopic nephrectomy were assigned to three groups: C (normal saline infusion), D1 (DEX 0.02 µg/kg/h), and D2 (DEX 0.04 µg/kg/h). The primary outcomes were the recorded times to first flatus, defecation, and eating after surgery. The secondary outcomes were postoperative pain, assessed using the numerical rating scale (NRS), adverse effects, and the duration of the postoperative hospital stay. RESULTS: The times to first flatus, defecation, and eating in groups D1 and D2 were significantly shorter than those in group C (P < 0.01). The NRS scores at 8 h and 24 h after surgery were significantly lower in groups D1 and D2 than in group C (P < 0.05). No adverse effects were observed (P > 0.05). CONCLUSION: Postoperative infusion of DEX at 0.04 µg/kg/h facilitates bowel movements in patients undergoing laparoscopic nephrectomy.

Endotracheal administration for intraoperative acute massive pulmonary embolism during laparoscopic hepatectomy: A case report.

INTRODUCTION: Acute pulmonary embolism (APE) during an operation is a very urgent occurrence, especially when the patient with hemodynamic instability. Generally, drugs are administered intravenously; however, these drugs have little effects under most circumstances. We present a case of successful resuscitation in a patient with endotracheal administration. PATIENT CONCERNS: A 67-year-old female presented for laparoscopic hepatectomy. Acute pulmonary gas embolism occurred during the operation with hemodynamic instability. The total amount of carbon dioxide and argon reached 300 mL. We used a novel way of administering drugs instead of intravenous administration for rescuing and the patient condition had improved greatly and was discharged from the hospital without any neurological deficits. DIAGNOSES: A diagnosis of APE was made because of a lot of gas was extracted out from central venous catheter and sudden observable decrease in end-tidal CO2. INTERVENTIONS: These measures included endotracheal administration, position adjustment, manual ventilation, and gas extraction. OUTCOMES: The patient was discharged from the hospital and had no signs of neurological deficits. CONCLUSION: Intravenous administration may not the best appropriate way of administration when patients occurred APE. Endotracheal administration as a unique method may work wonders and has the value of research and application.

Plasma long non-coding RNA MALAT1 is associated with distant metastasis in patients with epithelial ovarian cancer.

Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a newly identified metastasis-associated long non-coding RNA. In a previous study, it was identified that plasma levels of MALAT1 were significantly increased in gastric cancer patients with metastasis compared with gastric cancer patients without metastasis and healthy control individuals. However, it is unclear whether plasma levels of MALAT1 may act as a biomarker for evaluating the development of metastasis in epithelial ovarian cancer (EOC). In the present study, groups that consisted of 47 patients with EOC and metastasis (EOC/DM), 47 patients with EOC without metastasis (EOC/NDM), and 47 healthy control (HC) individuals were established. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the level of plasma MALAT1 in these groups. The results showed that levels of plasma MALAT1 were significantly increased in the EOC/DM group compared with the EOC/NDM and HC groups (P<0.001). Receiver operating characteristic (ROC) analysis indicated that plasma MALAT1 yielded an area under the curve (AUC) of 0.820 [95% confidence interval (CI), 0.734-0.905; P<0.001], distinguishing between EOC/DM and EOC/NDM. ROC analysis also yielded an AUC of 0.884 (95% CI, 0.820-0.949; P<0.001), with 89.4% sensitivity and 72.3% specificity for distinguishing between EOC/DM and HC. Furthermore, multivariate analysis indicated that overexpression of MALAT1, differentiation (poor), tumor-node-metastasis stage (IV), lymph node metastasis (N3), peritoneal invasion (present) and higher serum carbohydrate antigen 125 levels were independent predictors of survival (hazard ratio, 3.322; P=0.028) in patients with EOC. Kaplan-Meier analysis revealed that patients with increased MALAT1 expression had a poorer disease-free survival time. In conclusion, the levels of plasma MALAT1 may act as a valuable biomarker for the diagnosis of metastasis.

TIPE2 protein negatively regulates HBV-specific CD8⁺ T lymphocyte functions in humans.

Cytotoxic T cell-mediated killing of virus-infected hepatocytes is an important pathogenic process of hepatitis B. However, its underlying molecular mechanisms are not fully understood. TNFAIP8L2 (TIPE2) is a newly described anti-inflammatory protein that is essential for maintaining immune homeostasis. In this study, we found that the protein levels of TIPE2 in PBMCs of hepatitis B patients were significantly reduced and negatively correlated with the sera values of aminotransferases. Importantly, TIPE2 protein was downregulated preferentially in cytotoxic CD8(+) T cells, not CD4(+) helper T cells. The CD8(+) T cells with low TIPE2 expression were more activated and produced higher levels of perforin, granzyme B, and IFN-γ. As a result, their cytolytic activity was markedly enhanced. Interestingly, HBc18-27 peptide stimulation could reduce TIPE2 expression in PBMCs. These results indicate that TIPE2 plays an important role in regulating HBV-specific CD8(+) T cell functions in patients with hepatitis B.

The association between two common polymorphisms in MicroRNAs and hepatocellular carcinoma risk in Asian population.

BACKGROUND: Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) located in the miRNAs may influence the function of mature miRNAs and then affect the processing of carcinogenesis. It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and HCC risk, we performed this meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: We have conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs3746444 with susceptibility to HCC in PubMed, ScienceDirect, Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure databases for the period up to Sep 10th, 2012. A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. It was found that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk of HCC in all genetic models. Similarly, subgroup analysis in Asian population showed no associations between the two SNPs and the susceptibility to HCC. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions.

The association between polymorphism of P53 codon 72 Arg/Pro and hepatocellular carcinoma susceptibility: evidence from a meta-analysis of 15 studies with 3704 cases.

BACKGROUND: Emerging evidence has shown that p53gene participates in human carcinogenesis as tumor suppressors. Polymorphism of p53 gene codon 72 Arg/Pro (rs1042522) may influence the function of p53 protein and then affect the processing of carcinogenesis. It has been suggested that p53 codon 72 Arg/Pro polymorphism is associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To examine the validity of the association between the polymorphism and HCC risk, we performed this meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: We have conducted a search of case-control studies on the associations of p53 codon 72 polymorphism with susceptibility to HCC in PubMed, ScienceDirect, Bio-Med central, Springer-link, EBSCO, Wanfang databases and Chinese National Knowledge Infrastructure (CNKI) databases. A total of 15 studies were identified with 3704 cases and 4559 controls for codon 72 Arg/Pro polymorphism. The result did support a significant genetic association between Pro allele and susceptibility to HCC in all the genetic models. Similarly, subgroup analysis showed significant associations between the Arg/Pro polymorphism and susceptibility to HCC when stratifying by race, gender, source of controls and hepatitis virus infection status. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that p53 codon 72 Arg/Pro polymorphism may be associated with the risk of HCC, especially in subgroup analysis of Asian and Caucasian population, hospital-based population, the female, and the individuals infected with hepatitis virus. However, well-designed studies based on different ethnic groups with larger sample size and more detailed data are needed to confirm these conclusions.

Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Shigella between Europe-America and Asia-Africa from 1998 to 2009.

Shigella is becoming an increasing public health problem due to development of multiple antimicrobial resistance, frequently resulting in treatment failure. A systematic review was conducted based on a literature search of computerised databases. Random or fixed-effects models were used, based on the P-value considering the possibility of heterogeneity between studies, for meta-analysis. Statistical analyses were performed using STATA 10.0. In the area of Asia-Africa, resistance rates to nalidixic acid and ciprofloxacin were 33.6% [95% confidence interval (CI) 21.8-46.6%] and 5.0% (95% CI 2.8-7.8%), respectively, 10.5 and 16.7 times those of Europe-America. Moreover, resistance to nalidixic acid and ciprofloxacin in Asia-Africa progressively increased each year, reaching 64.5% (95% CI 13.8-99.3%) and 29.1% (95% CI 0.9-74.8%), respectively, in 2007-2009, whilst isolates in Europe-America remained at low levels of resistance (<5.0% and <1.0%, respectively). All Shigella flexneri strains showed higher resistance than Shigella sonnei in Europe-America: overall, 3.5% (95% CI 1.4-6.4%) vs. 2.6% (95% CI 1.0-5.0%) resistant to nalidixic acid and 1.0% (95% CI 0.3-2.2%) vs. 0.1% (95% CI 0.0-0.3%) resistant to ciprofloxacin. In Asia-Africa, a similar trend was found for ciprofloxacin [3.0% (95% CI 1.4-5.3%) vs. 0.5% (95% CI 0.2-0.8%)], whereas the trend was reversed for nalidixic acid [32.6% (95% CI 14.5-53.9%) vs. 44.3% (95% CI 26.9-62.5%). In conclusion, quinolone resistance in Shigella has increased at an alarming speed, reinforcing the importance of continuous monitoring of antimicrobial resistance in Shigella.