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Tao Li,1,2 Xin Li,1 Hui Chen,3 Kai-Zhao Huang,1 Qi Xie,1,2 Han-Yu Ge,1 Shen-Meng Gao,4 Jian-Hua Feng,4 Jun-Jun Yang,1 Zhan-Guo Chen,1 Xiao-Qun Zheng1,2 1Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, The Key Laboratory of Laboratory Medicine, Ministry of Education of China, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Zhan-Guo Chen; Xiao-Qun ZhengDepartment of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaTel +86-13968806755; +86-13906653839Email steve0577@126.com; jszhengxq@163.comPurpose: Red blood cell distribution width (RDW) has been considered as a potential indicator of the effects of treatment or as a prognostic indicator for various malignancies. Most chronic myeloid leukemia (CML) patients are in the chronic phase, but some have transformed to accelerated phase or blast phase (blast crisis). However, the clinical significance of RDW in CML remains limited.Patients and Methods: In the present study, detailed clinical information and the RDW of 168 healthy people and 153 CML patients (106 patients for the training cohort and 47 patients for the validation cohort) were retrospectively assessed.Results: Multivariate analysis demonstrated that patient age (OR, 1.081; 95CI% 1.039∼ 1.125; p < 0.001), platelet counts (OR, 0.997; 95CI% 0.994∼ 0.999; p = 0.001) and RDW at admission (OR,1.469; 95CI% 1.121∼ 1.925; p = 0.005) were significantly associated with the patients with advanced phase. Among CML patients in the chronic phase, higher RDW was significantly associated with overall survival (OS; p = 0.0008) and the event-free survival (EFS; p = 0.0221) among CML patients with chronic phase, but not with Transformation-free survival (TFS; p = 0.0821). Furthermore, higher RDW was associated with higher mortality compared to patients with low RDW (CML-associated deaths; p < 0.0001). In addition, a decline in RDW is associated with the treatment of CML patients with tyrosine kinase inhibitors, especially at 6 and 12 months after the start of treatment.Conclusion: Higher RDW is a potential prognostic biomarker for chronic CML patients.Keywords: red blood cell distribution width, chronic myeloid leukemia, chronic phase, adverse prognosis

The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. PERSPECTIVE: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate motor unit activity from a latent myofascial trigger point (MTP) in an antagonist muscle during isometric agonist muscle contraction. Intramuscular activity was recorded with an intramuscular electromyographic (EMG) needle inserted into a latent MTP or a non-MTP in the posterior deltoid muscle at rest and during isometric shoulder flexion performed at 25% of maximum voluntary contraction in 14 healthy subjects. Surface EMGs were recorded from the anterior and posterior deltoid muscles. Maximal pain intensity and referred pain induced by EMG needle insertion were recorded on a visual analogue scale. The results showed that higher local pain was observed following needle insertion into latent MTPs (4.64 ± .48 cm) than non-MTPs (2.35 ± .43 cm, P < .005). Referred pain was reported in 6/14 subjects following needle insertion into latent MTPs, but none into the non-MTPs. The intramuscular EMG activity, but not surface EMG activity, in the antagonist muscle was significantly higher at rest and during shoulder flexion at latent MTPs than non-MTPs (P < .05). The current study provides the first evidence that increased motor unit excitability is associated with reduced antagonist reciprocal inhibition. PERSPECTIVE: This study shows that MTPs are associated with reduced efficiency of reciprocal linhibition, which may contribute to the delayed and incomplete muscle relaxation following exercise, disordered fine movement control, and unbalanced muscle activation. Elimination of latent MTPs and/or prevention of latent MTPs from becoming active may improve motor functions. [ABSTRACT FROM AUTHOR]

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis.

Objective: To investigate the clinical features of septic shock in children with hematological malignancies compared with those without malignant tumor in the pediatric intensive care unit (PICU). Methods: This retrospective study enrolled children with septic shock at the PICU of Capital Institute of Pediatrics' Children's Hospital from June 2015 to July 2022. According to the presence of hematological malignancies, patients were divided into the hematological malignancies group and without malignant tumor group. Clinical data were compared between the two groups, and logistic regression analysis was used to identify related factors for mortality. Results: A total of 164 children (97 males and 67 females) with a median age of 3.6 (interquartile range 0.8, 7.8) years were enrolled, including 75 (45.7%) patients with hematological malignancies and 89 (54.3%) patients without malignant tumors. Patients in the hematological malignancies group were older [6.0(3.6, 9.4) years vs 1.2 (0.4, 4.3) years, P <0.001] and more experienced hospital-acquired infections [48.0%(36/75) vs 21.3%(19/89), P =0.001], compared with patients without malignant tumors. Surgical emergencies were more frequent in patients without malignant tumors (32.6% vs 14.7%, P =0.013). Patients with hematological malignancies mainly had blood stream infections (58.7%), with Gram-negative bacilli (46.7%), meanwhile, patients without malignant tumors more experienced Gram-positive cocci infections (22.5%) of the respiratory system (40.4%) or digestive system (28.1%). There were significant differences regarding the infection sites ( P <0.001) and pathogens ( P =0.001). The types of antibacterial agents ( P <0.001) and the frequency of noradrenaline ( P =0.013) used in patients with hematological malignancies were significantly higher than those without malignant tumors. Patients with hematological malignancies had a higher incidence of multiple organ dysfunction (MODS) [100.0%(75/75) vs 80.9%(72/89), P <0.001] and higher 28-day mortality [34.8%(23/66) vs 19.0%(15/79), P =0.048]. Multivariate logistic regression analysis showed that Pediatric Critical Illness Score (PCIS) was an independent factor for death (odds ratio, OR =1.387, 95% CI : 1.161-1.657, P <0.001) in patients with hematological malignancies, and PCIS ( OR =1.419, 95% CI : 1.140-1.767, P =0.002) and the 6-hour lactate clearance rate ( OR =65.857, 95% CI : 2.953-1 468.638, P =0.008) were independent factors for death in patients without malignant tumors. Conclusions: Children with hematological malignancies were older, more frequently experienced bloodstream infections, and had a higher incidence of MODS and higher 28-day mortality. PCIS is related to poor prognosis of septic shock in children.

Objective: To summarize and evaluate the value of applying the thyroid imaging reporting and data system (TI-RADS) released by American College of Radiology (ACR) in 2017 of the thyroid classification, and to propose an optimized classification method based on the result to facilitate more accurate and precise risk stratification of thyroid nodules., Methods: In the study, 342 thyroid nodules assessed by 2017 ACR TI-RADS were retrospectively analyzed. Each nodule had a score, and all the scores of nodules were compared with the pathological results. The proportion of malignant nodules in different scoring ranges was obtained. The diagnostic efficacy of all nodules, nodules above 1 cm and less than or equal to 1 cm was evaluated by ROC curve, respectively., Results: The AUC of all nodules, nodules above 1 cm and less than or equal to 1 cm were 0.907, 0.936 and 0.717, respectively. With the increase of the scores, the proportion of benign nodules decreased gradually, and the proportion of malignant nodules increased, especially nodules of 4-6 scores increased significantly. Based on the proportion of malignant nodules with 3 scores, the proportion of malignant nodules with 4, 5 and 6 scores increased 1.6, 3.8 and 5.3 times, respectively. The proportion of malignant nodules with 6-8 scores was 81%-84%, while the proportion of malignant nodules with 9 scores or more was 93%-94%. According to the distribution characteristics of malignant nodules, the classification of TI-RADS was adjusted. TI-RADS 4 was divided into TI-RADS 4a, TI-RADS 4b and TI-RADS 4c, corresponding to 4, 5 and 6-8 scores respectively, while the nodules with 9 scores or more were divided into TI-RADS 5., Conclusion: 2017 ACR TI-RADS has high diagnostic value for thyroid nodules above 1 cm, but it is not so effective for the nodules less than or equal to 1 cm. According to the proportion distribution of malignant nodules in different scoring ranges, appropriate adjustment of classification will be more accurate and precisely predict the malignant risk of nodules.

Rationale: Autologous peripheral nerve injury caused by crush syndrome due to alcohol intoxication is relatively rare, and to our knowledge, the compression of 3 upper limb nerves at the same time has not been reported previously. If a compressive peripheral nerve injury is not treated in a timely manner, it is difficult to recover neurological function, and the prognosis is poor., Patient Concerns: Here, we present a case of a 50-year-old man with ipsilateral radial nerve, median nerve, and ulnar nerve injuries caused by autogenous compression after drunkenness., Diagnosis: Electromyography and nerve conduction studies suggested peripheral nerve injury in the left upper limb. The diagnosis was injury to the radial nerve, median nerve, and ulnar nerve in the left upper arm., Interventions: Exploratory neurolysis surgery of the radial nerve, median nerve, and ulnar nerve was performed in the left upper arm. Postoperative oral neurotrophic drugs were administered, and functional exercise was performed., Outcomes: After timely diagnosis and treatment, the strength of the left upper arm muscle recovered, and the prognosis of neurological function was satisfactory during 3 years of follow-up sessions., Lessons: In the treatment of such patients, a comprehensive understanding of their medical history and a strict physical examination should be performed. Combined with neuroelectrophysiological and imaging examination, the diagnosis can be confirmed. After timely diagnosis and treatment, the prognosis is mostly excellent.

Background: Tumor deposits are one of the promising factors among the different edition of Tumor, Node, Metastasis classification. Despite improvement in the treatment of various types of metastatic disease the source and prognostic significance of tumor deposits in staging has not been deliberating the agreeable opinion. We investigated the possibility of tumor deposit as independent prognostic factor and evaluating its prognostic value in colorectal carcinoma patients. Methods: Author studied 313 colorectal cancer patients clinocopathological data and outcome who underwent radical resection. Data between 2011-2015 were retrospectively collected from Shanghai East Hospital, affiliated with Tongji University data information centre. The analysis was used to calculate 2 years disease free survival(DFS) and relation of tumor deposit with number of lymph node positive. Cox-regression analysis was performed to assess the prognostic factor. Results: Out of 313 colorectal patients included in the study, tumor deposits were detected in 17%. Tumor deposits (TDs) are relevantly associated with significant poor outcomes. The tumor deposit were significantly correlated with T-stage(P=<0.001), N-stage(P=<0.001), PLNC(P=<0.001), venous invasion(P=<0.001), TNM staging(P=<0.001), CEA(P=0.021) and CA19-9(P=0.042) of primary tumor. The Kaplan-Meier analysis revealed that disease-free survival of CRC patients with positive tumor deposit were significantly poorer that those with negative tumor deposit cohort(P=<0.001) And with multivariate analysis in different model, we found that positive tumor deposit were significantly associated with shorter DSF which is totally independent with lymph node status (P=0.001 and P=0.023 respectively). Subgroup analysis found that of 179 CRC patients with negative lymph node status, the DFS of patients with positive tumor deposit were significantly shorter that those with negative tumor deposit(P=,0.001). Of 134patients with positive lymph node status, the DFS of patients shows similar result. (P=<0.001). Conclusion: We have shown that TDs are not equal to lymph node metastasis with respect to biology and outcome. Tumor deposits are an independent adverse prognostic factor in CRC patient who have undergone radical resection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Pulmonary hypertension (PH) is a life‑threatening lung disease, characterized by an increase in pulmonary arterial pressure caused by vasoconstriction and vascular remodeling. The pathogenesis of PH is not fully understood, and there is a lack of potential biomarkers for the diagnosis and treatment of patients with PH. Non‑coding RNAs with a characteristic covalently closed loop structure, termed circular RNAs (circRNAs), are present in a number of pulmonary diseases. To the best of our knowledge, the present study is the first to use microarray analysis to determine the expression profile of circRNAs in lung tissues from mice with hypoxia‑induced PH. In total, 23 significantly upregulated and 41 significantly downregulated circRNAs were identified. Of these, 12 differentially expressed circRNAs were selected for further validation using reverse transcription‑quantitative polymerase chain reaction. Putative microRNAs (miRNAs) that bind to the dysregulated circRNAs were predicted. Subsequently, bioinformatics tools were used to construct circRNA‑miRNA‑mRNA networks for the two most promising circRNAs, namely mmu&#95;circRNA&#95;004592 and mmu&#95;circRNA&#95;018351. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of target genes of the dysregulated circRNAs revealed that these dysregulated circRNAs may serve an important role in the pathogenesis of hypoxia‑induced PH. Therefore, these dysregulated circRNAs are candidate diagnostic biomarkers and potential therapeutic targets for PH.

Efficient delivery routes are critical for the effectiveness of adipose-derived mesenchymal stem cells (ADMSCs) in treating inflammatory bowel disease (IBD). Conventional ADMSC delivery routes include local, intravenous and intraperitoneal injection. Whether mesenteric injection has potential in IBD treatment remains unknown. In the present study, we investigated the therapeutic effects of mesenteric injection of ADMSCs in a trinitrobenzene sulfonic acid-induced rat IBD model and explored whether this treatment affected T helper 17 (Th17)/regulatory T (Treg) cell ratio. The results showed that mesenteric injection of ADMSCs markedly reduced signs of colitis, colon shortening, weight loss and pathological damage. The treatment also decreased serum tumor necrosis factor alpha concentration, increased serum tumor necrosis factor alpha-stimulated gene protein 6 concentration, and augmented repair via proliferation (assessed by evaluating Ki-67 levels) in colonic tissue. Moreover, mesenteric injection of ADMSCs reduced interleukin (IL)-17A and IL-6 mRNA expression, and increased IL-10 and transforming growth factor-beta mRNA expression in colonic tissue. Protein analyses indicated that mesenteric injection of ADMSCs was associated with increased expression of forkhead box P3 + and IL-10 as well as decreased expression of retinoid-related orphan receptor λt and IL-17. Additionally, the treatment inhibited phosphorylation of signal transducer and activator of transcription (STAT) 3 and activated phosphorylation of STAT5. Taken together, these results suggest that mesenteric injection of ADMSCs is a promising approach to treating trinitrobenzene sulfonic acid-induced IBD, and achieves its therapeutic effect by regulating the pro/anti-inflammatory Th17/Treg cell balance., Competing Interests: None.

Increased lymph node count (LNC) has been associated with prolonged survival in colorectal cancer (CRC), but the underlying mechanisms are still poorly understood. The study aims to identify new predictors and develop a preoperative nomogram for predicting the probability of adequate LNC (≥ 12). 501 eligible patients were retrospectively selected to identify clinical-pathological factors associated with LNC ≥ 12 through univariate and multivariate logistic regression analyses. The nomogram was built according to multivariate analyses of preoperative factors. Model performance was assessed with concordance index (c-index) and area under the receiver operating characteristic curve (AUC), followed by internal validation and calibration using 1000-resample bootstrapping. Clinical validity of the nomogram and LNC impact on stage migration were also evaluated. Multivariate analyses showed patient age, CA19-9, circulating lymphocytes, neutrophils, platelets, tumor diameter, histology and deposit significantly correlated with LNC (P < 0.05). The effects were marginal for CEA, anemia and CRC location (0.05 < P < 0.1). The multivariate analyses of preoperative factors suggested decreased age, CEA, CA19-9, neutrophils, proximal location, and increased platelets and diameter were significantly associated with increased probability of LNC ≥ 12 (P < 0.05). The nomogram achieved c-indexes of 0.75 and 0.73 before and after correction for overfitting. The AUC was 0.75 (95% CI, 0.70-0.79) and the clinically valid threshold probabilities were between 10% and 60% for the nomogram to predict LNC < 12. Additionally, increased probability of adequate LNC before surgery was associated with increased LNC and negative lymph nodes rather than increased positive lymph nodes, lymph node ratio, pN stages or AJCC stages. Collectively, the results indicate the LNC is multifactorial and irrelevant to stage migration. The significant correlations with preoperative circulating markers may provide new explanations for LNC-related survival advantage which is reflected by the implication of regional and systemic antitumor immune responses., Competing Interests: The authors have declared that no competing interests exist.

Lymph node stages (pN stages) are primary contributors to survival heterogeneity of the 7 th AJCC staging system for colorectal cancer (CRC), indicating spaces for modifications. To implement the modifications, we selected eligible CRC patients from the Surveillance Epidemiology and End Results (SEER) database as participants in a training (n = 6675) and a test cohort (n = 6760), and verified tumor deposits to be metastatic lymph nodes to derive modified lymph node count (mLNC), lymph node ratio (mLNR), and positive lymph node count (mPLNC). After multivariate Cox regression analyses with forward stepwise elimination of the mLNC and mPLNC for the training cohort, a nomogram was constructed to predict overall survival (OS) via incorporating preoperative carcinoembryonic antigen, pT stages, negative lymph node count, mLNR and metastasis. Internal validations of the nomogram showed concordance indexes (c-index) of 0.750 (95% CI, 0.736-0.764) and 0.749 before and after corrections for overfitting. Serial performance evaluations indicated that the nomogram outperformed the AJCC stages (c-index = 0.725) with increased accuracy, net benefits, risk assessment ability, but comparable complexity and clinical validity. All the results were reproducible in the test cohort. In summary, the proposed nomogram may serve as an alternative to the AJCC stages. However, validations with longer follow-up periods are required.

Background: The predictive accuracy of the American Joint Committee on Cancer (AJCC) stages of colorectal cancer (CRC) is mediocre. This study aimed to develop postoperative nomograms to predict cancer-specific survival (CSS) and overall survival (OS) after CRC resection without preoperative therapy., Methods: Eligible patients with stage I to IV CRC (n = 56072) diagnosed from 2004 to 2010 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were allocated into training (n = 27,700), contemporary (n = 3158), and prospective (n = 25,214) validation cohorts. Clinically important variables were incorporated and selected using the Akaike information criterion in multivariate Cox regressions to derive nomograms with the training cohort. The performance of the nomograms was assessed and externally testified using the concordance index (c-index), bootstrap validation, calibration, time-dependent receiver-operating characteristic curves, Kaplan-Meier curves, mosaic plots, and decision curve analysis (DCA). Performance of the conventional AJCC stages was also compared with the nomograms using similar statistics., Results: The nomograms for CSS and OS shared common predictors: sex, age, race, marital status, preoperative carcinoembryonic antigen status, surgical extent, tumor size, location, histology, differentiation, infiltration depth, lymph node count, lymph node ratio, and metastasis. The c-indexes of the nomograms for CSS and OS were 0.816 (95 % CI 0.810-0.822) and 0.777 (95 % CI 0.772-0.782), respectively. Performance evaluations showed that the nomograms achieved considerable predictive accuracy, appreciable reliability, and significant clinical validity with wide practical threshold probabilities, while the results remained reproducible when applied to the validation cohorts. Additionally, model comparisons and DCA proved that the nomograms excelled in stratifying each AJCC stage into three significant prognostic subgroups, allowing for more robust risk classification with an improved net benefit., Conclusions: We propose two prognostic nomograms that exhibit improved predictive accuracy and net benefit for patients who have undergone CRC resection. The established nomograms are intended for risk assessment and selection of suitable patients who may benefit from adjuvant therapy and intensified follow-up after surgery. Independent external validations may still be required.

Background: Circulating cell-free DNA (cfDNA) is a promising candidate biomarker for detection, monitoring and survival prediction of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial. To derive a precise estimation of the prognostic significance of cfDNA, a meta-analysis was performed., Methods: We made a systematic search in data base of the Science Citation Index Embase and Pubmed for studies reporting prognostic data of cfDNA in CRC patients. The data of cfDNA on recurrences-free survival (RFS) and overall survival (OS) were extracted and measured in hazard rates (HRs) and 95% confident intervals (CIs). Subgroup analyses were carried out as well. Finally, the meta-analysis is accompanied with nine studies including 19 subunits., Results: The pooled HRs with 95% CIs revealed strong associations between cfDNA and RFS (HR [95%CI]=2.78[2.08-3.72], I(2)=32.23%, n=7) along with OS (HR [95%CI]=3.03[2.51-3.66], I(2)=29.24%, n=12) in patients with CRC. Entire subgroup analyses indicated strong prognostic value of cfDNA irrespective tumor stage, study size, tumor markers, detection methods and marker origin., Conclusions: All the results exhibits that appearance of cfDNA in blood is an indicator for adverse RFS and OS in CRC patients.

Arsenic trioxide (ATO) has been used to treat patients with acute promyelocytic leukemia. Recently, studies have shown that ATO can induce apoptosis in leukemic cells and blood vessel endothelial cells in a time- and dose-dependent manner through the inhibition of vascular endothelial growth factor A (VEGFA) production. VEGFA is a key factor in angiogenesis initiation. Targeted inhibition of VEGF or VEGFA expression can suppress angiogenesis; however, little is known about the mechanism by which ATO inhibits VEGFA expression. In this study, we investigated the role of miRNA-126 in the mechanism of action of ATO in human umbilical vein endothelial cells (HUVECs). ATO significantly decreased the viability and proliferation of HUVECs and decreased their migration at 48 h. Cell proliferation was inhibited by 50% (IC50) when 5.0 μmol/L ATO was used. ATO treatment induced miR-126 upregulation and HUVEC apoptosis. Transfection with a miR-126 mimic significantly downregulated VEGFA mRNA levels, and transfection with a miR-126 inhibitor significantly upregulated VEGFA mRNA levels. Finally, we showed that ATO treatment upregulated Ets-2 and miR-126 expression in HUVECs. These results demonstrate that ATO inhibits the growth of HUVECs and induces apoptosis by downregulating VEGFA. One mechanism by which this occurs is Ets-2 upregulation, which results in an increase in miR-126 levels and downregulation of VEGFA expression.

YABBY family genes play important roles in the development of leaf, flower, and fruit. The purpose of this research was to integrate all the YABBY genes and analyze the correlation between gene expression and fruit shape in tomato. Scanning of 24 genomes of sequenced species demonstrated that YABBY genes were very normal and stable in flowering plants except the seedless plants. Nine YABBY genes in tomato were computationally and experimentally characterized. The phylogeny was constructed based on whole proteins or the YABBY domain, and five distinct clades were observed as described in other angiosperms. A comparison of the expression patterns in tomatoes with large differences in fruit shape and/or size suggested that during the fruit development, YABBY genes had both negative and positive functions. The obtained information could provide a deeper understanding of the evolution of YABBY genes and can also be useful for tomato yield and shape breeding.

Aim: To compare the results of transvaginal cholecystectomy (TVC) and conventional laparoscopic cholecystectomy (CLC) for gallbladder disease., Methods: We performed a literature search of PubMed, EMBASE, Ovid, Web of Science, Cochrane Library, Google Scholar, MetaRegister of Controlled Trials, Chinese Medical Journal database and Wanfang Data for trials comparing outcomes between TVC and CLC. Data were extracted by two authors. Mean difference (MD), standardized mean difference (SMD), odds ratios and risk rate with 95%CIs were calculated using fixed- or random-effects models. Statistical heterogeneity was evaluated with the χ(2) test. The fixed-effects model was used in the absence of statistically significant heterogeneity. The random-effects model was chosen when heterogeneity was found., Results: There were 730 patients in nine controlled clinical trials. No significant difference was found regarding demographic characteristics (P > 0.5), including anesthetic risk score, age, body mass index, and abdominal surgical history between the TVC and CLC groups. Both groups had similar mortality, morbidity, and return to work after surgery. Patients in the TVC group had a lower pain score on postoperative day 1 (SMD: -0.957, 95%CI: -1.488 to -0.426, P < 0.001), needed less postoperative analgesic medication (SMD: -0.574, 95%CI: -0.807 to -0.341, P < 0.001) and stayed for a shorter time in hospital (MD: -1.004 d, 95%CI: -1.779 to 0.228, P = 0.011), but had longer operative time (MD: 17.307 min, 95%CI: 6.789 to 27.826, P = 0.001). TVC had no significant influence on postoperative sexual function and quality of life. Better cosmetic results and satisfaction were achieved in the TVC group., Conclusion: TVC is safe and effective for gallbladder disease. However, vaginal injury might occur, and further trials are needed to compare TVC with CLC.

The aim of this study was to investigate the mechanism underlying the drug resistance of Acinetobacter baumannii toward aminoglycosides. A total of 32 A. baumannii strains were identified by molecular identification and subsequently isolated. The isolates were then amplified by polymerase chain reaction to analyze the 9 aminoglycoside-modifying enzyme genes and 7 16S rRNA methylase genes. Five types of aminoglycoside-modifying enzyme genes and 1 type of 16S rRNA methylase gene were detected in the 32 drug-resistant A. baumannii strains. Positive genes included 7 detection modes, of which the all-6-gene-positive mode aac(2')-Ib+aac(3)-I+aac(6')-Ib+ant(3'')-I+aph(3')-I+armA exhibited the largest number of strains (12, 37.5%). The resistance of A. baumannii against aminoglycosides resulted from the presence of 5 types of aminoglycoside-modifying enzyme genes and the 16S rRNA methylase gene armA. This study is the first to isolate the aac(2')-Ib aminoglycoside-modifying enzyme gene from A. baumannii in a domestic clinical setting.

Myofascial trigger points (MTrPs) are common causes for chronic pain. Myelinated afferents were considered to be related with muscular pain, and our clinical researches indicated they might participate in the pathology of MTrPs. Here, we applied myofascial trigger spots (MTrSs, equal to MTrPs in human) of rats to further investigate role of myelinated afferents. Modified pyridine-silver staining revealed more nerve endings at MTrSs than non-MTrSs (P < 0.01), and immunohistochemistry with Neurofilament 200 indicated more myelinated afferents existed in MTrSs (P < 0.01). Spontaneous electrical activity (SEA) recordings at MTrSs showed that specific block of myelinated afferents in sciatic nerve with tetrodotoxin (TTX) led to significantly decreased SEA (P < 0.05). Behavioral assessment showed that mechanical pain thresholds (MPTs) of MTrSs were lower than those of non-MTrSs (P < 0.01). Block of myelinated afferents by intramuscular TTX injection increased MPTs of MTrSs significantly (P < 0.01), while MPTs of non-MTrSs first decreased (P < 0.05) and then increased (P > 0.05). 30 min after the injection, MPTs at MTrSs were significantly lower than those of non-MTrSs (P < 0.01). Therefore, we concluded that proliferated myelinated afferents existed at MTrSs, which were closely related to pathology of SEA and mechanical hyperalgesia of MTrSs.

Background: Musculoskeletal pain from the upper extremity and shoulder region is commonly reported by computer users. However, the functional status of central pain mechanisms, i.e., central sensitization and conditioned pain modulation (CPM), has not been investigated in this population. The aim was to evaluate sensitization and CPM in computer users with and without chronic musculoskeletal pain., Methods: Pressure pain threshold (PPT) mapping in the neck-shoulder (15 points) and the elbow (12 points) was assessed together with PPT measurement at mid-point in the tibialis anterior (TA) muscle among 47 computer users with chronic pain in the upper extremity and/or neck-shoulder pain (pain group) and 17 pain-free computer users (control group). Induced pain intensities and profiles over time were recorded using a 0-10 cm electronic visual analogue scale (VAS) in response to different levels of pressure stimuli on the forearm with a new technique of dynamic pressure algometry. The efficiency of CPM was assessed using cuff-induced pain as conditioning pain stimulus and PPT at TA as test stimulus., Results: The demographics, job seniority and number of working hours/week using a computer were similar between groups. The PPTs measured at all 15 points in the neck-shoulder region were not significantly different between groups. There were no significant differences between groups neither in PPTs nor pain intensity induced by dynamic pressure algometry. No significant difference in PPT was observed in TA between groups. During CPM, a significant increase in PPT at TA was observed in both groups (P < 0.05) without significant differences between groups. For the chronic pain group, higher clinical pain intensity, lower PPT values from the neck-shoulder and higher pain intensity evoked by the roller were all correlated with less efficient descending pain modulation (P < 0.05)., Conclusions: This suggests that the excitability of the central pain system is normal in a large group of computer users with low pain intensity chronic upper extremity and/or neck-shoulder pain and that increased excitability of the pain system cannot explain the reported pain. However, computer users with higher pain intensity and lower PPTs were found to have decreased efficiency in descending pain modulation.

Background: Circulating tumor cells (CTCs) are metastatic cells disseminated into the bloodstreams. They have been proposed to monitor disease progression for decades. However, the prognostic value of CTCs in gastric cancer (GC) remains controversial. We performed a meta-analysis to investigate the topic., Methods: A systematic search was made for relevant studies in academic data bases, involving the Medline, Embase, and Science Citation Index. Data on prognosis of GC patients, such as recurrence-free survival (RFS) and overall survival (OS), were extracted when possible. The meta-analysis was performed with the random effects model and the pooled hazard ratios (HRs) and their associated 95% confident intervals (95%CIs) were computed as effect measures., Results: Twenty six studies (including 40 subgroups) with peripheral blood samples of 1950 cases from 10 countries were included in the final analysis. The pooled results showed that GC patients with detectable CTCs (including circulating miRNAs) had a tendency to experience shortened RFS (HR=2.91, 95% CI [1.84-4.61], I2=52.18%, n=10). As for patient deaths, we found a similar association of CTC (including circulating miRNAs) presence with worse OS (HR=1.78, 95% CI [1.49-2.12], I2=30.71%, n=30). Additionally, subgroup analyses indicated strong prognostic powers of CTCs, irrespective of geographical, methodological, detection time and sample size differences of the studies., Conclusions: Our meta-analysis shows that CTCs (including circulating miRNAs) can predict the survival of GC patients. Large prospective studies are warranted to determine the best sampling time points, detection methods in homogeneous patients with GC in the future.

Objective: The aim of this study was to investigate pain patterns and the distribution of myofascial trigger points (MTPs) in whiplash-associated disorders (WADs II and III) as compared with mechanical neck pain (MNP)., Methods: Manual examination of suboccipital, upper trapezius, elevator scapula, temporalis, supraspinatus, infraspinatus, deltoid, and sternocleidomastoid muscles, was done to search for the presence of both active or latent MTPs in 49 WAD patients and 56 MNP patients. Local pain and referred pain from each active MTP was recorded on an anatomical map., Results: The mean number of active MTPs was significantly greater in the WAD group (6.71 ± 0.79) than in the MNP group (3.26 ± 0.33) (P < 0.001), but this was not found for the latent MTPs (3.95 ± 0.57 vs. 2.82 ± 0.34; P > 0.05). In the WAD group, the current pain intensity (visual analogue scale) of the patients was significantly correlated with the number of active MTPs (rs  = 0.03, P = 0.03) and the spontaneous pain area (rs  = 0.25, P = 0.07), and the number of active MTPs was significantly correlated with the spontaneous pain area (rs  = 0.3, P = 0.03). In the MNP group, significant correlation was found only between pain duration and spontaneous pain area (rs  = 0.29, P = 0.02)., Conclusions: Active MTPs are more prominent in WAD than MNP and related to current pain intensity and size of the spontaneous pain distribution in whiplash patients. This may underlie a lower degree of sensitization in MNP than in WAD., (Wiley Periodicals, Inc.)

Unlabelled: The aim of this study was to evaluate intramuscular muscle activity from a latent myofascial trigger point (MTP) in a synergistic muscle during isometric muscle contraction. Intramuscular activity was recorded with an intramuscular electromyographic (EMG) needle inserted into a latent MTP or a non-MTP in the upper trapezius at rest and during isometric shoulder abduction at 90° performed at 25% of maximum voluntary contraction in 15 healthy subjects. Surface EMG activities were recorded from the middle deltoid muscle and the upper, middle, and lower parts of the trapezius muscle. Maximal pain intensity and referred pain induced by EMG needle insertion and maximal pain intensity during contraction were recorded on a visual analog scale. The results showed that higher visual analog scale scores were observed following needle insertion and during muscle contraction for latent MTPs than non-MTPs (P < .01). The intramuscular EMG activity in the upper trapezius muscle was significantly higher at rest and during shoulder abduction at latent MTPs compared with non-MTPs (P < .001). This study provides evidence that latent MTPs are associated with increased intramuscular, but not surface, EMG amplitude of synergist activation. The increased amplitude of synergistic muscle activation may result in incoherent muscle activation pattern of synergists inducing spatial development of new MTPs and the progress to active MTPs., Perspective: This article presents evidence of increased intramuscular, but not surface, muscle activity of latent MTPs during synergistic muscle activation. This incoherent muscle activation pattern may overload muscle fibers in synergists during muscle contraction and may contribute to spatial pain propagation., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Breast tubular adenomas are rare benign breast tumors and detailed descriptions of their sonographic appearance are necessary for differential diagnosis from fibroadenomas or breast cancers. This study investigated twenty-one histology-proved tubular adenomas in 17 patients and also included 48 fibroadenomas in 35 patients as a control group. There was no significant difference between the two groups with clinical presentation, which was age, tumor location, tumor number (p>0.05). Statistic analysis showed three significant factors in the differential diagnosis of tubular adenomas and fibroadenomas, including macro-lobulation (p=0.01), "tiny branch like" patterns (p=0.001) and vascularity (p=0.02). Other ultrasonographic features such as echogenicity, border, uniformity of echotexture, posterior acoustic enhancement, lateral wall shadowing were of no clinical significance (p>0.05). Calcifications were seen in three tubular adenomas which were different from those of carcinomas. Although tubular adenomas have some typical characteristics on sonography, surgery and core needle biopsy are still needed for complex cases to exclude progress to malignancy.

The minimally invasive high-intensity focused ultrasound (HIFU) therapy is thermal ablation treatment for late-stage pancreatic carcinoma with widely recognized safety and effectiveness, but there are currently no instant assessment methods for its ablation effect. It is vital to find a real-time high-sensitive assessment method. This research aims to dynamically observe the variation rules of ultrasound reflection intensity, analyze the correlation between ultrasound reflection intensity and tumor ablation ratio, and find out the value of ultrasound reflection intensity in prognosis of HIFU ablation effect. HIFU intermittent therapies were retrospectively analyzed for 31 subjects with late-stage pancreatic carcinoma from March 2007 to December 2009 in the study. The variation rules of the ultrasound reflection intensity during HIFU therapy were summarized and the correlation between ultrasound reflection intensity and tumor ablation ratio was analyzed based on the tumor ablation ratio indicated by CT scanning. The conclusion is that variation of ultrasound reflection intensity can be used for initial assessment of tumor ablation in HIFU therapy and early prognosis of overall HIFU ablation, providing important clinical basis for improving safety and effectiveness of HIFU therapy. Ultrasound can work as a real-time imaging instrument for observation of HIFU ablation effect in treating late-stage pancreatic carcinoma.

Association mapping based on linkage disequilibrium (LD) provides a promising tool to identify quantitative trait loci (QTLs) in plant resources. A total of 141 eggplant (Solanum melongena L.) accessions were selected to detect simple sequence repeat (SSR) markers associated with nine fruit traits. Population structure analysis was performed with 105 SSR markers, which revealed that two subgroups were present in this population. LD analysis exhibited an extensive long-range LD of approximately 11 cM. A total of 49 marker associations related to eight phenotypic traits were identified to involve 24 different markers, although no association was found with the trait of fruit glossiness. To our knowledge, this is the 1st approach to use a genome-wide association study in eggplant with SSR markers. These results suggest that the association analysis approach could be a useful alternative to traditional linkage mapping to detect putative QTLs in eggplant.

We report an economic method for synthesis of highly ordered silica with a mixing surfactant system containing short-chain cationic surfactant (decyltrimethyl ammonium bromide, denoted C10TMAB) and short-chain anionic surfactant (sodium octyl sulfate, denoted SOS) as the templating agents. Highly ordered supermicroporous silica was synthesized by judiciously chosen mixing ratio of surfactants. The samples were characterized by small-angle X-ray diffraction, transmission electron microscopy, and N2 adsorption-desorption. The results showed that the pore structure of the resulting silica belongs to the two-dimensional hexagonal structure (space group 2D-p6mm) with a pore size of ca. 2.2nm. Moreover, the method proposed herein is expected to facilitate the synthesis of not only porous silicas but also materials with other framework compositions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Computer users often report musculoskeletal complaints and pain in the upper extremities and the neck-shoulder region. However, recent epidemiological studies do not report a relationship between the extent of computer use and work-related musculoskeletal disorders (WMSD).The aim of this study was to conduct an explorative analysis on short and long-term pain complaints and work-related variables in a cohort of Danish computer users., Methods: A structured web-based questionnaire including questions related to musculoskeletal pain, anthropometrics, work-related variables, work ability, productivity, health-related parameters, lifestyle variables as well as physical activity during leisure time was designed. Six hundred and ninety office workers completed the questionnaire responding to an announcement posted in a union magazine. The questionnaire outcomes, i.e., pain intensity, duration and locations as well as anthropometrics, work-related variables, work ability, productivity, and level of physical activity, were stratified by gender and correlations were obtained., Results: Women reported higher pain intensity, longer pain duration as well as more locations with pain than men (P < 0.05). In parallel, women scored poorer work ability and ability to fulfil the requirements on productivity than men (P < 0.05). Strong positive correlations were found between pain intensity and pain duration for the forearm, elbow, neck and shoulder (P < 0.001). Moderate negative correlations were seen between pain intensity and work ability/productivity (P < 0.001)., Conclusions: The present results provide new key information on pain characteristics in office workers. The differences in pain characteristics, i.e., higher intensity, longer duration and more pain locations as well as poorer work ability reported by women workers relate to their higher risk of contracting WMSD. Overall, this investigation confirmed the complex interplay between anthropometrics, work ability, productivity, and pain perception among computer users.

Objective: Muscle fatigue is prevalent in acute and chronic musculoskeletal pain conditions in which myofascial trigger points (MTPs) are involved. The aim of this study was to investigate the association of latent MTPs with muscle fatigue., Design: Intramuscular electromyographic (EMG) recordings were obtained from latent MTPs and non-MTPs together with surface EMG recordings from the upper trapezius muscles during sustained isometric muscle contractions in 12 healthy subjects., Outcome Measures: Normalized root mean square (RMS) EMG amplitude and mean power frequency (MNF) were analyzed. The rate of perceived exertion and pain intensity from MTP side and non-MTP side were recorded., Results: Pain intensity on the MTP side was significantly higher than the non-MTP side (P < 0.05). Intramuscular EMG from latent MTPs showed an early onset of decrease in MNF and a significant decrease at the end of fatiguing contraction as compared with non-MTPs (P < 0.05). Surface EMG from muscle fibers close to latent MTPs presented with an early onset of the increase in RMS amplitude and the increase was significantly higher than that from non-MTPs at the end of sustained isometric contraction (P < 0.05)., Conclusions: A latent MTP is associated with an accelerated development of muscle fatigue and simultaneously overloading active motor units close to an MTP. Elimination of latent MTPs and inactivation of active MTPs may effectively reduce accelerated muscle fatigue and prevent overload spreading within a muscle., (Wiley Periodicals, Inc.)

Aim: Gefitinib is effective in only approximately 20% of patients with non-small-cell lung cancer (NSCLC), and the underlying mechanism remains unclear. FoxM1 is upregulated in NSCLC and associated with a poor prognosis in NSCLC patients. In this study, we examined the possible role of FoxM1 in gefitinib resistance and the related mechanisms., Methods: Gefitinib resistant human lung adenocarcinoma cell line SPC-A-1 and gefitinib-sensitive human lung mucoepidermoid carcinoma cell line NCI-H292 were used. mRNA and protein expression of FoxM1 and other factors were tested with quantitative RT PCR and Western blot analysis. RNA interference was performed to suppress FoxM1 expression in SPC-A-1 cells, and lentiviral infection was used to overexpress FoxM1 in H292 cells. MTT assay and flow cytometry were used to examine the proliferation and apoptosis of the cells., Results: Treatment of SPC-A-1 cells with gefitinib (1 and 10 μmol/L) upregulated the expression of FoxM1 in time- and concentration-dependent manners, while gefitinib (1 μmol/L) downregulated in H292 cells. In SPC-A-1 cells treated with gefitinib (1 μmol/L), the expression of several downstream targets of FoxM1, including survivin, cyclin B1, SKP2, PLK1, Aurora B kinase and CDC25B, were significantly upregulated. Overexpression of FoxM1 increased the resistance in H292 cells, while attenuated FoxM1 expression restored the sensitivity to gefitinib in SPC-A-1 cells by inhibiting proliferation and inducing apoptosis., Conclusion: The results suggest that FoxM1 plays an important role in the resistance of NSCLC cells to gefitinib in vitro. FoxM1 could be used as a therapeutic target to overcome the resistance to gefitinib.

The title compound, C(21)H(18)N(2)O(2), was synthesized using a novel tandem annulation reaction between (1H-benzimidazol-2-yl)(phen-yl)methanone and (E)-ethyl 4-bromo-but-2-enoate under mild conditions. The dihedral angles between the mean planes of the five-membered imidazole ring and the pyridine, benzene and phenyl rings are 0.45 (6), 1.69 (1) and 70.96 (8)°, respectively. In the crystal, mol-ecules are linked through inter-molecular C-H⋯N hydrogen bonds.

In the crystal structure of the title 1:2 adduct, [Zn(2)(NCS)(4)(C(4)H(8)N(4))(2)]·2[Zn(NCS)(2)(C(4)H(8)N(4))(2)] or (Ia)·2(Ib), each Zn(II) atom is coordinated in a distorted tetra-hedral geometry by four N atoms from two triazole rings of two 4-amino-3,5-dimethyl-1,2,4-triazole (admt) ligands and two NCS(-) ligands. In (Ia), double N(1):N(2)-bridging admt ligands connect two Zn(II) atoms, forming a dimer with a Zn(2)(admt)(2) six-membered metallacycle located on a crystallographic inversion center. In (Ib), the admt ligands exhibit monodentate N(1)-coordination modes. Weak N-H⋯N, N-H⋯S and C-H⋯S hydrogen bonds play an important role in the inter-molecular packing. The S and C atoms of two thiocyanato ligands are disordered over two sets of sites in ratios of 0.57 (3):0.43 (3) and 0.63 (3):0.37 (3), respectively.

Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy.

Introduction: It has previously been reported that local and referred pain from active myofascial trigger points (MTPs) in the neck and shoulder region contribute to fibromyalgia (FM) pain and that the pain pattern induced from active MTPs can reproduce parts of the spontaneous clinical FM pain pattern. The current study investigated whether the overall spontaneous FM pain pattern can be reproduced by local and referred pain from active MTPs located in different muscles., Methods: A spontaneous pain pattern in FM was recorded in 30 FM patients and 30 healthy subjects served as controls. Local and referred pain patterns induced from active (patients) and latent (controls) MTPs were recorded following manual stimulation. The existence of MTPs was confirmed by intramuscular electromyographical registration of spontaneous electrical activity., Results: Local and referred pain areas induced from key active MTPs in FM were larger than pain areas from latent MTPs in healthy controls (P < 0.001), but were similar to the overall spontaneous FM pain area in FM (P > 0.05). The induced pain area was positively associated with current spontaneous pain intensity in FM (P < 0.01). The locations of key active MTPs in FM patients were found to have latent MTPs in healthy subjects. The muscles containing key active MTPs in FM are often observed in the muscles of extensor digitorum, trapezius, infraspinatus in the upper part of the body and of quadratus lumborum, gluteus medius in the lower part of the body., Conclusions: The overall spontaneous FM pain pattern can be reproduced by mechanical stimulation of active MTPs located in different muscles, suggesting that fibromyalgia pain is largely composed of pain arising from muscle pain and spasm. Targeting active MTPs and related perpetuating factors may be an important strategy in FM pain control., Trial Registration: ISRCTN ISRCTN43167547.

Purpose: Endostatin plays an important role in inhibiting corneal neovascularization (CNV). The aim of this study was to evaluate the antiangiogenic activities of lipid-mediated subconjunctival injection of the modified RGDRGD (arginine- glycin- aspartic- arginine- glycin- aspartic- endostatin gene in a rabbit model of neovascularization in vivo., Methods: A modified human endostatin gene containing an RGDRGD motif was obtained by rapid site-directed mutagenesis. Forty New Zealand white rabbits underwent alkaline burn and developed CNV, which were randomly divided into four groups: an experimental control group, a PCI empty vector group, a PCI-endostatin group, and a PCI-RGDRGD-endostatin group. The vector, endostatin, and RGDRGD-endostatin groups received injections into the superior bulbar conjunctiva after the burn. An injection of 5 μg was given twice at 1-week intervals. Four eyes of two rabbits received neither treatment nor alkaline burn and served as absolute normal controls. The areas of CNV were monitored after 7 and 14 days. Corneas were examined by histology, and VEGF (vascular endothelial growth factor) and CD31 (platelet endothelial cell adhesion molecule-1) expression was detected by immunohistochemistry after 7 and 14 days. Retina, liver, and kidney were examined by histology, and CD38 expression in the inflammatory cells was detected by immunohistochemistry at 90 days., Results: Subconjunctival injection of both native endostatin and modified RGDRGD-endostatin genes resulted in a significant suppression of CNV in vivo, with modified RGDRGD-endostatin being more effective than native endostatin. The mean concentration of VEGF in the PCI-RGDRGD-endostatin group significantly decreased compared to the means in the other groups. Upon histological examination, the endostatin-treated and RGDRGD-endostatin-treated eyes showed significantly less neovascular area and fewer vessels than the control and vector-injected groups. Retinal, hepatic, and renal tissue sections were normal, and there was no inflammatory cell infiltration observed., Conclusions: Native and modified endostatin can significantly inhibit CNV by suppressing the expression of VEGF. However, modified endostatin with the RGDRGD motif is far more effective than the endostatin gene in antiangiogenic activity.

Unlabelled: The aim of the study is to test if sustained nociceptive mechanical stimulation (SNMS) of latent myofascial trigger points (MTrPs) induces widespread mechanical hyperalgesia. SNMS was obtained by inserting and retaining an intramuscular electromyographic (EMG) needle within a latent MTrP or a nonMTrP in the finger extensor muscle for 8 minutes in 12 healthy subjects. Pain intensity (VAS) and referred pain area induced by SNMS were recorded. Pressure pain threshold (PPT) was measured immediately before and after, and 10-, 20-, and 30-minutes after SNMS at the midpoint of the contralateral tibialis anterior muscle. Surface and intramuscular EMG during SNMS were recorded. When compared to nonMTrPs, maximal VAS and the area under VAS curve (VASauc) were significantly higher and larger during SNMS of latent MTrPs (both, P < .05); there was a significant decrease in PPT 10 minutes, 20 minutes, and 30 minutes postSNMS of latent MTrPs (all, P < .05). Muscle cramps following SNMS of latent MTrPs were positively associated with VASauc (r = .72, P = .009) and referred pain area (r = .60, P = .03). Painful stimulation of latent MTrPs can initiate widespread central sensitization. Muscle cramps contribute to the induction of local and referred pain., Perspective: This study shows that MTrPs are one of the important peripheral pain generators and initiators for central sensitization. Therapeutic methods for decreasing the sensitivity and motor-unit excitability of MTrPs may prevent the development of muscle cramps and thus decrease local and referred pain., (Copyright © 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The aim of this present study is to test the hypotheses that the 18 predetermined sites of examination for tender points (TP sites) in fibromyalgia syndrome (FMS) are myofascial trigger points (MTrPs), and that the induced pain from active MTrPs at TP sites may mimic fibromyalgia pain. Each TP site was evaluated with manual palpation followed by intramuscular electromyographic (EMG) registration of spontaneous electrical activity to confirm or refute the existence of an MTrP in 30 FMS patients. Overall spontaneous pain intensity and pain pattern were recorded before manual identification of MTrPs. Local and referred pain pattern from active MTrPs were drawn following manual palpation at TP sites., Results: Showed that most of the TP sites are MTrPs. Local and referred pain from active MTrPs reproduced partly the overall spontaneous pain pattern. The total number of active MTrPs (r = .78, P < .0001), but not latent MTrPs (r = -.001, P = .99), was positively correlated with spontaneous pain intensity in FMS. The current study provides first evidence that pain from active MTrPs at TP sites mimics fibromyalgia pain. MTrPs may relate to generalized increased sensitivity in FMS due to central sensitization., Perspective: This article underlies the importance of active MTrPs in FMS patients. Most of the TP sites in FMS are MTrPs. Active MTrPs may serve as a peripheral generator of fibromyalgia pain and inactivation of active MTrPs may thus be an alternative for the treatment of FMS.

Purpose: The aim of this study was to apply topographical techniques to investigate changes in pressure pain sensitivity after induction of delayed onset muscle soreness (DOMS) in the elbow region in healthy subjects., Methods: Pressure pain thresholds (PPT) were assessed over 12 points forming a 3 x 4 matrix (4 points in the superior part, 4 points in the middle, and 4 points in the lower part around the lateral epicondyle) over the dominant elbow in 13 healthy men, and pressure sensitivity maps were calculated. DOMS, as a model for lateral epicondylalgia (LE), was induced by repetitive high-level eccentric contractions of the wrist extensor muscles. PPT maps were assessed before, immediately after, and 24 h after eccentric exercise (DOMS)., Results: The two-way repeated-measure ANOVA detected significant differences in mean PPT for the measurement points (F = 5.96, P < 0.001), with lower PPT over the points located over the extensor carpi radialis brevis muscle. There was also a significant effect of time (F = 121.3, P < 0.001) but no time x point location interaction (F = 0.7, P = 0.8). PPT were lower 24 h after (P < 0.001) but not immediately after (P > 0.05) eccentric exercise., Conclusions: The study provides new key information regarding mechanical pain hyperalgesia in experimentally induced LE. Topographical pressure pain sensitivity maps from the elbow region revealed heterogeneously distributed mechanical sensitivity before and during DOMS. The most sensitive localizations for PPT assessment correspond to the muscle belly of the extensor carpi radialis brevis. Our results support the implication of the extensor carpi radialis brevis muscle in LE.

Unlabelled: Fatiguing exercise can affect muscle pain sensitivity and muscle hardness, as seen with work-related neck and shoulder pain. Objective methods to assess muscle pain sensitivity are important because the reliability of manual assessment is generally poor. The aim of this study was (1) to compare coexistence of tender points identified by manual palpation and pressure algometry or hardness assessments and (2) to examine the influence of exercise on muscle pain sensitivity and hardness. Fourteen sites in the upper trapezius muscle were selected for assessments in 12 healthy subjects. Pressure pain thresholds and muscle hardness were examined by computer-controlled pressure algometry at baseline, immediately after static or dynamic exercise, and 20 minutes after static or dynamic exercise. Before recording of pressure pain thresholds, the trapezius muscle was examined for tender points by manual palpation. Two sites with low pressure pain thresholds were typical locations for tender points, and these were the least hard sites. However, manually detected tender points were often (29%) not colocalized with most sensitive sites according to the pressure algometry. A heterogeneous distribution of pressure pain sensitivity and muscle hardness was found in the upper trapezius. The short duration of exercise until exhaustion did not change muscle sensitivity or muscle hardness in asymptomatic muscles., Perspective: This study confirms clinical findings with heterogeniosity in pain sensitivity and hardness across the upper trapezius muscle. Developments of new techniques that objectively can identify tender points are important, but thus far, manual palpation is best clinical practice., (Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the safety and efficacy of high intensity focused ultrasound for palliation of inoperable pancreatic cancer in humans., Patients: Eighty-nine patients with advanced pancreatic cancer were treated with high intensity focused ultrasound. There were 4 patients with stage II, 39 patients with stage III, and 46 patients with stage IV disease. The location of the tumors was as follows: head of pancreas 34 patients, body and/or tail of pancreas 55 patients., Methods: Pain relief, local tumor control rate, median survival and complications were observed after high intensity focused ultrasound treatment., Results: In the clinical treatments in humans the following local tumor control was seen: complete response, 0%; partial response, 14.6%; no change, 57.3%; progressive disease, 28.1%. Pain relief was achieved in 80.6% of patients who had pain prior to high intensity focused ultrasound therapy. The median survival was 26.0 months for patients with stage II disease, 11.2 months for patients with stage III disease, and 5.4 months for patients with stage IV disease. One-year survival rate was as follows: stage II, 100%; stage III, 41.0%; and stage IV, 6.5%. Two-year survival rate was as follows: stage II, 75.0%; stage III, 10.3%; and stage IV, 0%. Complications included superficial skin burns (3.4%), subcutaneous fat sclerosis (6.7%), and an asymptomatic pancreatic pseudocyst (1.1%). There were no severe complications or adverse events related to high intensity focused ultrasound therapy seen in any of the patients treated., Conclusions: Although this retrospective study has significant limitations, preliminary results suggest that the clinical application of high intensity focused ultrasound for pancreatic cancer appears to be safe and is a promising modality of treatment for palliation of pain related to pancreatic cancer.

Previous compositional studies of pre-mRNA processing complexes have been performed in vitro on synthetic pre-mRNAs containing a single intron. To provide a more comprehensive list of polypeptides associated with the pre-mRNA splicing apparatus, we have determined the composition of the bulk pre-mRNA processing machinery in living cells. We purified endogenous nuclear pre-mRNA processing complexes from human and chicken cells comprising the massive (>200S) supraspliceosomes (a.k.a. polyspliceosomes). As expected, RNA components include a heterogeneous mixture of pre-mRNAs and the five spliceosomal snRNAs. In addition to known pre-mRNA splicing factors, 5' end binding factors, 3' end processing factors, mRNA export factors, hnRNPs and other RNA binding proteins, the protein components identified by mass spectrometry include RNA adenosine deaminases and several novel factors. Intriguingly, our purified supraspliceosomes also contain a number of structural proteins, nucleoporins, chromatin remodeling factors and several novel proteins that were absent from splicing complexes assembled in vitro. These in vivo analyses bring the total number of factors associated with pre-mRNA to well over 300, and represent the most comprehensive analysis of the pre-mRNA processing machinery to date.

The coordination geometry of the CdII atom in the title complex, [Cd(NCS)2(C12H12N6)2]n or [Cd(NCS)2(mbtz)2]n, where mbtz is 1,3-bis(1,2,4-triazol-1-ylmethyl)benzene, is a distorted compressed octahedron in which the CdII atom lies on an inversion centre, coordinated by four N atoms from the triazole rings of four mbtz ligands and two N atoms from two monodentate NCS- ligands. The structure is polymeric, with 24-membered spiro-fused rings extending along [100] and with the 24-membered ring containing two inversion-related mbtz molecules.

Pre-mRNA introns are spliced in a macromolecular machine, the spliceosome. For each round of splicing, the spliceosome assembles de novo in a series of ATP-dependent steps involving numerous changes in RNA-RNA and RNA-protein interactions. As currently understood, spliceosome assembly proceeds by addition of discrete U1, U2, and U4/U6*U5 snRNPs to a pre-mRNA substrate to form functional splicing complexes. We characterized a 45S yeast penta-snRNP which contains all five spliceosomal snRNAs and over 60 pre-mRNA splicing factors. The particle is functional in extracts and, when supplied with soluble factors, is capable of splicing pre-mRNA. We propose that the spliceosomal snRNPs associate prior to binding of a pre-mRNA substrate rather than with pre-mRNA via stepwise addition of discrete snRNPs.

We have purified the yeast U5 and U6 pre-mRNA splicing small nuclear ribonucleoproteins (snRNPs) by affinity chromatography and analyzed the associated polypeptides by mass spectrometry. The yeast U5 snRNP is composed of the two variants of U5 snRNA, six U5-specific proteins and the 7 proteins of the canonical Sm core. The U6 snRNP is composed of the U6 snRNA, Prp24, and the 7 Sm-Like (LSM) proteins. Surprisingly, the yeast DEAD-box helicase-like protein Prp28 is stably associated with the U5 snRNP, yet is absent from the purified U4/U6 x U5 snRNP. A novel yeast U5 and four novel yeast U4/U6 x U5 snRNP polypeptides were characterized by genetic and biochemical means to demonstrate their involvement in the pre-mRNA splicing reaction. We also show that, unlike the human tri-snRNP, the yeast tri-snRNP dissociated upon addition of ATP or dATP.