Inhibition of fibrotic changes in infrapatellar fat pad alleviates persistent pain and articular cartilage degeneration in monoiodoacetic acid-induced rat arthritis model.

OBJECTIVE: We have reported that fibrotic changes in infrapatellar fat pad (IFP) after acute joint inflammation are closely associated with persistent pain in rats. In this study, to examine the effects of anti-fibrotic treatment on persistent pain, we used C-type natriuretic peptides (CNP) at the recovery phase after acute joint inflammation. DESIGN: Thirty-two male Wistar rats were used in this study. Monoiodoacetic acid (MIA) was injected intra-articularly to induce IFP fibrosis and persistent pain. CNP was injected after acute inflammatory phase in the same knee joint. Time-course pain-avoidance behavior tests and histological analyses were performed to examine the effects of CNP. RESULTS: Histological evaluations indicated that intra-articular injection of CNP inhibited fibrotic changes in IFP after acute inflammation. Incapacitance tests indicated that MIA injection into rat knee joint quickly decreased the percent weight on ipsilateral limb. In the vehicle group, the decrease was maintained up to day 28, suggesting that pain persistence occurred after acute inflammation (Day 0/Day 28, Est Dif -8.15, CI -10.78∼-5.53, Linear mixed-effect model). In contrast, the pain was alleviated in the CNP group after day 14 (Day0/Day 14, -0.51, -2.62-1.59). In addition, we observed significant improvement in the degree of articular cartilage degeneration at day 14 in the CNP group (OARSI score: vehicle 16.14 ± 4.37 vs CNP 6.87 ± 3.44, P < 0.01; Wilcoxon rank sum test). CONCLUSION: Fibrotic changes in IFP may play important roles in both persistent pain and articular cartilage degeneration.

Notch1 inactivation promotes invasion and metastasis of nasopharyngeal carcinoma cells partly through Slug activation.

Nasopharyngeal carcinoma (NPC) is a rare form of the head and neck cancer of the epithelial lining of the nasopharynx and exhibits the highest metastatic rate among head and neck cancers. Underlying mechanisms of metastasis remain largely unknown. Here, we explored whether Notch1 affects the invasion and metastasis of NPC cells. In vitro migration and invasion capacities were evaluated after the knockdown of Notch1 expression in NPC cells. To investigate the role of Notch1 in in vivo metastasis, we examined the metastatic ability to the lungs following administration of cancer cells via mouse tail vein. The expression of epithelial-mesenchymal transition (EMT) markers associated with Notch1-mediated metastasis was investigated, and their roles in metastasis and relationship with Notch1 expression were investigated. Suppression of Notch1 expression increased the ability of NPC cells to invade Matrigel in vitro. Knockdown of Notch1 expression in NPC cells resulted in extensive lung metastasis in a mouse model and increased the mRNA expression of Slug in NPC cells. Slug-specific RNA interference resulted in the loss of the metastatic and invasion capacities in Notch1-suppressed NPC cells. These findings show that Notch1 has a significant suppressive role in the regulation of metastasis in NPCs, suggestive of its prudent use in clinical trials.

[Analysis of prognostic factors and therapeutic patterns of recurrent stage â b-â ¡a cervical squamous carcinoma treated with radical hysterectomy].

Objective: To analyze the prognosis and appropriate treatment modalities of the patients with recurrence of early stage (Ⅰb-Ⅱa) cervical squamous cancer primarily treated with radical hysterectomy. Methods: This retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰb and Ⅱa recurrent cervical squamous cancer who underwent radical hysterectomy primarily from January 2007 to July 2015. Kaplan-Meier method and Cox regression analysis were performed to analyze related prognostic factors of overall survival and progression-free survival, which included age, postoperative therapy, the site of recurrence, therapy-free interval (TFI) and treatment modality. The patients who were treated with palliative chemotherapy after recurrence were selected as a subgroup. The responses of palliative chemotherapy were evaluated and analyzed among different factors, included TFI, the site of recurrence and chemotherapy regime. Results: Of the 2 071 patients, 116 relapsed Ⅰb-Ⅱa cervical squamous cancer were included in the study with the average age of (45.6±7.2) years old. 3-year progression-free survival rate and 3-year overall survival rate after recurrence were 30.2% and 42.2%, respectively. Univariate analysis implied that postoperative radiotherapy, recurrence site, TFI and treatment modality were associated with progression-free survival (P<0.05), while postoperative radiotherapy, TFI and treatment modality with overall survival (P<0.05). Multivariate analysis showed that TFI and treatment modality were independent prognostic factors for progression-free survival (P<0.05), while postoperative radiotherapy at initial treatment, TFI and treatment modality were independent prognostic variables for overall survival (P<0.05). In the analysis of treatment modality, 3-year progression-free survival rate and 3-year overall survival rate of 47 patients who were treated with definitive local therapy were significantly higher than that of 69 patients who were treated with palliative chemotherapy (P<0.01). In the subgroup analysis of palliative chemotherapy, 15 patients achieved complete response (21.7%) and 16 displayed partial response (23.2%). The overall response rate (ORR) was 44.9%. TFI (P<0.01) and chemotherapy regime (P<0.05) were significant factors associated with ORR. The ORR of TFI ≥12 months was significantly higher than that of TFI <12 months. Besides, the ORR of paclitaxel plus platinum chemotherapy was prominently higher than that of other regimens, while there was no significant difference between the ORR of paclitaxel plus cisplatin and other platinum (P=0.408). Conclusions: For recurrent stageⅠb-Ⅱa cervical squamous carcinoma treated with radical hysterectomy, use of definitive local therapy for suitable patients is advised to achieve better prognosis. In terms of palliative chemotherapy, longer TFI may mean better ORR and the combination of paclitaxel plus platinum is preferred.

[Analysis of effects and postoperative clinicopathological prognosis factors of neoadjuvant chemotherapy in patients with stage â b2 and â ¡a2 squamous cell carcinoma of the cervix].

Objective: To explore the effects and postoperative prognostic factors in cervical cancer patients received neoadjuvant chemotherapy combined with surgery and post-operative adjuvant therapy. Methods: A total of 177 patients with cervical cancer at International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ b2, Ⅱ a2 who underwent neoadjuvant chemotherapy (NACT) followed by surgery with and without adjuvant therapy in Cancer Hospital, Chinese Academy of Medical Sciences were included. Univariate and multivariate analyses of 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate were performed. Results: Of 177 patients, 133 (75.1%) had stage Ⅰb2 and 44 (24.9%) had Ⅱa2 cancers. After NACT, overall response rate was 63.3% (112/177) including 12 cases of complete response (CR), 100 of partial response (PR) and no progressive disease (PD) case. At a median follow-up of 59.2 months, the 5-year DFS rate was 73.6% and the 5-year OS rate was 86.8%. Univariate analysis revealed that lymph node metastasis, deep stromal invasion and tumor size after NACT significantly affected 5-year DFS rate (P<0.05). Lymph node metastasis, deep stromal invasion and tumor size after NACT significantly affected 5-year OS rate (P<0.05). The multivariate analysis showed that, stromal invasion (outer 1/3 or outer 1/2) was independent risk factor of 5-year DFS rate (P<0.05), and 5-year OS rate was significantly affected by tumor size >3 cm after NACT (P<0.05). Conclusions: The effect of NACT in Ⅰ b2, Ⅱ a2 squamous carcinoma of the uterined cervix is confirmed. The independent risk factor for 5-year DFS rate in patients received NACT and hysterectomy is deep stromal invasion of the cervix. The presence of tumor size >3 cm after NACT adversely affect 5-year OS rate.

[Prevalence and attribution of high-risk HPV in different histological types of cervical cancer].

Objective: To investigate the prevalence of high-risk HPV subtypes in different pathological types of cervical cancer, and analyze the attribution of carcinogenic HPV subtypes in different pathological types. Methods: A total of 1 541 patients with cervical cancer were treated between February 2009 and October 2016 in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The median age at diagnosis was 49 years (ranged 20-82 years old). The numbers of patients with cervical cancer from North China, Northeast China, East China, Central China and other regions (including Northwest, Southwest and South China) were 961, 244, 175, 87 and 74 cases, respectively. Pathological types: 1 337 cases of squamous cell carcinoma (SCC), 87 usual adenocarcinoma (ADC), 23 adenosquamous carcinoma (ASC), 20 mucinous carcinoma (MC), 19 clear cell carcinoma (CCC), 12 endometrioid carcinoma (EC), 25 neuroendocrine carcinoma (NEC), 9 serous carcinoma (SC), 5 villous adenocarcinoma (VADC) and 4 minimal deviation adenocarcinoma (MDAC). The prevalence of high-risk HPV in different regions, age groups at diagnosis and pathological types in cervical cancer were analyzed. The attribution of 13 high-risk HPV subtypes in different pathological types of cervical cancer based on proportional attribution method, and the attribution of high-risk HPV subtypes prevented by 9-valent HPV vaccine in SCC and ADC were calculated. Results: (1) The prevalence of high-risk HPV in 1 541 patients with cervical cancer was 86.6% (1 335/1 541). The multiple high-risk HPV infection rate in patients with SCC ≥60 years old (23.0%, 37/161) was significantly higher than those in patients aged 45-59 years old and ≤44 years old [11.4% (85/747) vs 11.7% (50/429), P<0.01], and the high-risk HPV infection rates of patients with cervical cancer in North China, Northeast China, East China, Central China and other regions were respectively 86.8% (834/961), 87.7% (214/244), 83.4% (146/175), 83.9% (73/87) and 91.9% (68/74). SCC (86.8%, 1 337/1 541) and ADC (5.6%, 87/1 541) were the most common pathological types in cervical cancer. The high-risk HPV prevalence of SCC, ADC, ASC, MC, NEC and VADC were 90.1% (1 205/1 337), 74.7% (65/87), 87.0% (20/23), 65.0% (13/20), 72.0% (18/25) and 5/5 respectively. The high-risk HPV infection rates of SC, EC, CCC and MDAC were 4/9, 3/12, 2/19 and 0/4 respectively. (2) According to proportional attribution, HPV 16 (69.5%), HPV 18 (5.6%), HPV 58 (2.2%), HPV 31 (1.9%), HPV 52 (1.4%) and HPV 33 (1.3%) were the six common high-risk HPV subtypes in SCC. While, HPV 18 (44.1%), HPV 16 (20.5%), HPV 52 (2.3%), HPV 58 (1.2%) and HPV 51 (1.2%) were the main carcinogenic subtypes in ADC. The main carcinogenic high-risk HPV subtypes of ASC, NEC and MC were HPV 18 and HPV 16. The total attribution of HPV 16, 18, 31, 33, 45, 52 and 58 prevented by 9-valent HPV vaccine in SCC and ADC were 82.6% and 68.1% respectively; the attribution of HPV 45 in SCC and ADC were only 0.8% and 0. Conclusions: SCC and ADC are the main pathological types in cervical cancer. SCC, ADC, ASC, MC, NEC and VADC are closely related to high-risk HPV infection. HPV 16 is the main carcinogenic genotypes of SCC. HPV 18 maybe play an important role in the pathogenesis of ADC.

Human fatalities from cyanobacteria: chemical and biological evidence for cyanotoxins.

An outbreak of acute liver failure occurred at a dialysis center in Caruaru, Brazil (8 degrees 17' S, 35 degrees 58' W), 134 km from Recife, the state capital of Pernambuco. At the clinic, 116 (89%) of 131 patients experienced visual disturbances, nausea, and vomiting after routine hemodialysis treatment on 13-20 February 1996. Subsequently, 100 patients developed acute liver failure, and of these 76 died. As of December 1996, 52 of the deaths could be attributed to a common syndrome now called Caruaru syndrome. Examination of phytoplankton from the dialysis clinic's water source, analyses of the clinic's water treatment system, plus serum and liver tissue of clinic patients led to the identification of two groups of cyanobacterial toxins, the hepatotoxic cyclic peptide microcystins and the hepatotoxic alkaloid cylindrospermopsin. Comparison of victims' symptoms and pathology using animal studies of these two cyanotoxins leads us to conclude that the major contributing factor to death of the dialyses patients was intravenous exposure to microcystins, specifically microcystin-YR, -LR, and -AR. From liver concentrations and exposure volumes, it was estimated that 19.5 microg/L microcystin was in the water used for dialysis treatments. This is 19.5 times the level set as a guideline for safe drinking water supplies by the World Health Organization.

Phenotypic and functional analysis of bovine gammadelta lymphocytes.

The studies have provided the first comprehensive comparison of the factors regulating activation and proliferation of WC1+ and WC1- gammadelta T cells. The investigation has shown that accessory molecules essential for activation and function of WC1+ and WC1- gammadelta T cells and the sources and roles of cytokines in activation of gammadelta T cells through the T cell receptor (TCR). The study has also shown that the role of cytokines in activation and function of gammadelta T cells activated indirectly through cytokines secreted by ab T cells, accessory cells and antigen presenting cells (APC). Cytokines were differentially produced by subpopulations of gammadelta T cells under different conditions of activation. The investigation obtained in this study has revealed that factors account for activation and proliferation of gammadelta T cells in cultures designed to study MHC-restricted responses to antigens. Evidence obtained here has shown there is biological relevance to activation under these culture conditions that points to potential regulatory and effector functions of gammadelta T cells. The investigations have also provided the information needed to begin identifying and characterizing antigens recognized by the TCR repertoires of WC1+ and WC1- gammadelta T cells. Finally, the investigations have provided the information needed to begin analysis of the mechanisms by which gammadelta T cells modulate MHC restricted immune responses to pathogens and derived vaccines.

[Efficacy of pyquiton in the treatment of Echinochasmus liliputanus infection].

Two hundred cases of Echinochasmus liliputanus infection were randomly divided into three groups and treated with pyquiton at a single dose of 10.5 and 2.5 mg/kg, respectively. As assessed one month after treatment the egg negativity rates were 100%, 98.7% and 96.5%, respectively. The symptoms such as abdominal pain, distension, diarrhea and anorexia relieved. The results suggest that pyquiton is effective against Echinochasmus liliputanus infection.

Paradoxical response in HIV-negative patients with pleural tuberculosis: a retrospective multicentre study.

OBJECTIVE: To evaluate the incidence, clinical characteristics and predicting factors for the development of paradoxical response in human immunodeficiency virus negative patients with isolated pleural tuberculosis (TB). DESIGN: A multicentre, retrospective cohort study including 458 patients who were diagnosed and treated with isolated pleural TB between March 2005 and February 2010. RESULTS: Paradoxical response developed in 72 patients (16%) with isolated pleural TB. The mean time to development of paradoxical response was 8.8 ± 6.4 weeks after initiation of anti-tuberculosis treatment. The main presentation of paradoxical response was aggravation of pre-existing pleural effusion in 58 patients (81%). However, the majority of the patients who developed paradoxical response had no associated symptoms (n = 49, 68%). In multiple logistic regression analysis, development of paradoxical response was independently associated with the proportion of eosinophils (adjusted OR 1.293, 95%CI 1.077-1.553) and protein concentrations (adjusted OR 0.590, 95%CI 0.397-0.878) in the pleural fluid at the time of diagnosis. CONCLUSION: Paradoxical response developed in 16% of the patients approximately 2 months after initiation of anti-tuberculosis treatment, presenting with aggravation of pre-existing pleural effusion. Development of paradoxical response was associated with the proportion of eosinophils and protein concentrations in the pleural fluid at the time of diagnosis.

Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil.

BACKGROUND: Hemodialysis is a common but potentially hazardous procedure. From February 17 to 20, 1996, 116 of 130 patients (89 percent) at a dialysis center (dialysis center A) in Caruaru, Brazil, had visual disturbances, nausea, and vomiting associated with hemodialysis. By March 24, 26 of the patients had died of acute liver failure. METHODS: A case patient was defined as any patient undergoing dialysis at dialysis center A or Caruaru's other dialysis center (dialysis center B) during February 1996 who had acute liver failure. To determine the risk factors for and the source of the outbreak, we conducted a cohort study of the 130 patients at dialysis center A and the 47 patients at dialysis center B, reviewed the centers' water supplies, and collected water, patients' serum, and postmortem liver tissue for microcystin assays. RESULTS: One hundred one patients (all at dialysis center A) met the case definition, and 50 died. Affected patients who died were older than those who survived (median age, 47 vs. 35 years, P<0.001). Furthermore, all 17 patients undergoing dialysis on the Tuesday-, Thursday-, and Saturday-night schedule became ill, and 13 of them (76 percent) died. Both centers received water from a nearby reservoir. However, the water supplied to dialysis center B was treated, filtered, and chlorinated, whereas the water supplied to dialysis center A was not. Microcystins produced by cyanobacteria were detected in water from the reservoir and from dialysis center A and in serum and liver tissue of case patients. CONCLUSIONS: Water used for hemodialysis can contain toxic materials, and its quality should therefore be carefully monitored.