[Clinicopathological features of intravascular large B-cell lymphoma and collision tumors of five cases].

Objective: To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Methods: Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. Results: There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. Conclusions: IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.

[Development and validation of risk prediction model for new-onset cardiovascular diseases among breast cancer patients: Based on regional medical data of Inner Mongolia].

OBJECTIVE: To develop and validate a three-year risk prediction model for new-onset cardiovascular diseases (CVD) among female patients with breast cancer. METHODS: Based on the data from Inner Mongolia Regional Healthcare Information Platform, female breast cancer patients over 18 years old who had received anti-tumor treatments were included. The candidate predictors were selected by Lasso regression after being included according to the results of the multivariate Fine & Gray model. Cox proportional hazard model, Logistic regression model, Fine & Gray model, random forest model, and XGBoost model were trained on the training set, and the model performance was evaluated on the testing set. The discrimination was evaluated by the area under the curve (AUC) of the receiver operator characteristic curve (ROC), and the calibration was evaluated by the calibration curve. RESULTS: A total of 19 325 breast cancer patients were identified, with an average age of (52.76±10.44) years. The median follow-up was 1.18 [interquartile range (IQR): 2.71] years. In the study, 7 856 patients (40.65%) developed CVD within 3 years after the diagnosis of breast cancer. The final selected variables included age at diagnosis of breast cancer, gross domestic product (GDP) of residence, tumor stage, history of hypertension, ischemic heart disease, and cerebrovascular disease, type of surgery, type of chemotherapy and radiotherapy. In terms of model discrimination, when not considering survival time, the AUC of the XGBoost model was significantly higher than that of the random forest model [0.660 (95%CI: 0.644-0.675) vs. 0.608 (95%CI: 0.591-0.624), P < 0.001] and Logistic regression model [0.609 (95%CI: 0.593-0.625), P < 0.001]. The Logistic regression model and the XGBoost model showed better calibration. When considering survival time, Cox proportional hazard model and Fine & Gray model showed no significant difference for AUC [0.600 (95%CI: 0.584-0.616) vs. 0.615 (95%CI: 0.599-0.631), P=0.188], but Fine & Gray model showed better calibration. CONCLUSION: It is feasible to develop a risk prediction model for new-onset CVD of breast cancer based on regional medical data in China. When not considering survival time, the XGBoost model and the Logistic regression model both showed better performance; Fine & Gray model showed better performance in consideration of survival time.

[Summary of experience with patterning cropped and shaped mesh repair for perineal hernia after abdominoperineal excision in rectal cancer].

Objective: To examine the patterning cropped and shaped mesh repair for perineal hernia after abdominoperineal excision (APE) in rectal cancer. Methods: The clinical data of 8 patients with perineal hernia after APE who accepted surgical treatment in the Department of Hepatopancreatobiliary and Hernia Surgery, the First Affiliated Hospital of Fujian Medical University from March 2017 to December 2022 were retrospectively reviewed. There were 3 males and 5 females, aged (67.6±7.2) years (range: 56 to 76 years). Eight patients developed a perineal mass at (11.3±2.9) months (range: 5 to 13 months) after APE. After surgical separation of adhesion and exposing the pelvic floor defect, a 15 cm×20 cm anti-adhesion mesh was fashioned as a three-dimensional pocket shape to fit the pelvic defect, then fixed to the promontory or sacrum and sutured to the pelvic sidewalls and the anterior peritoneum, while two side slender slings were tailored in front of the mesh and fixed on the pectineal ligament. Results: The repair of their perineal hernias went well, with an operating time of (240.6±48.8) minutes (range: 155 to 300 minutes). Five patients underwent laparotomy, 3 patients tried laparoscopic surgery first and then transferred to laparotomy combined with the perineal approach. Intraoperative bowel injury was observed in 3 patients. All patients did not have an intestinal fistula, bleeding occurred. No reoperation was performed and their preoperative symptoms improved significantly. The postoperative hospital stay was (13.5±2.9) days (range: 7 to 17 days) and two patients had postoperative ileus, which improved after conservative treatment. Two patients had a postoperative perineal hernia sac effusion, one of them underwent placement of a tube to puncture the hernia sac effusion due to infection, and continued irrigation and drainage. The postoperative follow-up was (34.8±14.0) months (range: 13 to 48 months), and 1 patient developed recurrence in the seventh postoperative month, no further surgery was performed. Conclusions: Surgical repair of the perineal hernia after APE can be preferred transabdominal approach, routine application of laparoscopy is not recommended, combined abdominoperineal approach can be considered if necessary. The perineal hernia after APE can be repaired safely and effectively using the described technique of patterning cropped and shaped mesh repair.

[Clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy complicated by ischemic stroke].

Objective: To analyze the clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy (DCM) complicated with ischemic stroke (IS) (DCM-IS). Methods: The clinical data of patients with idiopathic DCM (n=613) in Beijing Anzhen Hospital, Liangxiang Hospital and Fuxing Hospital from January 2016 to December 2020 were retrospectively collected, and among them, 123 cases were DCM-IS. Clinical features of patients with DCM-IS were summarized and multivariate logistic regression model was utilized to analyze the independent risk factors of DCM-IS. Furthermore, 1-year follow-up was conducted and Kaplan-Meier curve was adopted to analyze the prognosis of DCM, using all-cause death and heart transplantation as adverse outcomes. Results: Among the 70 patients with DCM-IS, 6 patients (8.6%, 6/70) were in accordance with the subtype of large artery atherosclerosis, and 47 patients (67.1%, 47/70) were in line with the subtype of cardiogenic embolism, and small artery occlusion subtype (ie, lacunar infarction) were detected in 17 cases (24.3%, 17/70). Hypertension [odds ratio (OR)=1.617, 95% confidence interval (CI): 1.049-2.491, P=0.029], hyperlipidemia (OR=1.918, 95%CI: 1.198-3.073, P=0.007), atrial fibrillation (AF) (OR=1.617, 95%CI: 1.016-2.572, P=0.043), lower estimated glomerular filtration rate (eGFR) (OR=0.986, 95%CI: 0.977-0.996, P=0.005) and a higher incidence of intracardiac thrombus (OR=6.127, 95%CI: 3.174-11.827, P<0.001) were risk factors for DCM-IS. The overall 1-year survival rate was lower in DCM-IS patients (70.7%) than DCM patients without stroke (83.6%, P=0.004), and the main causes of death included obstinate heart failure (3 cases of DCM-IS, and 5 cases of non-DCM-IS) and malignant arrhythmia (DCM-IS) (22 cases of DCM-IS, and 18 cases of non-DCM-IS). Conclusions: Among IS patients with idiopathic DCM, cardioembolism is the most common, followed by lacunar infarction, and the large-artery atherosclerotic subtype is the least common.Hypertension, hyperlipidemia, AF, lower eGFR value and higher incidence of intracardiac thrombus are risk factors for DCM-IS. DCM patients complicated with IS have poor short-term prognosis, and obstinate heart failure and malignant arrhythmia are their main causes of death.

[Clinicopathological features of mixed cervical carcinoma with adenoid cystic pattern].

Objective: To investigate the clinicopathological characteristics, immunophenotype, molecular characteristics, differential diagnosis, clinical treatment and prognosis of mixed carcinoma of cervix with adenoid cystic pattern. Methods: Three cases of mixed cervical carcinoma with adenoid cystic pattern were collected at the Affiliated Hospital of Xuzhou University Medical School from 2018 to 2021.The clinicopathological characteristics were analyzed, immunohistochemistry (IHC) and in situ hybridization (ISH) were performed. The related literature was reviewed. Results: The three patients were postmenopausal women with a median age of 74.7 years. The clinical symptom was vaginal bleeding without obvious causes. One case was an endophytic tumor, and the others were exophytic. The median diameter of the three cases was 3.3 cm. Two patients underwent hysterectomy, the tumors infiltrated the external 1/3 and middle 1/3 of the cervix respectively. All the lymph nodes were negative. One patient had a previous biopsy. Microscopically, all three tumors were characterized by a cribriform structure, which were filled with basophilic myxoid substance and surrounded by tubules lined by two layers of cells. The tumor cells had scanty cytoplasm and showed the characteristics of cervical basal-like cells. All three cases were accompanied by high-grade squamous intraepithelial lesions and squamous cell carcinoma, and one also showed a non-specific spindle cell sarcomatoid component. Within the double-layered epithelial structure, the outer epithelium was positive for p63, CD117, p16INK4a (clone E6H4) and MYB protein and negative for S-100 by IHC. The combined positive score of PD-L1 (clone 22C3) was less than 1 in all three cases. Human papillomavirus (HPV) types 16 and 18 were detected in one patient preoperatively, while high-risk HPV were positive in the other two patients by RNAscope ISH postoperatively. None of the three cases showed MYB gene rearrangement by FISH. The mean follow-up time was 23.3 months (36, 28 and 6 months, respectively). Two patients underwent hysterectomy and radiotherapy survived without disease. One patient survived with tumor just by radiotherapy and drug therapy. Conclusions: Mixed cervical carcinoma with adenoid cystic pattern is extremely rare. It is a high-grade malignancy with poor prognosis. The tumor is associated with high-risk HPV infection, without MYB gene rearrangement, and with low PD-L1 immunoreactivity. Radical surgery combined with radiotherapy and chemotherapy is the mainstay of treatment at present.

[ALK-positive large B-cell lymphoma with EBV infection or cyclin D1 expression: a clinicopathological analysis of 3 cases].

Objective: To investigate the clinicopathological features and misdiagnosis factors of ALK positive large B-cell lymphoma (ALK+LBCL). Methods: The clinicopathological data of 3 patients with ALK+LBCL in the Department of Pathology, the Affiliated Hospital of Xuzhou Medical University from 2010 to 2021 were collected retrospectively. Immunohistochemistry (IHC) was used for immunophenotyping, in-situ hybridization (ISH) for EBV-encoded RNA (EBER) detection, in-situ fluorescence hybridization (FISH, break-apart probes) for ALK, MYC, and CCND1 translocations. Next-generation sequencing (NGS) was used for the detection of gene fusions and mutations. And clinicopathological features and prognosis of patients were analyzed. Results: Among the 3 ALK+LBCL patients, there were 2 males and 1 female, aged 42, 59, and 39 years, respectively, none of which presented with B symptoms. Case 1 showed systemic lymphadenopathy with elevated serum EBV DNA loading, while cases 2 and 3 presented with extranodal lesions in the nasal and hard palate, respectively. Bone marrow biopsies were performed in cases 1 and 3, and neither showed involvement. Case 1 was at clinical stage Ⅲ while both cases 2 and 3 were at stage Ⅰ, and IPI score ranged 0-1 in all cases. The morphology of these cases was similar. The architecture was effaced by sheets of cohesive large cells growing in extensive infiltration and intra-sinus growth pattern. The neoplastic cells showed immunoblastic or plasmablastic morphology, and large anaplastic cells were easily found. The tumor cells expressed ALK protein cytoplasmically in almost all cells, with ALK gene translocations detected by FISH. Common B-cell and T-cell markers, including CD20, PAX5, CD19, CD2, CD3, CD5, CD7, CD43, CD56, and bcl-2, were negative, while plasmacytic differentiation markers, including CD138, CD38, and MUM1, were positive; CD22, BOB1 and OCT2 were variably expressed. CD10 was strongly expressed only in case 3. All cases were negative for bcl-6 but positive for CD4, perforin, CD30 (partial cells), pSTAT3 (diffusely), and MYC (40%-50%). The Ki-67 index was ranged 60%-70%. MYC translocation was not detected in any case by FISH. In case 1, EBER was strongly positive in>90% of tumor cells. Case 3 was diffusely positive for cyclin D1 but negative for SOX11 expression and CCND1 translocation. All cases harbored ALK fusion genes detected by NGS. In case 1, the fusion partner was TFG, which had not been reported in DLBCL, while in the other 2 cases, ALK fused with the CTCL gene, which was commonly seen in ALK+LBCL. Cases 1 and 3 were treated with ECHOP-based chemotherapy for six cycles and were followed up for 70 and 27 months, respectively, and both achieved complete remission. Conclusions: ALK+LBCL cases with diffuse EBER-positivity reported in this study show TGF as a new fusion partner of ALK in DLBCL, together with cyclin D1 expression. These rare cases are easily confused with EBV positive diffuse large B-cell lymphoma, not otherwise specified (EBV+DLBCL, NOS), cyclin D1 positive diffuse large B-cell lymphoma (cyclin D1+DLBCL) and ALK positive anaplastic large cell lymphoma (ALK+ALCL), resulting in misdiagnosis. Being aware of these rare phenotypes is essential for pathologists to diagnose ALK+LBCL and guide appropriate treatment accurately.

[Cystic echinococcosis of the abdominal wall: a case report].

Cystic echinococcosis of the abdominal wall is relatively rare. Here, a 54-year-old patient with cystic echinococcosis of the abdominal wall was reported, who was admitted to hospital due to presence of abdominal mass for one year complicated by skin ulceration of the mass for 5 days. The case was initially diagnosed as cystic echinococcosis of the abdominal wall and given sub-abdominal echinococcosis cystectomy. Post-surgical pathological examinations revealed cystic echinococcosis (type of a single locule and multiple daughter cysts). This case report aimed to provide insights into the clinical diagnosis and treatment of cystic echinococcosis of the abdominal wall.

[Primary liver cancer complicated by hepatic cystic echinococcosis: a case report].

A primary liver cancer patient complicated by hepatic cystic echinococcosis was reported. The case was admitted to the hospital due to intermittent upper abdominal discomfort for more than half a month, and an auxiliary examination revealed primary liver cancer complicated by hepatic cystic echinococcosis. Then, hepatic artery infusion and chemoembolization was performed, and no treatment was given to cystic echinococcosis lesions. Following treatment, the patient had remarkable improvements in the liver functions.

[Prevalence investigation of solitary plasmacytoma in China: A calculation based on national urban medical insurance in 2016].

Objective: The aim of this study is to analyze the distribution features of patients with solitary plasmacytoma and calculate the prevalence of solitary plasmacytoma in China in the year 2016. Methods: This study was based on China's urban employees' basic medical insurance and the urban residences' basic medical insurance from 21 provinces from January 1, 2016 to December 31, 2016. Patients with solitary plasmacytoma were identified by disease names and codes. Subgroup analyses were carried out by sex, region, and age. Furthermore, sensitivity analyses were performed to test the robustness of the results. Age-adjusted prevalence was calculated based on the 2010 Chinese census data, the 2013 Revised European Standard Population, the 2010 US population, and the 2011 Australian population. Results: In 2016, the prevalence of solitary plasmacytoma in China was 1.18 per 100 000 population (95%CI, 1.06-1.31) , with 1.26 per 100 000 population (95% CI, 1.10-1.43) and 1.10 per 100 000 population (95% CI, 0.93-1.29) for males and females, respectively. The age-adjusted prevalence based on the 2010 Chinese census data was 0.85 per 100 000 population (95% CI, 0.82-0.88) . Conclusion: This study estimated the prevalence of solitary plasmacytoma in China on the basis of the national urban medical insurance, which can provide clues for the enactment of solitary plasmacytoma-related medical policies and basic studies about solitary plasmacytoma.

SNHG3 silencing suppresses the malignant development of triple-negative breast cancer cells by regulating miRNA-326/integrin α5 axis and inactivating Vav2/Rac1 signaling pathway.

OBJECTIVE: Long non-coding RNA small nucleolar RNA host gene 3 (SNHG3) has been shown to participate in several tumorigenesis. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer, which is the first leading cause of new cancer diagnoses in women globally. However, the role of SNHG3 remains little known in breast cancers, especially in TNBC. MATERIALS AND METHODS: Expression of SNHG3, miRNA-326-5p (miR-326) and integrin α5 (ITGA5) was detected using Real Time-PCR and Western blotting. Cell viability, apoptosis, migration, and invasion were measured by methyl thiazolyl tetrazolium assay, flow cytometry, and transwell assays, respectively. Vav2/Rac1 signaling pathway was evaluated by Western blotting by analyzing Vav2 and Rac1 levels. The interaction among miR-326, SNHG3 and ITGA5 was confirmed by Dual-Luciferase reporter assay. RESULTS: We found that the expression of SNHG3 and ITGA5 was upregulated and miR-326 was downregulated in TNBC tumors and cell lines (MDA-MB-231, BT-549, MDA-MB-468 and SUM159). Functionally, both SNHG3 silencing and miR-326 overexpression enhanced cell apoptosis, but depressed cell viability, migration and invasion in MDA-MB-231 and BT-549 cells, as well as inhibited Vav2 and Rac1 expression. Notably, miR-326 deletion could abolish the tumor-suppressive role of SNHG3 silencing; meanwhile, the similar anti-tumor effect of miR-326 overexpression was abrogated by ITGA5 restoration. Mechanically, SNHG3 silencing downregulated ITGA5 expression by functioning as a molecular "sponge" for miR-326. CONCLUSIONS: Silencing of SNHG3 suppressed the malignant development of TNBC cells, at least partially, through miR-326/ITGA5 axis and inhibiting Vav2/Rac1 signaling pathway.

Knockdown of protein phosphatase 5 (PPP5C) suppresses the growth of leukemic cell line U937.

Serine/threonine protein phosphatase 5 (PPP5C) participates in multiple signaling pathways including cell cycle control and cell growth. PPP5C is involved in the progression of human breast cancer and hepatocellular carcinoma. However, its function in acute myelogenous leukemia (AML) remains unknown. In this study, we constructed a lentivirus system to knock down the expression level of PPP5C in leukemic cell line U937. Cell proliferation and cell cycles were assessed by MTT assay and flow cytometry respectively. Western blot was used to determine the level of caspase-3, PARP (poly ADP-ribose polymerase), CDK4 and CyclinD1. Knockdown of PPP5C suppressed the proliferation ability of U937 cells, and led to G0/G1 phase arrest, inducing cell apoptosis in U937 cells. The apoptosis of the U937 cells was associated with upregulating cleaved caspase-3 and PARP, and downregulating CDK4 and CyclinD1. In conclusions, PPP5C knockdown inhibits U937 cell proliferation and might be used as a potential therapeutic target for the treatment of leukemia.

Cyclin I promotes cisplatin resistance via Cdk5 activation in cervical cancer.

OBJECTIVE: Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of cervical cancer (CC), but cancer cell acquired resistance to this drug during the course of its treatment. The aim of this study was to investigate the role of cyclin I to cisplatin resistance in CC cell. PATIENTS AND METHODS: Cervical tumor specimens from 30 patients were recruited in this study. We analyzed the expression of cyclin I by real-time polymerase chain reaction (qRT-PCR), Western blotting examination of downstream effectors. Cell proliferation assay and xenograft experiments were performed for cisplatin cytotoxicity assay. Lentivirus-mediated and siRNA-mediated genes overexpression or knockdown were applied to investigate the role of cyclin I to cisplatin resistance in CC cell. RESULTS: We found that high level of cyclin I was associated with cisplatin resistance in CC. Here, we described that cyclin I protein becomes highly expressed in human CC patients resistant to cisplatin chemotherapy. Stable overexpressed cyclin I promotes Hela cell resistance to higher concentrations of cisplatin. In addition, upregulated level of cyclin I increased tumor cells growth in vitro and enhanced tumor resistance to cisplatin in vivo. The further mechanism investigated showed that cyclin I upregulated the expression of cyclin-dependent kinase 5 (Cdk5) promoting cisplatin resistance by preventing apoptosis in CC cell line. Consistently, the cyclin I overexpressed Hela cell lines produce increased sensitivity to cisplatin treatment through knockdown of Cdk5 protein with siRNA. CONCLUSIONS: These data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in the process of generating cisplatin resistance in cervical cancer.

Clinical application of remifentanil in local anesthesia for tumor resection in functional brain area.

OBJECTIVE: The aim of this study was to investigate clinical application of remifentanil in local anesthesia for resection of tumors in functional brain area. PATIENTS AND METHODS: Twenty-four patients were randomly divided into two groups: control group and remifentanil group. In remifentanil group remifentanil was infused intravenously with micro pump in 0.05-0.1 µg·kg-1·min-1. The hemodynamic changes and complications during operation were monitored. RESULTS: The satisfactory degree for surgical procedure was evaluated. The surgery of two groups could be completed in a conscious state. Mean artery pressure (MAP), heart rate (HR) in remifentanil group during opening or closing skull or intra- cranial period were significantly lower than control group (p < 0.05). There were no conspicuous complications in two groups such as respiratory depression, nausea, vomitting and dysphoria. Satisfaction rate of remifentanyl group was significantly higher than control group (p < 0.05). CONCLUSIONS: Awake brain tumor surgery could be completed in rational use of remifentanil on the base of good local anesthesia, and hemodynamics were stable and the patients were well tolerated.

Elevated plasma levels and monocyte-associated expression of CD137 ligand in patients with acute atherothrombotic stroke.

BACKGROUND: CD137 ligand (CD137L) is expressed by various immune cells and exists in membrane-bound and soluble forms. Recently, CD137L was found to be localized to macrophages in human atherosclerotic lesions and CD137L levels were much higher in atherosclerotic lesions than in normal arteries. However, the role of CD137L with different forms in atherothrombotic stroke remains unclear. PATIENTS AND METHODS: The soluble CD137L (sCD137L) protein and CD137L expression on monocytes were analyzed by an enzyme-linked immunosorbent assay and flow cytometry in peripheral blood of patients with acute ischemic atherosclerotic stroke, atherosclerosis controls and normal controls. RESULTS: During the initial 24h after onset, the stroke patients had elevated plasma sCD137L levels (133.2 pg/ml) and CD137L expression on monocytes [7.9 ± 4.1%, 7.0 ± 4.0 mean fluorescence intensity (MFI)] as compared with normal controls (75 pg/ml, p < 0.05; 4.6 ± 2.4%, 4.1 ± 2.7 MFI, p < 0.05). CONCLUSIONS: The dysregulation of CD137L expression may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. Our results strongly suggest that the abnormal expression of CD137L on monocytes may lead to dyregulated CD137L/CD137 signaling and consequently form part of a positive-feedback, inflammation-promoting circuit in stroke, while the elevated sCD137L protein levels may function as a self-regulatory mechanism of CD137/CD137L interaction and costimulation.

Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol.

BACKGROUND AND PURPOSE: Growing evidence suggests that long-term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol. EXPERIMENTAL APPROACH: Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg(-1) ·day(-1), i.p.) and metoprolol (20 mg·kg(-1) ·day(-1), p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling-related proteins were evaluated. KEY RESULTS: Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine-treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co-administration of metoprolol. Consistently, the expressions of poly (ADP-ribose) polymerases-1, apoptosis-inducing factor and NF-κB-light-chain-enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth-associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy.

Decreased 4-1BB expression on CD4+CD25 high regulatory T cells in peripheral blood of patients with multiple sclerosis.

As a tumour necrosis factor receptor superfamily member, 4-1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25(high) T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25(high) Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4-1BB and soluble 4-1BB (s4-1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4-1BB expression in their CD4+C25(high) Tregs and increased plasma s4-1BB protein levels. Moreover, the plasma s4-1BB levels of MS patients were shown to be inversely correlated with the 4-1BB surface expression of CD4+CD25(high) Tregs. The down-regulated 4-1BB expression on CD4+CD25(high) Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity.

Enhanced plasma levels of LIGHT in patients with acute atherothrombotic stroke.

OBJECTIVES: As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) was recently found to be associated with platelets and released upon activation. Increased plasma levels of LIGHT have been reported in patients with myocardial infarction and unstable angina. The aim of the study was to analyze plasma levels of LIGHT in acute ischemic atherosclerotic stroke. MATERIALS AND METHODS: The soluble LIGHT protein was analyzed by an enzyme-linked immunosorbent assay in peripheral blood of patients with acute ischemic atherosclerotic stroke (n = 20), asymptomatic carotid stenosis (n = 19) and normal controls (n = 23). RESULTS: During the initial 24 h after onset, the stroke patients had an increased plasma LIGHT levels as compared with normal controls. Moreover, the plasma LIGHT levels of the stroke patients were correlated with blood platelet count (r = 0.6341, P = 0.0027). CONCLUSION: The elevated LIGHT levels may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. We speculate that this derangement of LIGHT may be important for atherogenetic process of ischemic stroke.