Prx II reduces oxidative stress and cell senescence in chondrocytes by activating the p16-CDK4/6-pRb-E2F signaling pathway.

OBJECTIVE: Osteoarthritis (OA) is a common clinical degenerative disease and has a high incidence in the elderly. The purpose of this study was to explore the anti-oxidative stress and anti-aging effects of Peroxiredoxin II (Prx II) on articular chondrocytes, as well as its molecular mechanism. MATERIALS AND METHODS: Articular cartilage tissues and culture human articular chondrocytes were selected. By constructing Prx II overexpressing lentivirus, the effects of Prx II on oxidative stress and cell senescence in chondrocytes were studied. Besides, the p16 overexpression lentivirus was constructed to investigate the effect of Prx II on the p16-CDK4/6-pRb-E2F signaling pathway (p16 signaling pathway). RESULTS: Articular cartilage tissues in patients with OA and IL-1ß-induced chondrocytes expressed lower Prx II and had higher p16 signaling pathway activity. The overexpression of Prx II significantly increased the expression of SOD1 and SOD2 and decreased the expression of ß-gal and P53/P21, indicating that Prx II can reduce the oxidative stress and senescence level of chondrocytes. Moreover, the overexpression of Prx II increased the expression of p16 signaling pathway-related molecules and the activation of the p16 signaling pathway attenuated the anti-oxidative stress and anti-aging effects of Prx II. CONCLUSIONS: Prx II can inhibit the p16 signaling pathway in chondrocytes to reduce the level of aging in chondrocytes, thereby reducing the level of oxidative stress in chondrocytes, and ultimately inhibiting the progression of OA.

MicroRNA-183-5p suppresses the malignant progression of osteosarcoma via binding to AKT.

OBJECTIVE: To clarify the role of microRNA-183-5p in the malignant progression of osteosarcoma (OS) and the potential mechanism. PATIENTS AND METHODS: Relative level of microRNA-183-5p in 40 paired OS tissues and matched normal tissues was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Correlation between microRNA-183-5p level and clinical indexes of OS patients was analyzed. By transfection of microRNA-183-5p mimics in SaOS-2 and MG63 cells, changes in proliferation and migration were evaluated. The potential target of microRNA-183-5p was verified by dual-luciferase reporter gene assay. Finally, the biological function of protein kinase B (AKT) in OS progression mediated by microRNA-183-5p was detected. RESULTS: MicroRNA-183-5p was downregulated in OS tissues compared to controls. Relative to OS patients with high expression of microRNA-183-5p, those with low expression had a higher rate of distant metastasis and lower overall survival. Transfection of microRNA-183-5p mimics attenuated proliferative and migratory abilities of SaOS-2 and MG63 cells. AKT was upregulated in OS and negatively correlated to microRNA-183-5p. Overexpression of AKT could abolish the inhibitory effect of microRNA-183-5p on proliferative and migratory abilities of OS cells. CONCLUSIONS: MicroRNA-183-5p is closely related to distant metastasis and poor prognosis of OS. It suppresses the malignant progression of OS by targeting AKT.

Peripheral T lymphocyte immunity and l-dopamine in patients with Parkinson's disease.

This study aimed to evaluate the efficacy of T-cell immune function and L-dopamine (L-DOPA) in patients with Parkinson’s disease (PD). Sixty subjects (included in the study group) with PD who were patients of the Neurology Department of The Affiliated Hospital of Hangzhou Normal University from July 2015 to March 2017 were selected. The study group was then categorized into groups according to the age of the patients, severity of disease, level of cognition, and treatment of L-DOPA. The control group (30 cases) was from the healthy population of the check-up center at The Affiliated Hospital of Hangzhou Normal University. The peripheral blood T-lymphocyte subsets of the study group were measured by direct immunofluorescence flow cytometry staining and compared with the control group. At the same time, correlation analysis was carried out on patients with different degrees of disease severity according to staging, different accompanying symptoms, and whether L-DOPA was administered. The results of the study show that the levels of CD4+, CD8+, CD3+, and CD4+/CD8+ peripheral blood in PD patients were significantly lower than those in the control group (P less than 0.05). It was found that the levels of CD4+, CD8+, CD3+, and CD4+/CD8+ decreased with age. The CD4+, CD8+, CD3+, and CD4+/CD8+ in patients with advanced stage PD were more significant than those with low PD stages (P less than 0.05). The levels of CD4+, CD8+, CD3+, and CD4+/CD8+ in the dementia group were significantly lower than those in the non-dementia group (P less than 0.05). The levels of CD4+, CD8+, CD3+, and CD4+/CD8+ in PD patients treated with L-DOPA were higher than those of PD patients without L-DOPA treatment (P less than 0.05). In conclusion, the immune function of T cells in patients suffering from PD is low, and the immune function of T cells in patients with severe disease is lower. Therefore, it is of certain significance to further study the pathophysiological mechanism of PD.

Cognitive impairment in Chinese neuromyelitis optica.

BACKGROUND: Cognitive dysfunction is frequently seen in neuromyelitis optica (NMO). However, the features and influencing factors of cognitive impairment of Chinese NMO patients are unclear. OBJECTIVE: To investigate the patterns of cognitive impairment in Chinese NMO patients, and correlate the neuropsychiatric scores with clinical and MRI parameters. METHODS: Thirty-six Chinese NMO patients, and 30 sex and age-matched healthy controls were recruited with extensive neuropsychological assessments, using the modified Minimal Assessment of Cognitive Function in MS (MACFIMS). The demographic and clinical characteristics as well as MRI parameters were compared between cognitively impaired (CI) and cognitively preserved (CP) patients. RESULTS: NMO patients were significantly impaired in the Paced Auditory Serial Addition Task (P<0.05), the Symbol Digit Modalities Test (P<0.001), the California Verbal Learning Test-Second Edition (P<0.05), the Brief Visuospatial Memory Test-Revised (P<0.05) and semantic fluency (P<0.001). Only lower education level was associated with cognitive dysfunction in NMO (odds ratio: 0.57, P<0.05). There were no significant differences of MRI parameters regarding white matter (WM) lesions, grey matter and WM brain volume between CI and CP patients. CONCLUSIONS: Chinese NMO patients particularly demonstrated cognitive impairment in information processing speed, executive function and memory. Lower education level was the main factor contributing to cognitive impairment in NMO.

Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.

Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.

Evaluation of myocardial viability in asymptomatic patients early after infarction with perfusion/metabolism single-photon-emission computed tomographic imaging and dobutamine echocardiography.

OBJECTIVE: To study the impact of detection of viability of myocardium in asymptomatic patients early (3-10 days) after Q-wave myocardial infarction on segmental recovery of left ventricular function after elective revascularization. METHODS: Patients were studied with low-dose dobutamine echocardiography (LDDE) and single photon-emission computed tomography with 99mTc sestamibi and [18F]-fluorodeoxyglucose (FDG) imaging. Viability of myocardium was defined as detection of improvement in segmental thickening of left ventricle by LDDE (versus baseline echocardiographic data), uptake of 99mTc sestamibi > 50% of maximum counts, uptake of [18F]-FDG > 50% of maximum normal, combined uptake of 99mTc sestamibi or [18F]-FDG > 50% of normal maximum, uptake of [18F]-FDG > 50% or mismatched pattern (uptake of [18F]-FDG greater than that of 99mTc sestamibi). Functional recovery was defined as improvement of segmental thickening of left ventricle detected at follow-up 8 weeks after infarction (versus baseline resting echocardiographic data). Interpretation of the tests was blinded with respect to the angiographic data and the results of the alternative method. RESULTS: In total 18 patients with 133 left-ventricle segments with abnormal contractile function at baseline were analysed; 29% were hypocontractile and 71% were noncontractile. Examination with LDDE showed that 18% of the segments had normal contractility and 26% were hypocontractile; the respective percentages were 29 and 28% according to follow-up resting echocardiography. Radionuclide tests for viability of myocardium gave positive results in 57% (uptake of [18F]-FDG > 50%) and 62% (uptake of 99mTc sestamibi > 50%) of cases. With respect to segmental analysis, there was a 25-27% positive concordance, a 24-27% negative concordance, and a 48-50% discordance between the LDDE and the radionuclide definitions of viability of myocardium. Additionally, there was no significant difference among sensitivities and specificities for the definitions of viability. The sensitivity was 69% for the uptake of 99mTc sestamibi > 50% criterion, and the highest specificity was 66% for the LDDE. Incorporation of imaging with [18F]-FDG into the analysis yielded a marginally higher sensitivity of 71% for the criterion of uptake of [18F]-FDG or 99mTc sestamibi > 50%, versus imaging with the 99mTc sestamibi alone. CONCLUSION: LDDE was more specific and radionuclide imaging more sensitive for detection of viability of myocardium in asymptomatic patients early after infarction. Possibly defective myocardial metabolization of glucose in the period early after infarction and the specific LDDE protocol applied account for the limited benefit of these studies in terms of facilitating prediction of segmental functional recovery after revascularization in this clinical setting.

Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect.

Lipid-lowering with statins reduces blood thrombogenicity. However, it is unknown whether this is purely due to LDL-cholesterol reduction, or it is related to a statin or agent specific effect. We investigated the relationship between reduction in blood thrombogenicity and the magnitude of low-density lipoprotein cholesterol (LDL-C) during pravastatin therapy. We prospectively followed for 6 months 57 hyperlipidemic patients who initiated therapy with pravastatin, and 36 patients who were randomized into placebo plus diet. Pravastatin-treated patients were grouped according to the LDL-C reduction at 6 months; (i) "adequate LDL-C reduction": LDL-C reduction >30% from baseline or LDL-C<125 mg/dl (n = 38; LDL-C reduction 74 +/- 4 mg/dl; 6-month LDL-C 119 +/- 5 mg/dl); (ii) "inadequate LDL-C reduction": neither of the above criteria (n = 19; LDL-C reduction 31 +/- 5 mg/dl; 6-month LDL-C 158 +/- 6 mg/dl). Placebo patients were divided into those "with LDL-C reduction" (n = 17, mean reduction 21 +/- 5 mg/dl) and those "without LDL reduction" (n = 19). The following parameters were altered at 6 months in both patients with "adequate" and "inadequate" LDL-C reduction: (1) tissue plasminogen activator decreased by 1.4 +/- 0.4 and 1.5 +/- 0.5 ng/ml respectively (p = NS); (2) plasminogen activator inhibitor-1 decreased by 8.7 +/- 2.0 and 10.1 +/- 2.7 ng/ml respectively (p = NS); (3) thrombus formation under dynamic flow conditions decreased by 3.5 +/- 0.9 and 2.8 +/- 1.2 microm2 x 10(3) respectively (p = NS). In contrast, no significant changes from baseline were noted in placebo-treated patients, regardless of their LDL-C reduction category, and multivariate analysis eliminated LDL-C reduction as an independent predictor of reduction in thrombogenicity. Therefore, the reduction in thrombogenicity was not proportional to the magnitude of LDL-C reduction suggesting that a class or agent specific property is primarily responsible for the pro-fibrinolytic/antithrombotic effects observed.

Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin.

Thrombotic risk in hyperlipidemic women and its response to lipid therapy is unknown. We prospectively studied 28 men and 29 women with high low-density lipoprotein (LDL) cholesterol during 6 months of therapy with pravastatin. Women had significantly higher high-density lipoprotein (HDL) cholesterol (54.2 +/- 1.7 vs 39.5 +/- 2.2 mg/dl, p <0.01), lower prevalence of coronary artery disease (41% vs 67%, p = 0.04), and otherwise similar baseline characteristics compared with men. Both genders achieved a 33% reduction in LDL at 6 weeks (188 +/- 6 to 133 +/- 5 mg/dl) and maintained similar LDL levels throughout the study. Systemic hemostatic markers and thrombus formation under dynamic flow conditions were evaluated at baseline, and at 3 and 6 months of follow-up. Prothrombin fragment F1.2, a marker of thrombin generation, was higher in women versus men at baseline (2.4 +/- 0.2 vs 1.4 +/- 0.3 nmol/L, p = 0.02). The levels decreased in women to 2.0 +/- 0.3 nmol/L at 3 months and to 1.6 +/- 0.2 nmol/L at 6 months (p <0.045, analysis of variance), whereas it remained unchanged in men. Plasminogen activator inhibitor-I significantly decreased at 3 and 6 months of follow-up: by 12.6% and 18.7%, respectively, in women, and by 18.8% and 23.5%, respectively, in men. Similarly, tissue plasminogen activator decreased significantly by 7.4% in women and 11.8% in men at 6 months compared with baseline. Fibrinogen showed an increase in both genders at follow-up. Thrombus formation was similar at baseline between the 2 genders, and decreased at 3 and 6 months compared with baseline by 12.5% and 29.5% in women, and by 18.6% and 19.4% in men (p <0.04 at 6 months vs baseline in both men and women). Other markers, including C-reactive protein, fibrinopeptide A, D-dimer, and factor VIIa, did not differ between genders and did not change with therapy. Thus, despite higher HDL, and lower incidence of coronary disease, women with high LDL had a comparable thrombotic and/or fibrinolytic profile to men and even evidence of increased thrombin generation at baseline. Blood thrombogenicity was reduced with pravastatin in both genders; in addition, thrombin generation was gradually reduced in women to a level similar to that of men by 6 months of follow-up.

The effect of early postinfarction revascularization of asymptomatic patients on left ventricular remodeling.

BACKGROUND: Patients with angina after a Q-wave myocardial infarction benefit from elective revascularization, but it is not known whether asymptomatic patients, including those with a totally occluded infarct-related artery, improve after revascularization. OBJECTIVE: To determine the effect of early postinfarction revascularization of asymptomatic patients on left ventricular remodeling. METHODS: We prospectively studied 31 consecutive asymptomatic patients (aged 57 +/- 2 years, 24 with anterior infarcts) after Q-wave myocardial infarction with > or = 70% stenosis of the infarct-related artery (IRA) who underwent early elective revascularization (days 4-10 after myocardial infarction). Group I consisted in patients with a totally occluded IRA (n = 10), and group II consisted in patients with a patent, though stenosed, IRA (n = 21). Resting echocardiography and low-dose dobutamine echocardiography were performed at baseline (day 3 +/- 1), and rest echocardiography was repeated after an 8-week follow-up. Significant myocardial viability was defined as > or = 2 wall segments improved (in a 16-segment model of left ventricle) versus baseline, and significant functional recovery as > or = 2 segments improved versus baseline on follow-up examination. Left ventricular end-systolic volume indices (ESVI) and end-diastolic volume indices and ejection fractions were measured by using a modified version of Simpson's rule (using apical two-chamber and four-chamber views). RESULTS: The left ventricular ESVI of patients in group I had decreased by 4.2 +/- 1.9 ml/m2, whereas for patients in group II the left ventricular ESVI had increased by 4.2 +/- 1.7 ml/m2 (P = 0.006). Similarly, the left ventricular end-diastolic volume index had decreased by 0.7 +/- 2.4 ml/m2 versus baseline at follow-up for patients in group I and increased by 7.8 +/- 2.1 ml/m2 for patients in group II (P = 0.02). The left ventricular ejection fraction increased by 7.3 +/- 3% for patients in group I and decreased by 0.4 +/- 2% for patients in group II (P = 0.04). CONCLUSION: There is less global left ventricular remodeling, a potentially deleterious process, after elective revascularization early after Q-wave myocardial infarction in asymptomatic patients who had had a totally occluded IRA before revascularization than there is in patients who had already had a patent, though stenosed, IRA before revascularization. These results suggest that restoration of patency of IRA after a Q-wave myocardial infarction is beneficial even for asymptomatic patients.

Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.

OBJECTIVES: The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. BACKGROUND: Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. METHODS: We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. RESULTS: Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01). CONCLUSIONS: Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.

Correlation of serum lipoprotein(a) with the angiographic and clinical presentation of coronary artery disease.

This study reports the association of elevated serum lipoprotein(a) levels with angiographically extensive coronary disease and the presence of totally occluded coronary arteries, as well as the association of elevated lipoprotein(a) with unstable angina. These results support the role of lipoprotein(a) in the human atherothrombotic process.

A survey of home nursing services in Taiwan.

This study investigated the current situation of home nursing services in Taiwan. A total of 93 home nursing agencies (response rate of 75%) responded to a mail survey. The majority of the agencies (63%) had been established within the last 3 years before the survey, were hospital-based (90%), and had less than 60 (89.3%) average total number of visits per month per nurse. Most of the home care nurses had taken home care nursing training courses and had at least 2 years of clinical experience. Half of the agencies provided care for patients on a respirator, and 28% provided in-home hospice care. Almost a third of the agencies performed poorly in the areas of supply management, supervision of home visits, and quality monitoring and improvement mechanisms. Several suggestions for the development of home nursing services in Taiwan are made.