Association of intraoperative cerebral and somatic tissue oxygen saturation with postoperative acute kidney injury in adult patients undergoing multiple valve surgery.

BACKGROUND: The association between tissue oxygenation with postoperative acute kidney injury (AKI) in adult patients undergoing multiple valve surgery has not been specifically studied. METHODS: In this prospective exploratory cohort study, 99 patients were enrolled. The left forehead, the left forearm, the left upper thigh, and the left renal region tissue oxygen saturation using near-infrared spectroscopy were monitored. The association between each threshold and AKI was assessed. The relative and absolute thresholds were < 70%, < 75%, < 80%, < 85%, < 90%, < 95%, and < 100% baseline, and baseline-standard deviation (SD), -1.5 SD, -2 SD, -2.5 SD, and -3 SD. Multivariate logistic regression analysis was adopted to explore the association. RESULTS: AKI occurred in 53 (54%) patients. The absolute value-based SrrO2 thresholds associated with AKI were baseline-3 SD (odds ratio [OR], 4.629; 95% confidence interval [CI], 1.238-17.314; P = 0.023) and baseline-2.5 SD (OR, 2.842; 95% CI, 1.025-7.881; P = 0.045) after adjusting for the potential confounders, those are renal region tissue oxygen saturation of 55% and 60%, but not statistically significant after correcting for multiple testing (corrected P = 0.114 and 0.179, respectively). CONCLUSION: The SrrO2 desaturation, defined as < baseline - 2.5 SD or < baseline - 3 SD, may be associated with AKI. The thresholds need to be verified in future large-scale studies. TRIAL REGISTRATIONS: The study was registered at ClinicalTrials.gov, first trial registration: 26/10/2017, identifier: NCT03323203.

Exploring the influencing factors of quality of life among the empty nesters in Shanxi, China: a structural equation model.

BACKGROUND: As China's aging trend intensifies and the proportion of empty nests increases, the health-related quality of life of the elderly is the focus of social attention. Previous studies focused on the quality of life of the elderly, rather than empty nesters, and lacked the discussion of the mechanism of influencing factors. Thus, this study aimed to explore the influencing factors of the quality of life (QOL) and interaction mechanisms among empty nesters in Shanxi Province, China, so as to provide practical reference for improving the QOL of empty nesters. METHODS: A total of 4901 empty nesters in Shanxi Province, China, were selected using multi-stage random cluster sampling method in this cross-sectional study. The quality of life was assessed with the Short Form 36 Health Survey (SF-36). Multiple linear regression analysis (stepwise) was performed to examine the factor associated with QOL. Structural equation model (SEM) approach was conducted to test the direct and indirect association between QOL influencing factors with QOL. RESULTS: The average QOL score of empty nesters was 63.34 (SD = 17.23). The multiple linear regression revealed that gender, age, education, monthly income, drinking status, exercise frequency, physical examination frequency, attention to daily nutritional health, relationship with a spouse and relationship with children were significant predictors of the empty nester's QOL (P < 0.05) (R2 = 0.128). SEM showed that behavioral lifestyle had a direct effect on QOL (ß = 0.446, P < 0.001). Socio-economic status had an indirect effect (ß = 0.288, P < 0.001) on QOL through behavioral lifestyle. The family relationship had an indirect effect (ß = 0.115, P < 0.001) on QOL. CONCLUSION: Behavioral lifestyle was the strongest influencing factor in the quality of life among empty nesters, followed by socio-economic status and family relationships. Thus, maintaining a healthy behavioral lifestyle was important to improve the QOL of the empty nesters. Our findings provide a concrete and strong reference for the formulation of targeted intervention strategies.

Multimorbidity patterns in old adults and their associated multi-layered factors: a cross-sectional study.

BACKGROUND: Influenced by various factors such as socio-demographic characteristics, behavioral lifestyles and socio-cultural environment, the multimorbidity patterns in old adults remain complex. This study aims to identify their characteristics and associated multi-layered factors based on health ecological model. METHODS: In 2019, we surveyed a total of 7480 participants aged 60+ by using a multi-stage random cluster sampling method in Shanxi province, China. Latent class analysis was used to discriminate the multimorbidity patterns in old adults, and hierarchical regression was performed to determine the multi-layered factors associated with their various multimorbidity patterns. RESULTS: The prevalence of multimorbidity was 34.70% among the old patients with chronic disease. Over half (60.59%) of the patients with multimorbidity had two co-existing chronic diseases. "Degenerative/digestive diseases", "metabolic diseases" and "cardiovascular diseases" were three specific multimorbidity patterns. Behavioral lifestyles-layered factors had the most explanatory power for the three patterns, whose proportions of explanatory power were 54.00, 43.90 and 48.15% individually. But the contributions of other multi-layered factors were different in different patterns; balanced diet, medication adherence, the size of family and friendship network, and different types of basic medical insurance might have the opposite effect on the three multimorbidity patterns (p < 0.05). CONCLUSIONS: In management of old patients with multimorbidity, we should prioritize both the "lifestyle change"-centered systematic management strategy and group-customized intervention programs.

The effectiveness of the "SMG" model for health-promoting lifestyles among empty nesters: a community intervention trial.

BACKGROUND: With the disintegration of the extended family in recent years, the empty-nest phenomenon is increasingly common in China and the health of empty nesters is attracting more attention. Lifestyles, accounting for 53% in determining death, play a vital role in improving the health of individuals. However, it was rarely studied in promoting the health of empty nesters. In this study, we proposed a "SMG" model in empty nesters, including the self-management, mutual management, and group management, to implement health-promoting lifestyles interventions among empty nesters to provide an effective means to improve their lifestyles and health. METHODS: We conducted a prospective intervention on 350 empty nesters in three communities located in Taiyuan, China. One hundred sixty-seven empty nesters were randomly assigned to the intervention group with SMG-based health-promoting lifestyles interventions used for 7-months, and 183 were randomly assigned to the control group with no measures imposed. The Health-Promoting Lifestyle Profile (HPLP-C) was used to rate the lifestyles of empty nesters. Generalized estimation model was used to analyze the differences between the intervention and control groups over time, adjusted for education and employment. RESULTS: After 7 months of health-promoting lifestyles intervention, HPLP-C score and each dimension score in the intervention group all increase from baseline. There were significant differences after intervention associated with time and group interaction effects in aspects of HPLP-C (mean score = 8.838, 95%CI:6.369-11.306), self-realization (mean score = 1.443, 95%CI:0.352-2.534), Health responsibility (mean score = 1.492, 95%CI:0.477-2.508), physical activity (mean score = 1.031, 95%CI:0.572-1.491), nutrition (mean = 0.827, 95%CI:0.177-1.476), interpersonal relations (mean = 2.917, 95%CI:2.365-3.469) and stress management (mean score = 0.729, 95%CI:0.131-1.327). And education is contributing to the effect of the health-promoting lifestyle intervention (Estimate:8.833, p < 0.001). CONCLUSIONS: SMG-based health-promoting lifestyles intervention in empty nesters effectively improved the lifestyles of empty nesters, and the outcome was affected by education. Lifestyle change requires ongoing intervention, and community service centres must be involved in implementing the "SMG" model to provide ongoing support and improve the effect of interventions among empty nesters. TRIAL REGISTRATION: Chinese Clinical Trial ChiCTR1800015884. Registration date: 26-04-2018. Retrospectively registered.

Risk factors of mental disorders among empty and non-empty nesters in Shanxi, China: a cross-sectional study.

BACKGROUND: China has the world's largest size of elderly population. Mental disorders of the elders deserve keen attention. This study aims to comparatively explore mental disorders and risk factors among empty and non-empty nesters. METHODS: Using the stratified random cluster sampling method, we recruited 8526 elders aged 60 years and above from 11 cities in Shanxi Province in central China, comprising 4901 empty and 3625 non-empty nesters. The mental disorders were assessed with the 12-item Chinese Health Questionnaire (CHQ-12). The binary logistic regression was performed to analyze the risk factors in the two groups. RESULTS: The prevalence of mental disorders in empty nesters was significantly higher than that in non-empty ones (26.9% vs 23.5%). Binary logistic regression showed that the empty nesters who lived alone or lived in an institution were more likely to suffer from mental disorders compared with the non-empty ones, empty nesters living with spouse showed no significant deviation. And single status, hardly or part self-care ability, having chronic diseases, having lower income, and paying less attention to daily healthy diet had positive associations with mental disorders for empty nesters, and no or partial self-care ability and having chronic diseases for non-empty nesters. CONCLUSIONS: The study indicated that empty nesters had a higher prevalence of mental disorders than non-empty ones. Empty nesters living alone, with no or partial self-care ability, chronic disease, lower income and less attention to daily healthy diet were more vulnerable to mental disorders. And the lack of self-care ability and having chronic diseases were risk factors of mental disorders for non-empty nesters.

Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery.

RATIONALE: No medical intervention has been identified that decreases acute kidney injury and improves renal outcome at 1 year after cardiac surgery. OBJECTIVES: To determine whether administration of nitric oxide reduces the incidence of postoperative acute kidney injury and improves long-term kidney outcomes after multiple cardiac valve replacement requiring prolonged cardiopulmonary bypass. METHODS: Two hundred and forty-four patients undergoing elective, multiple valve replacement surgery, mostly due to rheumatic fever, were randomized to receive either nitric oxide (treatment) or nitrogen (control). Nitric oxide and nitrogen were administered via the gas exchanger during cardiopulmonary bypass and by inhalation for 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: The primary outcome was as follows: oxidation of ferrous plasma oxyhemoglobin to ferric methemoglobin was associated with reduced postoperative acute kidney injury from 64% (control group) to 50% (nitric oxide group) (relative risk [RR], 0.78; 95% confidence interval [CI], 0.62-0.97; P = 0.014). Secondary outcomes were as follows: at 90 days, transition to stage 3 chronic kidney disease was reduced from 33% in the control group to 21% in the treatment group (RR, 0.64; 95% CI, 0.41-0.99; P = 0.024) and at 1 year, from 31% to 18% (RR, 0.59; 95% CI, 0.36-0.96; P = 0.017). Nitric oxide treatment reduced the overall major adverse kidney events at 30 days (RR, 0.40; 95% CI, 0.18-0.92; P = 0.016), 90 days (RR, 0.40; 95% CI, 0.17-0.92; P = 0.015), and 1 year (RR, 0.47; 95% CI, 0.20-1.10; P = 0.041). CONCLUSIONS: In patients undergoing multiple valve replacement and prolonged cardiopulmonary bypass, administration of nitric oxide decreased the incidence of acute kidney injury, transition to stage 3 chronic kidney disease, and major adverse kidney events at 30 days, 90 days, and 1 year. Clinical trial registered with ClinicalTrials.gov (NCT01802619).

Improvement of social support in empty-nest elderly: results from an intervention study based on the Self-Mutual-Group model.

BACKGROUND: China has the world's largest elderly population and an increasing number of empty-nest elderly. The purpose of this study is to evaluate the effectiveness of the Self-Mutual-Group model on social support of the empty-nest elderly, thus providing reference for improving their quality of life. METHODS: A intervention study was conducted between October 2016 and May 2017 at six communities in Taiyuan, Shanxi Province, China. A total of 350 empty-nest elderly aged 60-88 years were randomly assigned in the intervention group (n = 167) with a 7-month SMG-based intervention or to a control group (n = 183) with no intervention. The social support of the participating elderly (n = 350) was assessed by the Social Support Rating Scale (SSRS) at the baseline and 7 months later, respectively. RESULTS: A 7-month follow-up showed an increasing mean scores of SSRS, objective support, subjective support and support utilization of the intervention group, and reached statistical significance (P < 0.05). CONCLUSIONS: The Self-Mutual-Group model was considered to be a positive intervention and was effective in increasing social support among the empty-nest elderly. Furthermore, future research should extend the intervention period and introduce multi-point measurement to better evaluate the intervention process and outcomes. TRIAL REGISTRATION: Study on the 'SMG' Health Management Model Based on Community Organization Theory among empty-nest elderly (ChiCTR1800015884).

Health promoting lifestyles and influencing factors among empty nesters and non-empty nesters in Taiyuan, China: a cross-sectional study.

BACKGROUND: In China, the problems of population aging and empty nesting have become important issues which will affect the social stability and economic development. The aim of this study was to explore the health promoting lifestyles and influencing factors among empty nesters and compare with non-empty nesters to find out their differences, so as to provide a scientific evidence for people to formulate health management strategies for elderly. METHODS: A cross-sectional survey which used a stratified random cluster sampling method, was conducted among 500 elders in six districts of Taiyuan, China, there were 288 empty nesters and 212 non-empty nesters. The general information and health- promoting lifestyles were investigated by using the self-made General Information Questionnaire and Health Promoting Lifestyle Scale(HPLP). Two-sample t-test and Chi-square test were used to compare the sociodemographic factors, HPLP scores of empty nesters to non-empty nesters; Multiple stepwise linear regression was performed to estimate influencing factors related to the HPLP of empty nesters and non-empty nesters. RESULTS: The current findings showed that there were differences between the empty nesters and non-empty nesters in gender, resident, marital status, education and income, self-care ability, source of income, relationship with spouse and social activities (P < 0.05). Empty nesters were mostly male, married, had a higher education level, self-care ability and income and lived in urban compared with non-empty nesters. The health promoting lifestyles of the elderly in this survey were in the medium level, the highest score for all dimensions in both groups was in nutrition, whereas health responsibility was executed worst. The HPLP and six subscales scores of the empty nesters were higher than non-empty nesters, there were significant differences in total score of HPLP, self-realization and health responsibility (P < 0.01). Multiple regression analysis showed that the main predictive factors for the empty nesters were education, self-care ability and resident, whereas the main predictive factors for the non-empty nesters were parents-child relationship, source of income and age; social activity was the common factor for two group. CONCLUSION: The health promoting lifestyles of the empty nesters was better than that of the non-empty nesters. Health responsibility, interpersonal relations and stress management were key dimensions to be improved. Except social activity, education, self-care ability and resident were the unique influencing factors of health-promoting lifestyles for empty nesters, while the parents-child relationship, income and age were unique factors for non-empty nesters. The main target of Intervention strategy for elderly health promoting lifestyles should be the enhance of health responsibility, interpersonal relations and stress management by improving social activities, parent-child relationship, education and income of elderly.

Consistency of the anesthesia consciousness index versus the bispectral index during laparoscopic gastrointestinal surgery with sevoflurane anesthesia: A prospective multi-center randomized controlled clinical study.

Background: This study aimed to compare the consistency of anesthesia consciousness index (Ai) with that of bispectral index (BIS) in monitoring the depth of anesthesia (DOA) during sevoflurane anesthesia, to reveal the optimal cutoff values in different states of consciousness, and explore the stability of DOA monitoring during intraoperative injurious stimulation. Methods: We enrolled 145 patients (97 men and 48 women) from 10 medical centers. General anesthesia was induced using intravenous anesthetics and maintained with sevoflurane. Ai and BIS values were recorded. Results: The mean difference between the Ai and BIS was-0.1747 (95% confidence interval, -0.6660 to 0.3166; p = 0.4857). The regression equation of Ai and BIS from the Deming regression analysis was y = 5.6387 + 0.9067x (y is BIS, x is Ai), and the slope and intercept were statistically significant. Meanwhile, the receiver operating characteristic curve analysis of anesthesia-induced unconsciousness, loss of consciousness, and recovery of consciousness revealed that the accuracy of Ai and BIS were similar. In addition, the optimal cutoff values of the different states of consciousness were not sensitive to age, and both Ai and BIS had no correlation with hemodynamics. Conclusion: We conclude that Ai and BIS show no systematic deviation in readings with high consistency, similar accuracy, and good stability; these insights provide more data for clinical application.

Electroacupuncture pretreatment induces tolerance against focal cerebral ischemia through activation of canonical Notch pathway.

BACKGROUND: Electroacupuncture (EA) pretreatment can induce the tolerance against focal cerebral ischemia. However, the underlying mechanisms have not been fully understood. Emerging evidences suggest that canonical Notch signaling may be involved in ischemic brain injury. In the present study, we tested the hypothesis that EA pretreatment-induced tolerance against focal cerebral ischemia is mediated by Notch signaling. RESULTS: EA pretreatment significantly enhanced Notch1, Notch4 and Jag1 gene transcriptions in the striatum, except Notch1 intracellular domain level, which could be increased evidently by ischemia. After ischemia and reperfusion, Hes1 mRNA and Notch1 intracellular domain level in ischemic striatum in EA pretreatment group were increased and reached the peak at 2 h and 24 h, respectively, which were both earlier than the peak achieved in control group. Intraventricular injection with the γ-secretase inhibitor MW167 attenuated the neuroprotective effect of EA pretreatment. CONCLUSIONS: EA pretreatment induces the tolerance against focal cerebral ischemia through activation of canonical Notch pathway.

Activation of canonical notch signaling pathway is involved in the ischemic tolerance induced by sevoflurane preconditioning in mice.

BACKGROUND: A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model. METHODS: C57BL/6 mice were pretreated with 1-h sevoflurane exposure at a dose of 2.5% for 5 consecutive days. Twenty-four hours after the last exposure, all mice were subjected to focal cerebral ischemia by right middle cerebral artery occlusion for 60 min. Neurobehavioral scores, brain infarct volumes, and cellular apoptosis were determined at 72 h after reperfusion (n = 10 per group). The activation of Notch signaling was evaluated (n = 5 per group), and its role in ischemic tolerance was assessed by intraperitoneal administration of γ-secretase inhibitor DAPT (100 mg/kg, n = 10 per group) and conditional Notch-RBP-J knockout technique (n = 8 per group). RESULTS: Sevoflurane preconditioning reduced brain infarct volumes (42.5%), improved neurologic outcomes (P < 0.01 vs. control), and attenuated neuronal cell apoptosis (cells positive for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling reduced to 21.2%). The expression of Notch1 intracellular domain (1.35 folds) and the transcriptions of Hes1 (1.95 times) and Hes5 (1.48 times) were up-regulated. DAPT augmented the brain infarcts (1.64-fold) and decreased neurologic scores (P = 0.43 vs. sevoflurane) in sevoflurane-preconditioned mice. Brain infarct volumes, neurobehavioral scores, and apoptotic cell numbers showed no significance between Notch knockout mice with sevoflurane preconditioning and wild-type mice without preconditioning. CONCLUSIONS: Sevoflurane preconditioning-induced protective effects against transient cerebral ischemic injuries are mediated by the activation of canonical Notch signaling pathway in mice.

Heat shock protein 20 suppresses breast carcinogenesis by inhibiting the MAPK and AKT signaling pathways.

Heat shock protein (HSP) 20 belongs to the small HSP family and exhibits diverse functions, including tumor suppression, in addition to being a molecular chaperon, which is the classical property of HSPs. The present study aimed to examine the association between HSP20 expression and breast cancer (BC) progression in patients, and to explore the possible role of HSP20 in malignant phenotypes of BC cells. A series of experiments, including reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 and flow cytometry, were performed. Data from Gene Expression Omnibus and Kaplan-Meier Plotter revealed that HSP20 expression was significantly downregulated in BC tissues, and patients with BC with lower HSP20 expression exhibited poorer recurrence-free survival. The data revealed that HSP20 was closely associated with the pathological tumor stage (P=0.015) and pathological tumor node metastasis (P=0.031) of patients with BC. Additionally, HSP20 expression was markedly decreased in BC cell lines. Exogenous overexpression of HSP20 inhibited proliferation and accelerated apoptosis of BC cells. These cells exhibited decreased migration and invasion when HSP20 was overexpressed. Furthermore, HSP20 overexpression suppressed the MAPK and AKT signaling pathways, as evidenced by the reduced phosphorylation levels of AKT, ERK, JNK and p38. Knockdown of HSP20 exerted the opposite effects. Notably, the AKT agonist, SC79, and the ERK agonist, LM22B-10, reversed the decrease in cell proliferation and migration induced by HSP20 overexpression. Overall, the data suggest that the decreased expression of HSP20 in BC tissues may be associated with disease progression. HSP20 also attenuated the malignant phenotype of BC cells and the inhibition of MAPK and AKT signaling may be associated with this effect. Therefore, HSP20 may be a potential prognostic marker or a candidate therapeutic target for BC.

Percutaneous Intramyocardial Septal Radiofrequency Ablation in Patients With Drug-Refractory Hypertrophic Obstructive Cardiomyopathy.

Importance: Patients with hypertrophic obstructive cardiomyopathy (HOCM) and drug-refractory symptoms and outflow gradients have limited nonsurgical treatment options. The feasibility of percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) has been reported previously; however, procedural and medium-term outcomes are unknown. Objective: To describe the safety and medium-term outcomes of PIMSRA in a large patient cohort with drug-refractory HOCM. Design, Setting, and Participants: This was a single-arm, open-label study of PIMSRA in patients with drug-refractory HOCM. Patients presenting to the Xijing Hospital in Xi'an, China, between October 2016 to June 2020 with hypertrophic cardiomyopathy. Of 1314 patients presenting with HOCM, 244 fulfilled inclusion criteria of severe resting/provoked outflow gradients of 50 mm Hg or higher, and symptoms of New York Heart Association functional class of II or higher refractory to maximum tolerated medications. After discussion among the heart team, 40 patients underwent surgical or alcohol septal reduction therapy and 4 required treatment of significant coronary artery disease. Interventions: PIMSRA performed in patients. Main Outcomes and Measures: The primary outcome was 30-day major adverse clinical events: death, emergency surgery, severe effusion requiring intervention, procedure-related stroke, bleeding, and stroke. Secondary outcomes included 30-day technical success and 90-day improvement in outflow obstruction. Results: The mean (SD) age of 200 patients was 46.9 (14.0) years, and 125 (62.5%) were men. Resting or provoked left ventricular outflow tract gradients were 50 mm Hg or higher. The median (IQR) follow-up for all patients was 19 (6-50) months. Thirty-day major adverse clinical events rate was 10.5% (n = 21): there were 2 in-hospital/30-day deaths (1.0%), 7 patients (3.5%) with pericardial effusion requiring mini-thoracotomy, 12 patients (6%) with pericardial effusion requiring pericardiocentesis, and no bleeding or strokes. Other periprocedural complications included permanent right bundle branch block in 5 patients (2.5%), resuscitated ventricular fibrillation in 2 (1.0%), and septal branch aneurysm in 2 (1.0%). There were no permanent pacemaker implantations. At follow-up, maximum septal thickness was reduced from a mean (SD) of 24.0 (5.1) mm to 17.3 (4.4) mm (P < .001), and left ventricular outflow tract gradient was decreased from a mean (SD) of 79.0 (53.0) mm Hg to 14.0 (24.0) mm Hg (P < .001). Overall, 190 patients (96%) with HOCM were in New York Heart Association functional class I or II at last follow-up. Conclusions and Relevance: This study found that PIMSRA in patients with drug-refractory HOCM may be an effective procedure for relief of left ventricular outflow tract obstruction and symptoms with acceptable complication rates. These results are encouraging and support the design of a randomized clinical trial against well-established septal reduction therapies.

Disruption of the transcription factor recombination signal-binding protein-Jkappa (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice.

UNLABELLED: Liver sinusoid (LS) endothelial cells (LSECs) support hepatocytes in resting livers and proliferate during liver regeneration to revascularize regenerated liver parenchyma. We report that recombination signal-binding protein-Jkappa (RBP-J), the critical transcription factor mediating Notch signaling, regulates both resting and regenerating LSECs. Conditional deletion of RBP-J resulted in LSEC proliferation and a veno-occlusive disease-like phenotype in the liver, as manifested by liver congestion, deposition of fibrin-like materials in LSs, edema in the space of Disse, and increased apoptosis of hepatocytes. Regeneration of liver was remarkably impaired, with reduced LSEC proliferation and destroyed sinusoidal structure. LSEC degeneration was obvious in the regenerating liver of RBP-J-deficient mice, with some LSECs losing cytoplasm, and organelles protruding into the remnant plasma-membrane of LSs to hamper the microcirculation and intensify veno-occlusive disease during liver regeneration. Hepatocytes were also degenerative, as shown by dilated endoplasmic reticulum, decreased proliferation, and increased apoptosis during liver regeneration. Molecular analyses revealed that the dynamic expression of several related molecules-such as vascular endothelial growth factor, vascular endothelial growth factor receptors 1 and 2, interleukin-6, and hepatocyte growth factor-was disturbed. CONCLUSION: Notch/RBP-J signaling may play dual roles in LSECs: in resting liver it represses proliferation, and in regenerating liver it supports proliferation and functional differentiation.

Notch signaling inhibits the growth of the human chronic myeloid leukemia cell line K562.

Notch signaling functions in the development of some types of leukemia and lymphoma, but the relationship between Notch signaling and chronic myeloid leukemia (CML) remains to be elucidated. In this study, we examined the expression of Notch receptors and ligands in the human CML cell line K562. When the active form of Notch1, the Notch intra-cellular domain (NIC), was over-expressed in K562, the proliferation of K562 was mildly but significantly inhibited, accompanied by increased Hes1 mRNA level. On the other hand, when Notch signaling was attenuated by over-expression of a dominant-negative RBP-J, RBP-J(R218H), in K562 cells, the proliferation of K562 was increased. Moreover, we found that activation of Notch signaling inhibited while repression of Notch signaling promoted the colony-forming activity of K562 cells. We examined cell cycle-related molecules in K562 transfected with NIC or RBP-J(R218H), and found that the protein level of the retinoblastoma gene product (the Rb protein) was induced in K562 expressing NIC, and down-regulated in K562 expressing RBP-J(R218H). These data suggest that the Notch signaling may function as a tumor inhibitor in human CML cells.

RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice.

In adults, angiogenic abnormalities are involved in not only tumor growth but several human inherited diseases as well. It is unclear, however, concerning how the normal vascular structure is maintained and how angiogenesis is initiated in normal adults. Using the Cre-LoxP-mediated conditional gene deletion, we show in the present study that in adult mice disruption of the transcription factor recombination signal-binding protein Jkappa (RBP-J) in endothelial cells strikingly induced spontaneous angiogenesis in multiple tissues, including retina and cornea, as well as in internal organs, such as liver and lung. In a choroidal neovascularization model, which mimics the angiogenic process in tumor growth and age-related macular degeneration, RBP-J deficiency induced a more intensive angiogenic response to injury. This could be transmitted by bone marrow, indicating that RBP-J could modulate bone marrow-derived endothelial progenitor cells in adult angiogenesis. In addition, in the absence of RBP-J, proliferation of endothelial cells increased significantly, leading to accumulative vessel outgrowth. These findings suggest that in adults RBP-J-mediated Notch signaling may play an essential role in the maintenance of vascular homeostasis by repressing endothelial cell proliferation.

Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms.

Evidence has shown that Notch signaling modulates CD4(+)CD25(+) regulatory T-cells (Tregs). As transcription factor Foxp3 acts as a master molecule governing the development and function of Tregs, we investigated whether Notch signaling might directly regulate Foxp3 expression. Here, we provide evidence that Notch signaling can modulate the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. A conserved RBP-J-binding site and N-box sites were identified within the FOXP3 promoter. We show that the Notch intracellular domain (NIC), the active form of Notch receptors, activates a reporter driven by the FOXP3 promoter. Dissection of the FOXP3 promoter revealed bipartite effects of the RBP-J-binding site and the N-boxes: the RBP-J-binding site positively, while the N-boxes negatively regulated the FOXP3 promoter activity. Moreover, in freshly isolated Tregs, NIC-RBP-J complex is bound to the FOXP3 promoter in Tregs. Our results suggest that Notch signaling might be involved in the development and function of Tregs through regulating Foxp3 expression.

Critical periodic systemic blood pressure fluctuations during pulmonary valve replacement cardiac surgery in a patient with an incidentally discovered normotensive pheochromocytoma-A case report.

Standard management protocols for patients with pheochromocytoma (PHEO) have been described in current guidelines. However, the standard management approach for cardiac surgical patients with concurrent clinically silent PHEO has not been established yet. The effects of open heart surgery and cardiopulmonary bypass (CPB) on PHEO presentation are poorly documented. Here, we report in detail the anesthetic management and hemodynamic changes in a case of CPB-assisted pulmonary valve replacement surgery with an incidentally discovered normotensive PHEO. A 55-year-old male with normotensive PHEO underwent an open heart pulmonary valve replacement surgery. Blood pressure (BP) fluctuated with an inherent alternation rhythm during the whole process of the surgery with a peak at 230/130 mmHg and nadir at 40/30 mm Hg. Administration of fluids and vasoconstrictor/vasodilator was used for BP optimization. However, the BP changed intractably with delayed responses to the optimization management. The hemodynamic instability observed in this case indicated that the risk of occurrence and severity of the PHEO crisis did not decrease in cases with previously silent PHEO and may be triggered in any clinical scenario, not in tumor removal procedures alone. Careful preoperative evaluation and preparation with multidisciplinary cooperation are of paramount importance for such patients because open chest cardiac surgery and CPB could complicate the situation. In addition, there is little evidence about the benefits of a combined cardiac surgery with PHEO resection in such a clinical scenario, which validates further investigation.

Identification of CD36 as a new surface marker of marginal zone B cells by transcriptomic analysis.

Follicular (FO) B cells and marginal zone (MZ) B cells belong to the mature B cell population in spleen of mice. To identify new surface markers of these mature B cell subsets, we compared gene expression profiles of FO and MZ B cells by DNA microarray using FACS-sorted mouse FO and MZ B cells. From 14,000 mouse genes, 27 membrane proteins were expressed mainly in MZ B cells while another 22 membrane proteins expressed largely in FO B cells. Using FACS analysis, we identified that CD36, CD68, and CD49e were expressed on MZ B cells but not on FO B cells. In addition, using semi-quantitative PCR, we found that the mRNA of CD131 were much more abundant in MZ B cells. These results revealed new phenotypic properties of MZ and FO B cells, and would facilitate further studies in the differentiation and functions of these mature B cells.

Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.

Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly-ubiquitination and degradation of the FLT3 protein, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5, AKT and ERK. Furthermore, ATO combined with sorafenib, a FLT3 TKI, in vivo reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia.