Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial.

PURPOSE: This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab. EXPERIMENTAL DESIGN: Data from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: The baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively). CONCLUSIONS: A low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.

Association between emergence delirium and brain status parameters in children undergoing general anesthesia: A prospective observational study.

INTRODUCTION: Emergence delirium is a common postoperative neurological complication in children after general anesthesia. There is no valid tool to predict emergence delirium. Wavelet index, pain threshold index, anxiety index, and comfort index are real-time brain status parameters extracted from the electroencephalogram, which have recently been developed. The aim is to evaluate the association between real-time brain status parameters during emergence and emergence delirium in children undergoing general anesthesia. METHODS: One hundred and thirty patients between 3 and 6 years of age undergoing dental surgery under general anesthesia were enrolled in the study. Real-time electroencephalogram data were recorded at four different time points from end of anesthetics administration (T1), end of surgery (T2), extubation (T3), and response (eye opening, movement) to verbal stimulation (T4). Each patient was assessed for emergence delirium using the Pediatric Anesthesia Emergence Delirium scale. Receiver operating characteristics curves and the associated areas under the curves were computed to analyze the ability of wavelet index, pain threshold index, anxiety index, and comfort index to predict emergence delirium. RESULTS: One hundred and sixteen patients were included for final analysis. During recovery from general anesthesia, brain status parameters increased significantly from T1 (wavelet index, 59.5 ± 6.2; pain threshold index, 61.7 ± 5.3; anxiety index, 9.2 ± 2.5; comfort index, 21.6 ± 8.7) to T4 (wavelet index, 67.4 ± 9.4; pain threshold index, 73.2 ± 9.1; anxiety index, 38.6 ± 11.2; comfort index, 66.1 ± 16.5; p < .001). To predict emergence delirium, areas under the curves [95% CI] for anxiety index were 0.84 [0.75-0.93] (p < .001), and comfort index was 0.89 [0.81-0.96] (p < .001). The Pediatric Anesthesia Emergence Delirium scale scores of 37 patients were higher than 10 indicating emergence delirium, and the incidence of emergence delirium was 31.90%. The sensitivity and specificity of anxiety index with corresponding cutoff values in predicting emergence delirium were 73.0% and 89.9%, and the sensitivity and specificity of comfort index in predicting emergence delirium were 91.9% and 83.5%. The best cutoff values for anxiety index and comfort index to predict emergence delirium were 46.5 and 68.5, respectively. The areas under the curves [95% CI] of wavelet index to predict emergence delirium were 0.43 [0.31-0.35] (p = .27), while the areas under the curves [95% CI] of pain threshold index to predict emergence delirium were 0.49 [0.37-0.62] (p = .73). DISCUSSION: Both anxiety index and comfort index derived from electroencephalogram wavelet analysis were associated with emergence delirium in pediatric patients undergoing general anesthesia for dental surgery. Wavelet index and pain threshold index were not associated with emergence delirium during general anesthesia for dental surgery in children. CONCLUSIONS: AnXi and CFi might be used to guide anesthesiologists to identify and intervene ED in children.

Prevalence and characteristics of polycystic ovarian syndrome in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is frequently accompanied by endocrine disturbances. We compared the prevalence of polycystic ovary syndrome (PCOS) and related reproductive disorders between drug-naïve BD patients and matched healthy controls (HCs) and between drug-naïve BD patients and BD patients with long-term medication, as well as the clinical metabolic correlates among BD patients. METHODS: 72 drug-naïve BD patients, 98 HCs, and 72 BD patients with long-term medication were recruited in the study. Menstruation was recorded, reproductive hormone levels and metabolic indicators were measured, and a pelvic ultrasound examination was performed via transvaginal sensor for each participant. PCOS was defined using the Rotterdam criteria. RESULTS: After controlling for demographic variables, drug-naïve BD patients presented higher rates of PCOS than the HCs (OR: 3.02, 95 % CI: 1.09-8.36). Regression analysis showed that long-term treatment with valproate (OR: 3.89, 95 % CI: 1.13-13.37), age (OR: 0.37, 95 % CI: 0.14-0.95), and insulin resistance index (OR: 1.73, 95 % CI: 1.10-12.71) were correlated with PCOS in BD patients. CONCLUSIONS: Drug-naïve BD patients are susceptible to developing PCOS, and valproate is correlated with increased occurrence and development of PCOS. Therefore, PCOS in BD patients, especially those who use valproate, needs to be investigated and monitored closely by medical personnel.

Identification of mite-specific eosinophils in the colon of patients with ulcerative colitis.

The pathogenesis of ulcerative colitis (UC) is unclear. House dust mite (HDM) is associated with immune inflammation in the body. This study is designed to identify the association between HDM and UC clinical symptoms. UC patients (n = 86) and non-UC control (NC) subjects (n = 64) were recruited. Colon lavage fluids (CLF) were collected from HDM skin prick test positive patients during colonoscopy, and analyzed by immunological approaches. HDM was detected in fecal samples, which was positively correlated with UC clinical symptoms. HDM-specific eosinophils and Th2 cells were detected in CLF, which could be specifically activated by exposing to HDM in the culture. Direct exposure to HDM induced eosinophil activation in the colon of UC patients. UC patients displayed elevated levels of Th2 cytokines in the serum. UC clinical symptom scores were positively correlated with serum levels of Th2 cytokines. HDM was detected in UC patients' stools, which was positively correlated with UC clinical symptoms. Direct exposure to HDM could trigger eosinophilic activation of the colon.

CD38+ B cells affect immunotherapy for allergic rhinitis.

BACKGROUND: Allergen-specific immunotherapy (AIT) is the mainstay in the treatment of allergic diseases, but the therapeutic effects of AIT need to be improved. CD38+ B cells are an immune cell fraction involved in the pathogenesis of allergic diseases as well as in immune regulation. OBJECTIVE: We sought to elucidate the role of antigen-specific CD38+ B cells in AIT. METHODS: An analysis was carried out on AIT results of 48 patients with perennial allergic rhinitis (AR), among which peripheral blood immune cells were analyzed by flow cytometry; serum cytokine levels were determined by ELISA. An AR murine model was developed to test the role of CD38+ B cells in AIT. RESULTS: A fraction of antigen-specific CD38+ B cell was detected in AR patients. CD38+ B-cell frequency was negatively correlated with the therapeutic effects of AIT. A negative correlation was detected between the CD38+ B-cell frequency and regulatory T-cell frequency in AR patients treated with AIT. Exposure to specific antigens induced CD38+ B cells to produce IL-6, that converted Treg cells to TH17 cells. Coadministration of anti-CD38 antibody significantly promoted the therapeutic effects of AIT. CONCLUSIONS: Antigen-specific CD38+ B cells compromise AIT effects by producing IL-6 to convert regulatory T cells to TH17 cells. Inhibition of CD38+ B cells promotes the effects of AIT.

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury.

Lipoxin A4 (LXA4), as an endogenously produced lipid mediator, promotes the resolution of inflammation. Previously, we demonstrated that LXA4 stimulated alveolar fluid clearance through alveolar epithelial sodium channel gamma (ENaC-γ). In this study, we sought to investigate the mechanisms of LXA4 in modulation of ENaC-γ in lipopolysaccharide (LPS)-induced inflammatory lung injury. miR-21 was upregulated during an LPS challenge and downregulated by LXA4 administration in vivo and in vitro. Serum miR-21 concentration was also elevated in acute respiratory distress syndrome patients as compared with healthy volunteers. LPS increased miR-21 expression by activation of activator protein 1 (AP-1). In A549 cells, miR-21 upregulated phosphorylation of AKT activation via inhibition of phosphatase and tensin homolog (PTEN), and therefore reduced the expression of ENaC-γ. In contrast, LXA4 reversed LPS-inhibited ENaC-γ expression through inhibition of AP-1 and activation of PTEN. In addition, an miR-21 inhibitor mimicked the effects of LXA4; overexpression of miR-21 abolished the protective effects of LXA4. Finally, both AKT and ERK inhibitors (LY294002 and UO126) blocked effects of LPS on the depression of ENaC-γ. However, LXA4 only inhibited LPS-induced phosphorylation of AKT. In summary, LXA4 activates ENaC-γ in part via the miR-21/PTEN/AKT signaling pathway.

Plasma proteasomal chymotrypsin-like activity correlates with prostate cancer progression.

Previously, we demonstrated that inhibition of proteasomal chymotrypsin-like (CT-like) activity in human prostate cancer (PCa) PC-3 cultures and PC-3 xenografts results in accumulation of ubiquitinated proteins, followed by induction of cell death. Studies have shown that plasma CT-like proteasomal activity may be a powerful biomarker for risk stratification in hematologic malignancies. We hypothesized that circulating proteasomes could also be used to stratify risk for patients with PCa. A total of 109 patients with suspected PCa underwent prostatic biopsies were enrolled. Subjects were divided into non-cancer, low-risk PCa, and high-risk PCa groups. Three different proteasomal activity markers (CT-like, caspase-like, and trypsin-like) were measured and compared among the three groups. The proteasomal target proteins, Ub-prs, Hsp70, Bax, and P27 in plasma and prostate tissues were also evaluated. Multivariate analysis was used to assess whether CT-like activity was a predictor of PCa progression. Only proteasomal CT-like activity in the high-risk group was statistically higher than in the non-cancer group (P < 0.05). The expression of Ub-prs, Hsp70, Bax, and P27 protein was decreased in both plasma and PCa tissue of high-risk patients. CT-like activity was found to be an independent predictor of high-risk PCa. Subjects with CT-like activity ≥55 had a 2.15-fold higher risk of having high-risk PCa as compared to those with a CT-like activity of <55 (P = 0.021). We found CT-like activity to be an independent predictor of high-risk PCa, and as such, it may be a good candidate as a biomarker for high-risk PCa detection and stratification.

PSA density improves the rate of prostate cancer detection in Chinese men with a PSA between 2.5-10.0 ng ml (-1) and 10.1-20.0 ng ml (-1) : a multicenter study.

Chinese men should have a higher prostate-specific antigen (PSA) "gray zone" than the traditional value of 2.5-10.0 ng ml-1 since the incidence of prostate cancer (PCa) in Chinese men is relative low. We hypothesized that PSA density (PSAD) could improve the rate of PCa detection in Chinese men with a PSA higher than the traditional PSA "gray zone." A total of 461 men with a PSA between 2.5 and 20.0 ng ml-1 , who had undergone prostatic biopsy at two Chinese centers were included in the analysis. The men were then further divided into groups with a PSA between 2.5-10.0 ng ml-1 and 10.1-20.0 ng ml-1 . Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of PSA and PSAD for the diagnosis of PCa. In men with a PSA of 2.5-10.0 ng ml-1 or 10.1-20.0 ng ml-1 , the areas under the ROC curve were higher for PSAD than for PSA. This was consistent across both centers and the cohort overall. When the entire cohort was considered, the optimal PSAD cut-off for predicting PCa in men with a PSA of 2.5-10.0 ng ml-1 was 0.15 ng ml-1 ml-1 , with a sensitivity of 64.4% and specificity of 64.6%. The optimal cut-off for PSAD in men with a PSA of 10.1-20.0 ng ml-1 was 0.33 ng ml-1 ml-1 , with a sensitivity of 60.3% and specificity of 82.7%. PSAD can improve the effectiveness for PCa detection in Chinese men with a PSA of 2.5-10.0 ng ml-1 (traditional Western PSA "gray zone") and 10.1-20.0 ng ml-1 (Chinese PSA "gray zone").

MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA.

Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC.