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Triple negative breast cancer (TNBC) has the highest mortality among all breast cancer types and lack of targeted therapy is a key factor contributing to its high mortality rate. In this study, we show that 8-bromo-cAMP, a cyclic adenosine monophosphate (cAMP) analog at high concentration (> 1 mM) selectively suppresses TNBC cell growth. However, commonly-used cAMP-elevating agents such as adenylyl cyclase activator forskolin and pan phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) are ineffective. Inability of cAMP elevating agents to inhibit TNBC cell growth is due to rapid diminution of cellular cAMP through efflux and decomposition. By performing bioinformatics analyses with publically available gene expression datasets from breast cancer patients/established breast cancer cell lines and further validating using specific inhibitors/siRNAs, we reveal that multidrug resistance-associated protein 1/4 (MRP1/4) mediate rapid cAMP efflux while members PDE4 subfamily facilitate cAMP decomposition. When cAMP clearance is prevented by specific inhibitors, forskolin blocks TNBC's in vitro cell growth by arresting cell cycle at G1/S phase. Importantly, cocktail of forskolin, MRP inhibitor probenecid and PDE4 inhibitor rolipram suppresses TNBC in vivo tumor development. This study suggests that a TNBC-targeted therapeutic strategy can be developed by sustaining an elevated level of cAMP through simultaneously blocking its efflux and decomposition.

Breast cancer is the most common cancer in women worldwide; thus, the prolongation of survival, and the incidence and risk factors, including radiotherapy, for developing secondary malignancies are important. We compared the incidence of secondary and new primary cancers in women with breast cancer (CA) and well-matched for age, geographic region, and monthly income cancer-free controls (CA). The risk for secondary cancers with and without radiotherapy was also compared in CA women. We enrolled 2422 CA patients and CA 12,110 controls. In a 4-year follow-up, the secondary cancers risk was significant in the CA group (adjusted hazard ratio [AHR]: 1.59; 95% confidence interval [CI]: 1.17-2.18). Only the risk of uterine cancer was significant compared with the controls (AHR: 6.30; 95% CI: 2.28-17.38). CA patients and <50 years old had a higher risk for secondary cancers. Developing secondary cancers was significant in the first follow-up year (AHR: 1.51; 95% CI: 1.11-2.06). Radiotherapy had no significant effect on the CA group, but it was significant (P = 0.0298) in women ≥60 years old (elderly). We recommend monitoring secondary cancers in CA women, especially those <50 years old, and during the first year of follow-up. Radiotherapy should be used more carefully in elderly CA women., Competing Interests: The authors have no conflicts of interest to disclose.

There is no study about cervical herniated intervertebral disc (cervical HIVD) in physicians in the literature; therefore, we conceived a retrospective nationwide, population-based cohort study to elucidate the topic. We identified 26,038 physicians, 33,057 non-physician healthcare providers (HCPs), and identical numbers of non-HCP references (i.e., general population). All cohorts matched a 1:1 ratio with age and gender, and each were chosen from the Taiwan National Health Insurance Research Database (NHIRD). We compared cervical HIVD risk among physicians, nonphysician HCPs, and non-HCP references and performed a follow-up between 2007 and 2011. We also made comparisons among physician specialists. Both physicians and nonphysician HCPs had higher cervical HIVD risk than non-HCP references (odds ratio [OR]: 1.356; 95% confidence interval (CI): 1.162-1.582; OR: 1.383; 95% CI: 1.191-1.605, respectively). There was no significant difference of cervical HIVD risk between physicians and nonphysician HCPs. In the comparison among physician specialists, orthopedists had a higher cervical HIVD risk than other specialists, but the difference was not statistically significant (adjusted OR: 1.547; 95% CI: 0.782-3.061). Physicians are at higher cervical HIVD risk than the general population. Because unknown confounders could exist, further prospective studies are needed to identify possible causation., Competing Interests: The authors have no conflicts of interest to disclose.

Ethnopharmacological Relevance: Huangqi Decoction (HQD), a classical traditional Chinese medicine (TCM) formula, is used to treating liver injury in China. The aim of the study is to investigate mechanisms of HQD against dimethylnitrosamine (DMN)-induced liver fibrosis underlying metabolic profiles of bile acids., Materials and Methods: DMN-induced liver fibrosis rats were administrated HQD and its compounds, astragalosides (AS), glycyrrhizic acid (GA) and their combination. The anti-fibrosis effects were evaluated and targeted metabolomics by UPLC-MS was used to examine whether HQD had an influence on bile acid metabolism. The levels of mRNAs associated with bile acid metabolism were expressed by RT-PCR. Chenodeoxycholic acid (CDCA)-induced hepatic stellate cells (HSCs) proliferation and activation were examined using MTS assay and Western blot., Results: Histopathological changes and serum liver function in HQD group had significant improvements (P<0.01). Concentrations of free bile acids and taurine conjugates were significantly increased in DMN group (P<0.05). HQD and its compounds restored the increased bile acids to normal levels, and HQD was more effected on parts of bile acids. Furthermore, the levels of mRNAs related bile acid synthesis and reabsorption such as CYP7A1, CYP8B1, CYP27A1, OATP2, OATP3, OATP4 and NTCP were significantly down-regulated in DMN group (P<0.05), mRNAs related excretion such as MRP3 and BESP were up-regulated (P<0.01), and CYP7A1, CYP8B1, OATP3, OATP4, NTCP and MRP3 restored to normal levels by HQD treatment. Moreover, CDCA-induced HSCs proliferation and activation were weaken by HQD (P<0.05) with down-regulated α-SMA, TGF-β1, p-Smad2 and p-Smad3 expressions., Conclusions: HQD alleviated DMN-induced liver fibrosis with a better effect than its compounds, which may be involved in the regulation of bile acid metabolism enzyme. Moreover, HQD may inhibit CDCA-induced HSCs proliferation and activation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Healthcare providers have many health-related risk factors that might contribute to urolithiasis: a heavy workload, a stressful workplace, and an unhealthy quality of life. However, the urolithiasis risk in healthcare providers is not clear., Methods: Using Taiwan's National Health Insurance Research Database, we identified 50,226 physicians, 20,677 pharmacists, 122,357 nurses, and 25,059 other healthcare providers as the study cohort and then randomly selected an identical number of patients who are not healthcare providers (general population) as the comparison cohort for this study. Conditional logistical regression analysis was used to compare the urolithiasis risk between healthcare providers and comparisons. Physician specialty subgroups were also analyzed., Results: Physicians had a lower urolithiasis risk than did the general population (adjusted odds ratio [AOR]: 0.682; 95 % confidence interval [CI]: 0.634-0.732) and other healthcare providers (AOR: 0.661; 95 % CI 0.588-0.742) after adjusting for hypertension, diabetes, hyperlipidemia, coronary artery disease, and residence location. For pharmacists, nurses, and other healthcare providers, the urolithiasis risk was not significantly different than that for general population. Subgroup analysis showed that surgeons and family medicine physicians had a lower urolithiasis risk than did physician comparisons (AOR: 0.778; 95 % CI: 0.630-0.962 and AOR: 0.737; 95 % CI: 0.564-0.962, respectively)., Conclusions: Although job stress and heavy workloads affect physicians' health, physicians had a lower urolithiasis risk than did the general population and other healthcare providers. This might be attributable to their greater medical knowledge and access to healthcare. Our findings provide useful information for public health policy makers about the disease risks of healthcare providers.

This study is a retrospective, nationwide, matched cohort study to investigate the risk of band keratopathy following end-stage renal disease (ESRD). The study cohort included 94,039 ESRD on-dialysis patients identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), code 585 and registered between January 2000 to December 2009 at the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 94,039 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. In total, 230 ESRD patients and 26 controls had band keratopathy (P < 0.0001) during the follow-up period, indicating a significantly elevated risk of band keratopathy in the ESRD patients compared with controls (incidence rate ratio = 12.21, 95% confidence interval [CI] = 8.14-18.32). After adjustment for potential confounders including sarcoidosis, hyperparathyroidism, iridocyclitis, and phthisis bulbi, ESRD patients were 11.56 times more likely to develop band keratopathy in the full cohort (adjusted HR = 11.56, 95% CI = 7.70-17.35). In conclusion, ESRD increases the risk of band keratopathy. Close interdisciplinary collaboration between nephrologists and ophthalmologists is important to deal with band keratopathy following ESRD and prevent visual acuity impairments.

Background: Immune responses play a key role in the pathogenesis and progression of polypoidal choroidal vasculopath (PCV) and age-related macular degeneration (AMD). In this study, we determined the Th cell-associated immune responses by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) in both PCV and neovascular AMD (nAMD) patients., Methods: Twenty-seven nAMD patients, 33 PCV patients and a gender- and age-matched group of 18 healthy individuals were involved in this study. The Th-cell cytokine profiles including levels of interferon-gamma (INF-γ), interleukin (IL)-17A and IL-4 in cultures of PBMCs were determined by enzyme-linked immunosorbent assay (ELISA)., Results: IFN-γ,IL-17A and IL-4 production was significantly increased after stimulation with PHA. The levels of IFN-γ and IL-4 in PHA-stimulated cultures were higher in PCV and nAMD patients than that in healthy controls (P = 0.038,P = 0.014), while no difference was found between PCV and nAMD (all P > 0.05). No significant difference in IL-17A level in PHA-stimulated cultures was found among PCV, nAMD and control groups (P > 0.05)., Conclusions: These findings suggest that circulating IFN-γ and IL-4 producing Th1 and Th2 cells may involve in the pathogenesis of PCV and nAMD. PCV may have the similar immune responses with nAMD.

Purpose: Interleukin-37 is suggested as a novel proangiogenic factor in our previous study. In this study, the role of IL-37 was investigated in proliferative diabetic retinopathy (PDR)., Methods: Vitreous fluids from 10 patients with PDR and 8 controls were collected. The levels of IL-37 were determined by ELISA and the relationship between IL-37 and VEGF-A/Ang-2 was analyzed. The effects of IL-37 on chorioretinal endothelial cell (RF/6A) proliferation, migration, and tube formation were determined by BrdU incorporation assay, Boyden chamber assay, scratch-wound assay and tube formation assay., Results: The concentration of IL-37 in the PDR group was 95.09 ± 5.22 pg/mL and 34.91 ± 5.61 pg/mL in control group (P = 0.001). The level of IL-37 was highly related to the level of Ang-2 (P = 0.009, r = 0.772) and VEGF-A (P = 0.003, r = 0.827) in the PDR group, and VEGF expression in RF/6A cell was upregulated by IL-37 at low concentration. Interleukin-37 remarkably promoted RF/6A cell proliferation and migration. Interleukin-37 (1 ng/mL) remarkably stimulated tube formation with an increase of 85.3% for total tubule length and 74.1% for branching points compared with PBS control., Conclusions: The level of IL-37 is elevated in vitreous fluids of patients with PDR and correlates with the level of VEGF-A and Ang-2. Interleukin-37 stimulates proangiogenic response of retinal endothelial cells in vitro, suggesting the involvement of IL-37 in the pathogenesis of PDR.

There is globally increasing prevalence and incidence in end-stage renal disease (ESRD). These patients are frequently reported to have retinal abnormalities and both diseases share some systemic risk factors. Hence, it is clinically relevant to determine whether ESRD is a predictor of retinal artery occlusion (RAO).To investigate the risk of RAO in ESRD patients.A retrospective, nationwide, matched cohort study. The study included 93,766 ESRD patients recruited between 2000 and 2009 from the Taiwan National Health Insurance Research Database. The same number control group included age- and sex-matched patients without ESRD selected from the Taiwan Longitudinal Health Insurance Database, 2000. Data for each patient were collected from the index date until December 2011.The incidence and risk of RAO were compared between the 2 groups. The hazard ratio (HR) for RAO after adjustment for potential confounders was calculated using Cox proportional hazards regression. Kaplan-Meier analysis was used to calculate the cumulative RAO incidence rate.In total, 237 ESRD patients and 73 controls exhibited RAO during follow-up; thus, the RAO incidence rate in ESRD patients was 4.49 times (95% confidence interval (CI), 3.45-5.83) that in the control patients. After adjustment for potential confounders, including diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, and coronary artery disease, ESRD patients were 2.78 times (95% CI, 2.02-3.84) more likely to develop RAO in cohort for the total sample. Among patients with hypertension, the RAO incidence rate was significantly higher in the ESRD group, and hypertension significantly increased RAO risk even after adjustment for other confounders in the cohort.ESRD increases the risk of RAO, particularly in ESRD patients with hypertension. Therefore, clinicians should educate ESRD patients about RAO and ensure appropriate blood pressure control., Competing Interests: The authors have no funding and conflicts of interest to disclose.

To investigate the risk of nonarteritic anterior ischemic optic neuropathy (NAION) following end-stage renal disease (ESRD).A retrospective, nationwide, matched cohort study.ESRD patients identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 585.The study cohort included 93,804 ESRD patients registered with the Taiwan National Health Insurance Research Database between January 2000 and December 2009. An age- and sex-matched control group comprised 93,804 patients (case:control = 1:1) selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. The incidence and risk of NAION were compared between the ESRD and control groups. The adjusted hazard ratio (HR) for NAION after adjustment for potential confounders was obtained by a Cox proportional hazard regression analysis. A Kaplan-Meier analysis was used to calculate the cumulative incidence rate of NAION.The incidence of NAION following ESRD.In total, 133 ESRD patients (0.14%) and 51 controls (0.05%) had NAION (P < 0.001) during the follow-up period, leading to a significantly elevated risk of NAION in the ESRD patients compared with the controls (incidence rate ratio = 3.14, 95% confidence interval [CI] = 2.11-4.67). After adjustment for potential confounders including diabetes mellitus, hypertension, hypotension, hyperlipidemia, and 2-way interaction terms between any 2 factors, ESRD patients were 3.12 times more likely to develop NAION than non-ESRD patients in the full cohort (adjusted HR = 3.12, 95% CI = 2.10-4.64). Additionally, patients with hypertension and hyperlipidemia showed higher incidence rates of NAION in the ESRD group compared with the controls: 2.31 (95% CI = 1.40-3.82) for hypertension and 2.72 (95% CI = 1.14-6.50) for hyperlipidemia.ESRD increased the risk of NAION, which is an interdisciplinary emergency. Close collaboration between nephrologists and ophthalmologists is important in NAION management following ESRD to prevent fellow eye involvement., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: Limited data support the notion that lipid ratios are risk factors for nonalcoholic fatty liver disease (NAFLD). We evaluated the association between lipid ratios and NAFLD., Methods: This was a large population, cross-sectional, retrospective study. Data on NAFLD severity, blood pressure, fasting glucose, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels were obtained from 44,767 examinees at single health checkup center. The enrollees were stratified into four subgroups based on their TC/HDL-C and TG/HDL-C ratios. We used multivariate analyses to evaluate the odds between lipid ratios and NAFLD., Results: The prevalence rate of fatty liver in this study was 53.76%. In the baseline subgroup with the lowest TC/HDL-C and TG/HDL-C ratios, the prevalence of NAFLD, hypertension, and diabetes was lower than that of the other three subgroups. Patients with higher lipid ratios had a significantly greater risk for advanced NAFLD., Conclusions: Adults with high TC/HDL-C or TG/HDL-C ratios, or both, have a greater risk for NAFLD, especially advanced NAFLD., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Allergic conjunctivitis (AC) is an immunoglobulin E (IgE)-mediated and helper T cell 2 (Th2)--cell-mediated disease characterized by conjunctival eosinophilic infiltration. Previous study shows that IL-28A had anti-allergic activity in airway disease. In this study, we examined the effect of IL-28A on a mouse model of ovalbumin (OVA)-induced experimental allergic conjunctivitis (EAC)., Methods: Mouse EAC was induced by topical application of OVA after intraperitoneal (IP) sensitization with OVA in aluminum hydroxide (ALUM). Interleukin-28A was administered 1 hour before OVA challenge. Allergic conjunctivitis symptoms, eosinophil infiltration in the conjunctiva, antigen-specific IgE in the serum, and Th2 cytokine production by lymph node cells and splenocytes were subsequently analyzed., Results: Topical application of IL-28A to OVA-induced EAC reduced clinical symptoms, serum OVA-specific IgE, and the infiltration of eosinophils in the conjunctiva. In addition, topical administration of IL-28A suppressed the expression of IL-4, IL-5, and IL-13 (Th2-type cytokine) but promoted the expression of IFN-γ (Th1-type cytokine) by splenocytes and cervical lymph node cells in EAC mice. Immunofluorescence staining showed decrease expression of IL-4 and IL-5 in IL-28A-treated EAC conjunctiva., Conclusions: Interleukin-28A shows therapeutic potential for allergic conjunctival inflammation.

Backgrounds and Aim. Taiwan's population is gradually aging; however, there are no comparative data on emergency medical services (EMS) use between the elderly and nonelderly. Methods. We analyzed the emergency calls dealt with between January 1 and April 4, 2014, by EMS in one city in Taiwan. All calls were divided into two groups: elderly (≥65 years) and nonelderly (<65 years). Nontransport and transport calls were compared between the groups for demographic characteristics, transport time, reasons for calling EMS, vital signs, and emergency management. Results. There were 1,001 EMS calls: 226 nontransport and 775 transport calls. The elderly accounted for significantly (P < 0.05) fewer (28 (9.2%)) nontransport calls than did the nonelderly (136 (21.4%)). In the transport calls, 276 (35.6%) were the elderly. The elderly had a higher proportion of histories for cardiovascular disease, cerebrovascular disease, hypertension, diabetes, end-stage renal disease, cancer, Parkinson's disease, and Alzheimer's disease. In addition, the elderly had significantly longer total transport time, more nontrauma reasons, and poorer consciousness levels and lower oxygen saturation and needed more respiratory management and more frequent resuscitation during transport than did the nonelderly. Conclusion. The elderly have more specific needs than do the nonelderly. Adapting EMS training, operations, and government policies to aging societies is mandatory and should begin now.

Traditional Chinese medicine (TCM) syndrome, also known as TCM ZHENG or TCM pattern, is an integral and essential part of TCM theory that helps to guide the design of individualized treatments. A TCM syndrome, in essence, is a characteristic profile of all clinical manifestations in one patient that can be readily identified by a TCM practitioner. In this article, the authors reviewed the presentations of TCM syndromes in seven common malignancies (liver, lung, gastric, breast, colorectal, pancreatic and esophageal cancers), the objectivity and the standardization of TCM syndrome differentiation, the evaluation of TCM syndrome modeling in cancer research, and syndrome differentiation-guided TCM treatment of cancers. A better understanding of TCM syndrome theory, as well as its potential biological basis, may contribute greatly to the clinical TCM diagnosis and the treatment of cancer.

The complex pathology of cancer development requires correspondingly complex treatments. The traditional application of individual single-target drugs fails to sufficiently treat cancer with durable therapeutic effects and tolerable adverse events. Therefore, synergistic combinations of drugs represent a promising way to enhance efficacy, overcome toxicity and optimize safety. Chinese Herbal Medicines (CHMs) have long been used as such synergistic combinations. Therefore, we summarized the synergistic combinations of CHMs used in the treatment of cancer and their roles in chemotherapy in terms of enhancing efficacy, reducing side effects, immune modulation, as well as abrogating drug resistance. Our conclusions support the development of further science-based holistic modalities for cancer care.

Hyperglycemic crisis episodes (HCEs)-diabetic ketoacidosis and the hyperosmolar hyperglycemic state-are the most serious acute metabolic complications of diabetes. We aimed to investigate the subsequent mortality after HCE in the non-elderly diabetic which is still unclear. This retrospective national population-based cohort study reviewed, in Taiwan's National Health Insurance Research Database, data from 23,079 non-elder patients (≤65 years) with new-onset diabetes between 2000 and 2002: 7693 patients with HCE and 15,386 patients without HCE (1:2). Both groups were compared, and follow-up prognoses were done until 2011. One thousand eighty-five (14.1%) patients with HCE and 725 (4.71%) patients without HCE died (P < 0.0001) during follow-up. Incidence rate ratios (IRR) of mortality were 3.24 times higher in patients with HCE than in patients without HCE (P < 0.0001). Individual analysis of diabetic ketoacidosis and hyperosmolar hyperglycemic state also showed the similar result with combination of both. After stratification by age, mortality was significant higher in the middle age (40-64 years) [IRR 3.29; 95% confidence interval (CI) 2.98-3.64] and young adult (18-39 years) (IRR 3.91; 95% CI 3.28-4.66), but not in the pediatric subgroup (<18 years) (IRR 1.28; 95% CI 0.21-7.64). The mortality risk was highest in the first month (IRR 54.43; 95% CI 27.98-105.89), and still high after 8 years (IRR 2.05; 95% CI 1.55-2.71). After adjusting for age, gender, and selected comorbidities, the mortality hazard ratio for patients with HCE was still four times higher than for patients without HCE. Moreover, older age, male gender, stroke, cancer, chronic obstructive pulmonary disease, congestive heart failure, and liver disease were independent mortality predictors. HCE significantly increases the subsequent mortality risk in the non-elderly with diabetes. Strategies for prevention and control of comorbidities are needed as soon as possible.

Background: Huangqi decoction (HQD) is used for liver fibrosis and cirrhosis treatment in Chinese medicine. This study aims to investigate the pharmacological actions of HQD against liver fibrosis in rats by high-throughput gene expression profiling, network analysis and real-time qRT-PCR., Methods: We analyzed the profiles of differentially expressed genes (DEGs) in dimethylnitrosamine (DMN)-induced liver fibrosis in rat. The liver tissue samples of control group (n = 3), model group (n = 3) and HQD group (n = 3) were examined by microarrays. Pathways were analyzed by KEGG. Pathway-gene and protein-protein interaction (PPI) networks were constructed with Cytoscape software. The expression of candidate genes was verified by qRT-PCR. P values less than 0.05 indicated statistical significance., Results: Collagen deposition and hydroxyproline (Hyp) content were decreased in the HQD group compared with the model group (P < 0.001), while that of Hyp in the model group were increased compared with the control group (P < 0.001). In comparison with the model group, 1085 DEGs (all P < 0.05, |fold change| >1.5) and 52 pathways in the HQD group were identified. TGF-beta, ECM-receptor interaction, and the cell adhesion molecules pathways were significantly recovered by HQD (P < 0.001). A pathway-gene network was constructed, including 303 DEGs and 52 pathways, and 514 nodes and 2602 edges, among 142 genes with node degrees greater than 10. The expressions of PDGFra, PDGFrb, PDGFb, PDGFd, COL1A1, COL1A2, COL5A2, and THBS1 were significantly down-regulated by HQD (P < 0.001)., Conclusion: HQD down-regulated the expressions of PDGFra, PDGFrb, PDGFb, PDGFd, COL1A1, COL1A2, COL5A2 and THBS1, and TGF-β and PDGF signaling pathways in the DMN-induced liver fibrosis in rats.

Purpose: Chronic hepatitis B (CHB) is a kind of chronic liver disease caused by persistent hepatitis B virus (HBV) infection. The study aims to seek the factors of host resistance to HBV and investigate their roles., Experimental Design: Protein profiles of 58 healthy controls and 121 CHB patients were obtained by SELDI-TOF/MS. Predicted protein was validated by ELISA. Protein expression was evaluated by Western blot in the persistently HBV expressing cell line HepG2.2.15 and non-HBV expressing cell line HepG2. The level of HBV DNA was subsequently detected by quantitative real-time PCR in HepG2.2.15 cells with complement C4a treatment., Results: Significantly altered protein peaks were found through statistical analysis, and m/z 4300 was predicted by databases and successfully matched with the fragment of complement C4a. According to ELISA, serum complement C4a was found to be significantly lower in CHB patients compared with healthy controls (p < 0.001) and the area under receiver operating characteristics curve is 0.78. Furthermore, complement C4a showed lower expression in HepG2.2.5 cells and the secretion of HBV DNA was inhibited by complement C4a., Conclusions and Clinical Relevance: The present study implied the important role of complement C4a in inhibiting the HBV DNA secretion in CHB., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis., Approach and Results: We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy., Conclusions: Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings., (© 2015 American Heart Association, Inc.)

Prior studies of upper gastrointestinal bleeding (UGIB) and acute myocardial infarction (AMI) are small, and long-term effects of UGIB on AMI have not been delineated. We investigated whether UGIB in patients diagnosed with coronary artery disease (CAD) increased their risk of subsequent AMI. This was a population-based, nested case-control study using Taiwan's National Health Insurance Research Database. After propensity-score matching for age, gender, comorbidities, CAD date, and follow-up duration, we identified 1,677 new-onset CAD patients with AMI (AMI[+]) between 2001 and 2006 as the case group and 10,062 new-onset CAD patients without (AMI[-]) as the control group. Conditional logistic regression was used to examine the association between UGIB and AMI. Compared with UGIB[-] patients, UGIB[+] patients had twice the risk for subsequent AMI (adjusted odds ratio [AOR] = 2.08; 95% confidence interval [CI], 1.72-2.50). In the subgroup analysis for gender and age, UGIB[+] women (AOR = 2.70; 95% CI, 2.03-3.57) and patients < 65 years old (AOR = 2.23; 95% CI, 1.56-3.18) had higher odds of an AMI. UGIB[+] AMI[+] patients used nonsignificantly less aspirin than did UGIB[-] AMI[+] patients (27.69% vs. 35.61%, respectively). UGIB increased the risk of subsequent AMI in CAD patients, especially in women and patients < 65. This suggests that physicians need to use earlier and more aggressive intervention to detect UGIB and prevent AMI in CAD patients.

Cancer has been the leading cause of death in Taiwan since 1982. Physicians have many health-related risk factors which may contribute to cancer, such as rotating night shift, radiation, poor lifestyle, and higher exposure risk to infection and potential carcinogenic drugs. However, the cancer risk in physicians is not clear. In Taiwan's National Health Insurance Research Database, we identified 14,889 physicians as the study cohort and randomly selected 29,778 nonmedical staff patients as the comparison cohort for this national population-based cohort study. Cox proportional-hazard regression was used to compare the cancer risk between physicians and comparisons. Physician subgroups were also analyzed. Physicians had a lower all-cancer risk than did the comparisons (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.76-0.97). In the sex-based analysis, male physicians had a lower all-cancer risk than did male comparisons (HR 0.82, 95% CI 0.73-0.94); and female physicians did not (HR 1.29, 95% CI 0.88-1.91). In the cancer-type analysis, male physicians had a higher risk of prostate cancer (HR 1.72, 95% CI 1.12-2.65) and female physicians had twice the risk of breast cancer (HR 2.00, 95% CI 1.11-3.62) than did comparisons. Cancer risk was not significantly associated with physician specialties. Physicians in Taiwan had a lower all-cancer risk but higher risks for prostate and breast cancer than did the general population. These new epidemiological findings require additional study to clarify possible mechanisms., Competing Interests: No potential conflicts of interest relevant to this study were reported.

Background: Hemodialysis (HD) treatment for end-stage renal disease (ESRD) (HD(+ESRD)) may increase the risk of intracranial hemorrhage (ICH) after a head injury (HI) for which heparin is used. However, the results of noncontrast head computed tomography (CT) in such patients are not always clear. We aimed to evaluate the effect of HD on the risk of ICH in ESRD patients and in controls without ESRD with HD (HD(-ESRD)), and to determine whether to lower the threshold of head CT in HD(+ESRD) patients after HI., Methods: In this nationwide population-based study using Taiwan's National Health Insurance Research Database, we enrolled 6938 HD(+ESRD) HI patients for the case group and 13,876 randomly selected HD(-ESRD) HI patients for the control group. Measures of the post-HI association between HD(+ESRD) and ICH determined using conditional logistic regression., Results: Five hundred sixty-eight (2.74 %) patients had post-HI ICH: 185 in the HD(+ESRD) group (2.67 % of cases) and 383 were from the HD(-ESRD) group (2.76 % of controls). Conditional logistic regression analysis revealed that after adjusting for age, gender, diabetes, hypertension, congestive heart failure, stroke, cancer, and liver disease, HD(+ESRD) patients had no higher odds of ICH (adjusted odds ratio [AOR]: 0.91; 95 % confidence interval [CI]: 0.75-1.11) than did HD(-ESRD) patients. In the subgroup analysis of immediate ICH, HD(+ESRD) patients had lower odds than did HD(-ESRD) patients (AOR: 0.73; 95 % CI: 0.56-0.94)., Conclusions: HD(+ESRD) did not increase the post-HI risk of ICH. Therefore, it may not be necessary to lower the threshold of head CT in HD(+ESRD) patients.

Background: Hyperglycemia-induced inflammation causes the dysfunction of blood vessels, and Toll-like receptor 4 (TLR4) plays a key role in inflammation-induced angiogenesis. However, the impact of TLR4 on the pathogenesis of diabetic retinopathy (DR) is poorly understood. In this study, we examined the expression of TLR4 in retinal vascular endothelial cells of patients with DR and diabetic mice, and explored the role of TLR4 in mediating inflammatory responses by human microvascular endothelial cells (HMEC-1) under high-glucose condition., Methods: The expression of TLR4 in retinal vascular endothelial cells of patients with proliferative diabetic retinopathy and diabetic mice induced by streptozotocin was examined using immunofluorescence. HMEC-1 cells were cultured and the expression of TLR4, MyD88 and Interleukin-1β (IL-1β) was examined under high-glucose condition. Endothelial cells with TLR4 silencing and antagonist of TLR4 as well as endothelial cells from TLR4 deficient mice were used to study the effect of activated TLR4 on inflammation induced by high-glucose treatment., Results: We observed that TLR4 was detected in CD31-labled human retinal vascular endothelia and its expression was markedly increased in fibrovascular membranes from DR patients and in retinal vascular endothelial cells of diabetic mice. The expression of TLR4, MyD88 and IL-1β was enhanced by high glucose in cultured HMEC-1 and the expression of TLR4 and IL-1β was inhibited by TLR4 siRNA knock-down and TLR4 antagonist. The expression of IL-1β by endothelial cells from TLR4 deficient mice under high glucose condition was decreased., Conclusions: Our results revealed that hyperglycemia induced overexpression and activation of TLR4 in endothelial cells. This effect may lead to inflammatory responses contribute to the pathogenesis of diabetic retinopathy.

Previous studies demonstrated that annonaceous acetogenin (AA) was an antitumor drug with anti-angiogenic activity. However, the effect of AA on ocular neovascular disorders remains unclear. The aim of the present study is to explore the effect of AA092, an annonaceous acetogenin mimetic, on corneal neovascularization (CNV). In a mouse model of alkali-induced CNV, topical application of AA092 to the injured corneas attenuated CNV. In addition, in vivo treatment with AA092 down-regulated the expression of the pro-angiogenic factors VEGF, b-FGF, TGFβ1, EGF but up-regulated the expression of the anti-angiogenic factors Thrombospondin-1 (Tsp-1), Tsp-2 and ADAMTS-1 in the injured corneas. Furthermore, AA092 inhibited the expression of pro-angiogenic factors, migration, proliferation and tube formation by human microvascular endothelial cells (HEMC-1) in vitro. These data indicate that AA092 has therapeutic potential for angiogenesis-associated diseases such as CNV., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Endothelial progenitor cells (EPCs) promote both physiological and pathological neovascularization. Recently we found high-mobility group box-1 (HMGB1)-Toll-like receptor 4 (TLR4) signaling pathway promotes corneal neovascularization (CNV) induced by alkali in a mouse model. However, it is still unclear whether HMGB1-TLR4 promotes the mobility of EPCs. In this study, we explored the role of HMGB1-TLR4 signaling in EPC recruitment by modulating the activity of HMGB1-TLR4 signaling in the corneas of alkali-induced CNV mouse model. The level of EPC recruitment in injured corneas, as detected by flow cytometry, is increased and reaches the peak level 4days after injury. Activating TLR4 with exogenous HMGB1 or LPS enhances the EPC recruitment, whereas inhibiting the activity of HMGB1 and TLR4 with A-box (selective HMGB1 antagonist) or LPS-RS (selective TLR4 antagonist), respectively, reverses this phenotype. Moreover, the TLR4 mediated EPC recruitment is associated with up-regulation of stromal cell-derived factor-1 (SDF-1), a pivotal cytokine in EPC mobilization. Activation of TLR4 or HMGB1 leads to increased SDF-1 expression, while blocking TLR4 or HMGB1 inhibits the expression of SDF-1. Topical administration of AMD-3100, an antagonist of SDF-1 receptor, suppresses the TLR4-mediated EPC recruitment and ameliorates CNV. Our results indicated that activation of HMGB1-TLR4 signaling pathway promotes EPC recruitment in CNV, at least in part through up-regulation of SDF-1., (Copyright © 2015 Elsevier B.V. All rights reserved.)

CCNE1 gene amplification is present in 15-20% ovary tumor specimens. Here, we showed that Cyclin E1 (CCNE1) was overexpressed in 30% of established ovarian cancer cell lines. We also showed that CCNE1 was stained positive in over 40% of primary ovary tumor specimens regardless of their histological types while CCNE1 staining was either negative or low in normal ovary and benign ovary tumor tissues. However, the status of CCNE1 overexpression was not associated with the tumorigenic potential of ovarian cancer cell lines and also did not correlate with pathological grades of ovary tumor specimens. Subsequent experiments with CCNE1 siRNAs showed that knockdown of CCNE1 reduced cell growth only in cells with inherent CCNE1 overexpression, indicating that these cells may have developed an addiction to CCNE1 for growth/survival. As CCNE1 is a regulatory factor of cyclin-dependent kinase 2 (Cdk2), we investigated the effect of Cdk2 inhibitor on ovary tumorigenecity. Ovarian cancer cells with elevated CCNE1 expression were 40 times more sensitive to Cdk2 inhibitorSNS-032 than those without inherent CCNE1 overexpression. Moreover, SNS-032 greatly prolonged the survival of mice bearing ovary tumors with inherent CCNE1 overexpression. This study suggests that ovary tumors with elevated CCNE1 expression may be staged for Cdk2-targeted therapy.

Background: Liver-gallbladder dampness-heat (LGDH) and liver kidney yin deficiency (LKYD) syndromes are Chinese medicine (CM) zhengs in chronic hepatitis B (CHB) patients. This study aims to investigate the changes in cytokines and their profiles accompanied by different biological responses in LGDH and LKYD in CHB., Methods: During 2010-2012, a total of 138 morning fasting venous blood samples were obtained from participants in Shuguang Hospital, Shanghai University of Traditional Chinese Medicine in Shanghai, China. First, serum samples from 20 health controls (HCs) and 40 CHB patients (20 LGDH, 20 LKYD) were collected to detect the profiles of cytokines by multiplex biometric ELISA-based immunoassay. Random forest (RF) with a fivefold cross-validation was used to analyze the significant cytokines. Then the significant cytokines were validated using serum samples from an independent cohort of 60 CHB patients (30 LGDH, 30 LKYD) and 18 HCs., Results: There were different profiles of cytokines in LGDH and LKYD. Twenty-three significantly differentially expressed cytokines were detected, among which three cytokines, interleukin (IL)-17, macrophage inflammatory protein (MIP)-1α, and MIP-1β, with the largest Gini scores were identified by RF, and further evaluated for their significant changes in serum levels. A receiver-operator characteristic analysis revealed that the logistic regression panel could differentiate LGDH from LKYD (P < 0.001; AUC = 0.827). A functional pathway analysis showed that cytokine-cytokine receptor interaction, cytosolic DNA-sensing pathway, and chemokine signaling pathway overlapped between LGDH and LKYD, whereas Toll-like receptor signaling pathway, intestinal immune network for IgA production, NOD-like receptor signaling pathway, and Jak-STAT signaling pathway were only enriched in LGDH., Conclusions: There were characteristic cytokines profiles in LGDH and LKYD with different inflammatory and immune responses. IL-17, MIP-1α, and MIP-1β might be involved in the differentiation of LGDH and LKYD in CHB.

G protein-coupled chemoattractant receptors (GPCRs) have been implicated in cancer progression. Formylpeptide receptor 1 (FPR1) was originally identified as a GPCR mediating anti-microbial host defense. However, the role of FPR1 in tumorigenesis remains poorly understood. The current study aims to investigate the potential of FPR1 to regulate human hepatoma growth and invasion. We found the FPR1 gene and protein expression in human intratumoral and peritumoral tissues of hepatocellular carcinoma (HCC) specimens and in human hepatoma cell lines. FPR1 activation mediated the migration, calcium mobilization and ERK-dependent IL-8 production by hepatic cancer cells. FPR1 knockdown substantially reduced the tumorigenicity of hepatoma cells in nude mice. Necrotic hepatic tumor cells released factor(s) that activated FPR1 in live tumor cells. Our results indicate a critical role of FPR1 in the progression of malignant human hepatic cancer. FPR1 thus may represent a molecular target for the development of novel anti-hepatoma therapeutics.

Health care workers (HCWs) in Taiwan have heavy, stressful workloads, are on-call, and have rotating nightshifts, all of which might contribute to peptic ulcer disease (PUD). We wanted to evaluate the PUD risk in HCWs, which is not clear. Using Taiwan's National Health Insurance Research Database, we identified 50,226 physicians, 122,357 nurses, 20,677 pharmacists, and 25,059 other HCWs (dieticians, technicians, rehabilitation therapists, and social workers) as the study cohort, and randomly selected an identical number of non-HCW patients (i.e., general population) as the comparison cohort. Conditional logistical regression analysis was used to compare the PUD risk between them. Subgroup analysis for physician specialties was also done. Nurses and other HCWs had a significantly higher PUD risk than did the general population (odds ratio [OR]: 1.477; 95% confidence interval [CI]: 1.433-1.521 and OR: 1.328; 95% CI: 1.245-1.418, respectively); pharmacists had a lower risk (OR: 0.884; 95% CI: 0.828-0.945); physicians had a nonsignificantly different risk (OR: 1.029; 95% CI: 0.987-1.072). In the physician specialty subgroup analysis, internal medicine, surgery, Ob/Gyn, and family medicine specialists had a higher PUD risk than other physicians (OR: 1.579; 95% CI: 1.441-1.731, OR: 1.734; 95% CI: 1.565-1.922, OR: 1.336; 95% CI: 1.151-1.550, and OR: 1.615; 95% CI: 1.425-1.831, respectively). In contrast, emergency physicians had a lower risk (OR: 0.544; 95% CI: 0.359-0.822). Heavy workloads, long working hours, workplace stress, rotating nightshifts, and coping skills may explain our epidemiological findings of higher risks for PUD in some HCWs, which might help us improve our health policies for HCWs.

Diabetic retinopathy (DR) is a common complication of diabetes and has been recognized as a vascular dysfunction leading to blindness in working-age adults. It becomes increasingly clear that neural cells in retina play an important role in the pathogenesis of DR. Neural retina located at the back of the eye is part of the brain and a representative of the central nervous system. The neurosensory deficits seen in DR are related to inflammation and occur prior to the clinically identifiable vascular complications. The neural deficits are associated with abnormal reactions of retina glial cells and neurons in response to hyperglycemia. Improper activation of the innate immune system may also be an important contributor to the pathophysiology of DR. Therefore, DR manifests characteristics of both vasculopathy and chronic neuroinflammatory diseases. In this article, we attempt to provide an overview of the current understanding of inflammation in neural retina abnormalities in diabetes. Inhibition of neuroinflammation may represent a novel therapeutic strategy to the prevention of the progression of DR.

Acute anticholinesterase pesticide (organophosphate and carbamate) poisoning (ACPP) often produces severe complications, and sometimes death. We investigated the long-term mortality of patients with ACPP because it is not sufficiently understood. In this retrospective nationwide population-based cohort study, 818 patients with ACPP and 16,360 healthy comparisons from 1999 to 2010 were selected from Taiwan's National Health Insurance Research Database. They were followed until 2011. Ninety-four (11.5%) ACPP patients and 793 (4.9%) comparisons died (P < 0.01) during follow-up. The incidence rate ratios (IRRs) of death were 2.5 times higher in ACPP patients than in comparisons (P < 0.01). The risk of death was particularly high in the first month after ACPP (IRR: 92.7; 95% confidence interval [CI]: 45.0-191.0) and still high for ~6 months (IRR: 3.8; 95% CI: 1.9-7.4). After adjusting for age, gender, selected comorbidities, geographic area, and monthly income, the hazard ratio of death for ACPP patients was still 2.4 times higher than for comparisons. Older age (≥35 years), male gender, diabetes mellitus, coronary artery disease, hypertension, stroke, mental disorder, and lower monthly income also predicted death. ACPP significantly increased long-term mortality. In addition to early follow-up after acute treatment, comorbidity control and socioeconomic assistance are needed for patients with ACPP.

Aim: The geriatric population (aged ≥65 years) accounts for 12-24% of all emergency department (ED) visits. Of them, 10% have a fever, 70-90% will be admitted and 7-10% of will die within a month. Therefore, mortality prediction and appropriate disposition after ED treatment are of great concern for geriatric patients with fever. We tried to identify independent mortality predictors of geriatric patients with fever, and combine these predictors to predict their mortality., Methods: We enrolled consecutive geriatric patients visiting the ED between 1 June and 21 July 2010 with the following criteria of fever: a tympanic temperature ≥37.2°C or a baseline temperature elevated ≥1.3°C. We used 30-day mortality as the primary end-point., Results: A total of 330 patients were enrolled. Hypotension, bedridden, leukocytosis, thrombocytopenia and serum creatinine >2 mg/dL, but not age, were independently associated with 30-day mortality. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) ranged from 18.2% to 90.9%, 34.7% to 100%, 9.0% to 100% and 94.5% to 98.2%, respectively, depending on how many predictors there were., Conclusions: The 30-day mortality increased with the number of independent mortality predictors. With at least four predictors, 100% of the patients died within 30 days. With none of the predictors, just 1.8% died. These findings might help physicians make decisions about geriatric patients with fever., (© 2014 Japan Geriatrics Society.)

Introduction: Radix Glycyrrhiza has been used in China for thousand years to treat cancer. However, focus on its tumor-suppressing mechanism has been concentrated on its effect on tumor cell growth and apoptosis., Objectives: With the aid of a panel of human breast cancer cell lines, we reveal that glycyrrhetinic acid (GA), a major component of Radix Glycyrrhiza, is actually a significantly more potent agent to suppress invasion than cell survival., Results: GA effectively inhibits breast cancer cell MMP-2/MMP-9 expression; GA-induced reduction in the MMP-2/9 expression is apparently mediated by GA's ability to specifically inhibit the p38 MAPK activity and its downstream AP1 activation. Moreover, we show that GA down regulates the levels of Fra-1 and c-Jun, two main components of AP1 transcription complex in invasive breast cancer cells and that AP1-specific inhibitor abrogates breast cancer cell invasion. These results suggest that GA impairs the p38 MAPK-AP1 signaling axis, leading to the repression of breast cancer cell invasion. Finally, we demonstrate that GA effectively suppresses breast tumor outgrowth and pulmonary metastasis without causing animal weight loss or eliciting liver/kidney toxicity to the recipient animals., Conclusion: This study indicates that GA represents a good candidate compound for the potential development of therapeutic drug.

Objective: Hyperglycemic crisis is one of the most serious diabetes-related complications. The increase in the prevalence of diabetes in the geriatric population leads to a large disease burden, but previous studies of geriatric hyperglycemic crisis were focused on acute hyperglycemic crisis episode (HCE). This study aimed to delineate the long-term mortality risk after HCE., Research Design and Methods: This retrospective national population-based cohort study reviewed, in Taiwan's National Health Insurance Research Database, data from 13,551 geriatric patients with new-onset diabetes between 2000 and 2002, including 4,517 with HCE (case subjects) (ICD-9 code 250.1 or 250.2) and 9,034 without HCE (control subjects). The groups were compared and followed until 2011., Results: One thousand six hundred thirty-four (36.17%) case and 1,692 (18.73%) control subjects died (P < 0.0001) during follow-up. Incidence rate ratios (IRRs) of death were 2.82 times higher in case subjects (P < 0.0001). The mortality risk was highest in the first month (IRR 26.56; 95% CI 17.97-39.27) and remained higher until 4-6 years after the HCE (IRR 1.49; 95% CI 1.23-1.81). After adjustment for age, sex, selected comorbidities, and monthly income, the mortality hazard ratio was still 2.848 and 4.525 times higher in case subjects with one episode and two or more episodes of hyperglycemic crisis, respectively. Older age, male sex, renal disease, stroke, cancer, chronic obstructive pulmonary disease, and congestive heart failure were independent mortality predictors., Conclusions: Patients with diabetes had a higher mortality risk after HCE during the first 6 years of follow-up. Referral for proper education, better access to medical care, effective communication with a health care provider, and control of comorbidities should be done immediately after HCE., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aim: To evaluate the utility of carbohydrate antigen 19-9 (CA19-9) for differential diagnosis of pancreatic carcinoma and chronic pancreatitis., Methods: We searched the literature for studies reporting the sensitivity, specificity, and other accuracy measures of serum CA19-9 levels for differentiating pancreatic carcinoma and chronic pancreatitis. Pooled analysis was performed using random-effects models, and receiver operating characteristic (ROC) curves were generated. Study quality was assessed using Standards for Reporting Diagnostic Accuracy and Quality Assessment for Studies of Diagnostic Accuracy tools., Results: A total of 34 studies involving 3125 patients with pancreatic carcinoma and 2061 patients with chronic pancreatitis were included. Pooled analysis of the ability of CA19-9 level to differentiate pancreatic carcinoma and chronic pancreatitis showed the following effect estimates: sensitivity, 0.81 (95%CI: 0.80-0.83); specificity, 0.81 (95%CI: 0.79-0.82); positive likelihood ratio, 4.08 (95%CI: 3.39-4.91); negative likelihood ratio, 0.24 (95%CI: 0.21-0.28); and diagnostic odds ratio, 19.31 (95%CI: 14.40-25.90). The area under the ROC curve was 0.88. No significant publication bias was detected., Conclusion: Elevated CA19-9 by itself is insufficient for differentiating pancreatic carcinoma and chronic pancreatitis, however, it increases suspicion of pancreatic carcinoma and may complement other clinical findings to improve diagnostic accuracy.

Background: Predicting the neurological sequelae of carbon monoxide poisoning (COP) has not been well studied. We investigated the independent predictors of neurological sequelae in patients with COP and combined these predictors to predict the prognosis., Methods: This study was conducted at four hospitals in Shandong Province, China. Data were retrospectively collected from 258 patients with COP between November 1990 and October 2011. Thirty-day neurological sequelae were the primary endpoints., Results: A lack of pupil reflex and a loss of consciousness appear to be independent predictors for neurological sequelae in patients with COP. The presence of either one had a sensitivity of 77.0% (95% confidence interval [CI]: 69.3-83.2), a specificity of 47.1% (95% CI: 38.3-56.0), positive predictive value (PPV) of 62.9% (95% CI: 55.2-70.1), and a negative predictive value (NPV) of 63.6% (95% CI: 52.6-73.4). With both predictors present, the sensitivity was 11.5% (95% CI: 6.9 to 18.3), the specificity was 99.2 (95% CI: 94.7-100.0), the PPV was 94.1% (95% CI: 69.2-99.7), and the NPV was 49.0% (95% CI: 42.5-55.5)., Conclusions: The risk for neurological sequelae apparently increased with the number of independent predictors. In patients with both predictors, the risk for neurological sequelae was 94.1%. Almost all (99.2%) patients with neither predictor had no neurological sequelae. This finding may help physicians make decisions about and dispositions for patients with COP. For patients with a higher risk, earlier treatment and more appropriate utilization of health care services, including hyperbaric oxygen, should be considered.

Interleukin (IL)-22 has been implicated in inflammation and tumorigenesis. To date, no studies have investigated the role of IL-22 polymorphism in the carcinogenesis of gastric cancer (GC). In this study, we aimed to investigate the association of IL-22 polymorphisms with the risk of GC in a Chinese population. One hundred eight GC patients and 110 healthy controls were included in the study. IL-22 rs1179251, rs2227485, and rs2227473 polymorphisms were determined by PCR amplification and DNA sequencing. Haplotypes were constructed, and a possible association of these haplotypes with GC was assessed. The distribution of IL-22 rs1179251 polymorphism with clinical parameters was also analyzed. The IL-22 rs1179251 polymorphism was significantly associated with an increased risk of GC (p < 0.05). Stratified analysis revealed that rs1179251 was associated with advanced stages, lymph node metastases, and distant metastases of GC (p < 0.05). No associations were found between rs2227485 and rs2227473 and the risk of GC (p > 0.05). Three possible haplotypes (C(rs1179251)-C(rs2227485)-G(rs2227485), C(rs1179251)-T(rs2227485)-G(rs2227485), and G(rs1179251)-T(rs2227485)-A(rs2227485)) were identified, but no associations were found between these and the risk of GC (p > 0.05). In summary, our study demonstrates that the rs1179251 polymorphism of IL-22 was associated with an increased risk of GC and may influence the progression of GC. Future larger studies with other ethnic populations are required to confirm these findings.

Aim: To investigate the possible mechanism of how glucose promotes invasion and metastasis of colon cancer cells., Methods: CT-26 rat colorectal cancer cells were cultured in different concentrations of glucose environments (10, 20, and 30 mmol/L). Wound healing assay and transwell chamber invasion assay were utilized to test the migration and invasion, respectively. In order to understand the role of signal transducer and activator of transcription 3 (STAT3) in the process, STAT3 inhibitors, including Stattic (an STAT3 specific inhibitor) and small interfering RNA targeting STAT3, were used to block STAT3 function to evaluate their impact on CT-26 cell motion. To verify whether STAT3 and matrix metalloproteinase-9 (MMP-9) protein expression is associated with glucose-induced cell movement, Western blot was used to compare the differences in the expression of MMP-9 and STAT3 in cells incubated with and without STAT3 inhibitors in high glucose condition., Results: In both wound healing and invasion assays, the migration and invasion of CT-26 cells increased gradually with the increase in glucose concentration. However, the glucose-induced migration and invasion were obviously inhibited by STAT3 inhibitors (P<0.05). Similarly, in Western blot assessment, both MMP-9 and STAT3 expression increased under a high glucose environment and the highest expression was achieved when 30 mmol/L glucose was used. However, in cells treated with 30 mmol/L mannitol, either MMP-9 or STAT3 expression did not increase (P>0.05). When STAT3 inhibitors were added in the 30 mM glucose group, not only STAT3 but also MMP-9 expression decreased significantly (P<0.05)., Conclusion: Our study provides evidence that glucose can promote both migration and invasion of CT-26 cells, and that the STAT3-induced MMP-9 signal pathway is involved in this process.

Fuzheng-Huayu (FZHY) tablet was formulated based on Chinese medicine theory in treating liver fibrosis. A clinical trial has indicated that FZHY can against hepatitis B-caused liver cirrhosis (HBC), but the underlying mechanism of FZHY efficacy is unclear. Here, we report that miRNA expression levels are remarkably changed when FZHY formula was used in HBC patient's treatment as a paradigm of trials. Then, we functionally characterize the significant impact of potential kernel miRNAs by miRNA-target network analysis. Enrichment analysis show that the FZHY formula dramatically effecting the molecular regulated module in HBC. Thus, we infer that FZHY plays a critical function in HBC treatment process and directly regulated many important pathways, including but not limited to cell cycle, p53 signaling pathway, and TGF-β signaling pathway, suggesting a new strategy for investigating the molecular mechanism of FZHY treatment.

Objectives: The health benefits of breastfeeding are widely recognized. The World Health Organization recommends exclusive breastfeeding for six months after birth and for two years or longer together with nutritionally adequate complementary foods. To respond to the needs of industry, employed breastfeeding mothers must adapt to the rotating night shift (RNS). However, the RNS is associated with a higher risk of health problems in career women. We investigated the relationship between the RNS and breast milk volume., Methods: Mothers who used a breastfeeding room while working at a technology company in Taiwan voluntarily participated in this study from March 1 through April 30, 2013. We compared two groups: breastfeeding mothers on (RNS(+)) and not on a RNS (RNS(-)) to determine independent predictors for breast milk volume. We analyzed data from 109 participants: RNS(+) group n=56; RNS(-) group n=53., Results: There was no significant difference in daily milk collection volume between the groups. Daily milk collection frequency and exclusive breastfeeding were independent predictors for a daily breast milk collection volume >350 ml., Conclusions: The RNS may not affect the breast milk volume. This result may help the government and employers make policies more appropriate for supporting employed breastfeeding mothers.

Background: High stress levels and shift work probably trigger migraine in healthcare professionals (HCPs). However, the migraine risk differences between HCPs and the general population is unknown., Methods: This nationwide population-based cohort study used Taiwan's National Health Insurance Research Database. Physicians (50,226), nurses (122,357), and other HCPs (pharmacists, technicians, dietitians, rehabilitation therapists, social workers, etc.) (45,736) were enrolled for the study cohort, and randomly selected non-HCPs (218,319) were enrolled for the comparison cohort. Conditional logistical regression analysis was used to compare the migraine risks. Comparisons between HCPs and between physician specialties were also done., Results: Physicians, nurses, and other HCPs had higher migraine risks than did the general population (adjusted odds ratio [AOR]: 1.672; 95 % confidence interval [CI]: 1.468-1.905, AOR: 1.621; 95 % CI: 1.532-1.714, and AOR: 1.254; 95 % CI: 1.124-1.399, respectively) after stroke, hypertension, epilepsy, anxiety, depression, and insomnia had been adjusted for. Nurses and physicians had higher migraine risks than did other HCPs (AOR: 1.303; 95 % CI: 1.206-1.408, and AOR: 1.193; 95 % CI: 1.069-1.332, respectively). Obstetricians and gynecologists had a lower migraine risk than did other physician specialists (AOR: 0.550; 95 % CI: 0.323-0.937)., Conclusion: HCPs in Taiwan had a higher migraine risk than did the general population. Heavy workloads, emotional stress, and rotating night shift sleep disturbances appear to be the most important risk factors. These findings should provide an important reference for promoting occupational health in HCPs in Taiwan.

Proteomics technology, a major component of system biology, has gained comprehensive attention in the area of medical diagnosis, drug development, and mechanism research. On the holistic and systemic theory, proteomics has a convergence with traditional Chinese medicine (TCM). In this review, we discussed the applications of proteomic technologies in diseases-TCM syndrome combination researches. We also introduced the proteomic studies on the in vivo and in vitro effects and underlying mechanisms of TCM treatments using Chinese herbal medicine (CHM), Chinese herbal formula (CHF), and acupuncture. Furthermore, the combined studies of proteomics with other "-omics" technologies in TCM were also discussed. In summary, this report presents an overview of the recent advances in the application of proteomic technologies in TCM studies and sheds a light on the future global and further research on TCM.

The Fuzheng Huayu (FZHY) formula is being used in antiliver fibrosis treatment in China. For systemic evaluation of the curative effects of FZHY on liver fibrosis and cirrhosis progress, a total of 1392 subjects (714 cases and 678 controls) were found to be eligible for meta-analysis in this study. Standard mean differences (SMDs) with 95% confidence interval (CI) were calculated for changes between FZHY groups and controls by employing fixed effects or random effects model. In the overall analysis, alanine transaminase (ALT) (P = 0.003, SMD = -0.87, 95% CI: -1.46 to -0.29), total bilirubin (TBil) (P = 0.001, SMD = -1.30, 95% CI: -2.10 to -0.50), hyaluronic acid (HA) (P = 0.000, SMD = -0.94, 95% CI: -1.30 to -0.58), laminin (LN) (P = 0.000, SMD = -0.80, 95% CI: -1.20 to -0.41), type III procollagen (PC-III) (P = 0.000, SMD = -1.27, 95% CI: -1.93 to -0.60), and type IV procollagen (IV-C) (P = 0.000, SMD = -0.78, 95% CI: -1.05 to -0.51) were decreased after FZHY treatment; however, albumin (ALB) was increased (P = 0.037, SMD = 1.10, 95% CI: 0.07 to 2.12) significantly. Furthermore, the Child-Pugh score was reduced significantly and the life quality was improved after FZHY treatment in cirrhosis patients. The results of this meta-analysis indicated that FZHY effectively improves the liver function, alleviates hepatic fibrosis, decreases Child-Pugh score, and relieves TCM symptoms caused by liver dysfunction, indicating that FZHY may contribute to the alleviation of liver fibrosis and cirrhosis.

Physicians in Taiwan have a heavy workload and a stressful workplace, both of which may contribute to cardiovascular disease. However, the risk of acute myocardial infarction (AMI) in physicians is not clear. This population-based cohort study used Taiwan's National Health Insurance Research Database. We identified 28,062 physicians as the case group and randomly selected 84,186 nonmedical staff patients as the control group. We used a conditional logistic regression to compare the AMI risk between physicians and controls. Subgroup analyses of physician specialty, age, gender, comorbidities, area, and hospital level were also done. Physicians have a higher prevalence of HTN (23.59% versus 19.06%, P < 0.0001) and hyperlipidemia (21.36% versus 12.93%, P < 0.0001) but a lower risk of AMI than did the controls (adjusted odds ratio (AOR): 0.57; 95% confidence interval (CI): 0.46-0.72) after adjusting for DM, HTN, hyperlipidemia, and area. Between medical specialty, age, and area subgroups, differences in the risk for having an AMI were nonsignificant. Medical center physicians had a lower risk (AOR: 0.42; 95% CI: 0.20-0.85) than did local clinic physicians. Taiwan's physicians had higher prevalences of HTN and hyperlipidemia, but a lower risk of AMI than did the general population. Medical center physicians had a lower risk than did local clinic physicians. Physicians are not necessary healthier than the general public, but physicians, especially in medical centers, have a greater awareness of disease and greater access to medical care, which permits timely treatment and may prevent critical conditions such as AMI induced by delayed treatment.

Interleukin-28A (IL-28A), a member of type III interferons (IFN-λs), promotes antiviral, antitumor and immune responses. However, its ability to regulate autoimmune diseases is poorly understood. In this study, we examined the effect of IL-28A on retinal antigen-induced experimental autoimmune uveoretinitis (EAU), a mouse model of human T-cell-mediated autoimmune eye disease. We found that administration of IL-28A enhanced EAU scores and autoimmune response parameters including delayed-type hypersensitivity (DTH), Ag-specific T cell proliferation and the production of Ag-specific IL-17 and IFN-γ in the priming phase. The effect of IL-28A was abrogated by administration of a neutralizing antibody against IL-28A. Our results suggest that IL-28A is capable of exacerbating a T-cell-mediated autoimmune disease. Thus, targeting IL-28A may provide a new therapeutic approach to T cell-mediated autoimmune diseases such as uveitis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aims/introduction: Hyperglycemic crises without a history of diabetes have not been well studied. We compared the clinical characteristics of patients with and without a history of diabetes, and evaluated the glycated hemoglobin levels., Materials and Methods: Consecutive adult patients (aged >18 years) visiting the emergency department (ED) between January 2004 and December 2010 were enrolled if they met the criteria for a hyperglycemic crisis. Patients were separated into those without and those with a history of diabetes. The 30-day mortality was the primary end-point., Results: We enrolled 295 patients who made 330 visits to the ED. Patients without a history of diabetes made up 24.5% (81/330) of the hyperglycemic crises. Patients without a history of diabetes were more prone than patients with a history of diabetes to be younger and male, and to have better consciousness and renal function, more significant diabetic signs and symptoms (e.g., thirst, polydipsia, polyuria and bodyweight loss), higher blood sugar, and less opportunity of infection and mortality. Most of the patients (93.8%, 76/81) had glycated hemoglobin of ≥6.5%., Conclusions: The present study delineates the clinical characteristics of patients with hyperglycemic crises, but without a history of diabetes. Most patients had glycated hemoglobin ≥6.5%, which raises the argument of using this biomarker for routine screening of diabetes.