Bank Loan Covenants and Accrual Quality

We examine whether financial covenants in loan contracts motivate banks to monitor borrowers’ financial reporting practices and result in a higher quality of reported accruals. We document that, relative to loans without financial covenants, loans with financial covenants lead to a significant improvement in accrual quality measured by the extent to which accruals can be mapped into cash flows. The effect of loan covenants on accrual quality is stronger when external monitoring by non-bank stakeholders (i.e., institutional investors and financial analysts) is weaker. Furthermore, initiations of bank loans with financial covenants are related to subsequent improvements in analysts’ information environment. The evidence supports the view that bank monitoring improves accounting quality

Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation

<p>Abstract</p> <p>Background</p> <p>Apoptosis, neuroinflammation and blood-brain barrier (BBB) damage affect the susceptibility of the developing brain to hypoxic-ischemic (HI) insults. c-Jun N-terminal kinase (JNK) is an important mediator of insulin resistance in obesity. We hypothesized that neonatal overweight aggravates HI brain damage through JNK hyperactivation-mediated upregulation of neuronal apoptosis, neuroinflammation and BBB leakage in rat pups.</p> <p>Methods</p> <p>Overweight (OF) pups were established by reducing the litter size to 6, and control (NF) pups by keeping the litter size at 12 from postnatal (P) day 1 before HI on P7. Immunohistochemistry and immunoblotting were used to determine the TUNEL-(+) cells and BBB damage, cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP), and phospho-JNK and phospho-Bim_ELlevels. Immunofluorescence was performed to determine the cellular distribution of phospho-JNK.</p> <p>Results</p> <p>Compared with NF pups, OF pups had a significantly heavier body-weight and greater fat deposition on P7. Compared with the NF-HI group, the OF-HI group showed significant increases of TUNEL-(+) cells, cleaved levels of caspase-3 and PARP, and ED1-(+) activated microglia and BBB damage in the cortex 24 hours post-HI. Immunofluorescence of the OF-HI pups showed that activated-caspase 3 expression was found mainly in NeuN-(+) neurons and RECA1-(+) vascular endothelial cells 24 hours post-HI. The OF-HI group also had prolonged escape latency in the Morris water maze test and greater brain-volume loss compared with the NF-HI group when assessed at adulthood. Phospho-JNK and phospho-Bim_ELlevels were higher in OF-HI pups than in NF-HI pups immediately post-HI. JNK activation in OF-HI pups was mainly expressed in neurons, microglia and vascular endothelial cells. Inhibiting JNK activity by AS601245 caused more attenuation of cleaved caspase-3 and PARP, a greater reduction of microglial activation and BBB damage post-HI, and significantly reduced brain damage in OF-HI than in NF-HI pups.</p> <p>Conclusions</p> <p>Neonatal overweight increased HI-induced neuronal apoptosis, microglial activation and BBB damage, and aggravated HI brain damage in rat pups through JNK hyperactivation.</p

A novel role of sesamol in inhibiting NF-κB-mediated signaling in platelet activation

<p>Abstract</p> <p>Background</p> <p>Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-κB-mediated platelet function.</p> <p>Methods</p> <p>Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study.</p> <p>Results</p> <p>NF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were markedly activated by collagen (1 μg/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 μM)-mediated inhibitory effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB inhibitor, abolished IκBα degradation, phospholipase C (PLC)γ2 phosphorylation, protein kinase C (PKC) activation, [Ca²⁺]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca²⁺]i mobilization.</p> <p>Conclusions</p> <p>Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca²⁺]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-κB interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.</p

Fever Screening at Airports and Imported Dengue

Airport fever screening in Taiwan, July 2003–June 2004, identified 40 confirmed dengue cases. Results obtained by capture immunoglobulin (Ig) M and IgG enzyme-linked immunoassay, real time 1-step polymerase chain reaction, and virus isolation showed that 33 (82.5%) of 40 patients were viremic. Airport fever screening can thus quickly identify imported dengue cases

A predicted protein, KIAA0247, is a cell cycle modulator in colorectal cancer cells under 5-FU treatment

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and the leading cause of cancer death. The identification of genes related to CRC is important for the development of successful therapies and earlier diagnosis.</p> <p>Methods</p> <p>Molecular analysis of feces was evaluated as a potential method for CRC detection. Expression of a predicted protein with unknown function, KIAA0247, was found in feces evaluated using specific quantitative real-time polymerase chain reaction. Its cellular function was then analyzed using immunofluorescent staining and the changes in the cell cycle in response to 5-fluorouracil (5-FU) were assessed.</p> <p>Results</p> <p>Gastrointestinal tissues and peripheral blood lymphocytes ubiquitously expressed KIAA0247. 56 CRC patients fell into two group categories according to fecal KIAA0247 mRNA expression levels. The group with higher fecal KIAA0247 (<it>n </it>= 22; ≥ 0.4897) had a significantly greater five-year overall survival rate than the group with lower fecal KIAA0247 (<it>n </it>= 30; < 0.4897) (66.0 ± 11.6%; <it>p </it>= 0.035, log-rank test). Fecal expression of KIAA0247 inversely related to CRC tumor size (Kendall's tau-b = -0.202; <it>p </it>= 0.047). Immunofluorescent staining revealed that the cytoplasm of CRC cells evenly expresses KIAA0247 without 5-FU treatment, and KIAA0247 accumulates in the nucleus after 40 μM 5-FU treatment. In HCT116 p53^-/-cells, which lack p53 cell cycle control, the proportion of cells in the G2/M phase was larger (13%) in KIAA0247-silent cells than in the respective shLuc control (10%) and KIAA0247-overexpressing cells (7%) after the addition of low dose (40 μM) 5-FU. Expression of three cyclin genes (cyclin A2, cyclin B1, and cyclin B2) also downregulated in the cells overexpressing KIAA0247.</p> <p>Conclusions</p> <p>This is the first description of a linkage between KIAA0247 and CRC. The study's data demonstrate overexpression of KIAA0247 associates with 5-FU therapeutic benefits, and also identify the clinical significance of fecal KIAA0247 in CRC.</p

Does Long-Term Use of Silver Nanoparticles Have Persistent Inhibitory Effect on H. pylori Based on Mongolian Gerbil’s Model?

It is urgent to find alternative agents due to increasing failure rate of Helicobacter pylori (H. pylori) eradication. The study surveyed the long-term effect of silver nanoparticles (AgNP) on H. pylori based on Mongolian gerbil's model

The upper limits of risk ratios and recommendations for reporting risk ratios, odds ratios, and rate ratios

Background Relative measures, including risk ratios (RRs) and odds ratios (ORs), are reported in many epidemiological studies. RRs represent how many times a condition is likely to develop when exposed to a risk factor. The upper limit of RRs is the multiplicative inverse of the baseline incidence. Ignoring the upper limits of RRs can lead to reporting exaggerated relative effect sizes. Objectives This study aims to demonstrate the importance of such upper limits for effect size reporting via equations, examples, and simulations and provide recommendations for the reporting of relative measures. Methods Equations to calculate RRs and their 95% confidence intervals (CIs) were listed. We performed simulations with 10,000 simulated subjects and three population variables: proportions at risk (0.05, 0.1, 0.3, 0.5, and 0.8), baseline incidence (0.05, 0.1, 0.3, 0.5, and 0.8), and RRs (0.5, 1.0, 5.0, 10.0, and 25.0). Subjects were randomly assigned with a risk based on the set of proportions-at-risk values. A disease occurred based on the baseline incidence among those not at risk. The incidence of those at risk was the product of the baseline incidence and the RRs. The 95% CIs of RRs were calculated according to Altman. Results The calculation of RR 95% CIs is not connected to the RR upper limits in equations. The RRs in the simulated populations at risk could reach the upper limits of RRs: multiplicative inverse of the baseline incidence. The upper limits to the derived RRs were around 1.25, 2, 3.3, 10, and 20, when the assumed baseline incidence rates were 0.8, 0.5, 0.3, 0.2, and 0.05, respectively. We demonstrated five scenarios in which the RR 95% CIs might exceed the upper limits. Conclusions Statistical significance does not imply the RR 95% CIs not exceeding the upper limits of RRs. When reporting RRs or ORs, the RR upper limits should be assessed. The rate ratio is also subject to a similar upper limit. In the literature, ORs tend to overestimate effect sizes. It is recommended to correct ORs that aim to approximate RRs assuming outcomes are rare. A reporting guide for relative measures, RRs, ORs, and rate ratios, is provided. Researchers are recommended to report whether the 95% CIs of relative measures, RRs, ORs, and rate ratios, overlap with the range of upper limits and discuss whether the relative measure estimates may exceed the upper limits

Analgesic and Anti-Inflammatory Activities of the Ethanolic Extract of Artemisia morrisonensis Hayata in Mice

The aim of this study was to investigate the possible analgesic and anti-inflammatory mechanisms of the ethanolic extract of A. morrisonensis Hayata (AM EtOH ). Two models were employed for evaluation of the analgesic effects: acetic acid-induced writhing response and formalin-induced paw licking. The results demonstrated that AM EtOH decreased writhing response for both the acetic acid assay and the licking time in the formalin test. The anti-inflammatory effect was evaluated by paw edema of mice induced by λ-carrageenan. AM EtOH significantly decreased induced paw edema three to four hours after λ-carrageenan injection. Additionally, the results indicated that the anti-inflammatory mechanism of AM EtOH may be due to the declined levels of nitric oxide (NO) and malondialdehyde (MDA) in the edematous paw. Furthermore, AM EtOH decreased the tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels, leading to the reduction of prostaglandins and subsequently alleviated edema. Isolation and purification of the AM EtOH extract determined p-hydroxyacetophenone to be a major component at 130 mg/g of extract. No mortality was observed in the acute toxicity test given at the dose of 10 g/kg. This study demonstrated the possible mechanisms for the analgesic and anti-inflammatory effects of AM EtOH for mice and provided evidence for the ethnobotanical uses of A. morrisonensis in treating inflammatory diseases

Clinical meaning of age-related expression of fecal cytokeratin 19 in colorectal malignancy

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is one of the leading causes of malignant death worldwide. Because young age of onset is often considered a poor prognostic factor for CRC, it is important to identify the poor outcomes of CRC in a younger population and to consider an aggressive approach by implementing early treatment. Our aim was to specifically quantify the fecal cytokeratin 19 (CK19) transcript from CRC patients and investigate its correlation with clinical stage, tumor malignancy, and age.</p> <p>Methods</p> <p>The quantitation of fecal CK19 transcript was determined by a quantitative real-time reverse transcription polymerase chain in 129 CRC patients (45 younger than 60 years at diagnosis) and 85 healthy controls. The levels of CK19 protein were examined both in colonic cell lines and tissues.</p> <p>Results</p> <p>The analysis of 45 younger CRC patients (age ≤ 60 years) revealed that patients at the M1 stage had significantly higher expression levels of fecal CK19 mRNA when compared with healthy controls (<it>p </it>< 0.001) and patients at the M0 stage (<it>p </it>= 0.004). Additionally, the degree of consistency between the mean level of fecal CK19 mRNA and the distant metastatic rate in each age interval was up to 89% (<it>p </it>= 0.042).</p> <p>Conclusion</p> <p>These results indicate that high levels of fecal CK19 mRNA represent a potential marker for colorectal malignancy and for aggressive treatment of younger CRC patients.</p