Anti-inflammatory effects of naringin in chronic pulmonary neutrophilic inflammation in cigarette smoke-exposed rats

Naringin, a well-known flavanone glycoside of grapefruit and citrus fruits, was found to be as an effective anti-inflammatory compound in our previous lipopolysaccharide-induced acute lung injury mouse model via blockading activity of nuclear factor κB. The current study sought to explore the anti-inflammatory effects of naringin on chronic pulmonary neutrophilic inflammation in cigarette smoke (CS)-induced rats. Seventy Sprague-Dawley rats were randomly divided into seven groups to study the effects of CS with or without various concentrations of naringin or saline for 8 weeks. The results revealed that naringin supplementation at 20, 40, and 80mg/kg significantly increased body weight of CS-induced rats as compared to that in the CS group. Moreover, naringin of 20, 40, and 80mg/kg prevented CS-induced infiltration of neutrophils and activation of myeloperoxidase and matrix metalloproteinase-9, in parallel with suppression of the release of cytokines, such as tumor necrosis factor-α and interleukin-8 (IL-8). IL-10 in bronchoalveolar lavage fluid was significantly suppressed after CS exposure, but dose dependently elevated by naringin. The results from hematoxylin and eosin staining revealed that naringin dose dependently reduced CS-induced infiltration of inflammatory cells, thickening of the bronchial wall, and expansion of average alveolar airspace. In conclusion, our data suggest that naringin is an effective anti-inflammatory compound for attenuating chronic pulmonary neutrophilic inflammation in CS-induced rats. © Copyright 2012, Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition 2012.published_or_final_versio

Semiparametric Multivariate Accelerated Failure Time Model with Generalized Estimating Equations

The semiparametric accelerated failure time model is not as widely used as the Cox relative risk model mainly due to computational difficulties. Recent developments in least squares estimation and induced smoothing estimating equations provide promising tools to make the accelerate failure time models more attractive in practice. For semiparametric multivariate accelerated failure time models, we propose a generalized estimating equation approach to account for the multivariate dependence through working correlation structures. The marginal error distributions can be either identical as in sequential event settings or different as in parallel event settings. Some regression coefficients can be shared across margins as needed. The initial estimator is a rank-based estimator with Gehan's weight, but obtained from an induced smoothing approach with computation ease. The resulting estimator is consistent and asymptotically normal, with a variance estimated through a multiplier resampling method. In a simulation study, our estimator was up to three times as efficient as the initial estimator, especially with stronger multivariate dependence and heavier censoring percentage. Two real examples demonstrate the utility of the proposed method

Healthy Campus Trial: A multiphase optimization strategy (MOST) fully factorial trial to optimize the smartphone cognitive behavioral therapy (CBT) app for mental health promotion among university students: Study protocol for a randomized controlled trial

This is the final version. Available from the publisher via the DOI in this record.After the publication of the primary findings, the de-identified and completely anonymized individual participant-level dataset will be posted on the UMIN-ICDR website (http://www.umin.ac.jp/icdr/index-j.html) so that it can be accessed by qualified researchers.Background: Youth in general and college life in particular are characterized by new educational, vocational, and interpersonal challenges, opportunities, and substantial stress. It is estimated that 30-50% of university students meet criteria for some mental disorder, especially depression, in any given year. The university has traditionally provided many channels to promote students' mental health, but until now only a minority have sought such help, possibly owing to lack of time and/or to stigma related to mental illness. Smartphone-delivered cognitive behavioral therapy (CBT) shows promise for its accessibility and effectiveness. However, its most effective components and for whom it is more (or less) effective are not known. Methods/design: Based on the multiphase optimization strategy framework, this study is a parallel-group, multicenter, open, fully factorial trial examining five smartphone-delivered CBT components (self-monitoring, cognitive restructuring, behavioral activation, assertion training, and problem solving) among university students with elevated distress, defined as scoring 5 or more on the Patient Health Questionnaire-9 (PHQ-9). The primary outcome is change in PHQ-9 scores from baseline to week 8. We will estimate specific efficacy of the five components and their interactions through the mixed-effects repeated-measures analysis and propose the most effective and efficacious combinations of components. Effect modification by selected baseline characteristics will be examined in exploratory analyses. Discussion: The highly efficient experimental design will allow identification of the most effective components and the most efficient combinations thereof among the five components of smartphone CBT for university students. Pragmatically, the findings will help make the most efficacious CBT package accessible to a large number of distressed university students at reduced cost; theoretically, they will shed light on the underlying mechanisms of CBT and help further advance CBT for depression

Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB independent manner.

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt

Two-loop RGEs with Dirac gaugino masses

The set of renormalisation group equations to two loop order for general supersymmetric theories broken by soft and supersoft operators is completed. As an example, the explicit expressions for the RGEs in a Dirac gaugino extension of the (N)MSSM are presented.Comment: 10 pages + 24 pages of RGEs in appendix; no figure

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Beyond Volume: The Impact of Complex Healthcare Data on the Machine Learning Pipeline

From medical charts to national census, healthcare has traditionally operated under a paper-based paradigm. However, the past decade has marked a long and arduous transformation bringing healthcare into the digital age. Ranging from electronic health records, to digitized imaging and laboratory reports, to public health datasets, today, healthcare now generates an incredible amount of digital information. Such a wealth of data presents an exciting opportunity for integrated machine learning solutions to address problems across multiple facets of healthcare practice and administration. Unfortunately, the ability to derive accurate and informative insights requires more than the ability to execute machine learning models. Rather, a deeper understanding of the data on which the models are run is imperative for their success. While a significant effort has been undertaken to develop models able to process the volume of data obtained during the analysis of millions of digitalized patient records, it is important to remember that volume represents only one aspect of the data. In fact, drawing on data from an increasingly diverse set of sources, healthcare data presents an incredibly complex set of attributes that must be accounted for throughout the machine learning pipeline. This chapter focuses on highlighting such challenges, and is broken down into three distinct components, each representing a phase of the pipeline. We begin with attributes of the data accounted for during preprocessing, then move to considerations during model building, and end with challenges to the interpretation of model output. For each component, we present a discussion around data as it relates to the healthcare domain and offer insight into the challenges each may impose on the efficiency of machine learning techniques.Comment: Healthcare Informatics, Machine Learning, Knowledge Discovery: 20 Pages, 1 Figur

Novel antiviral activity of neuraminidase inhibitors against an avian influenza a virus

<p>Abstract</p> <p>Background</p> <p>Neuraminidase (NA) inhibitors used for influenza therapy are believed to prevent the release of progeny virus from the surface of an infected cell. In this study, we found that NA inhibitors have a novel antiviral function against an avian influenza virus.</p> <p>Results</p> <p>Madin-Darby canine kidney cells, commonly used for the isolation and propagation of the influenza virus, were infected with an avian influenza viral strain A/chicken/German/N/49(H10N7) (H10/chicken) or a human influenza viral strain A/Osaka/981/98(H3N2) (H3/Osaka) virus. Cells were incubated in a medium without or with a NA inhibitor, oseltamivir carboxylate (GS4071), from 1 to 13 h post infection (p.i.). Infected cells were washed 12 h p.i. to remove GS4071, incubated for 1 h without GS4071, and assayed for virus production. Incubation with GS4071 decreased the production of infectious viruses. When H10/chicken virus-infected cells were incubated with GS4071 from 12 to 13 h p.i. (i.e., 1 h before the virus production assay), the inhibitory effect was clearly observed, however, the same was not evident for H3/Osaka virus-infected cells. Furthermore, viral protein synthesis in infected cells was not affected by GS4071. Using a scanning electron microscope, many single spherical buds were observed on the surface of H3/Osaka virus-infected cells incubated without GS4071, whereas many aggregated particles were observed on the surface of cells incubated with GS4071. However, many long tubular virus-like structures, with no aggregated particles, were observed on the surface of H10/chicken virus-infected cells incubated with GS4071. The same results were obtained when another NA inhibitor, zanamivir, was used.</p> <p>Conclusions</p> <p>These results indicate that NA inhibitors interfered with virus particle formation in the H10/chicken virus-infected cells, in which the inhibitor caused the formation of long tubular virus-like structures instead of spherical virus particles.</p