Anti-tumor necrosis factor-Α antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust

Background/Aims Recent studies documented that sensitization and exposure to cockroach allergens significantly increase children's asthma morbidity as well as severity, especially among inner city children. TNF-Α has been postulated to be a critical mediator directly contributing to the bronchopulmonary inflammation and airway hyper-responsiveness in asthma. This study investigated whether an anti-TNF-Α antibody would inhibit pulmonary inflammation and methacholine (Mch) hyper-responsiveness in a mouse model of asthma induced by a house dust extract containing both endotoxin and cockroach allergens. Methods A house dust sample was extracted with phosphate-buffered saline and then used for immunization and two additional pulmonary challenges of BALB/c mice. Mice were treated with an intravenous injection of anti-TNF-Α antibody or control antibody 1  h before each pulmonary challenge. Results In a kinetic study, TNF-Α levels within the bronchoalveolar lavage (BAL) fluid increased quickly peaking at 2 h while BAL levels of IL-4, IL-5, and IL-13 peaked at later time-points. Mch hyper-responsiveness was measured 24 h after the last challenge, and mice were killed 24 h later. TNF inhibition resulted in an augmentation of these Th2 cytokines. However, the allergic pulmonary inflammation was significantly reduced by anti-TNF-Α antibody treatment as demonstrated by a substantial reduction in the number of BAL eosinophils, lymphocytes, macrophages, and neutrophils compared with rat IgG-treated mice. Mch hyper-responsiveness was also significantly reduced in anti-TNF-Α antibody-treated mice and the pulmonary histology was also significantly improved. Inhibition of TNF significantly reduced eotaxin levels within the lung, suggesting a potential mechanism for the beneficial effects. These data indicate that anti-TNF-Α antibody can reduce the inflammation and pathophysiology of asthma in a murine model of asthma induced by a house dust extract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73609/1/j.1365-2222.2005.02407.x.pd

The effects of theaflavin-enriched black tea extract on muscle soreness, oxidative stress, inflammation, and endocrine responses to acute anaerobic interval training: a randomized, double-blind, crossover study

<p>Abstract</p> <p>Background</p> <p>Muscle soreness and decreased performance often follow a bout of high-intensity exercise. By reducing these effects, an athlete can train more frequently and increase long-term performance. The purpose of this study is to examine whether a high-potency, black tea extract (BTE) alters the delayed onset muscle soreness (DOMS), oxidative stress, inflammation, and cortisol (CORT) responses to high-intensity anaerobic exercise.</p> <p>Methods</p> <p>College-age males (N = 18) with 1+ yrs of weight training experience completed a double-blind, placebo-controlled, crossover study. Subjects consumed the BTE (1,760 mg BTE·d^-1) or placebo (PLA) for 9 days. Each subject completed two testing sessions (T1 & T2), which occurred on day 7 of the intervention. T1 & T2 consisted of a 30 s Wingate Test plus eight 10 s intervals. Blood samples were obtained before, 0, 30 & 60 min following the interval sessions and were used to analyze the total to oxidized glutathione ratio (GSH:GSSG), 8-isoprostane (8-iso), CORT, and interleukin 6 (IL-6) secretion. DOMS was recorded at 24 & 48 h post-test using a visual analog scale while BTE or PLA continued to be administered. Significance was set at <it>P < 0.05</it>.</p> <p>Results</p> <p>Compared to PLA, BTE produced significantly higher average peak power (<it>P = 0.013</it>) and higher average mean power (<it>P = 0.067</it>) across nine WAnT intervals. BTE produced significantly lower DOMS compared to PLA at 24 h post test (<it>P < 0.001</it>) and 48 h post test (<it>P < 0.001</it>). Compared to PLA, BTE had a slightly higher GSH:GSSG ratio at baseline which became significantly higher at 30 and 60 min post test (<it>P < 0.002</it>). AUC analysis revealed BTE to elicit significantly lower GSSG secretion (<it>P = 0.009</it>), significantly higher GSH:GSSG ratio (<it>P = 0.001</it>), and lower CORT secretion (<it>P = 0.078</it>) than PLA. AUC analysis did not reveal a significant difference in total IL-6 response (<it>P = 0.145</it>) between conditions.</p> <p>Conclusions</p> <p>Consumption of theaflavin-enriched black tea extract led to improved recovery and a reduction in oxidative stress and DOMS responses to acute anaerobic intervals. An improved rate of recovery can benefit all individuals engaging in high intensity, anaerobic exercise as it facilitates increased frequency of exercise.</p

Metformin mitigates the impaired development of skeletal muscle in the offspring of obese mice

Background: Maternal obesity is linked with offspring obesity and type 2 diabetes. Skeletal muscle (SM) insulin resistance is central to the development of diabetes. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited in SM of fetuses born to obese mothers

HIV-1 gp41 and TCRα Trans-Membrane Domains Share a Motif Exploited by the HIV Virus to Modulate T-Cell Proliferation

Viruses have evolved several strategies to modify cellular processes and evade the immune response in order to successfully infect, replicate, and persist in the host. By utilizing in-silico testing of a transmembrane sequence library derived from virus protein sequences, we have pin-pointed a nine amino-acid motif shared by a group of different viruses; this motif resembles the transmembrane domain of the α-subunit of the T-cell receptor (TCRα). The most striking similarity was found within the immunodeficiency virus (SIV and HIV) glycoprotein 41 TMD (gp41 TMD). Previous studies have shown that stable interactions between TCRα and CD3 are localized to this nine amino acid motif within TCRα, and a peptide derived from it (TCRα TMD, GLRILLLKV) interfered and intervened in the TCR function when added exogenously. We now report that the gp41 TMD peptide co-localizes with CD3 within the TCR complex and inhibits T cell proliferation in vitro. However, the inhibitory mechanism of gp41 TMD differs from that of the TCRα TMD and also from the other two known immunosuppressive regions within gp41

Objective and subjective assessment of sleep in chronic low back pain patients compared with healthy age and gender matched controls: a pilot study

<p>Abstract</p> <p>Background</p> <p>While approximately 70% of chronic low back pain (CLBP) sufferers complain of sleep disturbance, current literature is based on self report measures which can be prone to bias and no objective data of sleep quality, based exclusively on CLBP are available. In accordance with the recommendations of The American Sleep Academy, when measuring sleep, both subjective and objective assessments should be considered as the two are only modestly correlated, suggesting that each modality assesses different aspects of an individual's sleep experience. Therefore, the purpose of this study was to expand previous research into sleep disturbance in CLBP by comparing objective and subjective sleep quality in participants with CLBP and healthy age and gender matched controls, to identify correlates of poor sleep and to test logistics and gather information prior to a larger study.</p> <p>Methods</p> <p>15 CLBP participants (mean age = 43.8 years (SD = 11.5), 53% female) and 15 healthy controls (mean age = 41.5 years (SD = 10.6), 53% female) consented. All participants completed the Pittsburgh Sleep Quality Index, Insomnia Severity Index, Pittsburgh Sleep Diary and the SF36v2. CLBP participants also completed the Oswestry Disability Index. Sleep patterns were assessed over three consecutive nights using actigraphy. Total sleep time (TST), sleep efficiency (SE), sleep latency onset (SL) and number of awakenings after sleep onset (WASO) were derived. Statistical analysis was conducted using unrelated t-tests and Pearson's product moment correlation co-efficients.</p> <p>Results</p> <p>CLBP participants demonstrated significantly poorer overall sleep both objectively and subjectively. They demonstrated lower actigraphic SE (p = .002) and increased WASO (p = .027) but no significant differences were found in TST (p = .43) or SL (p = .97). Subjectively, they reported increased insomnia (p =< .001), lower SE (p =< .001) and increased SL (p =< .001) but no difference between TST (p = .827) and WASO (p = .055). Statistically significant associations were found between low back pain (p = .021, r = -.589), physical health (p = .003, r = -.713), disability levels (p = .025, r = .576), and subjective sleep quality in the CLBP participants but not with actigraphy.</p> <p>Conclusion</p> <p>CLBP participants demonstrated poorer overall sleep, increased insomnia symptoms and less efficient sleep. Further investigation using a larger sample size and a longer period of sleep monitoring is ongoing.</p

De novo identification of viral pathogens from cell culture hologenomes

<p>Abstract</p> <p>Background</p> <p>Fast, specific identification and surveillance of pathogens is the cornerstone of any outbreak response system, especially in the case of emerging infectious diseases and viral epidemics. This process is generally tedious and time-consuming thus making it ineffective in traditional settings. The added complexity in these situations is the non-availability of pure isolates of pathogens as they are present as mixed genomes or hologenomes. Next-generation sequencing approaches offer an attractive solution in this scenario as it provides adequate depth of sequencing at fast and affordable costs, apart from making it possible to decipher complex interactions between genomes at a scale that was not possible before. The widespread application of next-generation sequencing in this field has been limited by the non-availability of an efficient computational pipeline to systematically analyze data to delineate pathogen genomes from mixed population of genomes or hologenomes.</p> <p>Findings</p> <p>We applied next-generation sequencing on a sample containing mixed population of genomes from an epidemic with appropriate processing and enrichment. The data was analyzed using an extensive computational pipeline involving mapping to reference genome sets and <it>de-novo </it>assembly. In depth analysis of the data generated revealed the presence of sequences corresponding to <it>Japanese encephalitis </it>virus. The genome of the virus was also independently <it>de-novo </it>assembled. The presence of the virus was in addition, verified using standard molecular biology techniques.</p> <p>Conclusions</p> <p>Our approach can accurately identify causative pathogens from cell culture hologenome samples containing mixed population of genomes and in principle can be applied to patient hologenome samples without any background information. This methodology could be widely applied to identify and isolate pathogen genomes and understand their genomic variability during outbreaks.</p

Abilities to explicitly and implicitly infer intentions from actions in adults with autism spectrum disorder

Previous research suggests that Autism Spectrum Disorder (ASD) might be associated with impairments on implicit but not explicit mentalizing tasks. However, such comparisons are made difficult by the heterogeneity of stimuli and the techniques used to measure mentalizing capabilities. We tested the abilities of 34 individuals (17 with ASD) to derive intentions from others’ actions during both explicit and implicit tasks and tracked their eye-movements. Adults with ASD displayed explicit but not implicit mentalizing deficits. Adults with ASD displayed typical fixation patterns during both implicit and explicit tasks. These results illustrate an explicit mentalizing deficit in adults with ASD, which cannot be attributed to differences in fixation patterns

Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins

In an attempt to improve TRAIL's (tumor necrosis factor-related apoptosis-inducing ligand) tumor selective activity a variant was designed, in which the three TRAIL protomers are expressed as a single polypeptide chain (scTRAIL). By genetic fusion with a single-chain antibody fragment (scFv) recognizing the extracellular domain of ErbB2, we further equipped scTRAIL with tumor-targeting properties. We studied tumor targeting and apoptosis induction of scFv–scTRAIL in comparison with non-targeted scTRAIL. Importantly, the tumor antigen-targeted scTRAIL fusion protein showed higher apoptotic activity in vitro, with a predominant action by TRAIL-R2 signaling. Pharmacokinetic studies revealed increased plasma half-life of the targeted scTRAIL fusion protein compared with scTRAIL. In vivo studies in a mouse tumor model with xenotransplanted Colo205 cells confirmed greater response to the ErbB2-specific scTRAIL fusion protein compared with non-targeted scTRAIL both under local and systemic application regimen. Together, in vitro and in vivo data give proof of concept of higher therapeutic activity of tumor-targeted scFv–scTRAIL molecules. Further, we envisage that through targeting of scTRAIL, potential side effects should be minimized. We propose that scFv-mediated tumor targeting of single-chain TRAIL represents a promising strategy to improve TRAIL's antitumoral action and to minimize potential unwanted actions on normal tissues