Leptonic Model for Neutrino Emission from Active Galactic Nuclei.

It is often stated that the observation of high-energy neutrinos from an astrophysical source would constitute indisputable proof for the acceleration of hadronic cosmic rays. Here, we point out that there exists a purely leptonic mechanism to produce TeV-scale neutrinos in astrophysical environments. In particular, very high-energy synchrotron photons can scatter with x rays, exceeding the threshold for muon-antimuon pair production.

Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition.

DNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD-consuming enzyme activated by strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has been previously linked to impaired glycolysis and mitochondrial dysfunction.

Synergistic and antagonistic interactions of binary mixtures of polycyclic aromatic hydrocarbons in the upregulation of CYP1 activity and mRNA levels in precision-cut rat liver slices.

The current studies investigate whether synergistic or antagonistic interactions in the upregulation of CYP1 activity occur in binary mixtures of polycyclic aromatic hydrocarbons (PAHs) involving benzo[a]pyrene and five other structurally diverse PAHs of varying carcinogenic activity. Precision-cut rat liver slices were incubated with benzo[a]pyrene alone or in combination with a range of concentrations of a second PAH, and ethoxyresorufin O-deethylase, CYP1A1 and CYP1B1 mRNA levels determined. Concurrent incubation of benzo[a]pyrene with either dibenzo[a,h]anthracene or fluoranthene in liver slices led to a synergistic interaction, at least at low concentrations, in that ethoxyresorufin O-deethylase activity was statistically higher than the added effects when the slices were incubated with the individual compounds.

Supporting Caregivers of Veterans Online: A Partnership of the National Council on Aging and VA.

The National Council on Aging's Building Better Caregivers program aims to improve the well-being of caregivers of veterans.

Inhibition of prenyltransferase activity by statins in both liver and muscle cell lines is not causative of cytotoxicity.

As inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, statins are an important first-line treatment for hypercholesterolemia. However, a recognized side-effect of statin therapy is myopathy, which in severe cases can present as potentially fatal rhabdomyolysis. This represents an important impediment to successful statin therapy, and despite decades of research the molecular mechanisms underlying this side-effect remain unclear.

The components of action planning and their associations with behavior and health outcomes.

Background: Based on the works of Kiesler and Bandura, action plans have become important tools in patient self-management programs. One such program, shown effective in randomized trials, is the Internet Chronic Disease Self-Management Program. An implementation of this program, Healthy Living Canada, included detailed information on action plans and health-related outcome measures.

Coding and evaluating facilitator posts for an online cancer survivor workshop.

One-hundred and forty-five people attended six online cancer survivor workshops. Each workshop was monitored by two facilitators, who generated a total of 1,537 online posts. The authors developed a scheme for coding facilitator posts, combining grounded codes with categories developed by Spiegel and Classen for coding therapist responses in cancer support groups.

Web-based self-management support training for health professionals: a pilot study.

Objective: To evaluate a web-based self-management training for health professionals. Patients spend 99% of their time outside the healthcare system. Thus self-management support from health professionals is central to optimal care.

The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor.

As the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices.

The South Australia health chronic disease self-management Internet trial.

Objectives: To evaluate the effectiveness of an online chronic disease self-management program for South Australia residents.

Method: Data were collected online at baseline, 6 months, and 12 months. The intervention was an asynchronous 6-week chronic disease self-management program offered online.

Phenethyl isothiocyanate, a naturally occurring phytochemical, is an antagonist of the aryl hydrocarbon receptor.

Scope: The aryl hydrocarbon (Ah) receptor is a ligand-activated transcription factor that is activated by many carcinogens, and its target gene products play a major role in tumour development, so that antagonists of the Ah receptor represent potential chemopreventive agents.

Methods And Results: Experimental evidence is presented herein that phenethyl isothiocyanate (PEITC), a phytochemical present in cruciferous vegetables, is such an antagonist. PEITC was a very weak ligand to the Ah receptor, as assessed using the chemical-activated luciferase expression (CALUX) assay, and a poor inducer of CYP1A1 mRNA levels when incubated in precision-cut rat liver slices for 24 h.

A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.

The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals.

Online diabetes self-management program: a randomized study.

Objective: We hypothesized that people with type 2 diabetes in an online diabetes self-management program, compared with usual-care control subjects, would 1) demonstrate reduced A1C at 6 and 18 months, 2) have fewer symptoms, 3) demonstrate increased exercise, and 4) have improved self-efficacy and patient activation. In addition, participants randomized to listserve reinforcement would have better 18-month outcomes than participants receiving no reinforcement.

Research Design And Methods: A total of 761 participants were randomized to 1) the program, 2) the program with e-mail reinforcement, or 3) were usual-care control subjects (no treatment).

The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1.

The mood stabilizing agents lithium chloride (LiCl) and sodium valproate (VPA) have recently gained interest as potential neuroprotective therapeutics. However, exploitation of these therapeutic applications is hindered by both a lack of molecular understanding of the mode of action, and a number of sub-optimal properties, including a relatively small therapeutic window and variable patient response. Human neuroblastoma cells (SH-SY5Y) were exposed to 1 mM lithium chloride or 1 mM sodium valproate for 6 h or 72 h, and transcriptomes measured by Affymetrix U133A/B microarray.

The Expert Patients Programme online, a 1-year study of an Internet-based self-management programme for people with long-term conditions.

Objectives: Evaluate the effectiveness of an online self-management programme (EPP Online) for England residents with long-term conditions.

Methods: A prospective longitudinal study. Data were collected online at baseline, 6 and 12 months.

The internet-based arthritis self-management program: a one-year randomized trial for patients with arthritis or fibromyalgia.

Objective: To determine the efficacy of an Internet-based Arthritis Self-Management Program (ASMP) as a resource for arthritis patients unable or unwilling to attend small-group ASMPs, which have proven effective in changing health-related behaviors and improving health status measures.

Methods: Randomized intervention participants were compared with usual care controls at 6 months and 1 year using repeated-measures analyses of variance. Patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia and Internet and e-mail access (n = 855) were randomized to an intervention (n = 433) or usual care control (n = 422) group.

Up-regulation of the glutathione S-transferase system in human liver by polycyclic aromatic hydrocarbons; comparison with rat liver and lung.

The cytosolic glutathione S-transferases (GSTs) comprise a pivotal enzyme system protecting the cell from electrophilic compounds. It plays a major role in the detoxication of the primary and dihydrodiol epoxides of polycyclic aromatic hydrocarbons (PAHs), so that modulation of this enzyme system by PAHs will impact on their carcinogenic activity. The potential of six structurally diverse PAHs, namely benzo[a]pyrene (B[a]P), fluoranthene, benzo[b]fluoranthene (B[b]F), dibenzo[a,l]pyrene, dibenzo[a,h]anthracene (D[a,h]A) and 1-methhylphenanthrene, to modulate hepatic GST activity was investigated in human precision-cut slices and compared to rat slices, a species frequently used in long-term carcinogenicity studies; changes were monitored at the activity, using three different substrates, protein and mRNA levels.

Differential response of human and rat epoxide hydrolase to polycyclic aromatic hydrocarbon exposure: studies using precision-cut tissue slices.

The potential of polycyclic aromatic hydrocarbons (PAHs) to modulate microsomal epoxide hydrolase activity, determined using benzo[a]pyrene 5-oxide as substrate, in human liver, was evaluated and compared to rat liver. Precision-cut liver slices prepared from fresh human liver were incubated with six structurally diverse PAHs, at a range of concentrations, for 24h. Of the six PAHs studied, benzo[a]pyrene, dibenzo[a,h]anthracene and fluoranthene gave rise to a statistically significant increase in epoxide hydrolase activity, which was accompanied by a concomitant increase in epoxide hydrolase protein levels determined by immunoblotting.

Up-regulation of CYP1A/B in rat lung and liver, and human liver precision-cut slices by a series of polycyclic aromatic hydrocarbons; association with the Ah locus and importance of molecular size.

Exposure of precision-cut rat liver slices to six structurally diverse polycyclic aromatic hydrocarbons, namely benzo[a]pyrene, benzo[b]fluoranthene, dibenzo[a,h]anthracene, dibenzo[a,l]pyrene, fluoranthene and 1-methylphenanthrene, led to induction of ethoxyresorufin O-deethylase, CYP1A apoprotein and CYP1A1 mRNA levels, but to a markedly different extent. In liver slices, constitutive CYP1A1 mRNA levels were higher, as well as being markedly more inducible by PAHs, compared with CYP1B1, a similar profile to that observed in human liver slices following exposure to the PAHs. Increase in ethoxyresorufin O-deethylase and in CYP1A1 apoprotein levels was also observed when precision-cut rat lung slices were incubated with the same PAHs, the order of induction potency being similar to that observed in liver slices.

Evaluation of the precision-cut liver and lung slice systems for the study of induction of CYP1, epoxide hydrolase and glutathione S-transferase activities.

The principal objective was to ascertain whether precision-cut tissue slices can be used to evaluate the potential of chemicals to induce CYP1, epoxide hydrolase and glutathione S-transferase activities, all being important enzymes involved in the metabolism of polycyclic aromatic hydrocarbons. Precision-cut rat liver and lung slices were incubated with a range of benzo[a]pyrene concentrations for various time periods. A rise in the O-deethylation of ethoxyresorufin was seen in both liver and lung slices exposed to benzo[a]pyrene, which was accompanied by increased CYP1A apoprotein levels.

Steroidogenic gene expression in H295R cells and the human adrenal gland: adrenotoxic effects of lindane in vitro.

The focus on the refinement, reduction and replacement of animal use in toxicity testing requires the development of cell-based systems that mimic the effects of xenobiotics in human tissues. The human adrenocortical carcinoma cell line, H295R, has been proposed as a model for studies on adrenal steroidogenesis and its disruption. In this study, expression profiles for nine adrenal steroidogenic genes were characterized in H295R cells using real-time RT-PCR.

Internet-based chronic disease self-management: a randomized trial.

Background: The small-group Chronic Disease Self-Management Program (CDSMP) has proven effective in changing health-related behaviors and improving health statuses. An Internet-based CDSMP was developed to reach additional chronic-disease patients.

Objectives: We sought to determine the efficacy of the Internet-based CDSMP.

Transcriptomic and phylogenetic analysis of Kpna genes: a family of nuclear import factors modulated in xenobiotic-mediated liver growth.

Objectives: We have identified a member of the karyopherin (importin) alpha family of nuclear import factors as being modulated in rat liver following exposure to the hypolipidaemic and liver growth agent Wy-14,643. To examine the hypothetical role of this protein family as a checkpoint in receptor-mediated signalling, we characterized the rat karyopherin alpha (Kpna) gene family and present cDNA sequences and gene structures for all six rat Kpna genes. Further, we have assembled a comprehensive panel of Kpna coding regions from a range of metazoa, which we have subjected to phylogenetic analysis: This represents by far the most complete phylogenetic study of metazoan karyopherins, including several evolutionary intermediates not previously examined.

A disease-specific self-help program compared with a generalized chronic disease self-help program for arthritis patients.

Objective: Both the Arthritis Self-Management Program (ASMP) and the generic Chronic Disease Self-Management Program (CDSMP) have been shown to be successful in improving conditions in patients with arthritis. This study compared the relative effectiveness of the 2 programs for individuals with arthritis.

Methods: Patients whose primary disease was arthritis were randomized to the ASMP (n = 239) or to the CDSMP (n = 116).

Strong polyadenylation and weak pausing combine to cause efficient termination of transcription in the human Ggamma-globin gene.

The human gamma-globin genes form part of a 5-kb tandem duplication within the beta-globin gene cluster on chromosome 11. Despite a high degree of identity between the two genes, we show that while the upstream Ggamma-globin gene terminates transcription efficiently, termination in the Agamma gene is inefficient. This is primarily due to the different strengths of the polyA signals of the two genes; Ggamma-globin has a functionally stronger polyA signal than the Agamma gene.