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The post VIDEO: AG Barr criticizes Mueller’s handling of Steele dossier appeared first on Dennis Michael Lynch.

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The post BREAKING: Founding Father of Rock Who Broke Musical Barriers, Dead at 87 appeared first on Dennis Michael Lynch.

Church bells rang out across the city of Barrie on Friday morning to commemorate the anniversary of the Victory in Europe Day on Friday.

Under 35s Forum

Event participants

6 November 2019

Toni Tripp-Reimer
Jan 1, 2001; 14:
Articles

Philip E. Cryer
Jan 1, 2002; 15:
Articles

Russell E. Glasgow
Jan 1, 2001; 14:
Articles

Toni Tripp-Reimer
Jan 1, 2001; 14:
Articles

P-glycoprotein (ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting the clearance of neurotoxic beta-amyloid (Aß) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease (AD) patients. Treatment with drugs which induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aß deposits in the brain by enhancing the clearance of Aß peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer ¹¹C-metoclopramide can measure ABCB1 induction at the BBB in a beta-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 days underwent ¹¹C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor (PXR) activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 days. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aß levels. In separate groups of mice, radiolabeled metabolites of ¹¹C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aß levels. There was a significant positive correlation between kE,brain values and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain values was found. Metabolite analysis showed that the majority of radioactivity in the brain was composed of unmetabolized ¹¹C-metoclopramide in all animal groups. Conclusion: ¹¹C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in AD patients to non-invasively evaluate strategies to enhance the clearance properties of the BBB.

Multidrug resistance-associated protein 1 (ABCC1) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. Aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-¹¹C-methylpurine (¹¹C-BMP), a prodrug radiotracer which is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571 and wild-type control rats underwent dynamic PET scans after administration of ¹¹C-BMP intravenously (i.v.) or by intratracheal aerosolization (i.t.). In vitro transport experiments were performed with unlabeled BMP in the human distal lung epithelial cell line NCI-H441. Results: Pulmonary kinetics of radioactivity were significantly different between wild-type and Abcc1(-/-) rats, but differences were more pronounced after i.t. than after i.v. administration. After i.v. administration lung exposure (AUClung) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower, whereas after i.t. administration AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after i.t. radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in presence than in absence of MK571. Conclusion: PET with pulmonary administered ¹¹C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms or concomitant drug intake on pulmonary ABCC1 activity.

Jeroen van Smeden
Apr 7, 2020; 0:jlr.RA120000639v1-jlr.RA120000639
Research Articles

Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) stratum corneum ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active, epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in stratum corneum ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered stratum corneum ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS. 

Sepsis is defined as the systemic, dysregulated host immune response to an infection that leads to injury to host organ systems, and, often, death. Complex interactions between pathogens and their hosts elicit microcirculatory dysfunction. Neutrophil myeloperoxidase (MPO) is critical for combating pathogens, but MPO-derived hypochlorous acid (HOCl) can react with host molecular species as well. Plasmalogens are targeted by HOCl, leading to the production of 2-chlorofatty acids (2-CLFAs). 2-CLFAs are associated with human sepsis mortality, decrease in vitroendothelial barrier function, and activate human neutrophil extracellular trap formation. Here, we sought to examine 2-CLFAs in an in vivorat sepsis model. Intraperitoneal cecal slurry sepsis with clinically relevant rescue therapies led to ~73% mortality and evidence of microcirculatory dysfunction. Plasma concentrations of 2-CLFAs assessed 8h after sepsis induction were lower in rats that survived sepsis than in non-survivors. 2-CLFA levels were elevated in kidney, liver, spleen, lung, colon and ileum in septic animals. In vivo, exogenous 2-CLFA treatments increased kidney permeability, and in in vitroexperiments 2-CLFA also increased epithelial surface expression of vascular cell adhesion molecule 1 and decreased epithelial barrier function. Collectively, these studies support a role of free 2-CLFAs as biomarkers of sepsis mortality, potentially mediated, in part, by 2-CLFA-elicited endothelial and epithelial barrier dysfunction.

Ceramides (Cers) with ultralong (~32-carbon) chains and -esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ~10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content—namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.

Amid aging populations and the growth of chronic diseases, the demand for skilled health-care professionals is on the rise in the United States, Canada, and Mexico. This report explores the policy implications, benefits, and challenges of harmonizing nursing qualifications in the region, suggesting that a more collaborative approach could result in greater supply and quality of nurses.

Marking the release of an MPI report, researchers and practitioners on this webinar discuss brain waste among college-educated immigrants and initiatives that ease the barriers foreign-educated newcomers confront with regards to credential recognition, employment, and relicensure, as well as recent policy developments and ongoing challenges in the field.

Marking the release of a report on the barriers foreign-trained high-skilled immigrants face in the United States, this webinar examines programs and initiatives that assist with credential recognition, employment, and relicensure, as well as recent policy developments. Discussants review recommendations for community-based organizations, employers, and policymakers to expand successful efforts aimed at preventing brain waste. 

Delicious fish dish for a summer night.

This recipe features on Foodie Tuesday, a weekly segment on 774 Drive with Raf Epstein, 3.30PM, shared by John Susman.

As millions of U.S. workers lose jobs and the health insurance associated with them, Medicaid and similar programs are increasingly important for people seeking COVID-19 testing and treatment. Yet many low-income uninsured noncitizens, including green-card holders, are excluded from such programs because of their immigration status, as this fact sheet explores.

John B. Buse
Jul 1, 2002; 20:
Feature Articles

"This report is the final report for the Orange-bellied Parrot Habitat Management and Restoration Project carried out on King Island. The report relates to the activity period starting 30th of June 2007 and finishing on the 25th of May 2008."--Introduction.

Paris : Didot le jeune, 1827.

London : H. Renshaw, 1861.

Paris : V.A. Delahaye, 1878.

In a case implicating the use of schools as voting locations as well as free speech in education, the justices said Minnesota went too far.

The Justice Department announced Thursday that it is dropping its criminal case against President Trump's first national security adviser Michael Flynn. Flynn twice admitted in court he lied to the FBI about his conversations with Russia's U.S. ambassador, and then cooperated in Special Counsel Robert Mueller's investigation. It was an unusual move by the Justice Department, and CNN's legal and political analysts smelled a rat."Attorney General [William] Barr is already being accused of creating a special justice system just for President Trump's friends," and this will only feed that perception, CNN's Jake Tapper suggested. Political correspondent Sara Murray agreed, noting that the prosecutor in the case, Brandon Van Grack, withdrew right before the Justice Department submitted its filing, just like when Barr intervened to request a reduced sentence for Roger Stone.National security correspondent Jim Sciutto laid out several reason why the substance of Flynn's admitted lie was a big deal, and chief legal analyst Jeffrey Toobin was appalled. "It is one of the most incredible legal documents I have read, and certainly something that I never expected to see from the United States Department of Justice," Toobin said. "The idea that the Justice Department would invent an argument -- an argument that the judge in this case has already rejected -- and say that's a basis for dropping a case where a defendant admitted his guilt shows that this is a case where the fix was in."Barr told CBS News' Cathrine Herridge on Thursday that dropping Flynn's case actually "sends the message that there is one standard of justice in this country." Herridge told Barr he would take flak for this, asking: "When history looks back on this decision, how do you think it will be written?" Barr laughed: "Well, history's written by the winners. So it largely depends on who's writing the history." Watch below. More stories from theweek.com Outed CIA agent Valerie Plame is running for Congress, and her launch video looks like a spy movie trailer 7 scathing cartoons about America's rush to reopen Trump says he couldn't have exposed WWII vets to COVID-19 because the wind was blowing the wrong way

Masaki Yamamoto
May 22, 2019; 39:4179-4192
Neurobiology of Disease

The severity of this year's bleaching is second only to 2016, during which a third of the reef’s corals died

The Mississauga Food Bank says a $100,000 donation made earlier this week by New York Knicks rookie RJ Barrett will provide 200,000 meals as part of the community's fight against the COVID-19 pandemic.

A Thousand Moons

IF ever we needed to indulge in a bout of collective escapism, if only for 60 minutes on a Sunday night, then that time is now. Thankfully ITV has just the thing – Belgravia, the latest big budget costume drama from Downton Abbey creator Julian Fellowes and a series that positively ripples with dimples, quiffs, honey-coloured chiffon frocks, eye-popping millinery and glamorous uniforms.

WHEN Malian quartet Songhoy Blues performed at last year's Celtic Connections, audiences were treated to a form of music appealingly dubbed “desert blues”. A user-friendly term, it sounds like it could have been dreamed up by a marketing agency and applied equally well to a perfume, a brand of jeans or a chain of upmarket Tex-Mex restaurants.

To the Editor: Education Week Teacher blogger Nancy Flanagan recently wrote about how some states require a higher score on state certification tests for teacher-licensing exams—which makes it "unreasonably difficult" to get into teaching—while others eliminate licensing requirements to fill classr.

“THE little island of Todday is a completely isolated community,” declares the voiceover at the start of the 1949 Ealing Studios classic Whisky Galore. “100 miles from the mainland, 100 miles from the nearest cinema or dancehall. Oh, but the islanders know how to enjoy themselves. They have all that they need. But in 1943, disaster overwhelmed this little island. Not famine, nor pestilence, nor Hitler’s bombs, or the hordes of an invading army, but something far, far worse: ‘There is n

Moonlight, Film 4, Wednesday, 9pm

Previous studies have identified barriers to providing optimal pediatric palliative care, including general communication issues between clinicians and family members. However, there is a paucity of data regarding the barriers specifically relating to advance care discussions.

This study identifies significant barriers to advance care discussions for children with life-threatening conditions. Clinicians perceive parental issues as the most common impediments to these discussions. Furthermore, providers believe that advance care discussions happen too late in the course of illness. (Read the full article)

Nonadherence to antiretroviral therapy among children and youth with HIV is a frequent problem that can result in treatment failure and disease progression for this population. Children and adolescents face different barriers to adherence than adults infected with HIV.

Few studies have examined specific barriers to adherence as reported by children with perinatally acquired HIV and their caregivers. This report examines the agreement between child and caregiver perceptions of adherence barriers and the factors associated with these barriers. (Read the full article)