Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers

Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids

We recently demonstrated that 12/15-lipoxygenase (LOX) derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy (DR) via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Here, we test whether PEDF ameliorates retinal vascular injury induced by HETEs and the underlying mechanisms. Furthermore, we pursue the causal relationship between LOX–NOX system and regulation of PEDF expression during DR. For these purposes, we used an experimental eye model in which normal mice were injected intravitreally with 12-HETE with/without PEDF. Thereafter, fluorescein angiography (FA) was used to evaluate the vascular leakage, followed by optical coherence tomography (OCT) to assess the presence of angiogenesis. FA and OCT reported an increased vascular leakage and pre-retinal neovascularization, respectively, in response to 12-HETE that were not observed in the PEDF-treated group. Moreover, PEDF significantly attenuated the increased levels of vascular cell and intercellular adhesion molecules, VCAM-1 and ICAM-1, elicited by 12-HETE injection. Accordingly, the direct relationship between HETEs and PEDF has been explored through in-vitro studies using Müller cells (rMCs) and human retinal endothelial cells (HRECs). The results showed that 12- and 15-HETEs triggered the secretion of TNF-α and IL-6, as well as activation of NFκB in rMCs and significantly increased permeability and reduced zonula occludens protein-1 (ZO-1) immunoreactivity in HRECs. All these effects were prevented in PEDF-treated cells. Furthermore, interest in PEDF regulation during DR has been expanded to include NOX system. Retinal PEDF was significantly restored in diabetic mice treated with NOX inhibitor, apocynin, or lacking NOX2 up to 80% of the control level. Collectively, our findings suggest that interfering with LOX–NOX signaling opens up a new direction for treating DR by restoring endogenous PEDF that carries out multilevel vascular protective functions.National Eye Institute 5R01EY023315-02, Qatar National Research Fund NPRP 4-1046-3-284, and Vision Discovery Institute (MA), Mr. and Mrs. Richards travel award (ASI)

Pigment Epithelium–Derived Factor Regulates Lipid Metabolism via Adipose Triglyceride Lipase

OBJECTIVE: Pigment epithelium-derived factor (PEDF) is an adipocyte-secreted factor involved in the development of insulin resistance in obesity. Previous studies have identified PEDF as a regulator of triacylglycerol metabolism in the liver that may act through adipose triglyceride lipase (ATGL). We used ATGL(-/-) mice to determine the role of PEDF in regulating lipid and glucose metabolism. RESEARCH DESIGN AND METHODS: Recombinant PEDF was administered to ATGL(-/-) and wild-type mice, and whole-body energy metabolism was studied by indirect calorimetry. Adipose tissue lipolysis and skeletal muscle fatty acid metabolism was determined in isolated tissue preparations. Muscle lipids were assessed by electrospray ionization-tandem mass spectrometry. Whole-body insulin sensitivity and skeletal muscle glucose uptake were assessed. RESULTS: PEDF impaired the capacity to adjust substrate selection, resulting in a delayed diurnal decline in the respiratory exchange ratio, and suppressed daily fatty acid oxidation. PEDF enhanced adipocyte lipolysis and triacylglycerol lipase activity in skeletal muscle. Muscle fatty acid uptake and storage were unaffected, whereas fatty acid oxidation was impaired. These changes in lipid metabolism were abrogated in ATGL(-/-) mice and were not attributable to hypothalamic actions. ATGL(-/-) mice were also refractory to PEDF-mediated insulin resistance, but this was not related to changes in lipid species in skeletal muscle. CONCLUSIONS: The results are the first direct demonstration that 1) PEDF influences systemic fatty acid metabolism by promoting lipolysis in an ATGL-dependent manner and reducing fatty acid oxidation and 2) ATGL is required for the negative effects of PEDF on insulin action

Microfluidic and Nanofluidic Cavities for Quantum Fluids Experiments

The union of quantum fluids research with nanoscience is rich with opportunities for new physics. The relevant length scales in quantum fluids, 3He in particular, are comparable to those possible using microfluidic and nanofluidic devices. In this article, we will briefly review how the physics of quantum fluids depends strongly on confinement on the microscale and nanoscale. Then we present devices fabricated specifically for quantum fluids research, with cavity sizes ranging from 30 nm to 11 microns deep, and the characterization of these devices for low temperature quantum fluids experiments.Comment: 12 pages, 3 figures, Accepted to Journal of Low Temperature Physic

House Dust Mite Subcutaneous Immunotherapy Does Not Induce New Sensitization to Tropomyosin: Does It Do the Opposite?

Abstract Background: It is still uncertain whether house dust mite (HDM) tropomyosin present in allergen extracts can cross-sensitize patients receiving subcutaneous immunotherapy (SCIT) and thus induce food allergy. Objectives: Our aim was to assess whether new sensitization to tropomyosin occurred during HDM-SCIT, and, if so, whether it was clinically relevant. Patients and Methods: The study sample comprised 56 HDM-allergic patients treated with SCIT using HDM extract. All patients were screened for specific IgE (sIgE) to mite tropomyosin (rDer p 10) before and after SCIT. In patients with a positive result, we also monitored the dynamics of sIgE to rDer p 10 and shrimp tropomyosin (rPen a 1) at several time points. The levels of sIgE were measured using the CAP System fluorescent-enzyme immunoassay. Results: sIgE to tropomyosin was found in only 5 patients, 3 of whom expressed low and clinically irrelevant levels of sIgE to Der p 10, while sIgE to Pen a 1 was not found. The remaining 2 patients expressed sIgE to both tropomyosins. In the first, the initial increase and subsequent decrease resembled the dynamics of the IgE antibodies usually seen in SCIT patients and were never accompanied by seafood-induced symptoms. In the other, a decrease in levels of sIgE to both tropomyosins resulted in the complete loss of his reactivity toward seafood. Conclusions: Immunotherapy using HDM extracts does not induce clinically relevant sensitization to tropomyosin. In certain cases of combined mite and seafood allergy, treatment may even lead to the improvement of food allergy symptoms. The levels of sIgE to Der p 10 and Pen a 1 may be useful monitoring markers. Key words: House dust mite. Seafood. Sensitization. Specific immunotherapy. Tropomyosin. n Resumen Antecedentes: Es un hecho incierto que la tropomiosina presente en los extractos alergénicos puede sensibilizar a los pacientes que reciben inmunoterapia Ag-específica e inducir alergia alimentaria. Objetivo: El objetivo de este estudio fue evaluar si una inmunoterapia subcutánea con extractos de ácaros del polvo de casa puede inducir a una sensibilización a tropomiosina y si esta podría ser clínicamente relevante. Métodos: Se incluyeron en el estudio 56 pacientes alérgicos al ácaro del polvo de casa, tratados con un extracto de ácaros. En todos los pacientes se analizó la IgE esp frente a tropomiosina del ácaro (rDer p 10) antes y después de la IT. En los pacientes con resultado positivo tambien se monitorizó la IgE esp frente a las tropomiosinas del ácaro y de la gamba (rPen a 1) en varios tiempos, mediante CAP-System FEIA. Resultados: En cuanto a los resultados obtenidos, la IgE esp frente a tropomiosina fue positiva únicamente en 5 pacientes, tres de los cuales mostraban valores bajos y clínicamente irrelevantes de IgE esp frente a Der p 10 y no se encontró en ningún caso IgE esp positiva frente a Pen a 1. Los otros dos pacientes mostraron IgE esp positiva a ambas tropomiosinas. En el primero de ellos se observó un incremento inicial y una posterior disminución tras la IT, dinámica similar a la observada habitualmente con los anticuerpos IgE en los pacientes sometidos a inmunoterapia subcutánea y que nunca se acompañaba de síntomas con la ingesta de marisco. En el otro caso, la disminución de la IgE esp frente a ambas tropomiosinas resultó en la completa pérdida de reactividad frente a marisco. Conclusiones: En conclusión, la inmunoterapia frente a ácaros del polvo de casa no induce a una sensibilización a tropomiosina clínicamente relevante. En algunos casos, la alergia frente a ácaros y marisco tratada con IT puede mejorar los síntomas de la alergia alimentaria. Los niveles de IgE específica frente a Der p 10 y Pen a 1 pueden ser marcadores útiles para monitorizar a estos pacientes. Palabras clave: Ácaro del polvo de casa. Marisco. Sensibilización. Inmunoterapia específica. Tropomiosina. B Pevec, et al

Statistical learning techniques applied to epidemiology: a simulated case-control comparison study with logistic regression

<p>Abstract</p> <p>Background</p> <p>When investigating covariate interactions and group associations with standard regression analyses, the relationship between the response variable and exposure may be difficult to characterize. When the relationship is nonlinear, linear modeling techniques do not capture the nonlinear information content. Statistical learning (SL) techniques with kernels are capable of addressing nonlinear problems without making parametric assumptions. However, these techniques do not produce findings relevant for epidemiologic interpretations. A simulated case-control study was used to contrast the information embedding characteristics and separation boundaries produced by a specific SL technique with logistic regression (LR) modeling representing a parametric approach. The SL technique was comprised of a kernel mapping in combination with a perceptron neural network. Because the LR model has an important epidemiologic interpretation, the SL method was modified to produce the analogous interpretation and generate odds ratios for comparison.</p> <p>Results</p> <p>The SL approach is capable of generating odds ratios for main effects and risk factor interactions that better capture nonlinear relationships between exposure variables and outcome in comparison with LR.</p> <p>Conclusions</p> <p>The integration of SL methods in epidemiology may improve both the understanding and interpretation of complex exposure/disease relationships.</p