The blood-brain barrier prevents the entry of many therapeutic agents into the brain. Various nanocarriers have been developed to help agents to cross this barrier, but they all have limitations, ...with regard to tissue-selectivity and their ability to cross the endothelium. This study investigated the potential for 4 nm coated gold nanoparticles to act as selective carriers across human brain endothelium and subsequently to enter astrocytes. The transfer rate of glucose-coated gold nanoparticles across primary human brain endothelium was at least three times faster than across non-brain endothelia. Movement of these nanoparticles occurred across the apical and basal plasma membranes via the cytosol with relatively little vesicular or paracellular migration; antibiotics that interfere with vesicular transport did not block migration. The transfer rate was also dependent on the surface coating of the nanoparticle and incubation temperature. Using a novel 3-dimensional co-culture system, which includes primary human astrocytes and a brain endothelial cell line hCMEC/D3, we demonstrated that the glucose-coated nanoparticles traverse the endothelium, move through the extracellular matrix and localize in astrocytes. The movement of the nanoparticles through the matrix was >10 µm/hour and they appeared in the nuclei of the astrocytes in considerable numbers. These nanoparticles have the correct properties for efficient and selective carriers of therapeutic agents across the blood-brain barrier.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract A new combination of tissue engineering techniques provides a simple and effective method for building aligned cellular biomaterials. Self-alignment of Schwann cells within a tethered type-1 ...collagen matrix, followed by removal of interstitial fluid produces a stable tissue-like biomaterial that recreates the aligned cellular and extracellular matrix architecture associated with nerve grafts. Sheets of this engineered neural tissue supported and directed neuronal growth in a co-culture model, and initial in vivo tests showed that a device containing rods of rolled-up sheets could support neuronal growth during rat sciatic nerve repair (5 mm gap). Further testing of this device for repair of a critical-sized 15 mm gap showed that, at 8 weeks, engineered neural tissue had supported robust neuronal regeneration across the gap. This is, therefore, a useful new approach for generating anisotropic engineered tissues, and it can be used with Schwann cells to fabricate artificial neural tissue for peripheral nerve repair.
In 2009 the NW and SE flanks of Anton Dohrn Seamount were surveyed using multibeam echosounder and video ground-truthing to characterise megabenthic biological assemblages (biotopes) and assess those ...which clearly adhere to the definition of Vulnerable Marine Ecosystems, for use in habitat mapping. A combination of multivariate analysis of still imagery and video ground-truthing defined 13 comprehensive descriptions of biotopes that function as mapping units in an applied context. The data reveals that the NW and SE sides of Anton Dohrn Seamount (ADS) are topographically complex and harbour diverse biological assemblages, some of which agree with current definitions of 'listed' habitats of conservation concern. Ten of these biotopes could easily be considered Vulnerable Marine Ecosystems; three coral gardens, four cold-water coral reefs, two xenophyophore communities and one sponge dominated community, with remaining biotopes requiring more detailed assessment. Coral gardens were only found on positive geomorphic features, namely parasitic cones and radial ridges, found both sides of the seamount over a depth of 1311-1740 m. Two cold-water coral reefs (equivalent to summit reef) were mapped on the NW side of the seamount; Lophelia pertusa reef associated with the cliff top mounds at a depth of 747-791 m and Solenosmilia variabilis reef on a radial ridge at a depth of 1318-1351 m. Xenophyophore communities were mapped from both sides of the seamount at a depth of 1099-1770 m and were either associated with geomorphic features or were in close proximity (< 100 m) to them. The sponge dominated community was found on the steep escarpment either side of the seamount over at a depth of 854-1345 m. Multivariate diversity revealed the xenophyophore biotopes to be the least diverse, and a hard substratum biotope characterised by serpulids and the sessile holothurian, Psolus squamatus, as the most diverse.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Case summary
A 6.4 kg 3-year-old male neutered indoor–outdoor domestic shorthair cat was referred for further evaluation of non-resolving lethargy and hyporexia of 4 days’ duration. Physical ...examination identified tachypnea with mild respiratory effort and muffled lung sounds bilaterally. Point-of-care ultrasound revealed a large volume of pleural and pericardial effusion (PCE), which was confirmed by thoracic radiography. Echocardiogram indicated normal cardiac function but revealed a mass-like structure along the left epicardium within the pericardial space. After 72 hours in hospital, re-evaluation via echocardiogram showed the epicardial mass lesion to have doubled in size and with apparent extension to involve the pericardium. The patient was hospitalized for 72 h of supportive care and intervention, including therapeutic pericardiocentesis, bilateral thoracocentesis, thoracic and cardiac imaging and infectious disease testing. On the third day of hospitalization, the patient developed cardiac tamponade. Further workup was discussed, including CT and subtotal pericardiectomy with biopsy, but the cat was euthanized due to clinical decline and rapid re-accumulation of effusion. Post-mortem histopathologic evaluation diagnosed an epicardial pleomorphic sarcoma, exclusive of mesothelioma or histiocytic sarcoma on immunohistochemistry (IHC).
Relevance and novel information
This report describes a case of epicardial undifferentiated pleomorphic sarcoma (UPS) in a young cat presenting with pleural and PCE. Pleomorphic sarcoma is a rarely reported mesenchymal neoplasia in the feline patient and has thus far primarily been identified in peripheral soft tissue structures. IHC is key to the correct histopathologic diagnosis. To our knowledge, epicardial UPS has not been previously reported in a cat.
Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include ...approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.
In 2009, the National Society of Genetic Counselors Service (NSGC) Delivery Model Task Force defined genetic counseling service delivery models including telephone (genetic counseling provided ...remotely by telephone) and telegenetics (counseling provided remotely using videoconferencing). Little is known about the experience of genetic counselors practicing telemedicine in the USA. We sought to evaluate perceived satisfaction, advantages, disadvantages, and barriers to the practice and implementation of telegenetics by practicing genetic counselors. A 21-question online survey was distributed via the NSGC’s member directory. Descriptive statistics and a thematic analysis were used to analyze data. A total of 344 surveys were completed of which 235 (68.3%) respondents had delivered genetic counseling via telemedicine and 109 (36.6%) had not. Overall genetic counseling providers who had provided telegenetics were satisfied or very satisfied with their position (91%) and those who were not performing telegenetics were at least slightly interested in a telehealth position (92%).The most common appealing reasons for working in or wanting to work in telemedicine included an innovative approach to healthcare delivery, aspects of remote positions such as the ability to work from home, and flexibility of hours. Unappealing characteristics of telemedicine included the inability to see nonverbals, limited psychosocial counseling, and limited social interaction with colleague that is associated with remote positions. Barriers to implementation of telegenetics were noted by 53% of respondents with the largest barrier being billing and reimbursement. The results of this work suggest that telegenetics service organizations could consider increasing social interactions, attempting to use the preferred method of care (video) to increase ability to see nonverbals, offering flexible work hours, and allowing time to address psychosocial issues as they arise in consultations.
During neuroinflammation, cytokines such as TNF-α and IFN-γ secreted by activated leukocytes and/or CNS resident cells have been shown to alter the phenotype and function of brain endothelial cells ...(BECs) leading to blood-brain barrier breakdown. In this study, we show that the human BEC line hCMEC/D3 expresses the receptors for TNF-α, TNF receptor 1 and TNF receptor 2, and for IFN-γ. BEC activation with TNF-α alone or in combination with IFN-γ induced endothelial leakage of paracellular tracers. At high cytokine concentrations (10 and 100 ng/ml), this effect was associated with caspase-3/7 activation and apoptotic cell death as evidenced by annexin V staining and DNA fragmentation (TUNEL) assays. In addition, inhibition of JNK and protein kinase C activation at these doses partially prevented activation of caspase-3/7, although only JNK inhibition was partially able to prevent the increase in BEC paracellular permeability induced by cytokines. By contrast, lower cytokine concentrations (1 ng/ml) also led to effector caspase activation, increased paracellular flux, and redistribution of zonula occludens-1 and VE-cadherin but failed to induce apoptosis. Under these conditions, specific caspase-3 and caspase-9, but not caspase-8, inhibitors partially blocked cytokine-induced disruption of tight and adherens junctions and BEC paracellular permeability. Our results suggest that the concentration of cytokines in the CNS endothelial microenvironment determines the extent of caspase-mediated barrier permeability changes, which may be generalized as a result of apoptosis or more subtle as a result of alterations in the organization of junctional complex molecules.
Cancer remains a leading cause of morbidity and mortality among children. Targeted therapies may improve survivorship; however, unique side‐effect profiles have also emerged with these novel ...therapies. Changes in hair, skin, and nails—termed dermatologic adverse events (AEs)—are among the most common sequelae and may result in interruption or discontinuation of therapy. Though dermatologic AEs have been detailed in adults, these findings are not well described in the pediatric population. We reviewed the literature to characterize dermatologic AEs to anticancer targeted therapies available as of July 2020 and summarized the spectrum of clinical findings as well as treatment recommendations for children. Dermatologic AEs are among the most common AEs reported in pediatric patients receiving targeted therapy, but morphologic and histologic descriptions are often lacking in current publications. Pediatric dermatologists are uniquely poised to recognize specific morphology of dermatologic AEs and make recommendations for prevention and treatment that may improve quality of life and enable ongoing cancer therapy.
In 2007, the upper part of a submarine canyon system located in water depths between 138 and 1165m in the South West (SW) Approaches (North East Atlantic Ocean) was surveyed over a 2 week period. ...High-resolution multibeam echosounder data covering 1106km2, and 44 ground-truthing video and image transects were acquired to characterise the biological assemblages of the canyons. The SW Approaches is an area of complex terrain, and intensive ground-truthing revealed the canyons to be dominated by soft sediment assemblages. A combination of multivariate analysis of seabed photographs (184–1059m) and visual assessment of video ground-truthing identified 12 megabenthic assemblages (biotopes) at an appropriate scale to act as mapping units. Of these biotopes, 5 adhered to current definitions of habitats of conservation concern, 4 of which were classed as Vulnerable Marine Ecosystems. Some of the biotopes correspond to descriptions of communities from other megahabitat features (for example the continental shelf and seamounts), although it appears that the canyons host modified versions, possibly due to the inferred high rates of sedimentation in the canyons. Other biotopes described appear to be unique to canyon features, particularly the sea pen biotope consisting of Kophobelemnon stelliferum and cerianthids.
The masses, atmospheric makeups, spin-orbit alignments, and system architectures of extrasolar planets can be best studied when the planets orbit bright stars. We report the discovery of three bodies ...orbiting HD 106315, a bright (V = 8.97 mag) F5 dwarf targeted by our K2 survey for transiting exoplanets. Two small transiting planets are found to have radii and and orbital periods 9.55 days and 21.06 days, respectively. A radial velocity (RV) trend of 0.3 0.1 m s−1 day−1 indicates the likely presence of a third body orbiting HD 106315 with period 160 days and mass 45 M⊕. Transits of this object would have depths 0.1% and are definitively ruled out. Although the star has v sin i = 13.2 km s−1, it exhibits a short-timescale RV variability of just 6.4 m s−1. Thus, it is a good target for RV measurements of the mass and density of the inner two planets and the outer object's orbit and mass. Furthermore, the combination of RV noise and moderate v sin i makes HD 106315 a valuable laboratory for studying the spin-orbit alignment of small planets through the Rossiter-McLaughlin effect. Space-based atmospheric characterization of the two transiting planets via transit and eclipse spectroscopy should also be feasible. This discovery demonstrates again the power of K2 to find compelling exoplanets worthy of future study.
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